Advanced BRAFV600-mutant Melanoma Research Articles

First-line encorafenib plus binimetinib and pembrolizumab for advanced BRAF V600-mutant melanoma: Safety lead-in results from the randomized phase III STARBOARD study

BackgroundBRAF inhibitors plus MEK inhibitors (BRAFi/MEKi) and immune checkpoint inhibitors (CPIs) are approved for BRAF V600-mutant advanced melanoma. Combinations of BRAFi/MEKi with CPIs may further improve outcomes and could offer additional treatment strategies. MethodsSTARBOARD (NCT04657991) is a phase III study with an initial safety lead-in (SLI) phase conducted to determine the recommended phase III dose (RP3D) for encorafenib in combination with binimetinib and pembrolizumab. Patients with untreated, unresectable locally advanced or metastatic BRAF V600E/K-mutant cutaneous melanoma received binimetinib 45 mg twice daily and pembrolizumab 200 mg every 3 weeks plus encorafenib 450 mg once daily (COMBO450 plus pembrolizumab) or 300 mg once daily (COMBO300 plus pembrolizumab). The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Secondary endpoints included safety, objective response, time to response, and duration of response. Progression-free survival was assessed post hoc. ResultsIn the SLI, the median follow-up duration was 19.4 months. Twenty patients received COMBO450 plus pembrolizumab and 17 received COMBO300 plus pembrolizumab. DLTs occurred in 1 of 17 DLT-evaluable patients in the COMBO450 plus pembrolizumab arm and in 2 of 17 DLT-evaluable patients in the COMBO300 plus pembrolizumab arm. No treatment-related deaths occurred in either treatment arm. The overall response rate was 65.0 % in the COMBO450 plus pembrolizumab arm and 47.1 % in the COMBO300 plus pembrolizumab arm. ConclusionThe STARBOARD SLI showed that safety across the cohorts was generally comparable to the known safety profile of each agent. The standard dose regimen of COMBO450 plus pembrolizumab was chosen as the RP3D.

The Evaluation of Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors in Different Therapy Lines for Metastatic Melanoma: A Retrospective Study.

Background: Nivolumab plus ipilimumab (nivo/ipi) combination therapy is highly effective in treating advanced melanoma, but serious immune-related adverse events (irAEs) are prevalent. The overall response rate (ORR) of the BRAF inhibitor plus MEK inhibitor (BRAFi/MEKi) combination therapy for BRAFV600-mutant advanced melanoma surpasses that of immune checkpoint inhibitors (ICIs). However, the OS and PFS of BRAFi/MEKi combination therapy are inferior to those of ICIs. Methods: We retrospectively evaluated 22 melanoma patients treated with nivo/ipi therapy and 13 patients treated with encorafenib plus binimetinib (enco/bini) between November 2018 and July 2023. Results: The ORR of nivo/ipi for metastatic melanoma patients was significantly higher in the first-line cohort [60.0% (95% CI: 31.2-83.3%)] than in the second-line or beyond cohort [8.3% (95% CI: 0-37.5%)], whereas the ORR of enco/bini was comparable between the first-line cohort [75.0% (95% CI: 28.9-96.6%)] and the second-line or beyond cohort [77.8% (95% CI: 44.3-94.7%)]. The median PFS of nivo/ipi significantly improved in the first-line cohort [7.7 months (95% CI: 2.0-11.9)] compared to the second-line or beyond cohort [2.3 months (95% CI: 0.5-6.0)] (p = 0.0109). In addition to efficacy, the incidence of grade 3 or greater AEs was comparable in the first-line and second-line or beyond cohorts. Conclusions: Although our present data are based on a small number of cases, they suggest that nivo/ipi should be administered as the first-line therapy for the treatment of BRAFV600-mutant metastatic melanoma, rather than enco/bini, aligning with findings from previous clinical trials.

Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study).

Encorafenib plus binimetinib (EB) is a standard-of-care treatment for advanced BRAFV600-mutant melanoma. We assessed the efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response. E-BRAIN/GEM1802 was a prospective, multicenter, single-arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved a partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression. Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%. The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After 2 months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial progression-free survival (PFS) and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grades 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%). Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high-grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.

A phase II study of tunlametinib in combination with vemurafenib in patients with BRAF V600-mutant advanced melanoma.

e21519 Background: The new MEK inhibitor tunlametinib combined with the BRAF inhibitor vemurafenib showed promising clinical activity in patients (pts) with BRAF V600-mutant solid tumors in a previous Phase I study (NCT03976050). Based on the result, we designed a phase IIa study to evaluate the efficacy and safety of tunlametinib plus vemurafenib in Chinese pts with BRAF V600 mutant melanoma. Methods: This open-label, single arm, multiple-center phase IIa study enrolled Chinese pts with BRAF V600E-mutant advanced melanoma, without restriction on the disease subtype (e.g., acral, mucosal, or cutaneous melanoma). Prior treatment was permitted, excluding BRAF/MEK inhibitors. Pts received oral tunlametinib at a dose of 9 mg twice daily and vemurafenib 720 mg twice daily. The primary endpoint was the objective response rate (ORR) per RECIST v1.1. Results: Between October 15, 2021, and June 22nd, 2022, 17 pts were enrolled and included in the analysis. Thirteen (76.5%) pts had received previous systemic antitumor therapy, with 12 (70.6%) receiving immunotherapy. Seven (41.2%) pts had acral melanoma, 8 (47.1%) pts had skin melanoma (non-acral) and 2 (11.8%) pts had mucosal melanoma. All pts had metastatic disease. With a median follow-up of 15.3 months (95%CI: 6.8; NE), 12 (70.6%) pts achieved confirmed partial response (PR), resulting in a confirmed ORR of 70.6% (95% CI: 44.0%-89.7%). The disease control rate was 100% (95% CI: 80.5%, 100.0%). The median progression-free survival (PFS) was 10.0 months (95% CI: 5. 5, NE). the duration of response (DOR) was 20.1 (95% CI: 4.2, NE). The overall survival (OS) was 21.6 months (95% CI: 14.5, NE), with a 12-months OS rate of 87.4% (95% CI: 58.1%, 96.7%). Subgroup analysis revealed that in pre-treated pts, the confirmed ORR was 76.9% (95% CI: 46.2%, 95.0%), the median PFS was 10.0 months (95% CI: 5.5, NE), while in previous untreated pts, the mPFS was 14.0 months (95% CI: 9.9, NE). In pts with skin melanoma, the confirmed ORR was 87.5% (47.3%, 99.7%), the mPFS was 10.0 months (95% CI: 5.5, NE), the mOS was 21.6 months (95% CI: 5.7, NE). In pts with acral melanoma, the ORR was 57.1% (95% CI: 18.4%,90.1%), the mPFS was 18.1 months (95% CI: 2.8, NE), the mOS not reached (12.3, NE). The most common adverse events included rash, pyrexia, and elevated blood creatin phosphokinase, most of which were of grade 1-2 severity. Grade 3 or higher TRAEs occurred in 12 (70.6%) pts, of which 41.2% were rash. Most AEs were manageable with supportive therapy or dose interruption. No treatment-related deaths were reported. Conclusions: The addition of a MEK inhibitor tunlametinib to vemurafenibexhibited promising clinical efficacy in Chinese patients with BRAF V600-mutant advanced melanoma, with a manageable safety profile. Additionally, notable effects were observed in pts with acral melanoma. The efficacy in pre-treated patients was comparable to that of similar agents in previous untreated patients. Clinical trial information: NCT05263453 .

A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAFV600 mutant advanced melanoma (INTERIM)

BackgroundBRAF+MEK inhibitors extend life expectancy of patients with BRAFV600 mutant advanced melanoma. Acquired resistance limits duration of benefit, but preclinical and case studies suggest intermittent dosing could overcome this limitation. INTERIM was a phase 2 trial evaluating an intermittent dosing regimen. MethodsPatients with BRAFV600 mutant advanced melanoma due to start dabrafenib+trametinib were randomised to receive either continuous (CONT), or intermittent (INT; dabrafenib d1–21, trametinib d1–14 every 28 days) dosing. A composite primary endpoint included progression-free survival (PFS) and quality of life (QoL). Secondary endpoints included response rate (ORR), overall survival (OS) and adverse events (AEs). Mutant BRAFV600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of > 1 % as the detection threshold. Results79 patients (39 INT, 40 CONT) were recruited; median age 67 years, 65 % AJCC (7th ed) stage IV M1c, 29 % had brain metastases. With 19 months median follow-up, INT was inferior in all efficacy measures: median PFS 8.5 vs 10.7mo (HR 1.39, 95 %CI 0.79–2.45, p = 0.255); median OS 18.1mo vs not reached (HR 1.69, 95 %CI 0.87–3.28, p = 0.121), ORR 57 % vs 77 %. INT patients experienced fewer treatment-related AEs (76 % vs 88 %), but more grade > 3 AEs (53 % vs 42 %). QoL favoured CONT. Detection of BRAFV600E ctDNA prior to treatment correlated with worse OS (HR 2.55, 95 %CI 1.25–5.21, p = 0.01) in both arms. A change to undetected during treatment did not significantly predict better OS. ConclusionINTERIM findings are consistent with other recent clinical trials reporting that intermittent dosing does not improve efficacy of BRAF+MEK inhibitors.

1111P A randomised phase II study of intermittent versus continuous dosing of targeted therapy in patients with BRAFV600 mutant advanced melanoma (INTERIM)

1111P A randomised phase II study of intermittent versus continuous dosing of targeted therapy in patients with BRAFV600 mutant advanced melanoma (INTERIM)

Single cell profiling of tumour biopsies and heterogeneity in response of dedifferentiated melanoma.

64 Background: Patients with advanced BRAFV600-mutant melanoma can be treated with immune checkpoint inhibitors or combination BRAF/MEK inhibitors. The sequence of these therapies can influence response to second-line treatment. Patients who progress on first-line PD1 blockade have poorer outcomes on BRAF/MEK inhibitors compared to patients who are treatment-naïve. Thus, defining the molecular features that are modified by therapy and that influence subsequent treatment responses require thorough characterization. Methods: In this study, tumor biopsies from five BRAF-mutant melanoma patients progressing on anti-PD1 (PROG) and five BRAF-mutant treatment-naïve (NAÏVE) patients were dissociated and treated ex vivo with BRAF/MEK inhibitors (dabrafenib+trametinib (DT)) before flow cytometry profiling and single cell transcriptome sequencing. Results: DT treatment did not alter tumor or immune cell proportions but effectively inhibited MAPK signaling by decreasing phosphorylated S6 levels in tumor cells within 8/10 melanoma samples. Single cell RNA-sequencing of the tumor dissociates identified four distinct melanoma differentiation states (e.g. melanocytic, transitory, neural crest-like and undifferentiated). The proportions of these cell states differed between tumor specimens, and were not affected by DT treatment. The neural crest-like and undifferentiated melanoma cells were enriched in PROG compared to NAIVE tumor samples and all differentiation states responded, albeit variably. For instance, MAPK inhibition after DT treatment was less pronounced in undifferentiated melanoma cells. Importantly, within the undifferentiated cell state, we identified a proportion of melanoma cells capable of responding to DT, and comparison of responding vs non-responding undifferentiated cells showed enrichment of pro-inflammatory IL-6 and TNFα signaling in the non-responding population. Elevated IL-6 and TNFα pathway activity correlated with decreased potency to MAPK inhibition, indicating that increased IL-6 and TNFα signaling in undifferentiated melanoma may contribute to resistance to MAPK inhibition. Conclusions: Ex vivo treatment of tumor dissociates coupled with single cell transcriptome sequencing identified cell state-specific responses to MAPK inhibition. Resistance to MAPK inhibition may be driven, in part, by tumor-intrinsic pro-inflammatory IL-6 and TNFα signalling.

Contribution of MEK Inhibition to BRAF/MEK Inhibitor Combination Treatment of BRAF-Mutant Melanoma: Part 2 of the Randomized, Open-Label, Phase III COLUMBUS Trial.

In COLUMBUS part 1, patients with advanced BRAFV600-mutant melanoma were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice a day (COMBO450), vemurafenib 960 mg twice a day, or encorafenib 300 mg once daily (ENCO300). As previously reported, COMBO450 improved progression-free survival (PFS) versus vemurafenib (part 1 primary end point) and ENCO300 (part 1 key secondary end point; not statistically significant). Part 2, requested by the US Food and Drug Administration, evaluated the contribution of binimetinib by maintaining the same encorafenib dosage in the combination (encorafenib 300 mg once daily plus binimetinib 45 mg twice daily [COMBO300]) and ENCO300 arms. In part 2, patients were randomly assigned 3:1 to COMBO300 or ENCO300. ENCO300 (parts 1 and 2) data were combined, per protocol, for PFS analysis (key secondary end point) by a blinded independent review committee (BIRC). Other analyses included overall response rate (ORR), overall survival, and safety. Two hundred fifty-eight patients received COMBO300, and 86 received ENCO300. Per protocol, ENCO300 arms (parts 1 and 2 combined) were also evaluated (n = 280). The median follow-up for ENCO300 was 40.8 months (part 1) and 57.1 months (part 2). The median PFS (95% CI) was 12.9 months (10.9 to 14.9) for COMBO300 versus 9.2 months (7.4 to 11.1) for ENCO300 (parts 1 and 2) and 7.4 months (5.6 to 9.2) for ENCO300 (part 2). The hazard ratio (95% CI) for COMBO300 was 0.74 (0.60 to 0.92; two-sided P = .003) versus ENCO300 (parts 1 and 2). The ORR by BIRC (95% CI) was 68% (62 to 74) and 51% (45 to 57) for COMBO300 and ENCO300 (parts 1 and 2), respectively. COMBO300 had greater relative dose intensity and fewer grade 3/4 adverse events than ENCO300. COMBO300 improved PFS, ORR, and tolerability compared with ENCO300, confirming the contribution of binimetinib to efficacy and safety.

Outcomes in patients with BRAFV600-mutated melanoma and brain metastases at baseline treated with dabrafenib plus trametinib.

Brain metastases (BM) and lactate dehydrogenase (LDH) levels above the upper limit of normal (ULN) are associated with poor prognosis in patients with melanoma. Although treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib have demonstrated long-term clinical benefit in patients with melanoma, data on their efficacy in patients with BM are limited. DESCRIBE Italy is an observational, retrospective, real-world study evaluating dabrafenib plus trametinib in 499 patients with BRAFV600-mutant stage III unresectable or stage IV melanoma from various sites across Italy. Here, we analyzed the clinical outcomes for the subgroup of patients receiving first-line treatment and presenting with BM at diagnosis and assessed the impact of predictive factors such as LDH levels and the presence of other metastases on median progression-free survival (mPFS). Overall, 325 evaluable patients were on first-line therapy and are the focus of this analysis; of these, 76 patients (23.4%) had BM at baseline. mPFS was lower for patients with BM at baseline compared with overall patients (8.7 months vs 9.3 months, respectively). Patients with BM at diagnosis and LDH >ULN had a considerably shorter mPFS compared with patients with LDH ⩽ULN (5.3 months vs 9.9 months, respectively). mPFS was noticeably longer for patients with cerebral metastases only compared with patients with cerebral and other metastases (15.0 months vs 8.7 months, respectively). Dabrafenib plus trametinib showed effectiveness in a real-world population of patients with advanced BRAFV600-mutated melanoma and BM at baseline, supporting its use in this population with poor outcomes.

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

AimImmunoCobiVem investigated whether a planned switch to atezolizumab after achieving tumour control during run-in with vemurafenib + cobimetinib improves progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAFV600-mutated melanoma. MethodsIn this multicenter phase 2 study, patients received vemurafenib plus cobimetinib. After 3months, patients without progressive disease (PD) were randomly assigned (1:1) to continue vemurafenib + cobimetinib (Arm A) or switch to atezolizumab (Arm B) until first documented PD (PD1). Primary outcome was PFS1 (time from start of run-in until PD1 or death). OS and safety were also assessed. ResultsOf 185 patients enroled between November 2016 and December 2019, 135 were randomly assigned after the run-in period (Arm A, n = 69; Arm B, n = 66). Median PFS1 was significantly longer in Arm A versus Arm B (13.9 versus 5.9months; hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.37–0.84; PStratified=0.001). Median OS was not reached in either arm (HR 1.22; 95%CI, 0.69–2.16; PStratified=0.389); 2-year OS was higher in Arm B versus Arm A (67%; 95%CI, 53–78 versus 58%; 95%CI, 45–70). Grade 3/4 AEs occurred in 55% of patients in Arm A and 64% in Arm B; treatment-related AEs led to discontinuation of any drug in 7% and 9% of patients, respectively. ConclusionIn patients with BRAFV600-mutated advanced melanoma who achieve tumour control with TT, early switch at 3months to atezolizumab led to rapid loss of tumour control but provided a numerical OS benefit at 2years compared with continued TT.

Phase III study of adjuvant encorafenib plus binimetinib versus placebo in fully resected stage IIB/C BRAFV600-mutated melanoma: COLUMBUS-AD study design.

TPS9601 Background: Significant progress has been made in the treatment of advanced BRAFV600-mutant melanoma. Encorafenib in combination with binimetinib is a well-tolerated and effective treatment option, providing sustained progression-free and overall survival benefit in unresectable or metastatic setting. The focus has shifted to early-stage disease in order to prevent recurrence. 18% of stage IIB and 25% stage IIC patients die due to melanoma within 10 years from the diagnosis [Gershenwald and al 2017], indicating an unmet medical need. Currently only immunotherapy has been approved in first countries across the world in this setting. There is a need for more treatment options for BRAF-mutated stage II disease. We report here the rationale and design of COLUMBUS-AD (NCT05270044). Methods: COLUMBUS-AD study is an international randomized, placebo-controlled, triple-blind, multicenter Phase III trial evaluating adjuvant encorafenib + binimetinib against placebo in patients with fully resected stage IIB/C BRAF V600-mutant melanoma. Approximately 815 patients will be enrolled. More than 170 sites in up to 26 countries worldwide will participate in the study conducted in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC). Patients will receive encorafenib + binimetinib or placebo for 12 months, or until disease recurrence and will be followed monthly during treatment period, then every 3 months up to year 3, and then at regular intervals. The participants will be followed for a total of 10 years. Patients included in the study must have undergone resection of a stage IIB/C cutaneous melanoma with a BRAFV600E/K mutation, confirmed on resected tumor sample by a central laboratory, and a negative result on sentinel node biopsy. Patients must have recovered from surgery, have an ECOG 0/1, and adequate hematologic, hepatic, cardiac, coagulation and renal functions. Eligible patients will be randomized 1:1 to receive either encorafenib 450 mg once daily plus binimetinib 45 mg twice daily or matching placebos. The primary objective of the study is to evaluate the efficacy of the combination of encorafenib+ binimetinib for prolonging recurrence-free survival (RFS). The secondary objectives are to compare distant metastasis-free survival (DMFS), overall survival (OS), health-related quality of life (QoL), and safety and tolerability between the two arms and to provide additional pharmacokinetic data. Conclusion: COLUMBUS-AD is the first phase 3 randomised trial to evaluate adjuvant BRAFi/MEKi in stage IIB/C melanoma. This study will evaluate whether the combination of encorafenib and binimetinib can decrease the risk for recurrence and improve distant metastasis-free survival and overall survival versus placebo in completely resected IIB/C BRAFV600E/K-mutant cutaneous melanoma. Clinical trial information: NCT05270044 .

Abstract CT069: Randomized phase 3 study (STARBOARD) evaluating encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of unresectable locally advanced or metastatic BRAF V600-mutant melanoma

Abstract Background BRAF V600 mutations are frequently found in metastatic melanoma. This mutation constitutively activates the MAPK pathway, which leads to melanoma progression. Patients with BRAF V600-mutant metastatic melanoma typically receive BRAF inhibitors (BRAFi) + MEK inhibitors (MEKi), such as enco + bini, or immune checkpoint inhibitors (CPIs; eg, pembro). However, these have limitations. BRAFi and MEKi may increase BRAF V600-mutant tumor sensitivity to CPIs. Previous studies reported improved progression-free survival (PFS) in patients with advanced BRAF V600-mutant melanoma receiving BRAFi + MEKi + CPI compared with targeted therapy alone. This phase 3 trial will evaluate the efficacy and safety of enco + bini + pembro vs placebo + pembro for unresectable locally advanced or metastatic BRAF V600-mutant melanoma. A safety lead-in (SLI) was built in to determine the recommended phase 3 dose (RP3D) prior to starting phase 3. Trial design STARBOARD (NCT04657991) is a randomized, double-blind, placebo-controlled, phase 3 study evaluating approximately 600 patients with BRAF V600 advanced melanoma. Patients will be stratified by prior systemic adjuvant treatment (CPI, BRAFi/MEKi, or none) and by disease stage (per AJCC 8th edition; IIIB, IIIC, IIID, IV M1a[0], and IV M1b[0] vs IV M1a[1], IV M1b[1], IV M1c[0], IV M1c[1], IV M1d[0], and IV M1d[1]). Patients must have measurable disease (per RECIST 1.1); ECOG performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients must not have received prior systemic therapy for unresectable or metastatic melanoma; adjuvant treatment with BRAFi/MEKi, anti-PD-1, or anti-CTLA-4 is permitted. Patients cannot have symptomatic brain metastases. Study treatments and end points are shown in Table 1. RP3D was established in May 2022; phase 3 enrollment began in June 2022. Table 1. Study treatments and end points Phase 3 Treatment (21-day cycle) RP3D from SLI: enco + bini + pembro Control: placebo + pembro Primary PFS (RP3D vs control; by BICR) Secondary Key: OS (RP3D vs control) Other: PFS by investigator assessment, objective response rate, duration of response, disease control rate, and time to response, all by BICR and investigator assessment, PFS2, quality of life, safety, pharmacokinetics BICR, blinded independent central review; OS, overall survival. Citation Format: Dirk Schadendorf, Reinhard Dummer, Caroline Robert, Antoni Ribas, Ryan J. Sullivan, Timothy Panella, Meredith McKean, Edgardo S. Santos, Jill Clancy, Anna Polli, Alessandra di Pietro, Paolo A. Ascierto. Randomized phase 3 study (STARBOARD) evaluating encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of unresectable locally advanced or metastatic BRAF V600-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT069.

Triple Combination of Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors in BRAFV600 Melanoma: Current Status and Future Perspectives.

Immune checkpoint inhibitors (ICIs), namely programmed cell death 1 (PD-1) or cytotoxic t-lymphocyte antigen 4 (CTLA-4) inhibitors, are currently the standard of care for the treatment of advanced melanoma, with robust and durable responses in a subset of patients. For BRAFV600-mutant melanoma, treatment with BRAF and MEK inhibitors has resulted in high objective response rates, but most responses are short-lived. Preclinical data suggest that BRAF and MEK inhibitors result in immunomodulatory changes in the tumor microenvironment; early data in murine models further suggest that these changes could enhance sensitivity to ICIs. Subsequently, the notion of combining the two therapy modalities for a more effective response was further evolved in early phase clinical trials. In this review, we analyzed the results of recent phase 2 and 3 clinical trials investigating the combination of ICIs with targeted therapy in BRAFV600-mutated advanced melanoma. Furthermore, we evaluated the results of recent studies investigating the first-line treatment sequencing of ipilimumab/nivolumab and BRAF/MEK inhibitors in these patients. We discussed the study limitations and interpreted how these recent advances could be incorporated into the treatment landscape of advanced BRAFV600-mutant melanoma.

4 Oral - Improved outcomes in women with BRAF-mutant melanoma treated with BRAF/MEK-targeted therapy across randomized clinical trials. A systematic review and meta-analysis

Background: Preclinical and clinical evidence suggests that patients’ sex could be associated with the outcome of patients with advanced BRAF V600-mutant melanoma, treated with the combination of B-RAF and MEK-inhibitors. We performed a systematic review and meta-analysis of all RCTs testing the combination of BRAF and MEK inhibitors, to assess the interaction between treatment effect and patients’ sex.

An open label, non-randomised, phase IIIb study of trametinib in combination with dabrafenib in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: A subgroup analysis of patients with brain metastases

BackgroundDespite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T). Patients and methodsThis phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at p < 0.05. ResultsBetween March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval [CI], 5.29–6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors. ConclusionThis is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOG >1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population.

First-line pembrolizumab versus dabrafenib/trametinib treatment for BRAF V600–mutant advanced melanoma

Limited data are available to assist the selection between immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors as first-line treatment for patients with BRAF-mutant advanced malignant melanoma. To investigate the outcomes associated with first-line pembrolizumab or dabrafenib/trametinib treatment for advanced melanoma with activating BRAF V600 mutation. Data of patients with BRAF V600-mutant melanoma who were treated with first-line pembrolizumab (n=40) or dabrafenib/trametinib (n=32) were analyzed. Tumor response, progression-free survival, and overall survival were evaluated. Immune evasion accompanied with emerging resistance to BRAF/mitogen-activated protein kinase kinase inhibitors was assessed. A longer overall survival was observed after first-line pembrolizumab treatment than after first-line dabrafenib/trametinib treatment (hazard ratio=2.910, 95% CI: 1.552-5.459), although there were no significant differences in progression-free survival (P=.375) and response rate (P=.123). Emergence of resistance to dabrafenib/trametinib co-occurred with immune evasion, enabling melanoma cells to escape recognition and killing by Melan-A-specific CD8+ T cells. Analysis was conducted in a retrospective manner. Pembrolizumab may be recommended over BRAF/mitogen-activated protein kinase kinase inhibitors as the first-line treatment in patients with advanced BRAF V600-mutant melanoma.

871P Predictive role of neutrophil-lymphocyte ratio (NLR) in patients (pts) with metastatic melanoma: A post hoc exploratory analysis from phase III COMBI-i trial

An elevated NLR is associated with poor survival in pts with a variety of solid cancers, including those treated with immunotherapies. Based on literature, NLR ≥5 was identified as a cutoff for NLR elevation in the metastatic setting. This post hoc exploratory analysis from COMBI-i trial aimed at evaluating the potential predictive role of NLR in pts with BRAFV600–mutant advanced melanoma who received spartalizumab + dabrafenib + trametinib (Sparta-DabTram) versus (vs) placebo + dabrafenib + trametinib (placebo-DabTram).

Clinical predictors of longer survival in patients with BRAFV600-mutated metastatic melanoma receiving immunotherapy prior to BRAF/MEK inhibition in the metastatic setting.

9555 Background: Patients with advanced BRAFV600-mutated melanoma are typically treated with immunotherapy in the first-line setting, followed by BRAF/MEKi upon disease progression based on an absolute 20% improvement in 2-year overall survival over initial treatment with BRAF/MEKi in the DREAMseq trial. Our goal was to identify clinical predictors of longer survival for patients treated in our institution with this approach. Methods: We identified 40 patients with BRAFV600-mutated metastatic melanoma treated at our institution from 2011 to 2020 with immunotherapy followed by BRAF/MEKi upon progression. Clinical data were collected and analyzed by Cox regression and Kaplan-Meier methods. Favorable outcome was defined as survival &gt; 2 years (y) after starting BRAF/MEKis. Results: Median follow up was 33 months (m, 3 – 172 m). Median age was 54 y (20 - 83). Most patients were female (n = 24, %). Most patients were initially treated with ipilimumab plus nivolumab (n = 34, 85%), with 13 of these patients (38%) tolerating all 4 cycles of initial ipilimumab. Adverse events of any grade were seen in 28 (70%) patients after first-line immunotherapy, with the most common being hepatitis, colitis, hypothyroidism, rash, and fatigue. Median duration of first-line immunotherapy was 3.5 m (.75 - 42.5 m). Most common sites of progression on immunotherapy were lymph nodes (n = 14, 35%), liver (n = 12, 30%), bone (n = 10, 25%) and brain (n = 10, 25%). Prior to BRAF/MEKis, median ECOG-PS was 1 (0-4) and median LDH was 268 mg/dL (151 - 11,300). Most common BRAF/MEKi regimen was dabrafenib plus trametinib (n = 34, 85%). Adverse events of any grade were seen in 30 (75%) patients, with the most common being fever, fatigue, nausea, and vomiting. Best response to BRAF/MEKi was CR (n = 4, 10%), PR (n = 26, 65%), SD (n = 4, 10%) and PD (n = 6, 15%), and at the data cutoff, 35 (87.5%) patients progressed on BRAF/MEKi. Median duration of BRAF/MEK inhibition was 7 m (0.5 – 106 m). Median survival since starting BRAF/MEKi was 19.2 m (1.7 – 106 m). On multivariable analyses assessing predictors of survival, presence of bone metastases after disease progression on first-line immunotherapy was associated with worse 2-year survival after initiation of BRAF/MEKi (OR 2.5, 95% CI, 0.51-5.6, p = 0.0121). Other factors, such as ECOG-PS 0-2, normal LDH prior to BRAF/MEKi, and age at metastatic diagnosis &lt; 60 years were not significantly associated with longer survival after initiation of BRAF/MEKi. Conclusions: We showed that the presence of bone metastases upon progression on first-line immunotherapy was associated with worse 2-y survival on salvage BRAF/MEKi for patients with BRAFV600-mutated metastatic melanoma. Predictive and prognostic biomarkers for long-term response to both immunotherapy and BRAF/MEKi are needed to optimize treatment strategies and patient outcomes.

Encorafenib plus binimetinib in patients with locally advanced, unresectable, or metastatic BRAFV600-mutant melanoma: Updated data from the multicenter, multinational, prospective, non-interventional longitudinal study BERINGMELANOMA.

9526 Background: For the treatment of advanced BRAFV600-mutated melanoma, targeted BRAF/MEK-inhibition is a standard of care. Encorafenib + binimetinib (EB) were approved 2018 in the EU and 2019 in Switzerland, based on positive results from COLUMBUS (NCT01909453), median progression-free survival (PFS) 14.9 mo (5-yr PFS: 23%), overall survival (OS) 33.6 mo (5-yr OS: 35%). As data from controlled trials are based on selected populations, BERINGMELANOMA investigates EB-use under real-world conditions in a broader population. Methods: BERINGMELANOMA (NCT04045691) is an ongoing, multi-national, prospective, longitudinal, non-interventional study. It analyzes the effectiveness (prim. endpoint: 1-yr PFS-rate), QoL and safety of EB-therapy in the unresectable advanced or metastatic setting under real-world conditions, focusing on the first- (1L) and second-line setting including an evaluation of the impact of prognostic factors. The project aims to enroll up to 750 patients (pts) in a total of 80 German, Austrian and Swiss sites (study duration: 8 yrs). So far (10/2019-01/2022), 280 pts have been included. Pts with prior BRAF-/MEK-inhibition (except adjuvant use completed &gt; 6 mo) and &gt; 1 prior therapy line with CPI in the palliative setting were excluded (adjuvant CPI allowed). Results: Here we present the 2nd planned interim snapshot based on the initial 200 enrolled pts (186 treated / 182 evaluable; median FU: 14.2 mo). This analysis set shows a median age of 60.5 yrs (range 20.0-89.0), 45% of pts were female. 87% presented with distant metastases (brain: 30%), with an involvement of ≥3 organ systems in 51% and elevated LDH in 43%. 54% of pts underwent any prior systemic therapy (adjuvant: 30%; 1L CPI palliative: 24%, mainly with ipilimumab + nivolumab). EB was mainly administered in the 1L-setting (60%). Main reasons for EB-selection were: efficacy (44%), physician's preference (34%), QoL (17%). Median estimated EB treatment duration was 11.6 mo (95%CI 8.8-18.6), median relative dose intensity for both drugs: 100%, main reasons EB-discontinuation: PD (55%), toxicity (16%). Treatment adaptations were required in 40% of pts (interruption E 26%, B 29%), toxicity as main reason (E 26%, B 29%). Adverse events were reported in 86% of pts (grade 3/4: 34%), mainly (≥10%, all grades): diarrhea, nausea, fatigue (each 17%), CK increase (16%), GGT increase (11%). No fatal toxicities were observed. Conclusions: This 2nd interim snapshot shows an investigation of EB in a real-world population with advanced disease. Despite the poorer prognosis configuration as compared to the pivotal study, the observed tolerability profile is largely consistent with data derived from COLUMBUS without any new safety signals. The 3rd interim snapshot will be performed after enrollment of 300 pts.

Current Therapeutics and Future Perspectives for Treatment of Advanced BRAF V600 mutant Melanoma

Current Therapeutics and Future Perspectives for Treatment of Advanced BRAF V600 mutant Melanoma