PD-1 or PD-L1 Blockade Adds Little to Combination of BRAF and MEK Inhibition in the Treatment of BRAF V600–Mutated Melanoma

Callahan, Margaret K.; Chapman, Paul B.

doi:10.1200/jco.21.02801

Cited by 10 publications

(7 citation statements)

References 13 publications

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“…Our study of vemurafenib and cobimetinib with pembrolizumab had a high ORR but closed early due to high rates of grade 3/4 AEs. In addition, the survival benefit of up-front combination immunotherapy compared to targeted therapy further puts into question which patients would benefit from triplet combination therapy ( 23 ). Overall, given the significant toxicities incurred with triplet therapy and modest PFS improvements, physicians must think carefully about which patients are best served with this treatment strategy.…”

Section: Discussionmentioning

confidence: 99%

Phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with metastatic melanoma

et al. 2022

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BackgroundPreclinical and translational evidence suggest BRAF/MEK inhibitors modulate the tumor microenvironment (TME), providing rationale for combination with immunotherapy.MethodsThis investigator-initiated, phase I trial evaluated pembrolizumab, vemurafenib, and cobimetinib in patients with untreated, BRAFV600E/K mutant advanced melanoma. The first 4 patients received vemurafenib with pembrolizumab, and the next 5 patients received vemurafenib and cobimetinib with pembrolizumab. Primary endpoints: safety and maximum tolerated dose of the triplet.Secondary endpointsobjective response rate (ORR), progression-free survival (PFS), overall survival (OS), and quality of life (QoL). The trial was closed after enrollment of 9 (planned 30) patients due to dose-limiting toxicity (DLT). Study NCT02818023 was approved by the IRB, and all patients provided informed consent.ResultsPatients received a median of 6 cycles of therapy. 8 of 9 experienced drug-related grade 3/4 AEs. DLTs included dermatitis (n=8), hepatitis (n=1), QTc prolongation (n=1), and arthralgias (n=1 each). QoL assessments identified a clinically significant decrease in self assessed QoL at 1 year compared to baseline (0.38 v 0.43). Median PFS was 20.7 months and median OS was 23.8 months for vemurafenib with pembrolizumab. Median PFS and OS were not reached for patients receiving triple therapy. ORR in the overall cohort was 78% (7/9). 2 patients experienced a complete response, 5 had a partial response, 1 had stable disease, and 1 had progressive disease. 4 patients had ongoing responses at data analysis. Peripheral blood flow cytometry identified significantly decreased PD1 expression on CD4+ T-cells at 3 and 9 weeks compared to baseline, not corresponding to clinical response.ConclusionsTriple therapy with vemurafenib, cobimetinib and pembrolizumab is associated with high response rates but significant adverse events, leading to early study closure.

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Section: Discussionmentioning

confidence: 99%

Phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with metastatic melanoma

et al. 2022

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“…Although the IMSpire150 trial of vemurafenib-cobimetinib with or without atezolizumab demonstrated a small but statistically significant investigator-assessed PFS benefit with triplet therapy, 37 this difference did not persist when PFS was assessed by independent review. Currently, we cannot recommend triplet therapy 38 …”

Section: Braf/mek-targeted Therapymentioning

confidence: 99%

A General Approach to Patients Presenting With Locally Advanced or Distant Metastatic Disease

Smithy,

Chapman

2024

Cancer J

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The widespread adoption of immune checkpoint inhibitors and small molecule inhibitors of the MAP kinase pathway has transformed the management of locally advanced and metastatic melanoma. Here, we provide a broad overview on the use of these agents in the first-line setting, incorporating a review of the clinical literature as well as the practice patterns of our respective melanoma groups. Throughout, we highlight areas of uncertainty that provide opportunities for future clinical investigation and additional improvement in outcomes for patients with melanoma.

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“…Preclinical trials provide a rationale for these combining strategies. 307 The phase III IMspire150 trial showed that treating BRAF V600‐mutant melanoma with atezolizumab, vemurafenib, and cobimetinib significantly increased PFS from 10.6 months with vemurafenib and cobimetinib to 15.1 months (HR, 0.78; 95%CI: 0.63, 0.97; p = 0.025) without obviously adding adverse events. 308 However, the phase III COMBI‐i trial evaluated spartalizumab plus dabrafenib and trametinib for BRAF V600‐mutant melanoma, the results of which showed that the addition of spartalizumab to targeted therapy with dabrafenib and trametinib did not significantly prolong PFS but increased grade ≥3 adverse events by 22% compared with the dabrafenib plus dabrafenib group.…”

Section: Selective Small Molecule Kinase Inhibitorsmentioning

confidence: 99%

“…The clinical benefit of combining PD‐1/PD‐L1 antibody with RAF and MEK inhibitors is inconsistent. Preclinical trials provide a rationale for these combining strategies 307 . The phase III IMspire150 trial showed that treating BRAF V600‐mutant melanoma with atezolizumab, vemurafenib, and cobimetinib significantly increased PFS from 10.6 months with vemurafenib and cobimetinib to 15.1 months (HR, 0.78; 95%CI: 0.63, 0.97; p = 0.025) without obviously adding adverse events 308 .…”

Section: Selective Small Molecule Kinase Inhibitorsmentioning

confidence: 99%

Small molecule inhibitors targeting the cancers

Liu

Chen

Zhang

et al. 2022

MedComm

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Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary targeted therapies for cancer. Due to their advantages in a wide range of targets, convenient medication, and the ability to penetrate into the central nervous system, many efforts have been devoted to developing more small molecule inhibitors. To date, 88 small molecule inhibitors have been approved by the United States Food and Drug Administration to treat cancers. Despite remarkable progress, small molecule inhibitors in cancer treatment still face many obstacles, such as low response rate, short duration of response, toxicity, biomarkers, and resistance. To better promote the development of small molecule inhibitors targeting cancers, we comprehensively reviewed small molecule inhibitors involved in all the approved agents and pivotal drug candidates in clinical trials arranged by the signaling pathways and the classification of small molecule inhibitors. We discussed lessons learned from the development of these agents, the proper strategies to overcome resistance arising from different mechanisms, and combination therapies concerned with small molecule inhibitors. Through our review, we hoped to provide insights and perspectives for the research and development of small molecule inhibitors in cancer treatment.

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PD-1 or PD-L1 Blockade Adds Little to Combination of BRAF and MEK Inhibition in the Treatment of BRAF V600–Mutated Melanoma

Abstract: Author affiliations and support information (if applicable) appear at the end of this article.

Cited by 10 publications

References 13 publications

Phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with metastatic melanoma

Phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with metastatic melanoma

A General Approach to Patients Presenting With Locally Advanced or Distant Metastatic Disease

Small molecule inhibitors targeting the cancers

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