Basket Study of Neratinib in Participants With Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations (SUMMIT)

• ClinicalTrials.gov Identifier: NCT01953926
• Recruitment Status: Terminated
• First Posted: October 1, 2013
• Results First Posted: March 12, 2024
• Last Update Posted: March 12, 2024
• Sponsor: Puma Biotechnology, Inc.
• Information provided by (Responsible Party): Puma Biotechnology, Inc.

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations
• Interventions: Drug: Neratinib; Drug: Fulvestrant; Drug: Trastuzumab; Drug: Paclitaxel
• Enrollment: 582

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Neratinib	Neratinib + Fulvestrant	Neratinib + Paclitaxel	Neratinib + Trastuzumab	Neratinib + Fulvestrant + Trastuzumab	Fulvestrant	Fulvestrant + Trastuzumab
Arm/Group Description	Neratinib Monotherapy (Neratinib 240 mg PO daily)	Neratinib + Fulvestrant (Neratinib 240 mg PO daily + Fulvestrant 500 mg IM on Days 1, 15 of the first month, then Day 1 of every 4-week cycle)	Neratinib + Paclitaxel (Neratinib 240 mg PO daily + Paclitaxel 80 mg/m2 IV on Days 1, 8, and 15 of every 4-week cycle)	Neratinib + Trastuzumab (Neratinib 240 mg PO daily + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)	Neratinib + Fulvestrant + Trastuzumab (Neratinib 240 mg PO daily + Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)	Fulvestrant (Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter)	Fulvestrant + Trastuzumab (Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)
Period Title: Overall Study
Started	318	45	23	92	90	7	7
Treated	317	45	22	92	90	7	7
Completed	231	31	14	70	32	2	0
Not Completed	87	14	9	22	58	5	7
Reason Not Completed
Withdrawal by Subject	23	3	3	5	6	0	1
Physician Decision	1	0	0	0	2	0	0
Lost to Follow-up	18	3	0	5	3	0	0
Protocol Violation	1	0	0	0	0	0	0
Other, Disease progression	2	1	0	0	1	0	0
Discontinuation of study by sponsor	41	7	5	12	46	5	6
Not Treated	1	0	1	0	0	0	0

Baseline Characteristics

Arm/Group Title		Neratinib	Neratinib + Fulvestrant	Neratinib + Paclitaxel	Neratinib + Trastuzumab	Neratinib + Fulvestrant + Trastuzumab	Fulvestrant	Fulvestrant + Trastuzumab	Total
Arm/Group Description		Neratinib Monotherapy (Neratinib 240 mg PO daily)	Neratinib + Fulvestrant (Neratinib 240 mg PO daily + Fulvestrant 500 mg IM on Days 1, 15 of the first month, then Day 1 of every 4-week cycle)	Neratinib + Paclitaxel (Neratinib 240 mg PO daily + Paclitaxel 80 mg/m2 IV on Days 1, 8, and 15 of every 4-week cycle)	Neratinib + Trastuzumab (Neratinib 240 mg PO daily + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)	Neratinib + Fulvestrant + Trastuzumab (Neratinib 240 mg PO daily + Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)	Fulvestrant (Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter)	Fulvestrant + Trastuzumab (Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)	Total of all reporting groups
Overall Number of Baseline Participants		317	45	22	92	90	7	7	580
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	317 participants	45 participants	22 participants	92 participants	90 participants	7 participants	7 participants	580 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	201 63.4%	28 62.2%	4 18.2%	57 62.0%	59 65.6%	6 85.7%	3 42.9%	358 61.7%
	>=65 years	116 36.6%	17 37.8%	18 81.8%	35 38.0%	31 34.4%	1 14.3%	4 57.1%	222 38.3%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	317 participants	45 participants	22 participants	92 participants	90 participants	7 participants	7 participants	580 participants
		59.4 (13.1)	60.6 (11.5)	69.4 (9.4)	60.4 (11.1)	59.2 (11.6)	58.3 (11.2)	62.0 (12.4)	60.0 (12.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	317 participants	45 participants	22 participants	92 participants	90 participants	7 participants	7 participants	580 participants
	Female	188 59.3%	45 100.0%	5 22.7%	58 63.0%	89 98.9%	7 100.0%	7 100.0%	399 68.8%
	Male	129 40.7%	0 0.0%	17 77.3%	34 37.0%	1 1.1%	0 0.0%	0 0.0%	181 31.2%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Race	Number Analyzed	317 participants	45 participants	22 participants	92 participants	90 participants	7 participants	7 participants	580 participants
	White	255 80.4%	38 84.4%	21 95.5%	70 76.1%	77 85.6%	7 100.0%	5 71.4%	473 81.6%
	Asian	18 5.7%	2 4.4%	0 0.0%	7 7.6%	1 1.1%	0 0.0%	0 0.0%	28 4.8%
	Black or African American	16 5.0%	1 2.2%	0 0.0%	4 4.3%	4 4.4%	0 0.0%	1 14.3%	26 4.5%
	American Indian or Alaska Native	2 0.6%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 14.3%	3 0.5%
	Other	6 1.9%	1 2.2%	0 0.0%	2 2.2%	0 0.0%	0 0.0%	0 0.0%	9 1.6%
	Unknown	7 2.2%	1 2.2%	0 0.0%	4 4.3%	1 1.1%	0 0.0%	0 0.0%	13 2.2%
	Not Reported	13 4.1%	2 4.4%	1 4.5%	5 5.4%	7 7.8%	0 0.0%	0 0.0%	28 4.8%
Tumor type [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	317 participants	45 participants	22 participants	92 participants	90 participants	7 participants	7 participants	580 participants
	Breast cancer HR+ or HR-	36 11.4%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	36 6.2%
	Breast cancer HR+	0 0.0%	45 100.0%	0 0.0%	0 0.0%	31 34.4%	0 0.0%	0 0.0%	76 13.1%
	Breast cancer HR+, prior CDK46 inhibitors	0 0.0%	0 0.0%	0 0.0%	0 0.0%	59 65.6%	7 100.0%	7 100.0%	73 12.6%
	Breast cancer HR-	0 0.0%	0 0.0%	0 0.0%	21 22.8%	0 0.0%	0 0.0%	0 0.0%	21 3.6%
	Lung Her2 mutant cancer	26 8.2%	0 0.0%	0 0.0%	52 56.5%	0 0.0%	0 0.0%	0 0.0%	78 13.4%
	Lung EGFR mutant exon 18 cancer	31 9.8%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	31 5.3%
	Biliary tract cancer	25 7.9%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	25 4.3%
	Cervical cancer	22 6.9%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	22 3.8%
	Bladder/Urinary Tract cancer	16 5.0%	0 0.0%	22 100.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	38 6.6%
	Brain EGFR mutant cancer	38 12.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	38 6.6%
	Colorectal cancer	12 3.8%	0 0.0%	0 0.0%	19 20.7%	0 0.0%	0 0.0%	0 0.0%	31 5.3%
	Salivary gland cancer	11 3.5%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	11 1.9%
	Endometrial cancer	7 2.2%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	7 1.2%
	Fibrolamellar carcinoma (FLC)	15 4.7%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	15 2.6%
	Gastroesophageal cancer	7 2.2%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	7 1.2%
	Ovarian cancer	10 3.2%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	10 1.7%
	HER2 NOS cancer	42 13.2%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	42 7.2%
	HER3 NOS cancer	16 5.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	16 2.8%
	HER4 NOS cancer	3 0.9%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	3 0.5%
		[1] Measure Description: Cohort by tumor type

Outcome Measures

1. Primary Outcome

Title	Confirmed Objective Response Rate (ORR) by Independent Central Review (Breast Cancer With Prior CDK46i Cohort)
Description	Percentage of participants who are confirmed by independent central review to have achieved complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (HR+, HER2 negative metastatic breast cancer cohorts). Per Response Evaluation Criteria in Sold Tumors Criteria (RECISTv1.1) for target lesions and assessed by MRI or CT: Complete response(CR),Disappearance of all target lesions; Partial response(PR),>=30% decrease in sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame	From enrollment date to first confirmed Complete or Partial Response, whichever came earlier, assessed up to 58 months

Outcome Measure Data

Analysis Population Description

Cohort of cancer type and treatment

Arm/Group Title	Breast HR+ w Prior CDK4/6i (Neratinib + Fulvestrant + Trastuzumab)	Breast HR+ w. Prior CDK4/6i (Fulvestrant)	Breast HR+ With Prior CDK4/6i (Fulvestrant + Trastuzumab)
Arm/Group Description:	Consisting of 33 patients from the randomized cohort and 26 from the non-randomized cohort in breast cancer who had prior CDK4/6 inhibitor, treated with (Neratinib + Fulvestrant + Trastuzumab)	Breast HR+ with Prior CDK4/6 inhibitor patients treated with Fulvestrant Monotherapy	Breast cancer HR+ w prior CDK4/6 inhibitor patients treated with combination of (Fulvestrant + Trastuzumab)
Overall Number of Participants Analyzed	59	7	7
Measure Type: Number; Unit of Measure: percentage of participants
	40.7	0	14.3

2. Primary Outcome

Title	Confirmed Objective Response Rate (ORR) by Investigator Review (Cervical Cancer Cohort)
Description	Percentage of participants who are confirmed by investigator review to have achieved complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (cervical cancer cohort). Per Response Evaluation Criteria in Sold Tumors Criteria (RECISTv1.1) for target lesions and assessed by MRI or CT: Complete response(CR),Disappearance of all target lesions; Partial response(PR),>=30% decrease in sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame	From enrollment date to first confirmed Complete or Partial Response, whichever came earlier, assessed up to 58 months

Outcome Measure Data

Analysis Population Description

Cohort of cancer type and treatment

Arm/Group Title	Cervical (Neratinib)
Arm/Group Description:	Cervical cancer patients treated with Neratinib Monotherapy
Overall Number of Participants Analyzed	22
Measure Type: Number; Unit of Measure: percentage of participants
	18.2

3. Primary Outcome

Title	Objective Response Rate (ORR) at First Assessment by Investigator Review (All Other Cohorts)
Description	Percentage of participants who achieve CR or PR per Response Evaluation Criteria in Sold Tumors Criteria (RECIST) v1.1, or other defined response criteria, at the first scheduled tumor assessment (all other cohorts), per RECIST (if assessed) or PERCIST. RECISTv1.1 for target lesions and assessed by MRI or CT: Complete response(CR),Disappearance of all target lesions; Partial response(PR),>=30% decrease in sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR PERCISTv1.0: Complete Metabolic Response - Complete resolution of 18F-FDG uptake within measurable target lesion so that it is less than mean liver activity and indistinguishable from surrounding background blood-pool levels Partial Metabolic Response - Reduction of minimum of 30% in target measurable tumour 18F-FDG SULpeak. Absolute drop in SUL must be at least 0.8 SUL units, as well. No new lesions. Positive Metabolic Response - Participants having either "Complete Metabolic Response" or "Part
Time Frame	From first treatment date to first Complete or Partial Response, whichever came earlier, assessed up to 8 or 9 weeks

Outcome Measure Data

Analysis Population Description

Cohort of cancer type and treatment

Arm/Group Title	Breast Cancer (Neratinib)	Breast Cancer HR+ (Neratinib + Fulvestrant)	Breast Cancer HR+ (Neratinib + Fulvestrant + Trastuzumab)	Breast Cancer HR- (Neratinib + Trastuzumab)	Lung Cancer HER2 Mutant (Neratinib)	Lung Cancer HER2 Mutant (Neratinib + Trastuzumab)	Lung Cancer EGFR Mutant Exon 18 (Neratinib)	Biliary Tract Cancer (Neratinib)	Bladder/Urinary Tract Cancer (Neratinib)	Bladder/Urinary Tract Cancer (Neratinib + Paclitaxel)	Brain Cancer (Neratinib)	Colorectal Cancer (Neratinib)	Colorectal Cancer (Neratinib + Trastuzumab)	Endometrial Cancer (Neratinib)	Ovarian Cancer (Neratinib)	Salivary Gland Cancer (Neratinib)	Gastroesophageal Cancer (Neratinib)	Fibrolamellar Carcinoma (FLC) (Neratinib)	HER2 NOS Cancer (Neratinib)	HER3 NOS Cancer (Neratinib)	HER4 NOS Cancer (Neratinib)
Arm/Group Description:	Breast cancer HR+ or HR- patients treated with Neratinib Monotherapy	Breast cancer HR+ patients treated with combination of (Neratinib + Fulvestrant)	Breast cancer HR+ patients treated with combination of (Neratinib + Fulvestrant + Trastuzumab)	Breast cancer HR- patients treated with combination of (Neratinib + Trastuzumab)	NSCLC Lung cancer HER2 mutant patients treated with Neratinib Monotherapy	NSCLC Lung cancer HER2 mutant patients treated with combination of (Neratinib + Trastuzumab)	NSCLC Lung cancer EGFR mutant exon 18 patients treated with Neratinib Monotherapy	Biliary tract cancer patients treated with Neratinib Monotherapy	Bladder/Urinary Tract cancer patients treated with Neratinib Monotherapy	Bladder/Urinary Tract cancer patients treated with combination of (Neratinib + Paclitaxel)	Primary brain tumors (glioblastoma multiforme (GBM), gliosarcoma, and/or Grade III glioma) patients treated with Neratinib Monotherapy	Colorectal cancer patients treated with Neratinib Monotherapy	Colorectal cancer patients treated with combination of (Neratinib + Trastuzumab)	Endometrial cancer patients treated with Neratinib Monotherapy	Ovarian cancer patients treated with Neratinib Monotherapy	Salivary gland cancer patients treated with Neratinib Monotherapy	Gastroesophageal cancer patients treated with Neratinib Monotherapy	Fibrolamellar carcinoma (FLC) patients treated with Neratinib Monotherapy	HER2 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy	HER3 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy	HER4 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy
Overall Number of Participants Analyzed	36	45	31	21	26	52	31	25	16	22	38	12	19	7	10	11	7	15	42	16	3
Measure Type: Number; Unit of Measure: percentage of participant
	36.1	42.2	48.4	33.3	3.8	15.4	19.4	12.0	0	13.6	0	0	5.3	0	0	36.4	0	0	4.8	0	0

4. Secondary Outcome

Title	Confirmed Objective Response Rate (ORR) by Investigator Review (Breast Cancer With Prior CDK46i Cohort)
Description	Percentage of participants who are confirmed by investigator review to have achieved complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (HR+, HER2 negative metastatic breast cancer cohorts). Per Response Evaluation Criteria in Sold Tumors Criteria (RECISTv1.1) for target lesions and assessed by MRI or CT: Complete response(CR),Disappearance of all target lesions; Partial response(PR),>=30% decrease in sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame	From enrollment date to first confirmed Complete or Partial Response, whichever came earlier, assessed up to 58 months

Outcome Measure Data

Analysis Population Description

Cohort of cancer type and treatment

Arm/Group Title	Breast HR+ w Prior CDK4/6i (Neratinib + Fulvestrant + Trastuzumab)	Breast HR+ w. Prior CDK4/6i (Fulvestrant)	Breast HR+ With Prior CDK4/6i (Fulvestrant + Trastuzumab)
Arm/Group Description:	Consisting of 33 patients from the randomized cohort and 26 from the non-randomized cohort in breast cancer who had prior CDK4/6 inhibitor, treated with (Neratinib + Fulvestrant + Trastuzumab)	Breast HR+ with Prior CDK4/6 inhibitor patients treated with Fulvestrant Monotherapy	Breast cancer HR+ w prior CDK4/6 inhibitor patients treated with combination of (Fulvestrant + Trastuzumab)
Overall Number of Participants Analyzed	59	7	7
Measure Type: Number; Unit of Measure: percentage of participants
	30.5	0	0

5. Secondary Outcome

Title	Confirmed Objective Response Rate (ORR) by Investigator Review (All Other Cohorts)
Description	Percentage of participants who achieve CR or PR per RECIST v1.1, or metabolic complete response via PERCIST v1.0. For RECIST, A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met. PERCIST criteria were used for patients without RECIST assessments.
Time Frame	From first treatment date to confirmed Complete or Partial Response, assessed up to 58 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Breast Cancer (Neratinib)	Breast Cancer HR+ (Neratinib + Fulvestrant)	Breast Cancer HR+ (Neratinib + Fulvestrant + Trastuzumab)	Breast Cancer HR- (Neratinib + Trastuzumab)	Lung Cancer HER2 Mutant (Neratinib)	Lung Cancer HER2 Mutant (Neratinib + Trastuzumab)	Lung Cancer EGFR Mutant Exon 18 (Neratinib)	Biliary Tract Cancer (Neratinib)	Bladder/Urinary Tract Cancer (Neratinib)	Bladder/Urinary Tract Cancer (Neratinib + Paclitaxel)	Brain Cancer (Neratinib)	Colorectal Cancer (Neratinib)	Colorectal Cancer (Neratinib + Trastuzumab)	Endometrial Cancer (Neratinib)	Ovarian Cancer (Neratinib)	Salivary Gland Cancer (Neratinib)	Gastroesophageal Cancer (Neratinib)	Fibrolamellar Carcinoma (FLC) (Neratinib)	HER2 NOS Cancer (Neratinib)	HER3 NOS Cancer (Neratinib)	HER4 NOS Cancer (Neratinib)
Arm/Group Description:	Breast cancer HR+ or HR- patients treated with Neratinib Monotherapy	Breast cancer HR+ patients treated with combination of (Neratinib + Fulvestrant)	Breast cancer HR+ patients treated with combination of (Neratinib + Fulvestrant + Trastuzumab)	Breast cancer HR- patients treated with combination of (Neratinib + Trastuzumab)	NSCLC Lung cancer HER2 mutant patients treated with Neratinib Monotherapy	NSCLC Lung cancer HER2 mutant patients treated with combination of (Neratinib + Trastuzumab)	NSCLC Lung cancer EGFR mutant exon 18 patients treated with Neratinib Monotherapy	Biliary tract cancer patients treated with Neratinib Monotherapy	Bladder/Urinary Tract cancer patients treated with Neratinib Monotherapy	Bladder/Urinary Tract cancer patients treated with combination of (Neratinib + Paclitaxel)	Primary brain tumors (glioblastoma multiforme (GBM), gliosarcoma, and/or Grade III glioma) patients treated with Neratinib Monotherapy	Colorectal cancer patients treated with Neratinib Monotherapy	Colorectal cancer patients treated with combination of (Neratinib + Trastuzumab)	Endometrial cancer patients treated with Neratinib Monotherapy	Ovarian cancer patients treated with Neratinib Monotherapy	Salivary gland cancer patients treated with Neratinib Monotherapy	Gastroesophageal cancer patients treated with Neratinib Monotherapy	Fibrolamellar carcinoma (FLC) patients treated with Neratinib Monotherapy	HER2 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy	HER3 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy	HER4 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy
Overall Number of Participants Analyzed	36	45	31	21	26	52	31	25	16	22	38	12	19	7	10	11	7	15	42	16	3
Measure Type: Number; Unit of Measure: percentage of participant
	25.0	28.9	35.5	33.3	3.8	9.6	32.3	16.0	0	13.6	2.6	0	5.3	0	0	9.1	0	0	2.4	0	0

6. Secondary Outcome

Title	Duration of Response (DOR) by Independent Central Review (Breast Cancer With Prior CDK46i Cohort)
Description	Time from which measurement criteria are met for response (whichever status is recorded first) until the first date of documented disease progression or death. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
Time Frame	From first response to first disease progression or death, assessed up to 58 months

Outcome Measure Data

Analysis Population Description

Number of confirmed responders

Arm/Group Title	Breast Cancer HR+ w Prior CDK4/6i (Neratinib + Fulvestrant + Trastuzumab)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant + Trastuzumab)
Arm/Group Description:	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Neratinib + Fulvestrant + Trastuzumab)	Breast cancer HR+ patients having prior CDK4/6i treated with Fulvestrant Monotherapy	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Fulvestrant + Trastuzumab)
Overall Number of Participants Analyzed	24	0	1
Median (95% Confidence Interval); Unit of Measure: month
	13.14 [1]; (6.41 to NA)		NA [2]; (NA to NA)

[1]

Upper limits of 95% Confidence Interval (CI) was not estimable due to insufficient number of events.

[2]

Median and Upper, lower limits of 95% Confidence Interval (CI) were not estimable due to insufficient number of events.

7. Secondary Outcome

Title	Duration of Response (DOR) by Investigator Review (All Cohorts)
Description	Time from which measurement criteria are met for response (whichever status is recorded first) until the first date of documented disease progression or death. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
Time Frame	From first response to first disease progression or death, assessed up to 58 months

Outcome Measure Data

Analysis Population Description

Number of confirmed responders

Arm/Group Title	Breast Cancer HR+ w Prior CDK4/6i (Neratinib + Fulvestrant + Trastuzumab)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant + Trastuzumab)	Breast Cancer (Neratinib)	Breast Cancer HR+ (Neratinib + Fulvestrant)	Breast Cancer HR+ (Neratinib + Fulvestrant + Trastuzumab)	Breast Cancer HR- (Neratinib + Trastuzumab)	Cervical Cancer (Neratinib)	Lung Cancer HER2 Mutant (Neratinib)	Lung Cancer HER2 Mutant (Neratinib + Trastuzumab)	Lung Cancer EGFR Mutant Exon 18 (Neratinib)	Biliary Tract Cancer (Neratinib)	Bladder/Urinary Tract Cancer (Neratinib)	Bladder/Urinary Tract Cancer (Neratinib + Paclitaxel)	Brain Cancer (Neratinib)	Colorectal Cancer (Neratinib)	Colorectal Cancer (Neratinib + Trastuzumab)	Endometrial Cancer (Neratinib)	Ovarian Cancer (Neratinib)	Salivary Gland Cancer (Neratinib)	Gastroesophageal Cancer (Neratinib)	Fibrolamellar Carcinoma (FLC) (Neratinib)	HER2 NOS Cancer (Neratinib)	HER3 NOS Cancer (Neratinib)	HER4 NOS Cancer (Neratinib)
Arm/Group Description:	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Neratinib + Fulvestrant + Trastuzumab)	Breast cancer HR+ patients having prior CDK4/6i treated with Fulvestrant Monotherapy	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Fulvestrant + Trastuzumab)	Breast cancer HR+ or HR- patients treated with Neratinib Monotherapy	Breast cancer HR+ patients treated with combination of (Neratinib + Fulvestrant)	Breast cancer HR+ patients treated with combination of (Neratinib + Fulvestrant + Trastuzumab)	Breast cancer HR- patients treated with combination of (Neratinib + Trastuzumab)	Cervical cancer patients treated with Neratinib Monotherapy	NSCLC Lung cancer HER2 mutant patients treated with Neratinib Monotherapy	NSCLC Lung cancer HER2 mutant patients treated with combination of (Neratinib + Trastuzumab)	NSCLC Lung cancer EGFR mutant exon 18 patients treated with Neratinib Monotherapy	Biliary tract cancer patients treated with Neratinib Monotherapy	Bladder/Urinary Tract cancer patients treated with Neratinib Monotherapy	Bladder/Urinary Tract cancer patients treated with combination of (Neratinib + Paclitaxel)	Primary brain tumors (glioblastoma multiforme (GBM), gliosarcoma, and/or Grade III glioma) patients treated with Neratinib Monotherapy	Colorectal cancer patients treated with Neratinib Monotherapy	Colorectal cancer patients treated with combination of (Neratinib + Trastuzumab)	Endometrial cancer patients treated with Neratinib Monotherapy	Ovarian cancer patients treated with Neratinib Monotherapy	Salivary gland cancer patients treated with Neratinib Monotherapy	Gastroesophageal cancer patients treated with Neratinib Monotherapy	Fibrolamellar carcinoma (FLC) patients treated with Neratinib Monotherapy	HER2 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy	HER3 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy	HER4 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy
Overall Number of Participants Analyzed	23	0	0	9	13	11	7	4	1	5	10	4	0	3	1	0	1	0	0	1	0	0	1	0	0
Median (95% Confidence Interval); Unit of Measure: month
	14.4; (7.8 to 18.6)			4.76; (3.71 to 16.62)	9.23; (5.49 to 38.97)	9.17 [1]; (4.14 to NA)	7.28 [1]; (4.17 to NA)	7.62; (5.55 to 12.25)	9.23 [2]; (NA to NA)	6.80 [1]; (4.17 to NA)	22.24; (4.01 to 30.03)	3.75; (2.99 to 4.67)		7.20; (2.76 to 7.59)	19.94 [2]; (NA to NA)		12.19 [2]; (NA to NA)			NA [3]; (NA to NA)			3.71 [2]; (NA to NA)

[1]

Upper limits of 95% Confidence Interval (CI) was not estimable due to insufficient number of events.

[2]

Upper and lower limits of 95% Confidence Interval (CI) were not estimable due to insufficient number of events.

[3]

Median and Upper, lower limits of 95% Confidence Interval (CI) were not estimable due to insufficient number of events.

8. Secondary Outcome

Title	Clinical Benefit Rate (CBR) by Independent Central Review (Breast Cancer With Prior CDK46i Cohort)
Description	Percentage of participants with CR + PR + stable disease ≥16, or ≥24 weeks for breast cancer, from the date of enrollment.
Time Frame	From enrollment date to first documented response or stable disease ≥16, or ≥24 weeks for breast cancer, assessed up to 58 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Breast Cancer HR+ w Prior CDK4/6i (Neratinib + Fulvestrant + Trastuzumab)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant + Trastuzumab)
Arm/Group Description:	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Neratinib + Fulvestrant + Trastuzumab)	Breast cancer HR+ patients having prior CDK4/6i treated with Fulvestrant Monotherapy	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Fulvestrant + Trastuzumab)
Overall Number of Participants Analyzed	59	7	7
Measure Type: Number; Unit of Measure: percentage of participant
	49.2	0	14.3

9. Secondary Outcome

Title	Clinical Benefit Rate (CBR) by Investigator Review (All Cohorts)
Description	Percentage of participants with CR + PR + stable disease ≥16, or ≥24 weeks for breast cancer, from the date of enrollment.
Time Frame	From enrollment date to first documented response or stable disease ≥16, or ≥24 weeks for breast cancer, assessed up to 58 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Breast Cancer HR+ w Prior CDK4/6i (Neratinib + Fulvestrant + Trastuzumab)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant + Trastuzumab)	Breast Cancer (Neratinib)	Breast Cancer HR+ (Neratinib + Fulvestrant)	Breast Cancer HR+ (Neratinib + Fulvestrant + Trastuzumab)	Breast Cancer HR- (Neratinib + Trastuzumab)	Cervical Cancer (Neratinib)	Lung Cancer HER2 Mutant (Neratinib)	Lung Cancer HER2 Mutant (Neratinib + Trastuzumab)	Lung Cancer EGFR Mutant Exon 18 (Neratinib)	Biliary Tract Cancer (Neratinib)	Bladder/Urinary Tract Cancer (Neratinib)	Bladder/Urinary Tract Cancer (Neratinib + Paclitaxel)	Brain Cancer (Neratinib)	Colorectal Cancer (Neratinib)	Colorectal Cancer (Neratinib + Trastuzumab)	Endometrial Cancer (Neratinib)	Ovarian Cancer (Neratinib)	Salivary Gland Cancer (Neratinib)	Gastroesophageal Cancer (Neratinib)	Fibrolamellar Carcinoma (FLC) (Neratinib)	HER2 NOS Cancer (Neratinib)	HER3 NOS Cancer (Neratinib)	HER4 NOS Cancer (Neratinib)
Arm/Group Description:	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Neratinib + Fulvestrant + Trastuzumab)	Breast cancer HR+ patients having prior CDK4/6i treated with Fulvestrant Monotherapy	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Fulvestrant + Trastuzumab)	Breast cancer HR+ or HR- patients treated with Neratinib Monotherapy	Breast cancer HR+ patients treated with combination of (Neratinib + Fulvestrant)	Breast cancer HR+ patients treated with combination of (Neratinib + Fulvestrant + Trastuzumab)	Breast cancer HR- patients treated with combination of (Neratinib + Trastuzumab)	Cervical cancer patients treated with Neratinib Monotherapy	NSCLC Lung cancer HER2 mutant patients treated with Neratinib Monotherapy	NSCLC Lung cancer HER2 mutant patients treated with combination of (Neratinib + Trastuzumab)	NSCLC Lung cancer EGFR mutant exon 18 patients treated with Neratinib Monotherapy	Biliary tract cancer patients treated with Neratinib Monotherapy	Bladder/Urinary Tract cancer patients treated with Neratinib Monotherapy	Bladder/Urinary Tract cancer patients treated with combination of (Neratinib + Paclitaxel)	Primary brain tumors (glioblastoma multiforme (GBM), gliosarcoma, and/or Grade III glioma) patients treated with Neratinib Monotherapy	Colorectal cancer patients treated with Neratinib Monotherapy	Colorectal cancer patients treated with combination of (Neratinib + Trastuzumab)	Endometrial cancer patients treated with Neratinib Monotherapy	Ovarian cancer patients treated with Neratinib Monotherapy	Salivary gland cancer patients treated with Neratinib Monotherapy	Gastroesophageal cancer patients treated with Neratinib Monotherapy	Fibrolamellar carcinoma (FLC) patients treated with Neratinib Monotherapy	HER2 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy	HER3 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy	HER4 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy
Overall Number of Participants Analyzed	59	7	7	36	45	31	21	22	26	52	31	25	16	22	38	12	19	7	10	11	7	15	42	16	3
Measure Type: Number; Unit of Measure: percentage of participant
	54.2	0	0	33.3	42.2	54.8	42.9	45.5	38.5	30.8	48.4	24.0	18.8	31.8	10.5	8.3	21.1	14.3	20.0	54.5	0	13.3	19.0	6.3	0

10. Secondary Outcome

Title	Progression-Free Survival (PFS) by Independent Central Review (Breast Cancer With Prior CDK46i Cohort)
Description	Number of months between first dose date and the first date on which recurrence, progression, or death due to any cause, is documented, censored at the last tumor assessment or at the initiation of new anticancer therapy. Progression was defined by RECIST criteria for those participants with RECIST assessments; and PERCIST criteria for other participants.
Time Frame	From enrollment date until the date of first documented progression, or date of death from any cause, whichever came first, assessed up to 58 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Breast Cancer HR+ w Prior CDK4/6i (Neratinib + Fulvestrant + Trastuzumab)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant + Trastuzumab)
Arm/Group Description:	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Neratinib + Fulvestrant + Trastuzumab)	Breast cancer HR+ patients having prior CDK4/6i treated with Fulvestrant Monotherapy	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Fulvestrant + Trastuzumab)
Overall Number of Participants Analyzed	59	7	7
Median (95% Confidence Interval); Unit of Measure: month
	8.11; (6.01 to 16.39)	2.27 [1]; (1.61 to NA)	4.11; (1.87 to 4.11)

[1]

Upper limit of 95% Confidence Interval (CI) was not estimable due to insufficient number of events.

11. Secondary Outcome

Title	Progression-Free Survival (PFS) by Investigator Review (All Cohorts)
Description	Number of months between first dose date and the first date on which recurrence, progression, or death due to any cause, is documented, censored at the last tumor assessment or at the initiation of new anticancer therapy. Progression was defined by RECIST criteria for those participants with RECIST assessments; and PERCIST criteria for other participants.
Time Frame	From enrollment date until the date of first documented progression, or date of death from any cause, whichever came first, assessed up to 58 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Breast Cancer HR+ w Prior CDK4/6i (Neratinib + Fulvestrant + Trastuzumab)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant)	Breast Cancer HR+ w Prior CDK4/6i (Fulvestrant + Trastuzumab)	Breast Cancer (Neratinib)	Breast Cancer HR+ (Neratinib + Fulvestrant)	Breast Cancer HR+ (Neratinib + Fulvestrant + Trastuzumab)	Breast Cancer HR- (Neratinib + Trastuzumab)	Cervical Cancer (Neratinib)	Lung Cancer HER2 Mutant (Neratinib)	Lung Cancer HER2 Mutant (Neratinib + Trastuzumab)	Lung Cancer EGFR Mutant Exon 18 (Neratinib)	Biliary Tract Cancer (Neratinib)	Bladder/Urinary Tract Cancer (Neratinib)	Bladder/Urinary Tract Cancer (Neratinib + Paclitaxel)	Brain Cancer (Neratinib)	Colorectal Cancer (Neratinib)	Colorectal Cancer (Neratinib + Trastuzumab)	Endometrial Cancer (Neratinib)	Ovarian Cancer (Neratinib)	Salivary Gland Cancer (Neratinib)	Gastroesophageal Cancer (Neratinib)	Fibrolamellar Carcinoma (FLC) (Neratinib)	HER2 NOS Cancer (Neratinib)	HER3 NOS Cancer (Neratinib)	HER4 NOS Cancer (Neratinib)
Arm/Group Description:	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Neratinib + Fulvestrant + Trastuzumab)	Breast cancer HR+ patients having prior CDK4/6i treated with Fulvestrant Monotherapy	Breast cancer HR+ patients having prior CDK4/6i treated with combination of (Fulvestrant + Trastuzumab)	Breast cancer HR+ or HR- patients treated with Neratinib Monotherapy	Breast cancer HR+ patients treated with combination of (Neratinib + Fulvestrant)	Breast cancer HR+ patients treated with combination of (Neratinib + Fulvestrant + Trastuzumab)	Breast cancer HR- patients treated with combination of (Neratinib + Trastuzumab)	Cervical cancer patients treated with Neratinib Monotherapy	NSCLC Lung cancer HER2 mutant patients treated with Neratinib Monotherapy	NSCLC Lung cancer HER2 mutant patients treated with combination of (Neratinib + Trastuzumab)	NSCLC Lung cancer EGFR mutant exon 18 patients treated with Neratinib Monotherapy	Biliary tract cancer patients treated with Neratinib Monotherapy	Bladder/Urinary Tract cancer patients treated with Neratinib Monotherapy	Bladder/Urinary Tract cancer patients treated with combination of (Neratinib + Paclitaxel)	Primary brain tumors (glioblastoma multiforme (GBM), gliosarcoma, and/or Grade III glioma) patients treated with Neratinib Monotherapy	Colorectal cancer patients treated with Neratinib Monotherapy	Colorectal cancer patients treated with combination of (Neratinib + Trastuzumab)	Endometrial cancer patients treated with Neratinib Monotherapy	Ovarian cancer patients treated with Neratinib Monotherapy	Salivary gland cancer patients treated with Neratinib Monotherapy	Gastroesophageal cancer patients treated with Neratinib Monotherapy	Fibrolamellar carcinoma (FLC) patients treated with Neratinib Monotherapy	HER2 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy	HER3 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy	HER4 mutant Solid tumors, not otherwise specified (NOS) patients treated with Neratinib Monotherapy
Overall Number of Participants Analyzed	59	7	7	36	45	31	21	22	26	52	31	25	16	22	38	12	19	7	10	11	7	15	42	16	3
Median (95% Confidence Interval); Unit of Measure: month
	8.3; (6.0 to 12.7)	4.1; (1.6 to 4.1)	3.9; (1.9 to 4.1)	3.48; (1.94 to 3.88)	5.36; (3.71 to 9.23)	8.21; (4.07 to 11.01)	6.24; (2.10 to 10.25)	5.09; (1.74 to 7.23)	4.17; (1.87 to 8.80)	4.01; (2.10 to 4.57)	5.75; (2.27 to 9.23)	2.76; (1.05 to 3.75)	1.77; (1.68 to 3.55)	3.75; (1.87 to 5.62)	1.81; (1.02 to 2.69)	1.71; (1.45 to 1.87)	2.04; (1.81 to 3.48)	1.87; (1.61 to 6.87)	2.37; (1.48 to 7.36)	5.32; (1.81 to 9.26)	1.74; (0.82 to 2.23)	3.58; (1.84 to 3.71)	1.84; (1.74 to 2.07)	1.69; (1.41 to 2.04)	1.71; (1.12 to 1.74)

12. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events
Description	The safety of neratinib in patients as measured by the incidence of treatment-emergent adverse events (TEAE), including serious adverse events (SAEs), in study participants. TEAEs are any adverse event that occurred on or after first dose of investigational product and up to 28 days after the last dose
Time Frame	From first dose through 28 days after the last dose, assessed up to 75 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Neratinib	Neratinib + Fulvestrant	Neratinib + Paclitaxel	Neratinib + Trastuzumab	Neratinib + Fulvestrant + Trastuzumab	Fulvestrant	Fulvestrant + Trastuzumab
Arm/Group Description:	Neratinib Monotherapy (Neratinib 240 mg PO daily)	Neratinib + Fulvestrant (Neratinib 240 mg PO daily + Fulvestrant 500 mg IM on Days 1, 15 of the first month, then Day 1 of every 4-week cycle)	Neratinib + Paclitaxel (Neratinib 240 mg PO daily + Paclitaxel 80 mg/m2 IV on Days 1, 8, and 15 of every 4-week cycle)	Neratinib + Trastuzumab (Neratinib 240 mg PO daily + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)	Neratinib + Fulvestrant + Trastuzumab (Neratinib 240 mg PO daily + Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)	Fulvestrant (Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter)	Fulvestrant + Trastuzumab (Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)
Overall Number of Participants Analyzed	317	45	22	92	90	7	7
Measure Type: Count of Participants; Unit of Measure: Participants
Any treatment-emergent adverse event	313 98.7%	45 100.0%	21 95.5%	92 100.0%	89 98.9%	7 100.0%	7 100.0%
Any treatment-emergent serious adverse event	144 45.4%	12 26.7%	13 59.1%	45 48.9%	28 31.1%	5 71.4%	0 0.0%

Adverse Events

Time Frame	All events from day 1 of study drug through 28 days after last dose are included, up to 75 months.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Neratinib	Neratinib + Fulvestrant	Neratinib + Paclitaxel	Neratinib + Trastuzumab	Neratinib + Fulvestrant + Trastuzumab	Fulvestrant	Fulvestrant + Trastuzumab
Arm/Group Description	Neratinib Monotherapy (Neratinib 240 mg PO daily)	Neratinib + Fulvestrant (Neratinib 240 mg PO daily + Fulvestrant 500 mg IM on Days 1, 15 of the first month, then Day 1 of every 4-week cycle)	Neratinib + Paclitaxel (Neratinib 240 mg PO daily + Paclitaxel 80 mg/m2 IV on Days 1, 8, and 15 of every 4-week cycle)	Neratinib + Trastuzumab (Neratinib 240 mg PO daily + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)	Neratinib + Fulvestrant + Trastuzumab (Neratinib 240 mg PO daily + Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)	Fulvestrant (Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter)	Fulvestrant + Trastuzumab (Fulvestrant 500 mg IM on Study Day 1, 15, and 29; once every 28 days thereafter + Trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks)
All-Cause Mortality
	Neratinib	Neratinib + Fulvestrant	Neratinib + Paclitaxel	Neratinib + Trastuzumab	Neratinib + Fulvestrant + Trastuzumab	Fulvestrant	Fulvestrant + Trastuzumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	231/317 (72.87%)	31/45 (68.89%)	14/22 (63.64%)	71/92 (77.17%)	32/90 (35.56%)	2/7 (28.57%)	0/7 (0.00%)
Serious Adverse Events
	Neratinib	Neratinib + Fulvestrant	Neratinib + Paclitaxel	Neratinib + Trastuzumab	Neratinib + Fulvestrant + Trastuzumab	Fulvestrant	Fulvestrant + Trastuzumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	144/317 (45.43%)	12/45 (26.67%)	13/22 (59.09%)	45/92 (48.91%)	28/90 (31.11%)	5/7 (71.43%)	0/7 (0.00%)
Blood and lymphatic system disorders
Anaemia † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Leukocytosis † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Neutropenia † 1	0/317 (0.00%)	0/45 (0.00%)	1/22 (4.55%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cardiac disorders
Atrial fibrillation † 1	3/317 (0.95%)	2/45 (4.44%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Atrial flutter † 1	0/317 (0.00%)	0/45 (0.00%)	1/22 (4.55%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cardiac failure † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Cardiac tamponade † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cardio-respiratory arrest † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Tachycardia † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Ventricular arrhythmia † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Eye disorders
Diplopia † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	17/317 (5.36%)	0/45 (0.00%)	3/22 (13.64%)	3/92 (3.26%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Abdominal pain upper † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Ascites † 1	4/317 (1.26%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Colitis † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Constipation † 1	4/317 (1.26%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Diarrhoea † 1	30/317 (9.46%)	1/45 (2.22%)	6/22 (27.27%)	12/92 (13.04%)	6/90 (6.67%)	3/7 (42.86%)	0/7 (0.00%)
Dysphagia † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Gastric ulcer † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Gastrointestinal haemorrhage † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Ileus † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Intestinal obstruction † 1	2/317 (0.63%)	0/45 (0.00%)	2/22 (9.09%)	1/92 (1.09%)	2/90 (2.22%)	0/7 (0.00%)	0/7 (0.00%)
Intestinal perforation † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Large intestinal haemorrhage † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Large intestinal obstruction † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Large intestine perforation † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Nausea † 1	9/317 (2.84%)	0/45 (0.00%)	1/22 (4.55%)	2/92 (2.17%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Obstruction gastric † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Pancreatitis † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Rectal haemorrhage † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Small intestinal obstruction † 1	4/317 (1.26%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Vomiting † 1	14/317 (4.42%)	1/45 (2.22%)	2/22 (9.09%)	6/92 (6.52%)	3/90 (3.33%)	0/7 (0.00%)	0/7 (0.00%)
General disorders
Asthenia † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	2/92 (2.17%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Fatigue † 1	3/317 (0.95%)	0/45 (0.00%)	1/22 (4.55%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Gait disturbance † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
General physical health deterioration † 1	3/317 (0.95%)	0/45 (0.00%)	1/22 (4.55%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Multiple organ dysfunction syndrome † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Non-cardiac chest pain † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Oedema peripheral † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Pain † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Pyrexia † 1	7/317 (2.21%)	0/45 (0.00%)	0/22 (0.00%)	3/92 (3.26%)	1/90 (1.11%)	1/7 (14.29%)	0/7 (0.00%)
Hepatobiliary disorders
Acute hepatic failure † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Bile duct stone † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Biliary obstruction † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cholangitis acute † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cholecystitis † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cholecystitis acute † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Gallbladder obstruction † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Jaundice † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Malignant biliary obstruction † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Infections and infestations
Abdominal infection † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Arthritis bacterial † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Bacteraemia † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
COVID-19 † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cellulitis † 1	2/317 (0.63%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Clostridium difficile colitis † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Clostridium difficile infection † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cystitis † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Device related infection † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Diverticulitis † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Enterocolitis infectious † 1	0/317 (0.00%)	0/45 (0.00%)	1/22 (4.55%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Gastroenteritis † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Herpes zoster † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Infection † 1	1/317 (0.32%)	0/45 (0.00%)	1/22 (4.55%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Influenza † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Kidney infection † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Liver abscess † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Lymphangitis † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Perirectal abscess † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Pneumonia † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	4/92 (4.35%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Pneumonia aspiration † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Pseudomonal sepsis † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Sepsis † 1	6/317 (1.89%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Septic shock † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Staphylococcal infection † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Urinary tract infection † 1	8/317 (2.52%)	0/45 (0.00%)	2/22 (9.09%)	1/92 (1.09%)	3/90 (3.33%)	0/7 (0.00%)	0/7 (0.00%)
Vascular device infection † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Injury, poisoning and procedural complications
Fall † 1	0/317 (0.00%)	2/45 (4.44%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Femur fracture † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Fracture † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Infusion related reaction † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Overdose † 1	1/317 (0.32%)	0/45 (0.00%)	1/22 (4.55%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Post procedural bile leak † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Toxicity to various agents † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Investigations
Alanine aminotransferase increased † 1	2/317 (0.63%)	0/45 (0.00%)	1/22 (4.55%)	2/92 (2.17%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Aspartate aminotransferase increased † 1	4/317 (1.26%)	0/45 (0.00%)	1/22 (4.55%)	2/92 (2.17%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Blood alkaline phosphatase increased † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Blood bilirubin increased † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Blood creatinine increased † 1	4/317 (1.26%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	2/90 (2.22%)	0/7 (0.00%)	0/7 (0.00%)
Blood lactate dehydrogenase increased † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Ejection fraction decreased † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Electrocardiogram QT prolonged † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
International normalised ratio increased † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Lymphocyte count decreased † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Neutrophil count decreased † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Troponin I increased † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Metabolism and nutrition disorders
Cachexia † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Decreased appetite † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Dehydration † 1	10/317 (3.15%)	0/45 (0.00%)	1/22 (4.55%)	1/92 (1.09%)	3/90 (3.33%)	0/7 (0.00%)	0/7 (0.00%)
Failure to thrive † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Hypercalcaemia † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Hyperglycaemia † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Hyperkalaemia † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Hypoalbuminaemia † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Hypokalaemia † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Hyponatraemia † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Malnutrition † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain † 1	4/317 (1.26%)	0/45 (0.00%)	2/22 (9.09%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Bone pain † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Flank pain † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Muscular weakness † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Musculoskeletal chest pain † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Osteonecrosis of jaw † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Pain in extremity † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Sacral pain † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Spinal pain † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	0/317 (0.00%)	2/45 (4.44%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Metastases to meninges † 1	1/317 (0.32%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Neoplasm malignant † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Non-Hodgkin's lymphoma † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Tumour associated fever † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Tumour pain † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Nervous system disorders
Aphasia † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Brain oedema † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cerebral haemorrhage † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cerebrovascular accident † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Coma † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Dizziness † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Dysarthria † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Encephalopathy † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Epilepsy † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Headache † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	2/92 (2.17%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Hypoaesthesia † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Nervous system disorder † 1	0/317 (0.00%)	0/45 (0.00%)	1/22 (4.55%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Neurological decompensation † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Partial seizures † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Seizure † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	2/92 (2.17%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Syncope † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Product Issues
Device malfunction † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Psychiatric disorders
Agitation † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Confusional state † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Disorientation † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Drug abuse † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Mental status changes † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	5/317 (1.58%)	0/45 (0.00%)	4/22 (18.18%)	6/92 (6.52%)	4/90 (4.44%)	0/7 (0.00%)	0/7 (0.00%)
Haematuria † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Hydronephrosis † 1	1/317 (0.32%)	0/45 (0.00%)	1/22 (4.55%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Renal failure † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Urinary tract obstruction † 1	1/317 (0.32%)	0/45 (0.00%)	1/22 (4.55%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Reproductive system and breast disorders
Pelvic pain † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Testicular pain † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	1/317 (0.32%)	0/45 (0.00%)	1/22 (4.55%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Aspiration † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cough † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Dyspnoea † 1	8/317 (2.52%)	0/45 (0.00%)	0/22 (0.00%)	2/92 (2.17%)	3/90 (3.33%)	0/7 (0.00%)	0/7 (0.00%)
Hypoxia † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
Lung disorder † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Pleural effusion † 1	3/317 (0.95%)	2/45 (4.44%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Pneumonitis † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Pneumothorax † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Productive cough † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Pulmonary embolism † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Respiratory failure † 1	3/317 (0.95%)	0/45 (0.00%)	1/22 (4.55%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Skin and subcutaneous tissue disorders
Drug eruption † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Surgical and medical procedures
Mammoplasty † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Pain management † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Vascular disorders
Aortic stenosis † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Aortic thrombosis † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Deep vein thrombosis † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Embolism † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Hypotension † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	2/92 (2.17%)	1/90 (1.11%)	0/7 (0.00%)	0/7 (0.00%)
1 Term from vocabulary, MedDRA (25.1); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Neratinib	Neratinib + Fulvestrant	Neratinib + Paclitaxel	Neratinib + Trastuzumab	Neratinib + Fulvestrant + Trastuzumab	Fulvestrant	Fulvestrant + Trastuzumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	304/317 (95.90%)	45/45 (100.00%)	20/22 (90.91%)	92/92 (100.00%)	89/90 (98.89%)	7/7 (100.00%)	7/7 (100.00%)
Blood and lymphatic system disorders
Anaemia † 1	44/317 (13.88%)	7/45 (15.56%)	4/22 (18.18%)	17/92 (18.48%)	13/90 (14.44%)	1/7 (14.29%)	1/7 (14.29%)
Neutropenia † 1	3/317 (0.95%)	3/45 (6.67%)	2/22 (9.09%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Cardiac disorders
Palpitations † 1	4/317 (1.26%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	1/7 (14.29%)	0/7 (0.00%)
Ear and labyrinth disorders
Tinnitus † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Endocrine disorders
Hypothyroidism † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Eye disorders
Dry eye † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	5/90 (5.56%)	0/7 (0.00%)	0/7 (0.00%)
Retinal detachment † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Visual acuity reduced † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Gastrointestinal disorders
Abdominal discomfort † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	1/90 (1.11%)	1/7 (14.29%)	0/7 (0.00%)
Abdominal distension † 1	13/317 (4.10%)	2/45 (4.44%)	1/22 (4.55%)	4/92 (4.35%)	9/90 (10.00%)	0/7 (0.00%)	0/7 (0.00%)
Abdominal pain † 1	60/317 (18.93%)	8/45 (17.78%)	5/22 (22.73%)	12/92 (13.04%)	26/90 (28.89%)	0/7 (0.00%)	1/7 (14.29%)
Abdominal pain lower † 1	5/317 (1.58%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Abdominal pain upper † 1	9/317 (2.84%)	3/45 (6.67%)	0/22 (0.00%)	7/92 (7.61%)	8/90 (8.89%)	1/7 (14.29%)	0/7 (0.00%)
Constipation † 1	111/317 (35.02%)	17/45 (37.78%)	7/22 (31.82%)	28/92 (30.43%)	34/90 (37.78%)	2/7 (28.57%)	3/7 (42.86%)
Diarrhoea † 1	211/317 (66.56%)	39/45 (86.67%)	16/22 (72.73%)	74/92 (80.43%)	82/90 (91.11%)	6/7 (85.71%)	6/7 (85.71%)
Dry mouth † 1	16/317 (5.05%)	3/45 (6.67%)	2/22 (9.09%)	1/92 (1.09%)	6/90 (6.67%)	1/7 (14.29%)	1/7 (14.29%)
Dyspepsia † 1	14/317 (4.42%)	4/45 (8.89%)	3/22 (13.64%)	8/92 (8.70%)	10/90 (11.11%)	1/7 (14.29%)	0/7 (0.00%)
Dysphagia † 1	8/317 (2.52%)	1/45 (2.22%)	0/22 (0.00%)	2/92 (2.17%)	5/90 (5.56%)	0/7 (0.00%)	0/7 (0.00%)
Flatulence † 1	4/317 (1.26%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	4/90 (4.44%)	0/7 (0.00%)	1/7 (14.29%)
Gastrointestinal disorder † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	1/7 (14.29%)
Gastrooesophageal reflux disease † 1	9/317 (2.84%)	3/45 (6.67%)	2/22 (9.09%)	2/92 (2.17%)	5/90 (5.56%)	0/7 (0.00%)	0/7 (0.00%)
Nausea † 1	133/317 (41.96%)	19/45 (42.22%)	11/22 (50.00%)	43/92 (46.74%)	59/90 (65.56%)	3/7 (42.86%)	3/7 (42.86%)
Stomatitis † 1	16/317 (5.05%)	4/45 (8.89%)	0/22 (0.00%)	12/92 (13.04%)	13/90 (14.44%)	1/7 (14.29%)	0/7 (0.00%)
Vomiting † 1	105/317 (33.12%)	10/45 (22.22%)	10/22 (45.45%)	42/92 (45.65%)	44/90 (48.89%)	1/7 (14.29%)	2/7 (28.57%)
General disorders
Asthenia † 1	26/317 (8.20%)	4/45 (8.89%)	4/22 (18.18%)	11/92 (11.96%)	17/90 (18.89%)	1/7 (14.29%)	0/7 (0.00%)
Chills † 1	10/317 (3.15%)	0/45 (0.00%)	2/22 (9.09%)	5/92 (5.43%)	9/90 (10.00%)	1/7 (14.29%)	1/7 (14.29%)
Fatigue † 1	98/317 (30.91%)	12/45 (26.67%)	10/22 (45.45%)	33/92 (35.87%)	33/90 (36.67%)	2/7 (28.57%)	1/7 (14.29%)
Induration † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	1/7 (14.29%)
Injection site pruritus † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Mass † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	1/7 (14.29%)
Oedema peripheral † 1	21/317 (6.62%)	8/45 (17.78%)	1/22 (4.55%)	8/92 (8.70%)	10/90 (11.11%)	0/7 (0.00%)	0/7 (0.00%)
Pain † 1	10/317 (3.15%)	1/45 (2.22%)	2/22 (9.09%)	1/92 (1.09%)	5/90 (5.56%)	1/7 (14.29%)	0/7 (0.00%)
Pyrexia † 1	27/317 (8.52%)	5/45 (11.11%)	3/22 (13.64%)	15/92 (16.30%)	7/90 (7.78%)	1/7 (14.29%)	1/7 (14.29%)
Immune system disorders
Food allergy † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	1/7 (14.29%)
Infections and infestations
Infection † 1	0/317 (0.00%)	0/45 (0.00%)	1/22 (4.55%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Influenza † 1	2/317 (0.63%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Localised infection † 1	1/317 (0.32%)	1/45 (2.22%)	0/22 (0.00%)	1/92 (1.09%)	1/90 (1.11%)	1/7 (14.29%)	0/7 (0.00%)
Nasopharyngitis † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	7/90 (7.78%)	0/7 (0.00%)	0/7 (0.00%)
Paronychia † 1	7/317 (2.21%)	4/45 (8.89%)	0/22 (0.00%)	7/92 (7.61%)	8/90 (8.89%)	0/7 (0.00%)	0/7 (0.00%)
Respiratory tract infection † 1	1/317 (0.32%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Upper respiratory tract infection † 1	8/317 (2.52%)	5/45 (11.11%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Urinary tract infection † 1	21/317 (6.62%)	3/45 (6.67%)	3/22 (13.64%)	5/92 (5.43%)	12/90 (13.33%)	0/7 (0.00%)	0/7 (0.00%)
Injury, poisoning and procedural complications
Infusion related reaction † 1	0/317 (0.00%)	0/45 (0.00%)	1/22 (4.55%)	2/92 (2.17%)	5/90 (5.56%)	0/7 (0.00%)	0/7 (0.00%)
Investigations
Alanine aminotransferase increased † 1	27/317 (8.52%)	2/45 (4.44%)	1/22 (4.55%)	6/92 (6.52%)	5/90 (5.56%)	0/7 (0.00%)	0/7 (0.00%)
Aspartate aminotransferase increased † 1	31/317 (9.78%)	4/45 (8.89%)	2/22 (9.09%)	4/92 (4.35%)	8/90 (8.89%)	1/7 (14.29%)	0/7 (0.00%)
Blood alkaline phosphatase increased † 1	19/317 (5.99%)	0/45 (0.00%)	2/22 (9.09%)	4/92 (4.35%)	4/90 (4.44%)	0/7 (0.00%)	0/7 (0.00%)
Blood creatinine increased † 1	14/317 (4.42%)	1/45 (2.22%)	6/22 (27.27%)	6/92 (6.52%)	9/90 (10.00%)	0/7 (0.00%)	0/7 (0.00%)
Ejection fraction decreased † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	1/92 (1.09%)	6/90 (6.67%)	0/7 (0.00%)	0/7 (0.00%)
Gamma-glutamyltransferase increased † 1	1/317 (0.32%)	0/45 (0.00%)	1/22 (4.55%)	1/92 (1.09%)	2/90 (2.22%)	1/7 (14.29%)	0/7 (0.00%)
Lymphocyte count decreased † 1	7/317 (2.21%)	1/45 (2.22%)	1/22 (4.55%)	3/92 (3.26%)	2/90 (2.22%)	0/7 (0.00%)	1/7 (14.29%)
Neutrophil count decreased † 1	5/317 (1.58%)	1/45 (2.22%)	2/22 (9.09%)	2/92 (2.17%)	2/90 (2.22%)	0/7 (0.00%)	0/7 (0.00%)
Weight decreased † 1	34/317 (10.73%)	5/45 (11.11%)	1/22 (4.55%)	15/92 (16.30%)	14/90 (15.56%)	0/7 (0.00%)	1/7 (14.29%)
Metabolism and nutrition disorders
Decreased appetite † 1	84/317 (26.50%)	13/45 (28.89%)	6/22 (27.27%)	25/92 (27.17%)	34/90 (37.78%)	3/7 (42.86%)	1/7 (14.29%)
Dehydration † 1	20/317 (6.31%)	2/45 (4.44%)	4/22 (18.18%)	3/92 (3.26%)	7/90 (7.78%)	0/7 (0.00%)	0/7 (0.00%)
Hyperglycaemia † 1	9/317 (2.84%)	2/45 (4.44%)	0/22 (0.00%)	5/92 (5.43%)	3/90 (3.33%)	0/7 (0.00%)	0/7 (0.00%)
Hyperkalaemia † 1	8/317 (2.52%)	1/45 (2.22%)	2/22 (9.09%)	1/92 (1.09%)	2/90 (2.22%)	0/7 (0.00%)	0/7 (0.00%)
Hypoalbuminaemia † 1	7/317 (2.21%)	1/45 (2.22%)	1/22 (4.55%)	6/92 (6.52%)	4/90 (4.44%)	0/7 (0.00%)	1/7 (14.29%)
Hypocalcaemia † 1	6/317 (1.89%)	4/45 (8.89%)	1/22 (4.55%)	5/92 (5.43%)	5/90 (5.56%)	0/7 (0.00%)	0/7 (0.00%)
Hypokalaemia † 1	15/317 (4.73%)	1/45 (2.22%)	1/22 (4.55%)	7/92 (7.61%)	12/90 (13.33%)	0/7 (0.00%)	0/7 (0.00%)
Hypomagnesaemia † 1	11/317 (3.47%)	3/45 (6.67%)	0/22 (0.00%)	5/92 (5.43%)	7/90 (7.78%)	0/7 (0.00%)	1/7 (14.29%)
Hyponatraemia † 1	9/317 (2.84%)	2/45 (4.44%)	2/22 (9.09%)	4/92 (4.35%)	4/90 (4.44%)	0/7 (0.00%)	2/7 (28.57%)
Hypophosphataemia † 1	11/317 (3.47%)	0/45 (0.00%)	1/22 (4.55%)	2/92 (2.17%)	7/90 (7.78%)	0/7 (0.00%)	0/7 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	23/317 (7.26%)	7/45 (15.56%)	5/22 (22.73%)	12/92 (13.04%)	11/90 (12.22%)	1/7 (14.29%)	2/7 (28.57%)
Back pain † 1	28/317 (8.83%)	8/45 (17.78%)	3/22 (13.64%)	11/92 (11.96%)	7/90 (7.78%)	0/7 (0.00%)	0/7 (0.00%)
Bone pain † 1	3/317 (0.95%)	2/45 (4.44%)	0/22 (0.00%)	2/92 (2.17%)	4/90 (4.44%)	1/7 (14.29%)	0/7 (0.00%)
Flank pain † 1	2/317 (0.63%)	0/45 (0.00%)	0/22 (0.00%)	4/92 (4.35%)	1/90 (1.11%)	1/7 (14.29%)	0/7 (0.00%)
Muscle spasms † 1	13/317 (4.10%)	3/45 (6.67%)	0/22 (0.00%)	5/92 (5.43%)	15/90 (16.67%)	0/7 (0.00%)	0/7 (0.00%)
Muscular weakness † 1	8/317 (2.52%)	1/45 (2.22%)	2/22 (9.09%)	2/92 (2.17%)	5/90 (5.56%)	1/7 (14.29%)	0/7 (0.00%)
Musculoskeletal chest pain † 1	12/317 (3.79%)	3/45 (6.67%)	1/22 (4.55%)	3/92 (3.26%)	4/90 (4.44%)	1/7 (14.29%)	1/7 (14.29%)
Musculoskeletal pain † 1	4/317 (1.26%)	1/45 (2.22%)	0/22 (0.00%)	2/92 (2.17%)	4/90 (4.44%)	0/7 (0.00%)	1/7 (14.29%)
Myalgia † 1	14/317 (4.42%)	5/45 (11.11%)	2/22 (9.09%)	2/92 (2.17%)	12/90 (13.33%)	1/7 (14.29%)	0/7 (0.00%)
Pain in extremity † 1	8/317 (2.52%)	6/45 (13.33%)	0/22 (0.00%)	8/92 (8.70%)	6/90 (6.67%)	1/7 (14.29%)	0/7 (0.00%)
Spinal disorder † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	1/7 (14.29%)
Spinal pain † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Nervous system disorders
Dizziness † 1	21/317 (6.62%)	4/45 (8.89%)	4/22 (18.18%)	9/92 (9.78%)	6/90 (6.67%)	1/7 (14.29%)	0/7 (0.00%)
Dysgeusia † 1	18/317 (5.68%)	2/45 (4.44%)	4/22 (18.18%)	5/92 (5.43%)	9/90 (10.00%)	0/7 (0.00%)	1/7 (14.29%)
Dysmetria † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Headache † 1	30/317 (9.46%)	8/45 (17.78%)	0/22 (0.00%)	6/92 (6.52%)	17/90 (18.89%)	2/7 (28.57%)	1/7 (14.29%)
Neuropathy peripheral † 1	5/317 (1.58%)	0/45 (0.00%)	5/22 (22.73%)	0/92 (0.00%)	4/90 (4.44%)	0/7 (0.00%)	0/7 (0.00%)
Paraesthesia † 1	4/317 (1.26%)	3/45 (6.67%)	1/22 (4.55%)	1/92 (1.09%)	5/90 (5.56%)	1/7 (14.29%)	0/7 (0.00%)
Psychiatric disorders
Anxiety † 1	13/317 (4.10%)	0/45 (0.00%)	1/22 (4.55%)	4/92 (4.35%)	4/90 (4.44%)	1/7 (14.29%)	0/7 (0.00%)
Daydreaming † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Depression † 1	7/317 (2.21%)	1/45 (2.22%)	2/22 (9.09%)	2/92 (2.17%)	5/90 (5.56%)	0/7 (0.00%)	0/7 (0.00%)
Disorientation † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Insomnia † 1	12/317 (3.79%)	6/45 (13.33%)	3/22 (13.64%)	5/92 (5.43%)	5/90 (5.56%)	1/7 (14.29%)	0/7 (0.00%)
Mood swings † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Renal and urinary disorders
Pollakiuria † 1	3/317 (0.95%)	2/45 (4.44%)	2/22 (9.09%)	0/92 (0.00%)	3/90 (3.33%)	0/7 (0.00%)	0/7 (0.00%)
Renal failure † 1	1/317 (0.32%)	0/45 (0.00%)	0/22 (0.00%)	2/92 (2.17%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Urinary tract obstruction † 1	1/317 (0.32%)	0/45 (0.00%)	2/22 (9.09%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	0/7 (0.00%)
Reproductive system and breast disorders
Breast mass † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	0/7 (0.00%)	1/7 (14.29%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	20/317 (6.31%)	4/45 (8.89%)	2/22 (9.09%)	10/92 (10.87%)	8/90 (8.89%)	0/7 (0.00%)	0/7 (0.00%)
Dyspnoea † 1	24/317 (7.57%)	7/45 (15.56%)	3/22 (13.64%)	12/92 (13.04%)	8/90 (8.89%)	0/7 (0.00%)	1/7 (14.29%)
Epistaxis † 1	9/317 (2.84%)	1/45 (2.22%)	2/22 (9.09%)	6/92 (6.52%)	6/90 (6.67%)	0/7 (0.00%)	0/7 (0.00%)
Hiccups † 1	0/317 (0.00%)	0/45 (0.00%)	0/22 (0.00%)	1/92 (1.09%)	0/90 (0.00%)	0/7 (0.00%)	1/7 (14.29%)
Nasal congestion † 1	8/317 (2.52%)	4/45 (8.89%)	0/22 (0.00%)	2/92 (2.17%)	4/90 (4.44%)	0/7 (0.00%)	0/7 (0.00%)
Skin and subcutaneous tissue disorders
Alopecia † 1	7/317 (2.21%)	3/45 (6.67%)	2/22 (9.09%)	3/92 (3.26%)	4/90 (4.44%)	0/7 (0.00%)	0/7 (0.00%)
Dermatitis acneiform † 1	11/317 (3.47%)	1/45 (2.22%)	3/22 (13.64%)	11/92 (11.96%)	5/90 (5.56%)	1/7 (14.29%)	0/7 (0.00%)
Dry skin † 1	20/317 (6.31%)	8/45 (17.78%)	1/22 (4.55%)	4/92 (4.35%)	9/90 (10.00%)	0/7 (0.00%)	1/7 (14.29%)
Nail disorder † 1	1/317 (0.32%)	0/45 (0.00%)	3/22 (13.64%)	1/92 (1.09%)	4/90 (4.44%)	0/7 (0.00%)	0/7 (0.00%)
Nail ridging † 1	1/317 (0.32%)	1/45 (2.22%)	0/22 (0.00%)	1/92 (1.09%)	2/90 (2.22%)	1/7 (14.29%)	0/7 (0.00%)
Onychoclasis † 1	3/317 (0.95%)	0/45 (0.00%)	0/22 (0.00%)	2/92 (2.17%)	6/90 (6.67%)	0/7 (0.00%)	1/7 (14.29%)
Pruritus † 1	18/317 (5.68%)	4/45 (8.89%)	1/22 (4.55%)	3/92 (3.26%)	8/90 (8.89%)	0/7 (0.00%)	0/7 (0.00%)
Rash † 1	26/317 (8.20%)	7/45 (15.56%)	4/22 (18.18%)	12/92 (13.04%)	13/90 (14.44%)	0/7 (0.00%)	2/7 (28.57%)
Rash maculo-papular † 1	11/317 (3.47%)	5/45 (11.11%)	0/22 (0.00%)	4/92 (4.35%)	6/90 (6.67%)	0/7 (0.00%)	0/7 (0.00%)
Vascular disorders
Haematoma † 1	0/317 (0.00%)	1/45 (2.22%)	0/22 (0.00%)	0/92 (0.00%)	0/90 (0.00%)	1/7 (14.29%)	0/7 (0.00%)
Hot flush † 1	4/317 (1.26%)	5/45 (11.11%)	0/22 (0.00%)	0/92 (0.00%)	8/90 (8.89%)	1/7 (14.29%)	0/7 (0.00%)
Hypertension † 1	19/317 (5.99%)	3/45 (6.67%)	1/22 (4.55%)	8/92 (8.70%)	10/90 (11.11%)	0/7 (0.00%)	2/7 (28.57%)
Lymphoedema † 1	3/317 (0.95%)	3/45 (6.67%)	0/22 (0.00%)	2/92 (2.17%)	1/90 (1.11%)	1/7 (14.29%)	0/7 (0.00%)
1 Term from vocabulary, MedDRA (25.1); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Sr Director, Clinical Operations
• Organization: Puma Biotechnology, Inc.
• Phone: 4242486500
• EMail: clinicaltrials@pumabiotechnology.com

Publications:

Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, Juric D, Quinn DI, Moreno V, Doger B, Mayer IA, Boni V, Calvo E, Loi S, Lockhart AC, Erinjeri JP, Scaltriti M, Ulaner GA, Patel J, Tang J, Beer H, Selcuklu SD, Hanrahan AJ, Bouvier N, Melcer M, Murali R, Schram AM, Smyth LM, Jhaveri K, Li BT, Drilon A, Harding JJ, Iyer G, Taylor BS, Berger MF, Cutler RE Jr, Xu F, Butturini A, Eli LD, Mann G, Farrell C, Lalani AS, Bryce RP, Arteaga CL, Meric-Bernstam F, Baselga J, Solit DB. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018 Feb 8;554(7691):189-194. doi: 10.1038/nature25475. Epub 2018 Jan 31. Erratum In: Nature. 2019 Feb;566(7745):E11-E12.

Smyth LM, Piha-Paul SA, Won HH, Schram AM, Saura C, Loi S, Lu J, Shapiro GI, Juric D, Mayer IA, Arteaga CL, de la Fuente MI, Brufksy AM, Spanggaard I, Mau-Sorensen M, Arnedos M, Moreno V, Boni V, Sohn J, Schwartzberg LS, Gonzalez-Farre X, Cervantes A, Bidard FC, Gorelick AN, Lanman RB, Nagy RJ, Ulaner GA, Chandarlapaty S, Jhaveri K, Gavrila EI, Zimel C, Selcuklu SD, Melcer M, Samoila A, Cai Y, Scaltriti M, Mann G, Xu F, Eli LD, Dujka M, Lalani AS, Bryce R, Baselga J, Taylor BS, Solit DB, Meric-Bernstam F, Hyman DM. Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer. Cancer Discov. 2020 Feb;10(2):198-213. doi: 10.1158/2159-8290.CD-19-0966. Epub 2019 Dec 5.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Shishido SN, Masson R, Xu L, Welter L, Prabakar RK, D' Souza A, Spicer D, Kang I, Jayachandran P, Hicks J, Lu J, Kuhn P. Disease characterization in liquid biopsy from HER2-mutated, non-amplified metastatic breast cancer patients treated with neratinib. NPJ Breast Cancer. 2022 Feb 18;8(1):22. doi: 10.1038/s41523-022-00390-5.

Oaknin A, Friedman CF, Roman LD, D'Souza A, Brana I, Bidard FC, Goldman J, Alvarez EA, Boni V, ElNaggar AC, Passalacqua R, Do KTM, Santin AD, Keyvanjah K, Xu F, Eli LD, Lalani AS, Bryce RP, Hyman DM, Meric-Bernstam F, Solit DB, Monk BJ. Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial. Gynecol Oncol. 2020 Oct;159(1):150-156. doi: 10.1016/j.ygyno.2020.07.025. Epub 2020 Jul 25.

Ulaner GA, Saura C, Piha-Paul SA, Mayer I, Quinn D, Jhaveri K, Stone B, Shahin S, Mann G, Dujka M, Bryce R, Meric-Bernstam F, Solit DB, Hyman DM. Impact of FDG PET Imaging for Expanding Patient Eligibility and Measuring Treatment Response in a Genome-Driven Basket Trial of the Pan-HER Kinase Inhibitor, Neratinib. Clin Cancer Res. 2019 Dec 15;25(24):7381-7387. doi: 10.1158/1078-0432.CCR-19-1658. Epub 2019 Sep 23.

Hanker AB, Brewer MR, Sheehan JH, Koch JP, Sliwoski GR, Nagy R, Lanman R, Berger MF, Hyman DM, Solit DB, He J, Miller V, Cutler RE Jr, Lalani AS, Cross D, Lovly CM, Meiler J, Arteaga CL. An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer. Cancer Discov. 2017 Jun;7(6):575-585. doi: 10.1158/2159-8290.CD-16-1431. Epub 2017 Mar 8. Erratum In: Cancer Discov. 2019 Feb;9(2):303.

• Responsible Party: Puma Biotechnology, Inc.
• ClinicalTrials.gov Identifier: NCT01953926
• Other Study ID Numbers: PUMA-NER-5201; 2013-002872-42 ( EudraCT Number )
• First Submitted: September 26, 2013
• First Posted: October 1, 2013
• Results First Submitted: December 21, 2023
• Results First Posted: March 12, 2024
• Last Update Posted: March 12, 2024