Effects of cobimetinib: A Synthesis of Findings from 20 Studies

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Original Abstract of the Article

Key Research Findings

Cobimetinib, a MEK inhibitor, has shown promising results in combination with BRAF inhibitors for the treatment of melanoma, particularly in patients with the BRAFV600 mutation. 7 A triple therapy regimen involving atezolizumab, vemurafenib, and cobimetinib has been approved as a first-line treatment for advanced melanoma patients with BRAFV600 mutations. 7 However, a phase 2 trial, ImmunoCobiVem, showed that early switching to atezolizumab after 3 months of vemurafenib plus cobimetinib treatment led to a rapid loss of tumor control in patients with advanced BRAFV600-mutated melanoma. 4 Cobimetinib has also demonstrated effectiveness in combination with other targeted therapies, such as venetoclax, for the treatment of relapsed/refractory multiple myeloma. 20 Moreover, a preclinical study using a mouse model suggests that cobimetinib exhibits antiviral properties and can promote tumor regression in human papillomavirus infection-induced tumorigenesis. 6

Benefits and Risks

Benefit Summary

Cobimetinib, when combined with BRAF inhibitors, has demonstrated efficacy in treating melanoma, particularly in patients with BRAFV600 mutations. 7 The triple therapy combination of atezolizumab, vemurafenib, and cobimetinib has been approved as a first-line treatment for these patients. 7 Cobimetinib has also shown promising results in combination with other targeted therapies, such as venetoclax, for the treatment of relapsed/refractory multiple myeloma. 20 Preclinical studies suggest that cobimetinib possesses antiviral properties and can promote tumor regression in human papillomavirus infection-induced tumorigenesis. 6

Risk Summary

Cobimetinib, like other MEK inhibitors, can cause side effects such as skin rash. 17

Comparison of Studies

Similarities in Studies

These studies consistently suggest that cobimetinib can be effective in treating cancers with BRAF mutations, often in combination with BRAF inhibitors. 4 , 12 , 10 , 3 , 14 , 1 , 5 , 2 Moreover, these studies highlight that cobimetinib can cause side effects such as skin rash. 17

Differences in Studies

These studies evaluate the efficacy and safety of cobimetinib in various cancer types, treatment regimens, and patient populations. For example, some studies focus on the effectiveness of cobimetinib in combination with BRAF inhibitors for treating advanced melanoma. 4 , 12 , 10 , 3 , 14 , 1 , 5 , 2 Others investigate the effectiveness of cobimetinib in combination with other targeted therapies, such as venetoclax, for the treatment of relapsed/refractory multiple myeloma or for patients with BRAFV600 wild-type melanoma who have progressed on prior anti-PD-1 therapy. 20 , 19 Furthermore, some studies, like the preclinical mouse model study, explore cobimetinib's antiviral properties and potential for tumor regression in human papillomavirus infection-induced tumorigenesis. 6

Consistency and Contradictions in Results

These studies demonstrate a consistent trend that cobimetinib is effective in treating cancers with BRAF mutations, especially in combination with BRAF inhibitors. 4 , 12 , 10 , 3 , 14 , 1 , 5 , 2 However, it's important to note that the efficacy and safety of cobimetinib can vary depending on the specific cancer type, treatment regimen, and patient population. 4 , 12 , 10 , 3 , 14 , 1 , 5 , 2

Implications for Everyday Life

Cobimetinib, in conjunction with BRAF inhibitors, has the potential to be a valuable treatment option for patients with BRAF-mutant cancers, particularly melanoma. 4 , 12 , 10 , 3 , 14 , 1 , 5 , 2 However, the decision to use cobimetinib should be made in consultation with a healthcare professional who can assess an individual's medical history, specific cancer type, treatment regimen, and potential risks. 4 , 12 , 10 , 3 , 14 , 1 , 5 , 2 Close monitoring for potential side effects is crucial. 17

Limitations of Current Research

The studies evaluating cobimetinib have been conducted on relatively small patient populations, requiring further research with larger cohorts to generalize findings. 4 , 12 , 10 , 3 , 14 , 1 , 5 , 2 Additionally, long-term efficacy and safety data are limited, necessitating further research to understand cobimetinib's long-term impact. 4 , 12 , 10 , 3 , 14 , 1 , 5 , 2

Future Research Directions

Future research should focus on evaluating the efficacy and safety of cobimetinib in larger patient populations over extended periods. 4 , 12 , 10 , 3 , 14 , 1 , 5 , 2 Comparative studies against other treatments are also essential to determine cobimetinib's place in the therapeutic landscape. 4 , 12 , 10 , 3 , 14 , 1 , 5 , 2

Conclusion

Cobimetinib holds promise as a valuable therapeutic agent for treating BRAF-mutant cancers, especially in combination with BRAF inhibitors. 4 , 12 , 10 , 3 , 14 , 1 , 5 , 2 However, further research is needed to solidify its role in treating various cancers and understand its long-term impact. It's crucial to engage with a healthcare professional to discuss personalized treatment options and monitor for potential side effects.

Literature analysis of 20 papers
Positive Content
17
Neutral Content
2
Negative Content
1
Article Type
4
1
1
2
19
1.

Cobimetinib Plus Vemurafenib in Patients With Solid Tumors With <i>BRAF</i> Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study.

Author: Meric-BernstamFunda, RotheMichael, MangatPam K, Garrett-MayerElizabeth, GutierrezRodolfo, AhnEugene R, CannonTimothy L, PowellSteven, KraussJohn C, ReynoldsChristopher M, von MehrenMargaret, BehlDeepti, CalfaCarmen J, DuvivierHerbert L, KaplanHenry G, LivingstonMichael B, SharmaManish R, UrbaWalter J, GranthamGina N, HinshawDominique C, GregoryAbigail, HalabiSusan, SchilskyRichard L

Antitumor activity

This Phase II basket study evaluated the antitumor activity of cobimetinib plus vemurafenib in patients with solid tumors harboring BRAF mutations. The study provides evidence of the effectiveness of this combination therapy in patients with these specific genomic alterations.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

2.

BRAF and MEK inhibitor combinations induce potent molecular and immunological effects in NRAS-mutant melanoma cells: Insights into mode of action and resistance mechanisms.

Author: DinterLisa, KaritzkyPaula C, SchulzAlexander, WurmAlexander A, MehnertMarie-Christin, SergonMildred, TungerAntje, LescheMathias, WehnerRebekka, MüllerAnja, KäublerTheresa, NiessnerHeike, DahlAndreas, BeissertStefan, SchmitzMarc, MeierFriedegund, SeligerBarbara, WestphalDana

Effective melanoma treatment
Resistance development

This study investigated the molecular and immunological effects of BRAF/MEK inhibitor combinations in sensitive NRAS-mutant melanoma cells. The combinations demonstrated potent antiproliferative, proapoptotic, and immunostimulatory effects, potentially offering new treatment strategies for NRAS-mutant melanoma. However, the study also identified mechanisms of resistance that may hinder treatment efficacy.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

3.

Combined BRAF, MEK, and heat-shock protein 90 (HSP90) inhibition in advanced BRAF V600-mutant melanoma.

Author: ErogluZeynep, ChenY Ann, SmalleyInna, LiJiannong, MarkowitzJoseph K, BrohlAndrew S, TettehLeticia, TaylorHayley, SondakVernon K, KhushalaniNikhil I, SmalleyKeiran S M

Melanoma treatment

Resistance to BRAF and MEK inhibitors is common in patients with BRAF V600-mutant melanoma. A Phase 1 study found that the combination of vemurafenib and the HSP90 inhibitor XL888 showed activity equivalent to that of BRAF and MEK inhibitors in patients with advanced melanoma.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

4.

Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial.

Author: LivingstoneE, GogasH, Kandolf-SekulovicL, MeierF, EigentlerT K, ZiemerM, TerheydenP A M, GesierichA H, HerbstR A, KählerK C, ZiogasD C, MijuskovicZ, GarzarolliM, GarbeC, RoeschA, UgurelS, GutzmerR, GrobJ J, KieckerF, UtikalJ, Windemuth-KieselbachC, EckhardtS, ZimmerL, SchadendorfD

Improved progression-free survival
Improved survival

ImmunoCobiVem is a clinical trial that investigated whether switching to atezolizumab after achieving tumor control with vemurafenib + cobimetinib improved progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAF<sup>V600</sup>-mutated melanoma.

Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Multicenter StudyResearch conducted in collaboration with multiple research institutions. It aims to collect a wide range of data and obtain more generalizable results.
Clinical Trial, Phase IIA Phase II trial is a trial that further evaluates the efficacy and safety of a new drug or treatment, whose safety has been confirmed to some extent in a Phase I trial, in a small number of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

5.

BRAF-MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas.

Author: BrastianosPriscilla K, TwohyErin, GeyerSusan, GerstnerElizabeth R, KaufmannTimothy J, TabriziShervin, KabatBrian, ThieraufJulia, RuffMichael W, BotaDaniela A, ReardonDavid A, CohenAdam L, De La FuenteMacarena I, LesserGlenn J, CampianJian, AgarwallaPankaj K, KumthekarPriya, MannBhupinder, VoraShivangi, KnoppMichael, IafrateA John, CurryWilliam T, CahillDaniel P, ShihHelen A, BrownPaul D, SantagataSandro, BarkerFred G, GalanisEvanthia

Safe and effective treatment for papillary craniopharyngiomas

This study explores the potential safety and efficacy of BRAF-MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy.

Clinical Trial, Phase IIA Phase II trial is a trial that further evaluates the efficacy and safety of a new drug or treatment, whose safety has been confirmed to some extent in a Phase I trial, in a small number of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

6.

The antiviral effects of a MEK1/2 inhibitor promote tumor regression in a preclinical model of human papillomavirus infection-induced tumorigenesis.

Author: LunaAdrian J, YoungJesse M, SterkRosa T, BonduVirginie, SchultzFred A, KusewittDonna F, KangHuining, OzbunMichelle A

Antiviral and anti-tumor properties
Papilloma regression

This study evaluated the antiviral and anti-tumor properties of MEK inhibitors in a mouse model of papillomavirus infection. Oral delivery of a MEK1/2 inhibitor effectively promoted papilloma regression, suggesting potential for developing MEK inhibitors as papillomavirus antiviral therapies.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

8.

A phase I/II study of LY3022855 with BRAF/MEK inhibition in patients with Melanoma.

Author: BuchbinderElizabeth I, Giobbie-HurderAnita, HaqRizwan, OttPatrick A

Complete response
Intolerance

This phase I/II clinical trial evaluated the safety and efficacy of LY3022855, a CSF-1R inhibitor, in combination with vemurafenib and cobimetinib for BRAF V600<sup>E/K</sup> mutant metastatic melanoma. The trial was terminated early due to safety concerns. While one patient achieved complete response, the combination was poorly tolerated, with three patients experiencing grade 3 events. Further investigation into this combination might be warranted despite the initial results.

Clinical Trial, Phase IThe first stage of clinical trials in humans. Evaluates the safety, tolerability, and pharmacokinetics of a new drug/treatment.
Clinical Trial, Phase IIA Phase II trial is a trial that further evaluates the efficacy and safety of a new drug or treatment, whose safety has been confirmed to some extent in a Phase I trial, in a small number of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

9.

Activity and safety of first-line treatments for advanced melanoma: A network meta-analysis.

Author: BoutrosAndrea, TandaEnrica Teresa, CroceElena, CatalanoFabio, CeppiMarcello, BruzzoneMarco, CecchiFederica, AreccoLuca, FragugliaMatteo, PronzatoPaolo, GenovaCarlo, Del MastroLucia, LambertiniMatteo, SpagnoloFrancesco

Improved survival
Melanoma treatment
Toxicity

Advanced melanoma is a type of skin cancer. This article presents a systematic review and network meta-analysis of the available treatment options for advanced melanoma, including the combination therapies relatlimab/nivolumab, ipilimumab/nivolumab, and atezolizumab/vemurafenib/cobimetinib.

Systematic ReviewA review that systematically collects, evaluates, and integrates relevant research to answer a specific research question.
Meta-AnalysisA statistical technique that integrates the results of multiple studies to draw more general conclusions about a particular issue.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

10.

[Unusual association of BRAF and MEK inhibitors: Clinical response of metastatic melanoma treated with dabrafenib-cobimetinib].

Author: LeenhardtFanny, MbatchiLitaty, EvrardAlexandre, CupissolDidier, LesageCandice

Melanoma treatment
Adverse events

A patient with metastatic melanoma achieved complete remission for 19 months using an off-label combination of dabrafenib (BRAFi) and cobimetinib (MEKi). This unusual combination was used to manage pyrexia and was closely monitored using therapeutic drug monitoring. This case report highlights the potential benefit of personalized treatment strategies in melanoma management.

Case ReportsIn the medical field, a report that describes in detail a unique case, an unusual medical condition, or the effect of a treatment. Provides new insights and possibilities for treatment through individual patient cases.
English AbstractA summary of a research paper/publication written in English for a wider audience.
LetterA written message for communication and exchange of information between individuals.

Language : French

11.

Clinical and exploratory biomarker findings from the MODUL trial (Cohorts 1, 3 and 4) of biomarker-driven maintenance therapy for metastatic colorectal cancer.

Author: DucreuxMichel, TaberneroJosep, GrotheyAxel, ArnoldDirk, O'DwyerPeter J, GilbergFrank, AbbasAlexander, ThakurMeghna Das, PrizantHen, IraharaNatsumi, TahiriAnila, SchmollHans-Joachim, Van CutsemEric, de GramontAimery

MODUL is an adaptable, signal-seeking trial of biomarker-driven maintenance therapy following first-line induction treatment in patients with metastatic colorectal cancer (mCRC). This report describes findings from Cohorts 1 (BRAFmut), 3 (HER2+) and 4 (HER2−/high microsatellite instability, HER2−/microsatellite stable [MSS]/BRAFwt or HER2−/MSS/BRAFmut/RASmut).

Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

12.

Long-Term Real-World Outcomes and Safety of Vemurafenib and Vemurafenib + Cobimetinib Therapy in Patients with BRAF-Mutated Melanoma.

Author: PiejkoKarolina, Cybulska-StopaBożena, ZiętekMarcin, DziuraRobert, GalusŁukasz, Kempa-KamińskaNatasza, ZiółkowskaBarbara, RutkowskaEwa, KopcińskiTomasz, KubiatowskiTomasz, BalWiesław, SuwińskiRafał, MackiewiczJacek, Kamińska-WinciorekGrażyna, CzarneckaAnna M, RutkowskiPiotr

Melanoma treatment efficacy

A retrospective study of 275 patients with unresectable or metastatic BRAF mutated melanoma found that vemurafenib plus cobimetinib (V + C) was associated with significantly improved median overall survival (mOS) and median progression-free survival (mPFS) compared to vemurafenib (V) alone, with no major increase in toxicity.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

14.

Successful treatment of non-Langerhans cell histiocytosis with the MEK inhibitor trametinib: a multicenter analysis.

Author: AaroeAshley, KurzrockRazelle, GoyalGaurav, GoodmanAaron M, PatelHarsh, RuanGordon, UlanerGary, YoungJason, LiZiyi, DustinDerek, GoRonald S, DiamondEli L, JankuFilip

ECD and RDD treatment
Rash

Trametinib, a MEK inhibitor, was found to be an effective treatment for Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD), even in patients without the BRAFV600E mutation. The drug was well tolerated, with the most common side effect being rash. This suggests that trametinib could be a valuable therapeutic option for these rare histiocytoses.

Multicenter StudyResearch conducted in collaboration with multiple research institutions. It aims to collect a wide range of data and obtain more generalizable results.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

18.

Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAF<sup>V600</sup> mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study.

Author: AsciertoPaolo A, StroyakovskiyDaniil, GogasHelen, RobertCaroline, LewisKarl, ProtsenkoSvetlana, PereiraRodrigo P, EigentlerThomas, RutkowskiPiotr, DemidovLev, ZhukovaNatalia, SchachterJacob, YanYibing, CaroIvor, HertigChristian, XueCloris, KustersLieke, McArthurGrant A, GutzmerRalf

Improved progression-free survival
Unknown

This study reports the results of a second, prespecified, interim overall survival analysis of the phase 3 IMspire150 study. The primary analysis showed improved progression-free survival with first-line atezolizumab, vemurafenib, and cobimetinib compared to placebo, vemurafenib, and cobimetinib in patients with BRAF<sup>V600</sup> mutation-positive melanoma.

Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Multicenter StudyResearch conducted in collaboration with multiple research institutions. It aims to collect a wide range of data and obtain more generalizable results.
Clinical Trial, Phase IIIA Phase III trial is a trial that further rigorously verifies the efficacy and safety of a new drug or treatment, whose efficacy and safety have been confirmed in a Phase II trial, in a large number of patients, and evaluates whether it is superior to existing treatments.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

19.

Phase 1b study of cobimetinib plus atezolizumab in patients with advanced BRAF<sup>V600</sup> wild-type melanoma progressing on prior anti-programmed death-1 therapy.

Author: SandhuShahneen, AtkinsonVictoria, CaoMaria González, MedinaTheresa, RivasAinara Soria, MenziesAlexander M, CaroIvor, RobertsLouise, SongYuyao, YanYibing, GuoYu, XueCloris, LongGeorgina V

BRAF therapy
Adverse events

A phase 1b study of 103 patients with advanced BRAF-mutated melanoma who had progressed on prior anti-PD-1 therapy found that combination therapy with cobimetinib and atezolizumab was effective in achieving objective response rates and disease control rates. The median duration of response was 12.7 months, and the median progression-free survival was 3.8 months. The most common side effects were diarrhea, dermatitis acneiform, and nausea.

Multicenter StudyResearch conducted in collaboration with multiple research institutions. It aims to collect a wide range of data and obtain more generalizable results.
Clinical Trial, Phase IThe first stage of clinical trials in humans. Evaluates the safety, tolerability, and pharmacokinetics of a new drug/treatment.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

20.

Cobimetinib Alone and Plus Venetoclax With/Without Atezolizumab in Patients With Relapsed/Refractory Multiple Myeloma.

Author: SchjesvoldFredrik, PaivaBruno, RibragVincent, Rodriguez-OteroPaula, San-MiguelJesus F, RobakPawel, HanssonMarkus, OnishiMaika, HamidiHabib, MalhiVikram, DailMonique, JaveryApurva, KuGrace, RaabMarc S

MM treatment

This phase Ib/II trial evaluated the safety and efficacy of cobimetinib, alone and in combination with venetoclax and atezolizumab, in patients with relapsed/refractory multiple myeloma (MM).

Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

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