Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study

Gogas, Helen; Dréno, Brigitte; Larkin, James; Демидов, Лев В.; Stroyakovskiy, Daniil; Eroglu, Zeynep; Ferrucci, Pier Francesco; Pigozzo, Jacopo; Rutkowski, Piotr; Mackiewicz, Jacek; Rooney, Isabelle; Voulgari, Athina; Troutman, Sarah M.; Pitcher, Bethany; Guo, Yu; Yan, Yibing; Castro, Marí­lia Germanos de; Mulla, Sohail; Flaherty, Keith T.; Arance, Ana

doi:10.1016/j.annonc.2020.12.004

Cited by 82 publications

(93 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the anti-PD(L)1 monotherapy subgroup, the corresponding RR of ORR was 1.13 (95% CI: 0.87-1.47, I 2 = 52.5%, P=0.122; Figure 2B ) with moderate heterogeneity. The hazard ratio (HR) of PFS in 2 studies ( 16 , 17 ) and overall survival (OS) in 2 studies ( 14 , 17 ) were 0.73 (95% CI: 0.58-0.93, I 2 = 0%, P=0.930; Figure 2C ) and 1.01 (95% CI: 0.52-1.96, I 2 = 89.3%, P=0.002; Figure 2D ), respectively. However, studies with opposite results were not included because of different objectives, such as TTF ( 18 ).…”

Section: Resultsmentioning

confidence: 99%

“…Preclinical evidence shows synergistic antitumor activity of MEK inhibition in combination with PD-L1 checkpoint blockade ( 27 ). In contrast, the phase 3 clinical trial of atezolizumab combined with cobimetinib in metastatic melanoma failed to demonstrate superior survival over anti-PD-1 monotherapy ( 16 ). Further studies are focusing on the sequence of immunotherapy and targeted therapy and dosing schedules such as intermittent versus continuous dosing of MAPK inhibitors ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

“…Six retrospective studies and 1 randomized clinical trial were relevant to our analyses (11)(12)(13)(14)(16)(17)(18). Study design, drug, number of patients, efficacy of immunotherapy (ORR, DCR, PFS, OS, TTF, et al) for NRAS mutant and wild-type advanced melanoma patients, and univariate and multivariate factors analyzed along with NRAS status were listed in Supplementary Table S1.…”

Section: Meta-analysismentioning

confidence: 99%

See 2 more Smart Citations

Association of NRAS Mutation With Clinical Outcomes of Anti-PD-1 Monotherapy in Advanced Melanoma: A Pooled Analysis of Four Asian Clinical Trials

et al. 2021

View full text Add to dashboard Cite

BackgroundAnti-PD-1 monotherapy is the standard therapy for advanced melanoma patients, including those with NRAS mutations. The influence of NRAS mutation on immunotherapy, especially in noncutaneous melanoma, is largely uncharacterized.Materials and MethodsWe analyzed clinical data of four clinical trials for advanced melanoma patients treated with anti-PD-1 monotherapy between 2016 and 2019. The impact of NRAS mutation on efficacy and outcome of immunotherapy were analyzed in cutaneous and noncutaneous groups separately.ResultsA total of 206 patients were assessed, including 92 cutaneous melanoma patients with 12 NRAS mutations and 114 noncutaneous melanoma patients with 21 NRAS mutations. In cutaneous melanoma, the response rates of NRAS mutant patients were lower than patients without NRAS mutations (9.5% vs. 23.9%), the median progression-free survival (PFS) and median overall survival (OS) were shorter for patients with NRAS mutations, although without significant difference for OS (P=0.081). In noncutaneous melanoma, the response rates were 0 and 13.7% for NRAS mutant and wild-type patients, the median PFS were 3.6 months (95% CI: 0.9-6.3) and 4.3 months (95%CI: 2.9-5.7) (P=0.015), and the median OS were 10.8 months (95% CI: 1.5-20.1) and 15.3 months (95% CI: 13.2-17.4) (P=0.025), respectively. In multivariate analysis, NRAS mutation, along with ECOG performance score and LDH level, was negatively associated with both PFS (HR 1.912, P=0.044) and OS (HR 2.210, P=0.025) in noncutaneous melanoma.ConclusionIn advanced Asian melanoma treated with anti-PD-1 monotherapy, NRAS mutant patients had lower response rates and poorer prognoses compared to wild-type patients, especially in noncutaneous subtypes.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Meta-analysismentioning

confidence: 99%

See 1 more Smart Citation

Association of NRAS Mutation With Clinical Outcomes of Anti-PD-1 Monotherapy in Advanced Melanoma: A Pooled Analysis of Four Asian Clinical Trials

et al. 2021

View full text Add to dashboard Cite

show abstract

“…BRAF/MEK-targeted therapies in combination with anti-PD-1 or anti-PD-L1 therapies have shown better overall toxicity profiles than that of anti-CTLA-4 therapy, however trial results have been variable. A randomized phase III trial (IMspire170) examining the benefit of adding a MEK inhibitor to PD-L1 blockade showed disappointing results, with the combination of cobimetinib (MEKi) and atezolizumab (anti-PD-L1) failing to increase PFS compared to pembrolizumab (anti-PD-1) alone (134). Trials examining the triplet combination of dual BRAF/MEK-targeted therapy and PD-(L)1 blockade have been more encouraging.…”

Section: Combining Mapk/erk-targeted Therapy With Immune Checkpoint Blockadementioning

confidence: 99%

Immunomodulatory Effects of BRAF, MEK, and CDK4/6 Inhibitors: Implications for Combining Targeted Therapy and Immune Checkpoint Blockade for the Treatment of Melanoma

et al. 2021

View full text Add to dashboard Cite

The recent advent of targeted and immune-based therapies has revolutionized the treatment of melanoma and transformed outcomes for patients with metastatic disease. The majority of patients develop resistance to the current standard-of-care targeted therapy, dual BRAF and MEK inhibition, prompting evaluation of a new combination incorporating a CDK4/6 inhibitor. Based on promising preclinical data, combined BRAF, MEK and CDK4/6 inhibition has recently entered clinical trials for the treatment of BRAFV600 melanoma. Interestingly, while BRAF- and MEK-targeted therapy was initially developed on the basis of potent tumor-intrinsic effects, it was later discovered to have significant immune-potentiating activity. Recent studies have also identified immune-related impacts of CDK4/6 inhibition, though these are less well defined and can be both immune-potentiating and immune-inhibitory. BRAFV600 melanoma patients are also eligible to receive immunotherapy, specifically checkpoint inhibitors against PD-1 and CTLA-4. The immunomodulatory activity of BRAF/MEK-targeted therapies has prompted interest in combination therapies incorporating these with immune checkpoint inhibitors, however recent clinical trials investigating this approach have produced variable results. Here, we summarize the immunomodulatory effects of BRAF, MEK and CDK4/6 inhibitors, shedding light on the prospective utility of this combination alone and in conjunction with immune checkpoint blockade. Understanding the mechanisms that underpin the clinical efficacy of these available therapies is a critical step forward in optimizing novel combination and scheduling approaches to combat melanoma and improve patient outcomes.

show abstract

“…Finally, on this topic, there is some preclinical evidence that in BRAF wild-type melanoma, the combination of MEKi with ICIs may enhance the antitumor effects. Preclinical data has shown that MEKi cobimetinib inhibits MAPK signaling and increases immune cell infiltration in the tumor, providing a strong rationale for combining cobimetinib with the anti-PD-L1 antibody atezolizumab [118]. Based on these findings, IMspire 170, a phase III trial, randomized 446 patients with advanced BRAF wild-type melanoma to receive either the MEKi cobimetinib plus atezolizumab, or the anti-PD1 monoclonal antibody pembrolizumab alone.…”

mentioning

confidence: 99%

Molecular Markers and Targets in Melanoma

Teixidó

Castillo

Martinez-Vila

et al. 2021

Cells

View full text Add to dashboard Cite

Melanoma develops as a result of several genetic alterations, with UV radiation often acting as a mutagenic risk factor. Deep knowledge of the molecular signaling pathways of different types of melanoma allows better characterization and provides tools for the development of therapies based on the intervention of signals promoted by these cascades. The latest World Health Organization classification acknowledged the specific genetic drivers leading to melanoma and classifies melanocytic lesions into nine distinct categories according to the associate cumulative sun damage (CSD), which correlates with the molecular alterations of tumors. The largest groups are melanomas associated with low-CSD or superficial spreading melanomas, characterized by frequent presentation of the BRAFV600 mutation. High-CSD melanomas include lentigo maligna type and desmoplastic melanomas, which often have a high mutation burden and can harbor NRAS, BRAFnon-V600E, or NF1 mutations. Non-CSD-associated melanomas encompass acral and mucosal melanomas that usually do not show BRAF, NRAS, or NF1 mutations (triple wild-type), but in a subset may have KIT or SF3B1 mutations. To improve survival, these driver alterations can be treated with targeted therapy achieving significant antitumor activity. In recent years, relevant improvement in the prognosis and survival of patients with melanoma has been achieved, since the introduction of BRAF/MEK tyrosine kinase inhibitors and immune checkpoint inhibitors. In this review, we describe the current knowledge of molecular pathways and discuss current and potential therapeutic targets in melanoma, focusing on their clinical relevance of development.

show abstract

Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study

Cited by 82 publications

References 37 publications

Association of NRAS Mutation With Clinical Outcomes of Anti-PD-1 Monotherapy in Advanced Melanoma: A Pooled Analysis of Four Asian Clinical Trials

Association of NRAS Mutation With Clinical Outcomes of Anti-PD-1 Monotherapy in Advanced Melanoma: A Pooled Analysis of Four Asian Clinical Trials

Immunomodulatory Effects of BRAF, MEK, and CDK4/6 Inhibitors: Implications for Combining Targeted Therapy and Immune Checkpoint Blockade for the Treatment of Melanoma

Molecular Markers and Targets in Melanoma

Contact Info

Product

Resources

About