Vemurafenib, Cobimetinib, Atezolizumab, and Tiragolumab in Treating Patients With High-Risk Stage III Melanoma
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| ClinicalTrials.gov Identifier: NCT03554083 |
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Recruitment Status :
Recruiting
First Posted : June 12, 2018
Last Update Posted : July 24, 2023
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Sponsor:
Mayo Clinic
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic
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Brief Summary:
This early phase I pilot trial studies how well vemurafenib, cobimetinib, and atezolizumab work in treating patients with high-risk stage III melanoma. Vemurafenib and cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as atezolizumab and tiragolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving vemurafenib, cobimetinib, and atezolizumab may work better in treating high-risk stage III melanoma. Giving atezolizumab and tiragolumab together may also work better in treating high-risk stage III melanoma.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Clinical Stage III Cutaneous Melanoma AJCC v8 Pathologic Stage III Cutaneous Melanoma AJCC v8 Pathologic Stage IIIA Cutaneous Melanoma AJCC v8 Pathologic Stage IIIB Cutaneous Melanoma AJCC v8 Pathologic Stage IIIC Cutaneous Melanoma AJCC v8 Pathologic Stage IIID Cutaneous Melanoma AJCC v8 | Drug: Atezolizumab Drug: Cobimetinib Biological: Tiragolumab Drug: Vemurafenib | Phase 2 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 30 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Neoadjuvant Therapy for Patients With High Risk Stage III Melanoma: A Pilot Clinical Trial |
| Actual Study Start Date : | June 22, 2018 |
| Estimated Primary Completion Date : | June 29, 2024 |
| Estimated Study Completion Date : | June 29, 2024 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Melanoma
MedlinePlus related topics:
Melanoma
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm A - CLOSED (vemurafenib, cobimetinib, atezolizumab)
Patients receive vemurafenib PO BID on days 1-28 and cobimetinib PO QD on days 1-21. Patients also receive atezolizumab intravenously (IV) over 30-60 minutes on days 1 and 15 of cycles 2 and 3. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks after treatment, patients undergo surgery then receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. |
Drug: Atezolizumab
Given IV
Other Names:
Drug: Cobimetinib Given PO
Other Names:
Drug: Vemurafenib Given PO
Other Names:
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Experimental: Arm B - CLOSED (cobimetinib, atezolizumab)
Patients receive cobimetinib as in Arm A and atezolizumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks after treatment, patients undergo surgery then receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
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Drug: Atezolizumab
Given IV
Other Names:
Drug: Cobimetinib Given PO
Other Names:
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Experimental: Arm C (atezolizumab, tiragolumab)
Patients with BRAF wild-type or BRAF mutant melanoma receive atezolizumab IV over 30-60 minutes and tiragolumab IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
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Drug: Atezolizumab
Given IV
Other Names:
Biological: Tiragolumab Given IV
Other Names:
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Primary Outcome Measures :
- Pathologic complete response rate (pCR) in patients with stage III BRAFm (mutant) melanoma (neoadjuvant phase) [ Time Frame: After 12 weeks of therapy ]Pathologic complete response rate defined as the percentage of patients with no residual disease found in the surgical specimen among the patients who began neo-adjuvant protocol treatment. An interval estimate will be obtained using the formula for a 90% binomial confidence interval for one sample proportion.
- Pathologic complete response rate in patients with stage III BRAFwt (wild type) melanoma (neoadjuvant phase) [ Time Frame: After 12 weeks of therapy ]Pathologic complete response rate defined as the percentage of patients with no residual disease found in the surgical specimen among the patients who began neo-adjuvant protocol treatment. An interval estimate will be obtained using the formula for a 90% binomial confidence interval for one sample proportion.
- Median recurrence-free (RFS) rate (adjuvant phase) [ Time Frame: From surgery assessed up to 3 years ]Recurrence-free survival is defined as the time from surgery to radiographic or histologic evidence of local, regional, or distant recurrence of melanoma or death due to any cause. For each regimen, the distribution of recurrence-free survival times [denoted as RFS(t)] will be estimated using the Kaplan-Meier method. A 90% confidence interval for V(t) = log [-log (RFS(t)] will be constructed and then the inverse transformation exp[-exp v(t)] will be used to obtain a confidence for RFS(t).
Secondary Outcome Measures :
- Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) (neoadjuvant phase) [ Time Frame: After 12 weeks of therapy ]For each cohort, the frequency and severity of toxicities will be documented using the CTCAE criteria and tabulated for the neo-adjuvant phase and post-operative visit separately.
- Change in the uptake on Positron emission tomography (PET)/computed tomography (CT) results [ Time Frame: Baseline to end of neo-adjuvant treatment ]For each cohort, the percent change in the uptake on PET/CT scan taken at the completion of neo-adjuvant treatment from that on PET/CT scan taken prior to the start of neo-adjuvant treatment will be determined. Also, the appearance of new sites of uptake in the post neo-adjuvant treatment scan and lack of uptake in the areas where uptake was seen in the pre-treatment scan will be noted.
Other Outcome Measures:
- Pretreatment soluble (s)PD-L1, pretreatment tumor PD-L1, and pretreatment intracellular Bim in tumor-related T cells [ Time Frame: Up to 3 years ]Stratified Cox modeling will be conducted with participant cohort as the strata to obtain a point and interval estimate of the hazard of recurrence among those with biomarker levels thought to be delirious relative to the hazard of recurrence among those with biomarker levels thought not to be delirious.
- Molecular features of melanomas and the tumor immune microenvironment evaluated with multiplexed immunohistochemistry (mIHC) and ribonucleic acid sequencing (RNASeq) [ Time Frame: Up to 3 years ]Graphs will be constructed to visually compare and contrast the levels of these biomarkers between those who achieve a pCR and those who did not. Binomial confidence intervals for the difference in two independent proportions or t confidence intervals for the difference in two independent means will be used to gain preliminary insights into the difference in these biomarkers among those who achieve a pCR and those who did not.
- Changes in the concentration of circulating tumor deoxyribonucleic acid (DNA) during neoadjuvant treatment [ Time Frame: Up to 3 years ]Will be correlated with pCR. Graphs will be constructed to visually compare and contrast the level of tumor DNA between those who achieve a pCR and those who do not.
- Changes in T cell receptor clonality [ Time Frame: Up to 3 years ]A waterfall plot of the percent change will be constructed by pCR status. A two sample Wilcoxon rank sum test will be used to assess whether the percent change in intra-tumoral T cells from the primary lesion or in peripheral blood T cells differ among those who have a pCR and those who do not. Also, the proportion of patients who have a change in intra-tumoral T cell clonality and the proportion of patients who have a change in peripheral blood T cell clonality will be determined. For each of these parameters, a 95% binomial confidence interval for the difference in the parameter between those who have a pCR and those who do not will be constructed. Finally, the ratio of the intra-tumoral T cell clonality in the involved lymph node to the intra-tumoral T cell clonality in the uninvolved lymph node will be determined. This ratio will be summarized descriptively using median and inter-quartile range.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- PRE-REGISTRATION: Age >= 18 years
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PRE-REGISTRATION: High-risk stage III melanoma, defined as (any of the following):
- Recurrent nodal metastasis, or
- Clinically detectable nodal metastasis, or
- Metastatic involvement of more than one nodal basin
- NOTE: For the purpose of pre-registration, high-risk stage III melanoma is defined based on clinical and imaging assessment (positron emission tomography/computed tomography [PET/CT], CT, or magnetic resonance imaging [MRI]). Histologic confirmation of nodal metastatic disease is not needed at the time of pre-registration, provided there is histologic confirmation of primary melanoma or a prior lymph node metastasis.
- PRE-REGISTRATION: Willing to submit archival tissue from a lymph node biopsy or undergo a needle biopsy (with clip placement) for BRAF testing and for research purposes.
- PRE-REGISTRATION: Willing to forego anticancer treatments or investigational agents during pre-registration period.
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PRE-REGISTRATION: The following laboratory values obtained =< 28 days prior to pre-registration:
- Only for patients receiving therapeutic anticoagulation: stable anticoagulant regimen and stable international normalized ratio (INR).
- REGISTRATION: Histologic confirmation of stage III melanoma, as defined by the American Joint Committee on Cancer, 8th revised edition.
- REGISTRATION: Arms A and B only: Documentation of BRAFV600 mutation status in melanoma tumor tissue (archival or newly obtained) through use of a Clinical Laboratory Improvement Amendments (CLIA)-approved clinical mutation test.
- REGISTRATION: Surgically resectable disease, as determined by a melanoma surgical oncologist.
- REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- REGISTRATION: Life expectancy >= 26 weeks.
- REGISTRATION: Absolute neutrophil count (ANC) >= 1500/mm^3 obtained =< 14 days prior to registration.
- REGISTRATION: Platelet count >= 100,000/mm^3 obtained =< 14 days prior to registration.
- REGISTRATION: Hemoglobin >= 9.0 g/dL obtained =< 14 days prior to registration.
- REGISTRATION: Direct bilirubin =< institutional upper limit of normal (ULN) obtained =< 14 days prior to registration.
- REGISTRATION: Aspartate transaminase (AST) and alanine transaminase (ALT) =< 2 x ULN obtained =< 14 days prior to registration.
- REGISTRATION: Alkaline phosphatase < 2.5 x ULN obtained =< 14 days prior to registration.
- REGISTRATION: Creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 45 mL/min on the basis of measured CrCl from a 24-hour urine collection or Cockcroft-Gault glomerular filtration rate estimation obtained =< 14 days prior to registration.
- REGISTRATION: Arms A and B only: Left ventricular ejection fraction (LVEF) >= 50% or institutional lower limit of normal (LLN) =< 6 months prior to registration.
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REGISTRATION: Arms A and B only: Average corrected QT interval (QTc) =< 450 ms on triplicate 12 lead electrocardiography (ECG) =< 28 days prior to registration.
- NOTE: QTc intervals will be corrected using Fridericia's formula.
- REGISTRATION: Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only.
- REGISTRATION: For persons of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for 6 months after the last dose of study treatment.
- REGISTRATION: For persons able to father a child: agreement to remain abstinent (refrain from heterosexual intercourse with a person of childbearing potential) or use contraceptive measures, and agreement to refrain from donating sperm during the treatment period and for 6 months after the last dose of study treatment.
- REGISTRATION: Provide written informed consent.
- REGISTRATION: Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).
- REGISTRATION: Willing to provide tissue, blood, and stool samples for correlative research purposes.
- REGISTRATION: Arm C Only: Negative serology for acute Epstein-Barr virus (EBV) infection (negative EBV viral capsid antigen [VCA] immunoglobulin M [IgM]).
Exclusion Criteria:
- PRE-REGISTRATION: Prior systemic anti-cancer therapy for melanoma (e.g., chemotherapy, hormonal therapy, targeted therapy, immunotherapy including anti-PD-1, anti-PDL1 agents, or other biologic therapies), with the following exceptions: adjuvant treatment with interferon, IL-2, granulocyte-macrophage colony-stimulating factor (GM-CSF) or vaccine therapies are allowed, if discontinued >= 28 days prior to pre-registration.
- PRE-REGISTRATION: Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
- PRE-REGISTRATION: For patients with concurrent diagnosis of primary melanoma with nodal involvement, major surgical procedure other than lymph node biopsy or wide local excision of primary melanoma =< 4 weeks prior to pre-registration, or anticipation of need for a major surgical procedure for reasons other than melanoma during the course of the study.
- PRE-REGISTRATION: For patients with nodal recurrence, surgical procedure or anti-cancer therapy for this recurrence (other than lymph node biopsy) or anticipation of need for a major surgical procedure for reasons other than melanoma during the course of the study.
- PRE-REGISTRATION: Prior radiotherapy for melanoma.
- PRE-REGISTRATION: History of non-nodal melanoma metastasis or central nervous system (CNS) lesion(s) proven or clinically suspected to be metastasis.
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PRE-REGISTRATION: Active malignancy (other than melanoma) or malignancy =< 3 years prior to pre-registration.
- NOTE: Exceptions: Asymptomatic papillary thyroid cancer (not requiring treatment), resected basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, non-muscle-invasive bladder cancer, Stage I uterine cancer, or other curatively treated malignancies from which the patient has been disease-free for at least 3 years prior to pre registration.
- PRE-REGISTRATION: Prior allogeneic stem cell or solid organ transplantation.
- PRE-REGISTRATION: History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
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PRE-REGISTRATION: History of autoimmune disease requiring systemic immunosuppressive or immune-modulatory therapy =< 5 years prior to pre-registration.
- NOTE: Exceptions are allowed for hypothyroidism on thyroid replacement therapy; or Type 1 diabetes on insulin regimen.
- PRE-REGISTRATION: Active psoriasis requiring therapy (systemic or topical).
- PRE-REGISTRATION: Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, and other inherited liver disease as well as active viral disease.
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PRE-REGISTRATION: Arms A and B only: History of or evidence of retinal pathology on ophthalmologic examination including but not limited to:
- Neurosensory retinal detachment
- Central serous chorioretinopathy
- Retinal vein occlusion (RVO)
- Neovascular macular degeneration
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PRE-REGISTRATION: Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy.
- NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
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PRE-REGISTRATION: Uncontrolled intercurrent illness including, but not limited to:
- Ongoing or active infection (including but not limited to tuberculosis)
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Clinically significant cardiac dysfunction including:
- Symptomatic congestive heart failure defined as New York Heart Association class II or higher
- Unstable angina pectoris or new-onset angina =< 3 months prior to pre-registration
- Unstable cardiac arrhythmia
- Myocardial infarction =< 3 months prior to pre-registration
- Congenital long QT syndrome
- Clinically significant stroke, reversible ischemic neurological defect, or transient ischemic attack =< 6 months prior to pre-registration
- Any grade 3 hemorrhage or bleeding event =< 4 weeks prior to pre-registration
- Uncontrolled diabetes or symptomatic hyperglycemia
- Psychiatric illness/social situations that, in the judgement of the investigator, would: a) limit compliance with study requirements, or b) make the patient inappropriate for entry into this study, or c) interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
- PRE-REGISTRATION: Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells (example [ex]: recombinant follicle-stimulating hormone [FSH]).
- PRE-REGISTRATION: Known hypersensitivity to any components of the atezolizumab (all arms), tiragolumab (Arm C only), cobimetinib (Arms A and B only), or vemurafenib (Arms A and B only) formulations.
- PRE-REGISTRATION: History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
- REGISTRATION: Received anticancer treatments or investigational agents during pre-registration period.
- REGISTRATION: Clinically suspected non-nodal metastatic melanoma.
- REGISTRATION: Arm A only: For BRAF-mutant patients only: anticipated use of any concomitant medication =< 7 days prior to registration that is known to cause QT prolongation (which may lead to torsade de pointes).
- REGISTRATION: Arms A and B only: History of malabsorption or other clinically significant metabolic dysfunction that may interfere with absorption of oral study treatment or inability or unwillingness to swallow oral medication.
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REGISTRATION: Signs or symptoms of infection or has received antibiotics =< 14 days prior to registration.
- NOTE: Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
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REGISTRATION: Any of the following because this study involves investigational agents whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
- Pregnant persons
- Nursing persons
- Persons of childbearing potential who are unwilling to employ adequate contraception
- REGISTRATION: Treatment with a live, attenuated vaccine =< 4 weeks prior to registration, or anticipation of need for such a vaccine during the course of the study.
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REGISTRATION: Treatment with systemic immunosuppressive medication (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF)-alpha agents) =< 2 weeks prior to registration, or anticipation of need for systemic immunosuppressive medication during the course of the study.
- NOTE: Patients who have received acute, low-dose systemic steroids (=< 10 mg/day oral prednisone or equivalent) prior to registration or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.
- NOTE: The use of inhaled corticosteroids for chronic obstructive pulmonary disease or asthma, mineralocorticoids (e.g., fludrocortisone), or low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
- REGISTRATION: Requirement for concomitant therapy or food that is prohibited during the study.
- REGISTRATION: Arms A and B only: Inability to abstain from alcohol during neoadjuvant phase.
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REGISTRATION: Arm C only: Known Epstein-Barr virus (EBV) infection.
- NOTE: Patients with symptoms such as splenomegaly, fever, sore throat, non-malignant cervical lymphadenopathy, and/or tonsillar exudate, should undergo an EBV polymerase chain reaction (PCR) test to screen for acute infection or suspected chronic active infection. Patients with a positive EBV PCR test are excluded.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03554083
Locations
| United States, Florida | |
| Mayo Clinic in Florida | Recruiting |
| Jacksonville, Florida, United States, 32224-9980 | |
| Contact: Clinical Trials Referral Office 855-776-0015 mayocliniccancerstudies@mayo.edu | |
| Principal Investigator: Roxana S. Dronca, M.D. | |
| United States, Minnesota | |
| University of Minnesota/Masonic Cancer Center | Recruiting |
| Minneapolis, Minnesota, United States, 55455 | |
| Contact: Evidio Domingo-Musibay 612-625-8942 musib024@umn.edu | |
| Principal Investigator: Evidio Domingo-Musibay, M.D. | |
| Mayo Clinic in Rochester | Recruiting |
| Rochester, Minnesota, United States, 55905 | |
| Contact: Clinical Trials Referral Office 855-776-0015 mayocliniccancerstudies@mayo.edu | |
| Principal Investigator: Matthew S. Block, M.D. | |
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Matthew S Block | Mayo Clinic |
| Responsible Party: | Mayo Clinic |
| ClinicalTrials.gov Identifier: | NCT03554083 |
| Other Study ID Numbers: |
MC1776 NCI-2018-01018 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) MC1776 ( Other Identifier: Mayo Clinic in Rochester ) P30CA015083 ( U.S. NIH Grant/Contract ) |
| First Posted: | June 12, 2018 Key Record Dates |
| Last Update Posted: | July 24, 2023 |
| Last Verified: | July 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | No |
Additional relevant MeSH terms:
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Melanoma Melanoma, Cutaneous Malignant Skin Neoplasms Neuroendocrine Tumors Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Nerve Tissue Nevi and Melanomas Neoplasms by Site Skin Diseases |
Atezolizumab Vemurafenib Antibodies, Monoclonal Immune Checkpoint Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Immunological Antineoplastic Agents Immunologic Factors Physiological Effects of Drugs Protein Kinase Inhibitors Enzyme Inhibitors |