What, if Any, Role Is There for BRAF-Targeted Therapy in BRAF-Mutant Melanoma?

Activating mutations in BRAFV600 are present in 40%-50% of patients with melanoma, and mutant-specific inhibition with small molecule inhibitors of BRAF and MEK are associated with significant clinical benefit.¹ Specifically, the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitor trametinib each have demonstrated improvements in clinical outcomes compared with cytotoxic chemotherapy in patients with advanced melanoma, defined as unresectable stage III or stage IV, and received regulatory approval as single agents.^2–4 Building upon this success, combination regimens of BRAF and MEK were compared with single-agent BRAF inhibitors and have been associated with improved response rates, progression-free survival (PFS) and overall survival (OS) without substantially increased toxicity.^5–8 On the basis of these data, three such combinations (dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib) have received US Food and Drug Administration approval. More recently, the long-term survival of each of BRAF/MEK combinations has been reported.^9–11 In the pooled analysis of the dabrafenib/trametinib arms of the COMBI-d and COMBI-v studies, the 5-year survival was 34%. In the co-BRIM trial, the 5-year survival of combined vemurafenib/cobimetinib was 31% and single-agent vemurafenib was 26%.¹⁰ In the article that accompanies this editorial, Dummer et al¹¹ present the long-term data of the COLUMBUS study, which randomly assigned 577 patients with advanced melanoma to encorafenib/binimetinib (192 patients), vemurafenib (191), or encorafenib (194). The 5-year OS of encorafenib/binimetinib was 35%, compared with 21% and 35%, respectively, in the vemurafenib and encorafenib arms. Remarkably, the toxicity profile of encorafenib and binimetinib is more favorable than encorafenib alone, thus favoring the use of the approved combination over single-agent encorafenib.^8,11

THE TAKEAWAY

• In the article that accompanies this editorial, Dummer and colleagues¹¹ present the long‐term data of the COLUMBUS study. The combination of encorafenib and binimetinib is associated with impressive 5-year progression-free and overall survival in patients with previously untreated, BRAF-mutant advanced melanoma compared with historical controls and consistent with other BRAF/MEK inhibitor combinations. However, past and emerging data support the use of frontline immunotherapy instead of BRAF-targeted therapy in this patient population, which has required rethinking into the optimal use of these highly effective therapies.

To place these data into context, treatment options for advanced melanoma before 2011 consisted of ineffective chemotherapies, high-dose interleukin 2, and enrollment onto clinical trials. In a remarkable summary of three decades (1975-2005) worth of survival data from more than 2,000 patients with advanced melanoma enrolled onto cooperative group clinical trials, the median OS was 6.2 months, and the 1-year survival was approximately 25%.¹² There have been seven single agents (ipilimumab, vemurafenib, dabrafenib, trametinib, pembrolizumab, nivolumab, and talimogene laherparepvec) and six combinations (dabrafenib/trametinib, ipilimumab/nivolumab, vemurafenib/cobimetinib, encorafenib/binimetinib, vemurafenib/cobimetinib/atezolizumab, and nivolumab/relatlimab) approved by regulatory authorities to treat advanced melanoma, all of which are options for patients with BRAFV600 mutations (Fig 1A). Importantly, nearly all data generated on the pivotal trials leading to these approvals were in the frontline setting and demonstrate 5-year survival rates of > 20%.^{9–11,13–16}

FIG 1.

A timeline of US Food and Drug Administration approvals for the treatment of advanced (unresectable stage III or stage IV) melanoma. (A) Agents in red are either BRAF or MEK inhibitors and are only approved for patients with BRAFV600-mutant melanoma. (B) Agents in blue are immunotherapies. The long-term survival of frontline therapy for advanced melanoma is shown. COBI, cobimetinib; DAB/TRAM, dabrafenib plus trametinib¹⁰; DTIC, dacarbazine; ENCO/BINI, encorafenib plus binimetinib; FDC, fixed dose combination; IL-2, interleukin 2; IPI, ipilimumab^13,14; IPI/NIVO, combination of ipilimumab plus nivolumab¹³; NIVO, nivolumab¹³; PEMBRO, pembrolizumab¹⁴; TVEC, talimogene laherparepvec¹⁵; VEM, vemurafenib^9,11; VEM/COBI, vemurafenib plus cobimetinib.⁹

Looking at the data via cross trial comparisons (Fig 1B), it appears that monoclonal antibodies against programmed death receptor 1 (PD-1) given alone or in combination with anti-cytotoxic T lymphocyte–associated receptor 4 is the best frontline treatment option. In multiple clinical trials, 40%-50% of patients with advanced melanoma will have long-term survival.^13,14 More recently, prospective data were presented from the DREAMSeq trial, a phase III study that randomly assigned patients with advanced, previously untreated BRAFV600-mutant melanoma to up-front BRAF-targeted therapy (dabrafenib plus trametinib) or combined immune checkpoint inhibitor therapy (ipilimumab plus nivolumab).¹⁷ This study demonstrated, with over 27 months of a median follow-up, a significant improvement in OS for those randomized to ipilimumab and nivolumab versus dabrafenib and trametinib, with a 2-year OS of 72% versus 52% (P = .0095), respectively. In aggregate, the entire data support offering previously untreated patients with advanced, BRAFV600-mutant melanoma anti–PD-1–based therapy. Still, BRAF-targeted therapy doublets are highly effective. Thus, it is critical to think about to which patients we should offer BRAF-targeted therapy, when in the treatment course to do so, and how we can make BRAF-targeted therapy more effective.

In the frontline setting, there are scenarios where the risk of rapid progression and death are so high that BRAF-targeted therapy is required to stabilize the patient's condition. To this point, analysis of the DREAMSeq OS Kaplan-Meier curves reveals that for the first 10 months after random assignment, OS is numerically better for BRAF-targeted therapy than immunotherapy before the curves crossing and significantly showing the opposite result over time.¹⁷ In the scenario of newly diagnosed, immediately life-threatening BRAF-mutant metastatic disease, treating to maximal tumor regression or even for a set amount of time with BRAF-targeted therapy and then switching to immunotherapy, typically combined ipilimumab and nivolumab given its higher response rate, is a possibility. Another available option in this scenario is to treat with triplet therapy of BRAF/MEK inhibition in combination with anti–PD-1 or anti–PD-1 ligand (PD-L1) therapy. There have been three randomized trials of triplet combination compared with BRAF/MEK inhibition.^18–20 In each, there was improved PFS and duration of response; however, in two of the three trials (Keynote 022, Part 3; COMBI-i), the improvement in PFS did not meet statistical significance.^18,19 In the third (IMSpire150), patients treated with a lead-in month of vemurafenib and cobimetinib followed by triplet with the addition of the anti–PD-L1 atezolizumab after 28 days had statistically significant PFS improvement compared with those treated with vemurafenib and cobimetinib doublet.²⁰ Given these data, this triplet regimen was approved by the US Food and Drug Administration in 2020. In subgroup analyses of the data from the two phase III studies (COMBI-I, IMSpire150), it appears there is a discrepancy regarding whether patients with the highest risk disease have the most benefit from triplet therapy as this was seen in the COMBI-I study but not the IMSpire150 study.^19,20

Except in rare instances as outlined above, initial therapy for patients with advanced, BRAF-mutant melanoma will be immune checkpoint inhibition, saving BRAF-targeted therapy for second- or further-line therapy. There are limited long-term data with BRAF-targeted therapy doublets in the postimmunotherapy setting; however, the available retrospective data suggest that response rates remain relatively preserved, but the duration of benefit is lower.^17,21–23 Thus, BRAF-targeted therapy essentially is used as a last resort when options associated with more durable benefit are no longer available, and no patient with advanced BRAF-mutated melanoma should die of progressing metastatic disease without treatment with BRAF-targeted therapy. This approach, although backed up by clinical trial data, seems to be using these agents in a way that limits their impact as BRAF-targeted therapy is most effective in patients with the least amount of disease. For example, the pooled long-term data of the dabrafenib and trametinib arms from the COMBI-v and COMBI-d suggest that patients with the least amount of disease (< 3 organs sites of metastatic disease) and a normal lactate dehydrogenase have the best outcomes from frontline BRAF-targeted therapy, with a 5-year PFS and OS of 31% and 55%, respectively.¹⁰ Similarly, Dummer et al¹¹ in the most recent report from the COLUMBUS study showed that the 5-year PFS and OS in a similar patient population subgroup (< 3 disease sites, normal lactate dehydrogenase) was 39% and 48%, respectively, in patients treated with frontline encorafenib and binimetinb.

One possible way to optimize BRAF-targeted therapy is to use these in an even lower disease burden setting, namely as adjuvant therapy. Dabrafenib and trametinib are approved in patients with resected stage III melanoma and have similar landmark relapse review survival and distant metastasis-free survival as nivolumab and pembrolizumab do, when comparing across clinical trials.^24–26 Importantly, the effectiveness of subsequent anti–PD-1 therapy following recurrence after adjuvant BRAF-targeted therapy is high. For example, in a retrospective analysis of 85 patients who recurred after adjuvant dabrafenib and trametinib, 32 received anti–PD-1–based therapy and 20 (63%) had response to therapy.²⁷ A second way to optimize BRAF-targeted therapy is to develop three and possibly four drug combinations in the post–PD-1 setting. As described above, triplet regimens targeting BRAF, MEK, and PD-1/PD-L1 may have been evaluated in the frontline advanced BRAF-mutant melanoma setting but have not been tested after prior anti–PD-1–based therapy.^18–20 Additionally, three drug-targeted therapy regimens are being tested predominantly in the post–PD-1 setting including a combination of dabrafenib, trametinib, and hydroxychloroquine, which was associated with an 82% response rate in a relatively small, 34 patient phase I/II study. A second phase I/II trial is ongoing (ClinicalTrials.gov identifier: NCT03754179), and a randomized trial of dabrafenib and trametinib with or without hydroxychloroquine is ongoing (ClinicalTrials.gov identifier: NCT04527549).²⁸ Another combination of dabrafenib and trametinib with or without navitoclax has recently completed accrual, and analysis is anticipated soon (ClinicalTrials.gov identifier: NCT01989585). A third targeted therapy combination has involved the combination of BRAF with or without MEK inhibitor therapy with HSP90 inhibition. Two studies have been completed including a phase I/II trial of vemurafenib plus XL888 in patients with BRAF-mutant melanoma, which was associated with a response rate of 75% (15 of 20 treated patients) and a phase I trial of the triplet regimen of dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors (ClinicalTrials.gov identifier: NCT02097225).^29,30 This later study enrolled six patients with melanoma, all of whom were treated with prior BRAF-targeted therapy, with one response seen and four with stable disease as best response.³⁰ Obviously, the data from these and follow-up studies will be necessary to determine if any of these approaches will be an improvement over BRAF/MEK doublets.

In summary, frontline BRAF-targeted therapy with combined BRAF and MEK inhibitor therapy in patients with advanced BRAF-mutant melanoma is associated with impressive 5-year outcomes compared with historical data sets. However,fixed dose combination cross-trial comparisons and a more recent prospective randomized trial demonstrate that up-front immune checkpoint inhibitor therapy is preferred to BRAF-targeted therapy for this patient population. The optimal use of BRAF-targeted therapy is unknown but may be in patients with earlier stage disease, such as in the adjuvant, resected stage III setting, or as a last-resort therapy after progression on adjuvant anti–PD-1 therapy and/or combined immune checkpoint inhibition. Triplet therapies are being studied, but the data from these trials are not yet mature enough to know whether these regimens will be folded into routine clinical practice. What is clear is that more research is needed to answer these critical questions and that investigations are ongoing to do so.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

What, if Any, Role Is There for BRAF-Targeted Therapy in BRAF-Mutant Melanoma?

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