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A Trial of Lenvatinib (E7080) Plus Pembrolizumab in Participants With Selected Solid Tumors

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ClinicalTrials.gov Identifier: NCT02501096
Recruitment Status : Completed
First Posted : July 17, 2015
Results First Posted : July 20, 2023
Last Update Posted : July 20, 2023
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Eisai Inc.

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Tumors
Interventions Drug: Lenvatinib
Drug: Pembrolizumab
Enrollment 357
Recruitment Details Participants took part in the study at 62 investigative sites in the United States, Spain and Norway from 22 July 2015 to 11 July 2022.
Pre-assignment Details Total of 454 participants were screened, of which 357 were enrolled/treated. A total of 13 participants were enrolled in Phase 1b, of which 3 participants received lenvatinib 24 mg/day+pembrolizumab 200 mg and 10 participants received lenvatinib 20 mg/day+pembrolizumab 200 mg while in Phase 2, 344 participants received lenvatinib 20 mg/day+pembrolizumab 200 mg. As planned,Phase 1b/2 data for participants who received lenvatinib 20 mg/day+pembrolizumab 200 mg was combined and presented together.
Arm/Group Title Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: NSCLC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description Participants with Renal Cell Carcinoma (RCC) received lenvatinib 24 milligram per day (mg/day), capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, once every three weeks (Q3W) on Day 1 of each cycle (cycle length=21 days) until disease progression (PD), development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participant with Non-small Cell Lung Cancer (NSCLC) received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with Endometrial Carcinoma (EC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with Squamous Cell Carcinoma of Head and Neck (HNSCC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with Urothelial Carcinoma (UC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Period Title: Overall Study
Started 2 1 124 145 21 21 22 20 1
Phase 1b Participants Who Received, Lenvatinib 20 mg/Day + Pembrolizumab 200 mg. 0 0 2 6 1 1 0 0 0
Phase 2 Participants Who Received, Lenvatinib 20 mg/Day + Pembrolizumab 200 mg 0 0 122 139 20 20 22 20 1
Completed 0 0 0 0 0 0 0 0 0
Not Completed 2 1 124 145 21 21 22 20 1
Reason Not Completed
Lost to Follow-up             0             0             0             0             1             1             3             0             0
Withdrawal by Subject             1             0             7             13             2             2             2             3             0
Survival follow-up discontinued by sponsor             0             0             29             58             3             2             2             1             0
Death             1             1             88             74             15             16             15             16             1
Arm/Group Title Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: NSCLC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma Total
Hide Arm/Group Description Participants with RCC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participant with NSCLC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Total of all reporting groups
Overall Number of Baseline Participants 2 1 124 145 21 21 22 20 1 357
Hide Baseline Analysis Population Description
The safety analysis set included all participants who received at least one dose of study drug.
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2 participants 1 participants 124 participants 145 participants 21 participants 21 participants 22 participants 20 participants 1 participants 357 participants
<65 years
0
   0.0%
0
   0.0%
47
  37.9%
88
  60.7%
16
  76.2%
9
  42.9%
9
  40.9%
4
  20.0%
1
 100.0%
174
  48.7%
>=65 years
2
 100.0%
1
 100.0%
77
  62.1%
57
  39.3%
5
  23.8%
12
  57.1%
13
  59.1%
16
  80.0%
0
   0.0%
183
  51.3%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2 participants 1 participants 124 participants 145 participants 21 participants 21 participants 22 participants 20 participants 1 participants 357 participants
Female
0
   0.0%
1
 100.0%
124
 100.0%
32
  22.1%
4
  19.0%
10
  47.6%
4
  18.2%
6
  30.0%
1
 100.0%
182
  51.0%
Male
2
 100.0%
0
   0.0%
0
   0.0%
113
  77.9%
17
  81.0%
11
  52.4%
18
  81.8%
14
  70.0%
0
   0.0%
175
  49.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2 participants 1 participants 124 participants 145 participants 21 participants 21 participants 22 participants 20 participants 1 participants 357 participants
Hispanic or Latino
1
  50.0%
0
   0.0%
3
   2.4%
17
  11.7%
2
   9.5%
0
   0.0%
1
   4.5%
2
  10.0%
0
   0.0%
26
   7.3%
Not Hispanic or Latino
1
  50.0%
1
 100.0%
121
  97.6%
128
  88.3%
19
  90.5%
21
 100.0%
21
  95.5%
18
  90.0%
1
 100.0%
331
  92.7%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2 participants 1 participants 124 participants 145 participants 21 participants 21 participants 22 participants 20 participants 1 participants 357 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
1
   0.8%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   0.3%
Asian
0
   0.0%
0
   0.0%
5
   4.0%
3
   2.1%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
8
   2.2%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
1
   0.8%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   0.3%
Black or African American
0
   0.0%
0
   0.0%
7
   5.6%
6
   4.1%
0
   0.0%
3
  14.3%
2
   9.1%
0
   0.0%
1
 100.0%
19
   5.3%
White
2
 100.0%
1
 100.0%
108
  87.1%
125
  86.2%
19
  90.5%
18
  85.7%
20
  90.9%
19
  95.0%
0
   0.0%
312
  87.4%
More than one race
0
   0.0%
0
   0.0%
2
   1.6%
8
   5.5%
1
   4.8%
0
   0.0%
0
   0.0%
1
   5.0%
0
   0.0%
12
   3.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
3
   2.1%
1
   4.8%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
4
   1.1%
1.Primary Outcome
Title Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Lenvatinib
Hide Description MTD was confirmed if no more than 3 participants experience dose-limiting toxicities(DLTs)during first 3 weeks (Cycle 1) of treatment.If MTD was not confirmed at dose level,then enrollment was proceeded to next lower dose level.Sponsor and investigators reviewed all participants' safety;clinical data to jointly determine RP2D of combination of treatment.DLT may be any of following: hematological/nonhematological toxicities considered to be at least possibly related to Lenvatinib/pembrolizumab occurring during Cycle 1;Failure to administer greater than or equal to (>=) 75 percent (%) of planned dosage of lenvatinib as result of treatment-related toxicity during Cycle 1;Who discontinue treatment due to treatment-related toxicity.Greater than 2 week delay in starting Cycle 2 because of treatment-related toxicity,even if toxicity does not meet DLT criteria.Toxicity was evaluated as per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03(NCI CTCAE v 4.03).
Time Frame Cycle 1 (21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
The MTD analysis set included all participants who completed Cycle 1 of treatment in Phase 1b or discontinued early due to DLT.
Arm/Group Title Phase 1b: All Participants
Hide Arm/Group Description:
All participants with selected solid tumors (RCC, EC, NSCLC and Melanoma) received lenvatinib 24 or 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 13
Measure Type: Number
Unit of Measure: milligram (mg)
MTD 20
RP2D 20
2.Primary Outcome
Title Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs) of Lenvatinib
Hide Description A DLT was defined as any of the following: any of the hematological or nonhematological toxicities considered to be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1. Failure to administer >=75% of the planned dosage of lenvatinib as a result of treatment-related toxicity during Cycle 1. Participants who discontinue treatment due to treatment-related toxicity. Greater than 2 week delay in starting Cycle 2 because of a treatment-related toxicity, even if the toxicity does not meet DLT criteria. Toxicity was evaluated as per NCI CTCAE v 4.03.
Time Frame Cycle 1 (21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
The MTD analysis set included all participants who completed Cycle 1 of treatment in Phase 1b or discontinued early due to DLT.
Arm/Group Title Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: NSCLC Phase 1b, Lenvatinib 20 mg/Day + Pembrolizumab 200 mg: NSCLC Phase 1b, Lenvatinib 20 mg/Day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 20 mg/Day + Pembrolizumab 200 mg: EC Phase 1b, Lenvatinib 20 mg/Day + Pembrolizumab 200 mg: Melanoma
Hide Arm/Group Description:
Participants with RCC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with NSCLC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 2 1 1 6 2 1
Measure Type: Count of Participants
Unit of Measure: Participants
1
  50.0%
1
 100.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3.Primary Outcome
Title Objective Response Rate (ORR) Based on Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) Version 1.1 at Week 24
Hide Description ORR was defined as the percentage of participants whose best overall response (BOR) was immune related complete response (irCR) or immune related partial response (irPR) based on investigator assessment according to irRECIST version 1.1. irCR was defined as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (<) 10 millimeter (mm). irPR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set (FAS) included all participants who entered the study treatment period.
Arm/Group Title Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description:
Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 124 145 21 21 22 20 1
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
39.5
(30.9 to 48.7)
56.6
(48.1 to 64.8)
47.6
(25.7 to 70.2)
23.8
(8.2 to 47.2)
31.8
(13.9 to 54.9)
25.0
(8.7 to 49.1)
0 [1] 
(NA to NA)
[1]
Here, 95% CI could not be estimated as insufficient number of participants were available for analysis in this arm.
4.Secondary Outcome
Title Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Hide Description TEAE: adverse event (AE) emerged during treatment, having been absent at pretreatment or reemerged during treatment, present at pretreatment but stopped before treatment or worsened in severity during treatment relative to pretreatment state, when AE is continuous. AE: any untoward medical occurrence in participant administered an investigational product. TEAEs were based on participants laboratory tests, regular measurement of vital signs, echocardiograms/multigated acquisition scans to assess left ventricular ejection fraction and electrocardiograms parameter values. TESAE: any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; a congenital anomaly/birth defect or was medically important due to reasons other than above criteria.
Time Frame From date of first dose up to 30 days after the last dose of study drugs (Up to 74 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all participants who received at least one dose of study drug.
Arm/Group Title Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: NSCLC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description:
Participants with RCC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with NSCLC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 2 1 124 145 21 21 22 20 1
Measure Type: Count of Participants
Unit of Measure: Participants
TEAEs
2
 100.0%
1
 100.0%
124
 100.0%
145
 100.0%
21
 100.0%
21
 100.0%
22
 100.0%
20
 100.0%
1
 100.0%
TESAEs
1
  50.0%
1
 100.0%
73
  58.9%
81
  55.9%
12
  57.1%
15
  71.4%
12
  54.5%
17
  85.0%
0
   0.0%
5.Secondary Outcome
Title Objective Response Rate (ORR) Based on irRECIST Version 1.1
Hide Description ORR was defined as the percentage of participants whose BOR was irCR or irPR according to irRECIST version 1.1. irCR was defined as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. irPR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time Frame From date of first dose of study drug administration until immune related (irPD), development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor (up to 73 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS included all participants who entered the study treatment period.
Arm/Group Title Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description:
Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 124 145 21 21 22 20 1
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
40.3
(31.6 to 49.5)
63.4
(55.1 to 71.3)
47.6
(25.7 to 70.2)
23.8
(8.2 to 47.2)
40.9
(20.7 to 63.6)
25.0
(8.7 to 49.1)
NA [1] 
(NA to NA)
[1]
Here, number and 95% CI could not be estimated as insufficient number of participants were available for analysis in this arm.
6.Secondary Outcome
Title Progression-free Survival (PFS) Based on irRECIST Version 1.1
Hide Description PFS was defined as the time from the first dose date to the date of irPD or date of death (whichever occurred first) according to irRECIST version 1.1. irPD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions was also considered progression).
Time Frame From date of first dose of study drug administration to date of irPD or date of death, whichever occurred first (up to 73 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS included all participants who entered the study treatment period.
Arm/Group Title Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description:
Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 124 145 21 21 22 20 1
Median (95% Confidence Interval)
Unit of Measure: months
7.5
(5.3 to 9.7)
14.1
(11.6 to 18.4)
5.5
(2.6 to 15.8)
5.4
(2.3 to 7.4)
4.4
(4.0 to 9.8)
5.4
(1.3 to 42.3)
1.35 [1] 
(NA to NA)
[1]
Here, 95% CI could not be estimated as insufficient number of participants were available for analysis in this arm.
7.Secondary Outcome
Title Overall Survival (OS)
Hide Description OS was defined as the time from the first dose date to the date of death from any cause.
Time Frame From the first dose until death from any cause, up to 73 months
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS included all participants who entered the study treatment period.
Arm/Group Title Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description:
Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 124 145 21 21 22 20 1
Median (95% Confidence Interval)
Unit of Measure: months
19.9
(16.2 to 25.9)
32.2
(29.8 to 55.8)
25.4
(8.6 to 39.5)
11.4
(3.6 to 23.3)
16.2
(8.6 to 31.8)
6.1
(2.4 to 30.1)
16.56 [1] 
(NA to NA)
[1]
Here, 95% CI could not be estimated as insufficient number of participants were available for analysis in this arm.
8.Secondary Outcome
Title Disease Control Rate (DCR) Based on irRECIST Version 1.1
Hide Description DCR: percentage of participants with a confirmed irCR, irPR, or ir-stable disease (SD) (duration of irSD greater than or equal to [>=] 5 weeks). DCR was assessed on irRECIST v1.1. irCR: disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have reduction in their short axis to <10 mm. irPR: at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference baseline sum of longest diameter. irSD: neither sufficient shrinkage to qualify for irPR nor sufficient increase to qualify for irPD, taking as reference smallest sum diameters while on study. irPD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study).
Time Frame From first dose of the study drug until irPD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor (up to 73 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS included all participants who entered the study treatment period.
Arm/Group Title Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description:
Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 124 145 21 21 22 20 1
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
84.7
(77.1 to 90.5)
93.8
(88.5 to 97.1)
81.0
(58.1 to 94.6)
76.2
(52.8 to 91.8)
90.9
(70.8 to 98.9)
70.0
(45.7 to 88.1)
NA [1] 
(NA to NA)
[1]
Here, Number and 95% CI could not be estimated as insufficient number of participants were available for analysis in this arm.
9.Secondary Outcome
Title Clinical Benefit Rate (CBR) Based on irRECIST Version 1.1
Hide Description CBR was defined as the percentage of participants with BOR of irCR or irPR or irdurable stable disease (irdSD) (duration of irSD >=23 weeks) [irCR + irPR + irdSD] based on irRECIST v1.1. irCR: disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have reduction in their short axis to <10 mm. irPR: at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference baseline sum of longest diameter. irSD: neither sufficient shrinkage to qualify for irPR nor sufficient increase to qualify for irPD, taking as reference smallest sum diameters while on study. irPD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study).
Time Frame From first dose date until irPD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor (up to 73 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS included all participants who entered the study treatment period.
Arm/Group Title Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description:
Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 124 145 21 21 22 20 1
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
58.9
(49.7 to 67.6)
80.0
(72.6 to 86.2)
61.9
(38.4 to 81.9)
57.1
(34.0 to 78.2)
45.5
(24.4 to 67.8)
40.0
(19.1 to 63.9)
NA [1] 
(NA to NA)
[1]
Here, Number and 95% CI could not be estimated as insufficient number of participants were available for analysis in this arm.
10.Secondary Outcome
Title Durable Stable Disease Rate (DSDR) Based on irRECIST Version 1.1
Hide Description Durable SD rate is defined as the percentage of participants whose observed BOR is irSD and the duration of irSD is >=23 weeks based on irRECIST v1.1.
Time Frame From first dose date until irPD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor (up to 73 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS included all participants who entered the study treatment period. As planned, data for this outcome measure dSD rate (where SD>=23 weeks) was not analyzed and collected separately but was included and analyzed in outcome measure CBR (irCR+irPR+[irSD duration >=23 weeks]).
Arm/Group Title Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description:
Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
11.Secondary Outcome
Title Duration of Objective Response (DOR) Based on irRECIST Version 1.1
Hide Description DOR: time from date of first observation of response (irPR or irCR) to date of the first observation of progression based on irRECIST 1.1, or date of death, whatever the cause. irCR: disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have reduction in their short axis <10 mm. irPR: at least 30% decrease in sum of diameter (SOD) of target lesions, taking as reference baseline sum diameters. irPD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in SOD of target lesions, taking as reference smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Time Frame First documentation of irCR or irPR until first documentation of progression or death (up to 73 months)
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Hide Analysis Population Description
The FAS included all participants who entered the study treatment period. Here "overall number of participants analyzed, N" signifies participants who had irCR or irPR. Here, "N" for Phase1b and 2, Lenvatinib 20 mg/day + Pembrolizumab 200 mg: Leiomyosarcoma was zero as there were no events of irCR or irPR in this arm.
Arm/Group Title Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description:
Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 50 92 10 5 9 5 0
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(8.5 to NA)
16.6
(9.7 to 18.4)
12.5
(2.7 to 28.6)
14.5 [2] 
(2.4 to NA)
7.1
(2.2 to 16.8)
41.0 [2] 
(4.6 to NA)
[1]
Median and Upper limit of 95% CI could not be estimated because high number of participants in this arm were censored from the analyses.
[2]
Here, Upper limit of 95% CI could not be estimated as insufficient number of participants were available for analysis in this arm.
12.Secondary Outcome
Title Phase 1b: Plasma Concentrations of Lenvatinib
Hide Description Observed plasma concentration of Lenvatinib was reported here quantified by liquid chromatography with tandem mass spectrometry (LCMS/MS) method.
Time Frame Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post dose; Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours post dose, Cycle 2 Day 1: predose, 2-12 hour postdose and Cycles 3,4,5,6 Day 1 predose (Cycle length =21 days)
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Hide Analysis Population Description
The Pharmacokinetic (PK) analysis set included all participants who had received at least 1 dose of lenvatinib and had evaluable concentration data. Here number analyzed "n" signifies number of participants who were evaluable for given time points.
Arm/Group Title Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: NSCLC
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Participants with RCC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with NSCLC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 2 1
Mean (Standard Deviation)
Unit of Measure: microgram per liter (mcg/L)
Cycle 1 Day 1: 0.5-4 hour Number Analyzed 2 participants 1 participants
102.5  (136.44) 198.0 [1]   (NA)
Cycle 1 Day 1: 6-10 hour Number Analyzed 2 participants 0 participants
210.5  (65.76)
Cycle 1 Day 15: Predose Number Analyzed 1 participants 1 participants
53.9 [1]   (NA) 1.8 [1]   (NA)
Cycle 1 Day 15: 0.5-4 hour Number Analyzed 1 participants 1 participants
78.4 [1]   (NA) 2.6 [1]   (NA)
Cycle 1 Day 15: 6-10 hour Number Analyzed 1 participants 1 participants
366.0 [1]   (NA) 424.0 [1]   (NA)
Cycle 2 Day 1: Predose Number Analyzed 2 participants 1 participants
35.4  (13.08) 364.0 [1]   (NA)
Cycle 2 Day 1: 2-12 hour Number Analyzed 2 participants 1 participants
491.0  (247.49) 374.0 [1]   (NA)
Cycle 3 Day 1: Predose Number Analyzed 2 participants 1 participants
23.3  (31.92) 118.0 [1]   (NA)
Cycle 4 Day 1: Predose Number Analyzed 2 participants 1 participants
28.0  (13.93) 176.0 [1]   (NA)
Cycle 5 Day 1: Predose Number Analyzed 2 participants 1 participants
19.9  (14.91) 2.5 [1]   (NA)
Cycle 6 Day 1: Predose Number Analyzed 2 participants 1 participants
44.4  (42.64) 210.0 [1]   (NA)
[1]
Standard deviation could not be calculated because only one participant was available for analysis.
13.Secondary Outcome
Title Plasma Concentrations of Lenvatinib
Hide Description Observed plasma concentration of Lenvatinib was reported here quantified by LCMS/MS method.
Time Frame Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post dose; Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours post dose, Cycle 2 Day 1: predose, 2-12 hour postdose and Cycles 3,4,5,6 Day 1 predose (Cycle length =21 days):
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Hide Analysis Population Description
The PK analysis set included all participants who had received at least 1 dose of lenvatinib and had evaluable concentration data. Here, overall number of participants analyzed, N signifies participants who were evaluable for this outcome measure and number analyzed "n" signifies number participants who were evaluable for given time points.
Arm/Group Title Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description:
Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
Overall Number of Participants Analyzed 122 138 20 20 22 20 1
Mean (Standard Deviation)
Unit of Measure: mcg/L
Cycle 1 Day 1:0.5-4 hour Number Analyzed 122 participants 138 participants 20 participants 20 participants 22 participants 20 participants 0 participants
82.2  (145.44) 35.5  (78.13) 24.0  (33.59) 79.9  (118.94) 41.8  (100.34) 123.8  (169.05)
Cycle 1 Day 1:6-10 hour Number Analyzed 116 participants 111 participants 18 participants 16 participants 19 participants 16 participants 1 participants
231.7  (109.67) 190.8  (96.25) 154.3  (69.56) 224.1  (109.95) 169.7  (95.78) 214.2  (86.51) 116 [1]   (NA)
Cycle 1 Day 15:Predose Number Analyzed 103 participants 125 participants 16 participants 13 participants 16 participants 14 participants 1 participants
66.6  (36.56) 67.2  (80.70) 52.1  (61.70) 62.9  (87.36) 60.9  (46.38) 61.1  (69.54) 52.2 [1]   (NA)
Cycle 1 Day 15:0.5-4 hour Number Analyzed 103 participants 117 participants 18 participants 13 participants 17 participants 15 participants 1 participants
129.3  (109.72) 122.4  (114.62) 93.1  (117.35) 275.3  (305.30) 142.8  (149.90) 153.9  (135.79) 45.9 [1]   (NA)
Cycle 1 Day 15:6-10 hour Number Analyzed 99 participants 104 participants 17 participants 13 participants 15 participants 15 participants 1 participants
271.3  (103.60) 206.3  (97.29) 241.8  (241.52) 266.8  (146.41) 210.6  (78.37) 249.7  (91.65) 161 [1]   (NA)
Cycle 2 Day 1:Predose Number Analyzed 109 participants 134 participants 20 participants 17 participants 19 participants 13 participants 1 participants
57.2  (60.58) 54.6  (64.43) 49.2  (46.63) 51.6  (66.72) 42.0  (48.16) 22.3  (21.61) 26.1 [1]   (NA)
Cycle 2 Day 1:2-12 hour Number Analyzed 101 participants 120 participants 17 participants 13 participants 15 participants 9 participants 0 participants
199.7  (155.08) 171.7  (119.34) 218.6  (83.83) 295.0  (190.80) 166.5  (128.95) 204.7  (174.60)
Cycle 3 Day 1:Predose Number Analyzed 105 participants 128 participants 17 participants 15 participants 18 participants 12 participants 0 participants
53.2  (59.53) 59.0  (67.58) 62.8  (65.77) 99.4  (132.33) 43.7  (50.45) 37.9  (29.19)
Cycle 4 Day 1:Predose Number Analyzed 100 participants 124 participants 15 participants 15 participants 18 participants 11 participants 1 participants
50.7  (52.16) 56.0  (61.56) 65.8  (115.31) 53.4  (81.66) 34.3  (54.94) 18.8  (34.33) 61.9 [1]   (NA)
Cycle 5 Day 1:Predose Number Analyzed 88 participants 121 participants 14 participants 12 participants 17 participants 11 participants 0 participants
53.5  (56.69) 52.1  (65.15) 60.8  (58.38) 71.8  (134.39) 37.7  (42.97) 39.0  (29.50)
Cycle 6 Day 1:Predose Number Analyzed 79 participants 111 participants 13 participants 10 participants 14 participants 8 participants 0 participants
40.6  (33.66) 51.8  (49.19) 114.0  (189.97) 49.9  (68.97) 36.9  (34.12) 34.2  (31.86)
[1]
Standard deviation could not be calculated because only one participant was available for analysis.
Time Frame From date of first dose of the study drugs up to 30 days after the last dose (up to 74 months)
Adverse Event Reporting Description The safety analysis set included all participants who received at least one dose of study drug.
 
Arm/Group Title Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: NSCLC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Hide Arm/Group Description Participants with RCC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participant with NSCLC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participants with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor. Participant with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
All-Cause Mortality
Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: NSCLC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/2 (50.00%)      1/1 (100.00%)      88/124 (70.97%)      74/145 (51.03%)      15/21 (71.43%)      16/21 (76.19%)      15/22 (68.18%)      16/20 (80.00%)      1/1 (100.00%)    
Hide Serious Adverse Events
Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/Day + Pembrolizumab 200 mg: NSCLC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: EC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: RCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: Melanoma Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: NSCLC Phase 1b and 2,Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: HNSCC Phase 1b and 2, Lenvatinib 20 mg/Day+Pembrolizumab 200 mg: UC Phase1b and 2, Lenvatinib 20mg/Day+Pembrolizumab 200 mg: Leiomyosarcoma
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/2 (50.00%)      1/1 (100.00%)      73/124 (58.87%)      81/145 (55.86%)      12/21 (57.14%)      15/21 (71.43%)      12/22 (54.55%)      17/20 (85.00%)      0/1 (0.00%)    
Blood and lymphatic system disorders                   
Anaemia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Autoimmune haemolytic anaemia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Leukocytosis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Thrombocytopenia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Cardiac disorders                   
Acute coronary syndrome  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Acute myocardial infarction  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Angina pectoris  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 2/145 (1.38%)  2 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Atrial fibrillation  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 1/21 (4.76%)  1 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Atrial tachycardia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Cardiac arrest  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 3/145 (2.07%)  3 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Cardiac failure  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Cardiac failure congestive  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 1/22 (4.55%)  1 1/20 (5.00%)  1 0/1 (0.00%)  0
Coronary artery disease  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Intracardiac thrombus  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Myocardial infarction  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 3/145 (2.07%)  3 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Pericardial effusion  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Supraventricular tachycardia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 1/22 (4.55%)  1 0/20 (0.00%)  0 0/1 (0.00%)  0
Tachycardia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Endocrine disorders                   
Adrenal insufficiency  1  0/2 (0.00%)  0 0/1 (0.00%)  0 3/124 (2.42%)  3 2/145 (1.38%)  3 1/21 (4.76%)  1 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hypothyroidism  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Eye disorders                   
Retinal vein occlusion  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Gastrointestinal disorders                   
Abdominal pain  1  0/2 (0.00%)  0 0/1 (0.00%)  0 6/124 (4.84%)  9 4/145 (2.76%)  4 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Abdominal pain upper  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Anal fistula  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Ascites  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Colitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 2/145 (1.38%)  2 0/21 (0.00%)  0 1/21 (4.76%)  2 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Colitis ischaemic  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Constipation  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 2/145 (1.38%)  2 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Diarrhoea  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 3/145 (2.07%)  3 0/21 (0.00%)  0 2/21 (9.52%)  2 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Dysphagia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  2 0/21 (0.00%)  0 0/21 (0.00%)  0 1/22 (4.55%)  1 0/20 (0.00%)  0 0/1 (0.00%)  0
Enterovesical fistula  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 1/22 (4.55%)  1 0/20 (0.00%)  0 0/1 (0.00%)  0
Gastric perforation  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Gastric ulcer  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Gastrointestinal haemorrhage  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Gastrointestinal perforation  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Immune-mediated enterocolitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 2/145 (1.38%)  2 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Intestinal obstruction  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  3 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Intestinal ulcer perforation  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Jejunal perforation  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Large intestinal obstruction  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Large intestinal ulcer  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Large intestine perforation  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Nausea  1  0/2 (0.00%)  0 0/1 (0.00%)  0 6/124 (4.84%)  6 3/145 (2.07%)  3 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Pancreatitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 3/124 (2.42%)  3 1/145 (0.69%)  1 1/21 (4.76%)  1 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Pancreatitis acute  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Pneumoperitoneum  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Proctalgia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Rectal ulcer haemorrhage  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Small intestinal haemorrhage  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Small intestinal obstruction  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  3 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Small intestinal perforation  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 1/21 (4.76%)  1 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Upper gastrointestinal haemorrhage  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Vomiting  1  0/2 (0.00%)  0 0/1 (0.00%)  0 3/124 (2.42%)  3 2/145 (1.38%)  2 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
General disorders                   
Asthenia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  3 1/145 (0.69%)  1 1/21 (4.76%)  1 0/21 (0.00%)  0 0/22 (0.00%)  0 2/20 (10.00%)  3 0/1 (0.00%)  0
Chest pain  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Fatigue  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 1/22 (4.55%)  1 0/20 (0.00%)  0 0/1 (0.00%)  0
General physical health deterioration  1  0/2 (0.00%)  0 0/1 (0.00%)  0 3/124 (2.42%)  5 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Non-cardiac chest pain  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 1/145 (0.69%)  1 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Pain  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Pyrexia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 3/124 (2.42%)  3 2/145 (1.38%)  3 0/21 (0.00%)  0 1/21 (4.76%)  1 1/22 (4.55%)  1 0/20 (0.00%)  0 0/1 (0.00%)  0
Sudden death  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hepatobiliary disorders                   
Cholecystitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 3/145 (2.07%)  3 2/21 (9.52%)  2 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Cholecystitis acute  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hepatic failure  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 2/145 (1.38%)  3 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hepatitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Immune-mediated hepatitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Portal vein thrombosis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 1/22 (4.55%)  2 0/20 (0.00%)  0 0/1 (0.00%)  0
Immune system disorders                   
Contrast media allergy  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Infections and infestations                   
Clostridial sepsis  1  1/2 (50.00%)  1 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Abdominal infection  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 1/21 (4.76%)  2 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Abscess limb  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Abscess oral  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 1/22 (4.55%)  2 0/20 (0.00%)  0 0/1 (0.00%)  0
Anorectal infection  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Appendicitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
COVID-19 pneumonia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Cellulitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Diverticulitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 3/145 (2.07%)  4 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Diverticulitis intestinal haemorrhagic  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Enterocolitis infectious  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 1/21 (4.76%)  1 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Epiglottitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 1/22 (4.55%)  1 0/20 (0.00%)  0 0/1 (0.00%)  0
Escherichia sepsis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Groin infection  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Infection  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  2 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Influenza  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Necrotising fasciitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Pelvic abscess  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Peritonitis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Pneumonia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 6/145 (4.14%)  8 0/21 (0.00%)  0 1/21 (4.76%)  2 1/22 (4.55%)  1 2/20 (10.00%)  3 0/1 (0.00%)  0
Post procedural infection  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Psoas abscess  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Pyelonephritis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Rectal abscess  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Respiratory tract infection  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Sepsis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  2 3/145 (2.07%)  5 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 3/20 (15.00%)  5 0/1 (0.00%)  0
Staphylococcal sepsis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 1/21 (4.76%)  2 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Upper respiratory tract infection  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 1/21 (4.76%)  1 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Urinary tract infection  1  0/2 (0.00%)  0 0/1 (0.00%)  0 3/124 (2.42%)  3 1/145 (0.69%)  1 1/21 (4.76%)  1 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Urosepsis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  2 0/1 (0.00%)  0
Wound infection  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 1/21 (4.76%)  1 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Injury, poisoning and procedural complications                   
Hypobarism  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Post procedural haemorrhage  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 1/21 (4.76%)  1 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Post procedural oedema  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Rib fracture  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Spinal compression fracture  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  3 1/22 (4.55%)  1 1/20 (5.00%)  2 0/1 (0.00%)  0
Thoracic vertebral fracture  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Vascular pseudoaneurysm  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 1/22 (4.55%)  1 0/20 (0.00%)  0 0/1 (0.00%)  0
Investigations                   
Alanine aminotransferase increased  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Amylase increased  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Aspartate aminotransferase increased  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Blood bilirubin increased  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Blood creatinine increased  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Lipase increased  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Troponin increased  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Metabolism and nutrition disorders                   
Cachexia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Decreased appetite  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Dehydration  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 6/145 (4.14%)  7 1/21 (4.76%)  1 1/21 (4.76%)  1 1/22 (4.55%)  1 0/20 (0.00%)  0 0/1 (0.00%)  0
Failure to thrive  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 1/22 (4.55%)  1 0/20 (0.00%)  0 0/1 (0.00%)  0
Hypercalcaemia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hyperglycaemia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hyperkalaemia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hypoalbuminaemia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hypocalcaemia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hypomagnesaemia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hyponatraemia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 3/124 (2.42%)  3 3/145 (2.07%)  3 1/21 (4.76%)  1 1/21 (4.76%)  1 1/22 (4.55%)  1 0/20 (0.00%)  0 0/1 (0.00%)  0
Metabolic acidosis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Musculoskeletal and connective tissue disorders                   
Arthralgia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Back pain  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  3 2/145 (1.38%)  2 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Flank pain  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  3 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Muscular weakness  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 1/145 (0.69%)  3 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Musculoskeletal pain  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Myopathy toxic  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Pain in extremity  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 2/145 (1.38%)  2 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Pathological fracture  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 2/145 (1.38%)  2 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Rhabdomyolysis  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                   
Acute myeloid leukaemia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Cancer pain  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Intracranial tumour haemorrhage  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  2 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Invasive ductal breast carcinoma  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Malignant pleural effusion  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Metastases to bone  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Metastases to central nervous system  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Squamous cell carcinoma of skin  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Tumour associated fever  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Nervous system disorders                   
Encephalopathy  1  0/2 (0.00%)  0 1/1 (100.00%)  1 3/124 (2.42%)  4 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Cerebral ischaemia  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Cognitive disorder  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Dizziness  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Dysarthria  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Generalised tonic-clonic seizure  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Haemorrhage intracranial  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  3 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Headache  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 1/145 (0.69%)  1 1/21 (4.76%)  1 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hydrocephalus  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Hypertensive encephalopathy  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Intraventricular haemorrhage  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Metabolic encephalopathy  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Nervous system disorder  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Peripheral sensory neuropathy  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Posterior reversible encephalopathy syndrome  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Ruptured cerebral aneurysm  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Seizure  1  0/2 (0.00%)  0 0/1 (0.00%)  0 1/124 (0.81%)  1 0/145 (0.00%)  0 2/21 (9.52%)  4 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Subarachnoid haemorrhage  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Syncope  1  0/2 (0.00%)  0 0/1 (0.00%)  0 2/124 (1.61%)  2 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Transient ischaemic attack  1  0/2 (0.00%)  0 0/1 (0.00%)  0 3/124 (2.42%)  3 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Psychiatric disorders                   
Confusional state  1  0/2 (0.00%)  0 0/1 (0.00%)  0 3/124 (2.42%)  3 1/145 (0.69%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 0/1 (0.00%)  0
Mental status changes  1  0/2 (0.00%)  0 0/1 (0.00%)  0 0/124 (0.00%)  0 0/145 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/22 (0.00%)  0 1/20 (5.00%)  1 0/1 (0.00%)  0
Renal and urinary disorders                   
Acute kidney injury  1  0/2 (0.00%)  0 0/1 (0.00%)