Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review

We reviewed the literature to assess the efficacy and risk of constitutional, cardiac, gastrointestinal, and dermatological toxicities of combined BRAF plus MEK inhibitors versus BRAF inhibitors alone in patients with metastatic melanoma with BRAF mutations. Searches were conducted in PubMed, Cochrane Database of Systematic Reviews, Google scholar, ASCO, Scopus, and EMBASE for reports published from January 2010 through March 2019. Efficacy, including progression-free survival (PFS) and overall survival (OS) rates, were assessed by hazard ratio (HR); objective response rates (ORR) were assessed by odds ratio (OR). The randomized clinical trials (RCTs) with comparison to vemurafenib monotherapy were included to determine constitutional, gastrointestinal, cardiac, and dermatological toxicities using PRISMA statistical analysis with relative risk (RR) for equal comparison to avoid inclusion bias. Five RTCs comprising 2307 patients were included to assess efficacy, while three of the five RCTs comprising 1776 patients were included to assess adverse events. BRAF plus MEK inhibitor combination therapy demonstrated overall better efficacy compared to BRAF inhibitor monotherapy. Combination therapies appear to have favorable dermatologic side effect profiles, similar constitutional and cardiac profiles, and slightly worse gastrointestinal profiles compares to monotherapy regimens.

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Panniculitis Associated with MEK Inhibitor Therapy: An Uncommon Adverse Effect

Case Reports in Dermatology ◽

10.1159/000461571 ◽

2017 ◽

Vol 9 (1) ◽

pp. 80-85 ◽

Cited By ~ 7

Author(s):

Miruna Negulescu ◽

Florian Deilhes ◽

Vincent Sibaud ◽

Emilie Tournier ◽

Laurence Lamant ◽

...

Keyword(s):

Metastatic Melanoma ◽

Histopathological Examination ◽

Combined Therapy ◽

Combined Treatment ◽

Braf Inhibitor ◽

Mek Inhibitor ◽

Braf Inhibitors ◽

Mek Inhibitors ◽

Upper And Lower Extremities ◽

Hand Foot Syndrome

The combination of MEK inhibitor (cobimetinib, trametinib) and BRAF inhibitor (vemurafenib, dabrafenib) is now the first-line treatment in patients with BRAF V600-mutated metastatic melanoma. This association reduces cutaneous adverse events induced by BRAF inhibitors alone, including photosensitivity, hand-foot syndrome, hyperkeratosis, alopecia, skin papillomas, keratoacanthomas, and squamous-cell carcinomas. While panniculitis has exceptionally been reported with BRAF inhibitors, this rare side effect has never been described with the use of MEK inhibitors. We present here the first observation of panniculitis strictly induced by MEK inhibitors. Indeed, 10 days after the initiation of combined treatment with cobimetinib and vemurafenib for metastatic melanoma, our patient developed panniculitis predominantly on the upper and lower extremities. These cutaneous nodules disappeared during cobimetinib intermissions and recurred while the molecule was resumed. Recurrence of cutaneous nodules was observed after initiation of trametinib combined with dabrafenib, and resolved once again with trametinib discontinuation. We believe that clinicians should be aware of this cutaneous adverse event in patients treated with combined therapy, which can lead to unfounded BRAF inhibitor treatment discontinuation and compromise the antitumor response. Our case suggests a class effect linked with the MEK inhibition pharmacodynamic activity. Finally, laboratory investigation and histopathological examination are mandatory to exclude other panniculitis etiologies and subcutaneous metastasis of melanoma.

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Response to Ipilimumab/Nivolumab Rechallenge and BRAF Inhibitor/MEK Inhibitor Rechallenge in a Patient with Advanced Metastatic Melanoma Previously Treated with BRAF Targeted Therapy and Immunotherapy

Case Reports in Oncological Medicine ◽

10.1155/2020/4392562 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Caitlyn N. Myrdal ◽

Srinath Sundararajan

Keyword(s):

Targeted Therapy ◽

Metastatic Melanoma ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Objective Response ◽

Braf Inhibitor ◽

Mek Inhibitor ◽

Optimal Sequencing ◽

The Right

Little is known about the optimal sequencing of targeted therapy and immunotherapy in the treatment of patients with BRAFV600-mutated metastatic melanoma. BRAF/MEK inhibition often has the benefit of rapid disease regression; however, resistance is frequently seen with long-term use. Treatment with immune checkpoint inhibitors offers the potential for long-term response but displays a lower rate of objective response. The benefit of synergy between therapies is apparent; however, there is limited data regarding optimal sequencing in the treatment of advanced melanoma. We present the case of a 62-year-old gentleman with advanced BRAFV600-mutated melanoma who followed an unconventional treatment path. After progressing on single-agent vemurafenib, he had response to multiple modalities of immunotherapy before progression. After, he had a substantial response to multiple BRAF/MEK inhibitor rechallenges before developing resistance. The patient is now stable after a retrial of combination immunotherapy. Our case illustrates that with the right sequencing of therapy, meaningful clinical responses can be elicited with rechallenging of targeted therapy and immunotherapy in metastatic melanoma.

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Addition of Bevacizumab to Fluorouracil-Based First-Line Treatment of Metastatic Colorectal Cancer: Pooled Analysis of Cohorts of Older Patients From Two Randomized Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2008.17.7931 ◽

2009 ◽

Vol 27 (2) ◽

pp. 199-205 ◽

Cited By ~ 123

Author(s):

Fairooz F. Kabbinavar ◽

Herbert I. Hurwitz ◽

Jing Yi ◽

Somnath Sarkar ◽

Oliver Rosen

Keyword(s):

Colorectal Cancer ◽

Adverse Events ◽

Older Patients ◽

Statistical Power ◽

Randomized Clinical Trials ◽

Objective Response ◽

Progression Free Survival ◽

Pooled Analysis ◽

First Line ◽

Younger Patients

PurposeColorectal cancer (CRC) occurs predominantly in older persons. To provide more statistical power to assess risk/benefit in older patients, we examined the clinical benefit of bevacizumab (BV) plus fluorouracil-based chemotherapy in first-line metastatic CRC (mCRC) treatment in patients aged ≥ 65 years, using data pooled from two placebo-controlled studies.Patients and MethodsPooled efficacy data for 439 patients ≥ 65 years old randomized to BV plus chemotherapy (n = 218) or placebo plus chemotherapy (n = 221) in study 1 and study 2 were retrospectively analyzed on an intent-to-treat basis for overall survival (OS), progression-free survival (PFS), and objective response. Safety analysis was based on reports of targeted adverse events in treated patients.ResultsMedian OS with BV plus chemotherapy was 19.3 v 14.3 months with placebo plus chemotherapy (hazard ratio [HR] = 0.70; 95% CI, 0.55 to 0.90; P = .006). Patients treated with BV plus chemotherapy had a median PFS of 9.2 v 6.2 months for placebo plus chemotherapy patients (HR = 0.52; 95% CI, 0.40 to 0.67; P < .0001). The objective response rate was 34.4% with BV plus chemotherapy versus 29.0% with placebo plus chemotherapy (difference not statistically significant). Rates of BV-associated adverse events in the pooled BV plus chemotherapy group were consistent with those reported in the overall populations for the two studies.ConclusionAnalysis of pooled patient cohorts age ≥ 65 years from two similar trials in mCRC indicates that adding bevacizumab to fluorouracil-based chemotherapy improved OS and PFS, similar to the benefits in younger patients. Also, the risks of treatment do not seem to exceed those in younger patients with mCRC.

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BEACON CRC (binimetinib [BINI], encorafenib [ENCO], and cetuximab [CTX] combined to treat BRAF-mutant metastatic colorectal cancer [mCRC]): A multicenter, randomized, open-label, three-arm phase III study of ENCO plus CTX plus or minus BINI vs irinotecan (IRI)/CTX or infusional 5-fluorouracil/folinic acid/IRI (FOLFIRI)/CTX with a safety lead-in of ENCO + BINI + CTX in patients (Pts) with BRAFV600E mCRC.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps3622 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS3622-TPS3622 ◽

Cited By ~ 3

Author(s):

Sanne Huijberts ◽

Jan H. M. Schellens ◽

Marwan Fakih ◽

Marc Peeters ◽

Scott Kopetz ◽

...

Keyword(s):

Kinase Inhibitor ◽

Objective Response ◽

Progression Free Survival ◽

Mek Inhibitor ◽

Phase Iii ◽

Braf Mutations ◽

Open Label ◽

Egfr Inhibition ◽

Metastatic Setting

TPS3622 Background: BRAF mutations are found in ≈10% of mCRC cases. Pts with BRAFV600E mCRC have a poor prognosis, with shorter progression-free survival (PFS) and overall survival (OS) than pts with BRAFwt mCRC (Van Cutsem et al 2011; Modest et al 2012; Sorbye et al 2015). The benefits of combined BRAF + EGFR inhibition in mCRC have been demonstrated in vitro (Corcoran et al 2012; Prahallad et al 2012; Yang et al 2012), and preclinical evidence suggests that adding MEK signaling inhibition improves antitumor activity. Early clinical data indicate that BRAF + EGFR + MEK inhibition has greater activity than BRAF + EGFR inhibition in pts with BRAFV600E mCRC (Van Cutsem et al 2016). Our study will examine the combination of BINI (a MEK inhibitor) + ENCO (a selective BRAF kinase inhibitor) + CTX (an anti-EGFR antibody) and of ENCO + CTX in pts with BRAFV600E mCRC. Methods: BEACON CRC (NCT02928224) is enrolling pts with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. A safety lead-in phase (≈30 pts) will determine the safety and tolerability of oral ENCO 300 mg QD + oral BINI 45 mg BID + intravenous CTX 400 mg/m2 followed by 250 mg/m2 QW. In the phase 3 portion, ≈615 pts will be randomized 1:1:1 to triplet (ENCO + BINI + CTX), doublet (ENCO + CTX), or control (investigator’s choice of IRI/CTX or FOLFIRI/CTX) arms. Pts will be treated in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, or death. The primary endpoint is OS (triplet vs control). Secondary endpoints include OS (doublet vs control), confirmed investigator-assessed objective response rate according to RECIST version 1.1 (triplet or doublet vs control; triplet vs doublet), PFS (triplet or doublet vs control), duration of response, time to response, pharmacokinetics, and pt-reported outcomes. Safety will be summarized using standard adverse event reporting. Clinical trial information: NCT02928224.

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Cobimetinib

Annals of Pharmacotherapy ◽

10.1177/1060028016672037 ◽

2016 ◽

Vol 51 (2) ◽

pp. 146-153 ◽

Cited By ~ 15

Author(s):

Jessie Signorelli ◽

Arpita Shah Gandhi

Keyword(s):

Metastatic Melanoma ◽

Literature Search ◽

Data Extraction ◽

Objective Response ◽

Progression Free Survival ◽

Liver Function Tests ◽

Mek Inhibitor ◽

Phase Iii ◽

Reversible Inhibitor ◽

Grade 3

Objective: To review and summarize data on cobimetinib, which was approved by the US Food and Drug Administration (FDA) in November 2015 for use in combination with vemurafenib for unresectable or metastatic melanoma with a BRAFV600E or V600K mutation. Data Sources: A literature search using PubMed was conducted using the terms cobimetinib, MEK inhibitor, and melanoma from January 2000 to June 2016. Study Selection and Data Extraction: The literature search was confined to human studies published in English. Trials of cobimetinib for melanoma were prioritized. Data Synthesis: Cobimetinib is a reversible inhibitor of MEK1 and MEK2. Its FDA approval was based on a phase III, randomized trial of vemurafenib monotherapy (n = 248) or vemurafenib and cobimetinib (n = 247) in unresectable stage IIIC or IV melanoma with a BRAFV600 mutation. Cobimetinib was administered as 60 mg orally daily for 21 days/7 days off, whereas vemurafenib was administered as 960 mg twice daily. Vemurafenib and cobimetinib were associated with an objective response rate of 68%, and median progression-free survival of 9.9 months. The overall survival was not reached at the time of first interim analysis. Clinically relevant grade ≥3 adverse events were diarrhea (6%), rash (6%), photosensitivity (2%), elevated liver function tests (LFTs) (8%-12%), increased creatine kinase (11%), and retinal detachment (3%). Conclusion: Cobimetinib combined with vemurafenib is an alternative BRAF/MEK inhibitor therapy for unresectable or metastatic melanoma with BRAFV600 mutation. The role of cobimetinib in melanoma and other solid tumors is likely to expand as the results from ongoing studies become available.

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Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.688 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 688-688 ◽

Cited By ~ 11

Author(s):

Scott Kopetz ◽

Axel Grothey ◽

Rona Yaeger ◽

Pieter-Jan AR Cuyle ◽

Sanne Huijberts ◽

...

Keyword(s):

Objective Response ◽

Braf Inhibitor ◽

Progression Free Survival ◽

Standard Of Care ◽

Mek Inhibitor ◽

Weekly Dose ◽

Current Standard ◽

Grade 3 ◽

Tract Infections

688 Background: BRAFV600E mutation occurs in 10%-15% of patients (pts) with mCRC and confers a poor prognosis. After first-line therapy, standard second-line therapies provide limited benefit, with objective response rates (ORRs) < 10%, and overall survival (OS) of 46 months (mo). BEACON CRC (NCT02928224) is a 3-arm phase 3 trial of triplet therapy with the BRAF inhibitor ENCO + MEK inhibitor BINI + antiEGFR antibody CETUX vs ENCO + CETUX vs a control arm (irinotecan/FOLFIRI + CETUX) in pts with BRAFV600E mCRC in the second or third-line setting. A safety lead-in (SLI) of the triplet therapy was conducted in 30 pts prior to initiation of the randomized part of the trial. Previously reported confirmed ORR in 29 pts with BRAFV600E mCRC was 48% and median progression-free survival (PFS) was 8.0 mo (Van Cutsem E, et al. Ann Oncol. 2018;29:O-027). Here we present updated safety and efficacy results including mature OS. Methods: All pts in the SLI received ENCO 300 mg once daily + BINI 45 mg twice daily + CETUX standard weekly dose. Assessments included efficacy (ORR, duration of response, time to response, PFS, and OS), safety, and tolerability. Results: Among 30 pts treated, 1 had a BRAF non-V600E mutation and is not included in the efficacy analyses. At data cutoff, the median follow-up time for survival was 18.2 mo and median exposure was 7.8 mo (range 0.521.4 mo). The confirmed ORR and median PFS remain unchanged from the previous report (ORR, 48% [95%CI, 29.467.5]; PFS, 8.0 mo [95% CI, 5.69.3 mo]). Mature median OS is 15.3 mo (95% CI, 9.6 monot reached). The triplet continues to be well-tolerated with no unexpected toxicities. The most common grade 3/4 toxicities were fatigue (13%), anemia, increases in creatine phosphokinase and/or aspartate aminotransferase, and urinary tract infections (each 10%). The rate of grade 3/4 skin toxicities continues to be lower than generally observed with CETUX in mCRC. Conclusions: With longer follow-up, triplet therapy with ENCO + BINI + CETUX continues to be well tolerated. Median PFS and now mature median OS are substantially improved over historical data for current standard-of-care options. Clinical trial information: NCT02928224.

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Cautious addition of targeted therapy to PD-1 inhibitors after initial progression of BRAF mutant metastatic melanoma on checkpoint inhibitor therapy

BMC Cancer ◽

10.1186/s12885-021-08906-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wolfram Samlowski ◽

Camille Adajar

Keyword(s):

Targeted Therapy ◽

Metastatic Melanoma ◽

Checkpoint Inhibitor ◽

Combined Treatment ◽

Objective Response ◽

Progression Free Survival ◽

Mek Inhibitor ◽

Inhibitor Therapy ◽

Antibody Treatment ◽

Line Therapy

Abstract Background Virtually all metastatic patients with metastatic melanoma who progress after initial treatment with PD-1 or CTLA-4 directed antibodies will die of their disease. Salvage options are urgently needed. It is theoretically attractive to combine immunotherapy with targeted agents in progressing patients with BRAF mutation positive melanoma, but the toxicity of combined treatment has proven challenging. Methods We performed a retrospective analysis of our patient database and identified 23 patients who progressed on initial checkpoint inhibitor treatment, who subsequently had cautious addition of BRAF±MEK inhibitor therapy to continued PD-1 antibody treatment. Results We found an objective response rate of 55% in second line therapy, with a median progression-free survival of 33.4 months and median overall survival of 34.1 months, with 40% of patients in unmaintained remission at over 3 years. Ten of 12 responding patients were able to discontinue all therapy and continue in unmaintained remission. Toxicity of this approach was generally manageable (21.7% grade 3–5 toxicity). There was 1 early sudden death for unknown reasons in a responding patient. Discussion Our results suggest that 2nd line therapy with PD-1 inhibitors plus BRAF±MEK inhibitors has substantial activity and manageable toxicity. This treatment can induce additional durable complete responses in patients who have progressed on initial immunotherapy. These results suggest further evaluation be performed of sequential PD-1 antibody treatment with cautious addition of targeted therapy in appropriate patients.

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Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma

Journal of Clinical Oncology ◽

10.1200/jco.21.00675 ◽

2021 ◽

pp. JCO.21.00675

Author(s):

Adi Diab ◽

Scott S. Tykodi ◽

Gregory A. Daniels ◽

Michele Maio ◽

Brendan D. Curti ◽

...

Keyword(s):

Adverse Events ◽

Metastatic Melanoma ◽

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

First Line ◽

Free Survival ◽

Median Progression Free Survival ◽

Immune Mediated ◽

Grade 3

PURPOSE Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma. METHODS A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers. RESULTS At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was −78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response. CONCLUSION BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.

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Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma: Review of the Literature

Dermatology Research and Practice ◽

10.1155/2016/5361569 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 27

Author(s):

Bilgen Gençler ◽

Müzeyyen Gönül

Keyword(s):

Side Effects ◽

Metastatic Melanoma ◽

Mapk Pathway ◽

Case Reports ◽

Mitogen Activated Protein Kinase ◽

Braf V600e ◽

Braf Inhibitors ◽

Braf Mutations ◽

Cutaneous Side Effects ◽

Downstream Signaling

The incidence of melanoma has recently been increasing. BRAF mutations have been found in 40–60% of melanomas. The increased activity of BRAF V600E leads to the activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway, which plays a key role as a regulator of cell growth, differentiation, and survival. The use of BRAF inhibitors in metastatic melanoma with BRAF mutation ensures clinical improvement of the disease. Vemurafenib and dabrafenib are two selective BRAF inhibitors approved by the Food and Drug Administration (FDA). Both drugs are well tolerated and successfully used in clinical practice. However, some adverse reactions have been reported in patients in the course of treatment. Cutaneous side effects are the most common adverse events among them with a broad spectrum. Both the case reports and several original clinical trials reported cutaneous reactions during the treatment with BRAF inhibitors. In this review, the common cutaneous side effects of BRAF inhibitors in the treatment of metastatic melanoma with BRAF V600E mutation were reviewed.

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A Phase 2 Clinical Trial of Trametinib and Low-Dose Dabrafenib in Patients with Advanced Pretreated NRASQ61R/K/L Mutant Melanoma (TraMel-WT)

Cancers ◽

10.3390/cancers13092010 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2010

Author(s):

Gil Awada ◽

Julia Katharina Schwarze ◽

Jens Tijtgat ◽

Giuseppe Fasolino ◽

Hendrik Everaert ◽

...

Keyword(s):

Clinical Trial ◽

Low Dose ◽

Objective Response ◽

Braf Inhibitor ◽

Skin Toxicity ◽

Mek Inhibitor ◽

Phase 2 ◽

Cutaneous Toxicity ◽

Full Dose ◽

Phase 2 Clinical Trial

Background: MEK-inhibitor monotherapy has activity in advanced NRASQ61R/K/L mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAFV600E/K mutant melanoma) has low cutaneous toxicity. It is unknown whether a low dose of BRAF-inhibitor can mitigate the skin toxicity associated with full-dose MEK-inhibitor treatment in patients with advanced NRASQ61R/K/L mutant melanoma. Methods: This two-stage phase 2 clinical trial investigated trametinib 2 mg once daily in patients with advanced NRASQ61R/K/L mutant melanoma who were pretreated with immune checkpoint inhibitors. In case of trametinib-related cutaneous toxicity, low-dose dabrafenib (50 mg twice daily) was added to prevent recurrent cutaneous toxicity (pre-amendment). Following an amendment, trametinib was combined upfront with low-dose dabrafenib (post-amendment). Objective response rate (ORR) served as the primary endpoint. Results: All 6 patients enrolled pre-amendment developed trametinib-related cutaneous toxicity, necessitating treatment interruption. Combining trametinib with low-dose dabrafenib prevented recurrent skin toxicity thereafter. Trametinib-related skin toxicity was effectively mitigated in all 10 patients post-amendment. In all 16 included patients, the ORR and disease control rate was 6.3% (1 partial response) and 50.0%, respectively. The trial was halted after the first stage. Conclusions: Combining full-dose trametinib with low-dose dabrafenib can mitigate MEK-inhibitor-related skin toxicity but was insufficiently active in this patient population. This combination can be of further interest for the treatment of MEK-inhibitor-sensitive tumors.

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