BRAFV600-mutated Metastatic Melanoma Research Articles

Combination of Dabrafenib and Trametinib in Patients with Metastatic BRAFV600E-Mutated Thyroid Cancer.

BRAF mutations are detected in 30-80% of papillary thyroid cancer (PTC) cases. Dabrafenib and trametinib showed promising antitumor activity in patients with BRAFV600E-mutated metastatic melanoma and non-small cell lung cancer. This study aimed to evaluate the efficacy and safety of dabrafenib and trametinib in patients with metastatic BRAFV600E-mutated thyroid cancer. This was a retrospective study to evaluate the efficacy of dabrafenib and trametinib in patients with metastatic BRAFV600E-mutated PTC. The patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily at the Samsung Medical Center. This study evaluated the progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) overall survival (OS), and safety of dabrafenib and trametinib. Between December 2019 and January 2022, 27 PTC patients including 8 patients with poorly differentiated or anaplastic transformation, received dabrafenib and trametinib. The median age was 73.0 years, and the median follow-up period was 19.8 months. The majority (81.5%) had undergone thyroidectomy, while 8 patients had received prior systemic treatments. ORR was 73.1%, with 19 partial responses, and DCR was 92.3%. Median PFS was 21.7 months, and median OS was 21.7 months. Treatment-related adverse events included generalized weakness (29.6%), fever (25.9%), and gastrointestinal problems (22.2%). Dose reduction due to adverse events was required in 81.5% of the patients. Dabrafenib and trametinib demonstrated a high ORR with promising PFS; however, most patients with BRAFV600E-mutated metastatic PTC required a dose reduction.

Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial

No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.

Clinical Predictors of Survival in Patients With BRAFV600-Mutated Metastatic Melanoma Treated With Combined BRAF and MEK Inhibitors After Immune Checkpoint Inhibitors.

Prospective and between trial comparisons indicate that first-line treatment with immune checkpoint inhibitors improves survival outcomes compared to first-line therapy with combined BRAF and MEK inhibitors in metastatic melanoma containing BRAFV600E/K mutations. Long-term outcomes for BRAF/MEK inhibition after progression on immunotherapy have not been reported. Moreover, clinical variables associated with outcome from treatment with combined BRAF/MEK inhibition were previously identified in the first-line setting but have not been investigated when targeted therapies are administered after progression on immune therapy. We performed a retrospective single institution analysis of 40 metastatic melanoma patients receiving combined BRAF/MEK inhibitors after progression on an anti-PD-1 or ipilimumab plus nivolumab to assess response rate by RECIST 1.1, progression-free and overall survival (PFS and OS). Pretreatment clinical variables were analyzed for association with OS. Ipilimumab/nivolumab was the first-line immunotherapy regimen in 39 patients (97.5%), and BRAFV600E/K mutations were present in 33 (83%) and 7 (17%) patients, respectively. The median OS from start of BRAF/MEK inhibitors was 20.3 months (1.73-106.4+, 95% CI of median 13.3-30.7). Clinical characteristics associated with worse survival prior to starting BRAF/MEK inhibitors included age > 60 years (median OS 14 vs. 28 months; HR 2.5; 95% CI 0.91-6.87, P = .023), ECOG-PS > 2 (median OS 7 vs. 33 months; HR 2.89; 95% CI 0.78-10.76, P = .018), and presence of bone metastases (median OS 9 vs. 52 months; HR 3.17; 95% CI 1.33-7.54, P = .002). These associations with shorter survival maintained their significance on multivariate analysis. If confirmed in larger cohorts, the identified prognostic variables can be used for stratification of patients in future randomized trials.

1117P Overall survival (OS) in patients with metastatic BRAF V600-mutant melanoma treated with encorafenib plus binimetinib (ENCO+BINI): Comparing real-world vs clinical trial data

1117P Overall survival (OS) in patients with metastatic BRAF V600-mutant melanoma treated with encorafenib plus binimetinib (ENCO+BINI): Comparing real-world vs clinical trial data

Treatment experience with encorafenib plus binimetinib for BRAF V600-mutant metastatic melanoma: management insights for clinical practice.

For patients with locally advanced or metastatic melanoma who have BRAF V600 activating mutations, combination therapy with BRAF and MEK inhibitors is now the standard of care. The combination of encorafenib, a highly selective adenosine triphosphate-competitive BRAF inhibitor, plus binimetinib, a potent, selective, allosteric, non-adenosine triphosphate-competitive MEK1/2 inhibitor, was approved by the US Food and Drug Administration for unresectable or metastatic melanoma with BRAF V600E or V600K mutations based on data from the phase III COLUMBUS study (NCT01909453). Clinical data evaluating BRAF and MEK inhibitor combinations in advanced melanoma indicate a specific profile of adverse events that includes serious retinopathy, skin disorders, and cardiovascular toxicities. Here we provide an overview of the rationale for combining BRAF and MEK inhibitors for the treatment of melanoma, long-term safety results from COLUMBUS, and guidance on managing the most common adverse events associated with this combination based on clinical experience. Proactive and appropriate management of adverse events can allow for longer treatment durations and may result in better treatment outcomes.

Cost-effectiveness of encorafenib with binimetinib in unresectable or metastatic BRAF-mutant melanoma.

The objective of this study was to determine the cost-effectiveness of encorafenib with binimetinib (EncoBini) as compared to other targeted double combination therapies, namely dabrafenib with trametinib (DabraTrame) and vemurafenib with cobimetinib (VemuCobi), for the treatment of BRAF V600-mutant unresectable or metastatic melanoma (MM) from the French payer perspective. A partitioned survival model was developed considering a lifetime horizon. The model structure simulated the clinical pathway of patients with BRAF V600-mutant MM. Clinical effectiveness and safety inputs were sourced from the COLUMBUS trial, a network meta-analysis and published literature. Costs, resource use, and the quality of life inputs were obtained from the literature and appropriate French sources. Over a lifetime horizon, EncoBini was associated, on average, with reduced costs and increased quality adjusted life years (QALYs), dominating both targeted double combination therapies. For a willingness-to-pay threshold of €90,000 per QALY, the probability of EncoBini being cost-effective against either comparator remained above 80%. The most influential model parameters were the hazard ratios for the overall survival of EncoBini vs DabraTrame and VemuCobi, the pre- and post-progression utility values, as well as treatment dosages and the relative dose intensity of all interventions. EncoBini is associated with reduced costs and increased QALYs, dominating other targeted double combination therapies (DabraTrame, VemuCobi) for patients with BRAF V600-mutant MM in France. EncoBini is a highly cost-effective intervention in MM.

Encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for unresectable locally advanced or metastatic BRAF V600-mutant melanoma: Results from STARBOARD safety lead-in (SLI).

9531 Background: BRAF inhibitors (BRAFi) + MEK inhibitors (MEKi) (eg, enco + bini) and immune checkpoint inhibitors (CPIs) (eg, pembro) are approved for patients (pts) with BRAF V600-mutant metastatic melanoma. Combinations of BRAFi + MEKi with CPIs further improve outcomes and may offer additional treatment strategies. STARBOARD (NCT04657991) is an ongoing randomized, double-blinded, placebo-controlled, phase 3 study of enco + bini + pembro vs pembro in pts with unresectable locally advanced or metastatic BRAF V600-mutant cutaneous melanoma. Here we present the SLI results. Methods: Key inclusion criteria were histologically confirmed unresectable/metastatic BRAF V600E/K-mutant cutaneous melanoma and ≤1 prior systemic therapy for unresectable/metastatic disease. Pts received enco 450 mg QD + bini 45 mg BID + pembro 200 mg IV Q3W (COMBO450+P) or enco 300 mg QD + bini 45 mg BID + pembro 200 mg IV Q3W (COMBO300+P). The primary objective was to identify the recommended phase 3 dose (RP3D). The primary endpoint was dose-limiting toxicity (DLT) incidence; secondary endpoints included safety, objective response rate (ORR), time to response (TTR), and PFS (post hoc). Results: 20 pts received COMBO450+P and 17 COMBO300+P (cutoff: Dec 2, 2022). See table for baseline characteristics. 1 pt had a DLT with COMBO450+P: Grade (G) 3 drug-induced liver injury with concurrent G4 ALT increase and G3 bilirubin increase that resolved. 2 pts had DLTs with COMBO300+P: 1 with G3 rheumatoid arthritis flare and 1 with inability to receive drug due to G4 arthralgia, G4 back pain, G4 pyrexia, G3 chills, G3 headache, G3 paranesthesia, and G3 maculopapular rash. Drug-related AEs led to permanent discontinuation in 4, 5, and 6 pts for enco, bini, and pembro, respectively. 1 pt in the COMBO300+P arm died <28 days after discontinuing all study treatments due to disease progression. See table for antitumor activity data. Conclusions: Safety across cohorts was comparable and consistent with the known safety profile of each agent. Both regimens were generally tolerable; COMBO450+P was chosen as the RP3D based on the totality of the safety data. The phase 3 portion of STARBOARD is ongoing. Clinical trial information: NCT04657991 . [Table: see text]

BRAF V600-Mutated Metastatic Melanoma and Targeted Therapy Resistance: An Update of the Current Knowledge.

Melanoma is the most common cause of death in skin cancer due to its high metastatic potential. While targeted therapies have improved the care of patients with metastatic melanoma harboring the BRAFV600E mutation, these treatments are associated with a high frequency of resistance. Resistance factors are related to cellular adaptation as well as to changes in the tumor microenvironment. At the cellular level, resistance involves mutations, overexpression, activation, or inhibition of effectors involved in cell signaling pathways such as MAPK, PI3K/AKT, MITF, and epigenetic factors (miRNAs). In addition, several components of the melanoma microenvironment, such as soluble factors, collagen, and stromal cells also play a crucial role in this resistance. In fact, extracellular matrix remodeling impacts the physical and chemical properties with changes in the stiffness and acidity, respectively of the microenvironment. The cellular and immune components of the stroma are also affected, including immune cells and CAF. The aim of this manuscript is to review the mechanisms responsible for resistance to targeted therapies in BRAFV600E-mutated metastatic melanoma.

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.

819P Efficacy of dabrafenib (D) trametinib (T) plus spartalizumab (S) by baseline site of metastases in patients (pts) with previously untreated BRAF V600-mutant unresectable or metastatic melanoma: Post hoc analysis of phase III COMBI-i trial

Pts with high tumour burden may benefit from adding anti-PD-1 to targeted therapy.1 Although COMBI-i trial (NCT02967692) did not meet its primary endpoint for overall population, progression-free survival (PFS) was significantly longer with S (anti-PD-1) +DT vs placebo (PBO)+DT in pts with ≥3 metastatic (met) sites (hazard ratio [HR]=0.63; 95% confidence interval [CI] 0.46–0.87).2 This post hoc analysis of COMBI-i examined S+DT vs PBO+DT based on met site.

Truth or dare: switching BRAF/MEK inhibitors after acute interstitial nephritis in a patient with metastatic melanoma – A case report and review of the literature

ABSTRACT Introduction The introduction of BRAF/MEK inhibitors has significantly improved overall survival of patients with BRAF V600-mutant advanced or metastatic melanoma. Most patients treated with BRAF/MEK inhibitors will experience adverse events during the course of their treatment. Kidney impairment, however, was rarely reported in the pivotal trials. To date, there are only three cases of biopsy-proven acute interstitial nephritis associated with dabrafenib and trametinib reported in the literature. Case report A 50-year-old man diagnosed with metastatic melanoma was hospitalized in August 2021, 5 months after treatment initiation with dabrafenib and trametinib. He presented with acute kidney injury, with serum creatinine of 3.34 mg/dL and eGFR of 20.3 mL/min/m². Kidney biopsy revealed acute interstitial nephritis. Management & Outcome He was treated with methylprednisolone 16 mg qd, and both dabrafenib and trametinib were permanently discontinued, with recuperation of his kidney function. Another BRAF/MEK inhibitor combination, encorafenib and binimetinib, was introduced, with preserved kidney function and excellent disease control. Discussion We report the first case of biopsy-proven interstitial nephritis in a patient treated with dabrafenib and trametinib, with successful introduction of another BRAF/MEK inhibitor combination. Although rare, clinicians should be aware of the risk of renal adverse events associated with BRAF/MEK inhibitors. Renal biopsy is mandatory in the absence of a clear explanation or rapid recovery of renal failure. In case of proven interstitial nephritis, corticosteroids should be initiated. Switching to another BRAF/MEK inhibitor combination can be considered for patients with complete recovery of renal function and limited treatment options.

Comparison Between First Line Target Therapy and Immunotherapy in Different Prognostic Categories of BRAF Mutant Metastatic Melanoma Patients: An Italian Melanoma Intergroup Study.

BackgroundBRAF and MEK inhibitors target therapies (TT) and AntiPD1 immunotherapies (IT) are available first-line treatments for BRAF v600 mutant metastatic melanoma patients. ECOG PS (E), baseline LDH (L), and baseline number of metastatic sites (N) are well-known clinical prognostic markers that identify different prognostic categories of patients. Direct comparison between first-line TT and IT in different prognostic categories could help in first line treatment decision.MethodsThis is a retrospective analysis conducted in 14 Italian centers on about 454 metastatic melanoma patients, divided in 3 groups: group A—patients with E = 0, L within normal range, and N less than 3; group B—patients not included in group A or C; group C—patients with E > 0, L over the normal range, and N more than 3. For each prognostic group, we compared TT and IT in terms of progression free survival (PFS), overall survival (OS), and disease control rate (DCR).ResultsIn group A, results in 140 TT and 36 IT-treated patients were, respectively, median PFS 35.5 vs 11.6 months (HR (95% CI) 1.949 (1.180–3.217) p value 0.009); median OS not reached vs 55 months (HR (95% CI) 1.195 (0.602–2.373) p value 0.610); DCR 99% vs 75% p value <0.001). In group B, results in 196 TT and 38 IT-treated patients were, respectively, median PFS 11.5 vs 5 months (HR 1.535 (1.036–2.275) p value 0.033); median OS 19 vs 20 months (HR 0.886 (0.546–1.437) p value 0.623); DCR 85% vs 47% p value <0.001). In group C, results in 41 TT and 3 IT-treated patients were, respectively, median PFS 6.4 vs 1.8 months (HR 4.860 (1.399–16) p value 0.013); median OS 9 vs 5 months (HR 3.443 (0.991–11.9) p value 0.052); DCR 66% vs 33% p value 0.612).ConclusionsIn good prognosis, group A—TT showed statistically significant better PFS than IT, also in a long-term period, suggesting that TT can be a good first line option for this patient category. It is only in group B that we observed a crossing of the survival curves after the 3rd year of observation in favor of IT. Few patients were enrolled in group C, so few conclusions can be made on it.

Early quality of life (QOL) and symptom analysis from the DREAMseq phase III randomized control trial of combination immunotherapy versus targeted therapy in patients (pts) with BRAF-mutant metastatic melanoma (MM) (ECOG-ACRIN EA6134).

9559 Background: Combinations of either immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) or BRAF/MEK-targeted therapies have shown significant clinical benefit in pts with BRAFV600 mutant MM. Until recently, little prospective data existed to guide the choice of initial therapy or sequence. Results of the DREAMseq Trial showed that the treatment sequence beginning with nivolumab/ipilimumab (Nivo/Ipi) immunotherapy produced a clinically meaningful 20% improvement in 2-year overall survival (OS) compared to the sequence beginning with dabrafenib/trametinib (Dab/Tram) targeted therapy. The OS and progression-free survival (PFS) curves were biphasic crossing at 10 and 6 months, respectively. Our aim is to characterize QOL trends within and between the initial therapies through 24 weeks (wks). Methods: 265 pts were randomly assigned to Nivo/Ipi for up to 12 wks then Nivo alone (Arm A) or Dab/Tram continuously (Arm B) and at disease progression (PD) received the alternate therapy. QOL was assessed by the PROMIS Profile 29 at baseline, wk 12 (end of cycle (C) 2), and wk 24 (end of C4). Wilcoxon Signed Rank test was used to examine changes over time within treatment arms. OS was estimated by Kaplan-Meier method to compare between pts who stopped treatment for toxicity on Arm A by C2 and who continued on Arm A therapy to C4. A complete case analysis compared QOL domain means for (C2) vs. (C4). Pt-reported adverse events were also collected. Results: Baseline completion rates for the PROMIS-29 for Arm A (n = 108, 81.2%) and Arm B (n = 117, 88.6%) and decreased to 28.6% and 53.8%, respectively at C4. Through C4, the principal reasons for dropout were toxicity (35.2% for Arm A and 11.9% for Arm B) and PD (26.1% for Arm A and 18.6% for Arm B). From Baseline to C2: Arm B reported statistically significant improvements in Pain Interference (-3.45, P = 0.007), Sleep (-2.11, P = 0.014), and Anxiety (-3.74, P &lt; 0.001). By C4, these early differences had dissipated (mean diff. = 0.73 – 1.73, all p = NS). For pts remaining on treatment to C4 (n = 157), a complete case analysis indicates no significant QOL differences between C2 vs C4. Pts stopping for toxicity on Arm A after C2 had similar 2-yr OS to pts who continued on Arm A to C4. QOL at C2 (Arm A: stopping for toxicity vs. on treatment) were meaningful, but underpowered (Physical Health (PH) mean difference = -3.5, p = 0.18). Conclusions: Over the first 12 wks, Dab/Tram is associated with significant improvement in overall function and less disturbance in in sleep, pain, physical function, and PH than Nivo/Ipi as expected by PFS curves and toxicity profiles. These differences dissipate by 24 wks when Arm A therapy has switched to Nivo alone and PFS curves cross. Early QOL and treatment cessation due to Nivo/Ipi toxicity was not associated with differences in 2-yr OS. Clinical trial information: NCT02224781.

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.

Real-world evaluation of the association between baseline metastatic patterns and clinical outcomes among patients with BRAF-positive metastatic melanoma.

9532 Background: While immunotherapy (IO) and BRAF-targeted therapy (TT) have benefit in BRAFV600 mutant (BRAF+) metastatic melanoma (MM), there is a paucity of real-world data on the impact of systemic therapy choice on outcomes based on key characteristics such as site and number of baseline metastases. Patients with &gt;1 baseline site and certain sites of metastases are also underrepresented or excluded in clinical trials. The aim of this study was to evaluate the association between these characteristics and survival among BRAF+ MM patients. Methods: This was a retrospective cohort study using the Novartis BRAF+ meLanoma patients ObsErvational (NOBLE) dataset – harmonized customized data from Flatiron and ConcertAI. It included patients ≥18 years, who received treatment with a first-line (1L) IO (anti-PD-1 mono or combination therapy ipilimumab + nivolumab) or TT (any BRAF/MEK-inhibitors) after 1/1/2014. Progression free survival (PFS) and overall survival (OS) for IO and TT were analyzed according to number (1, 2, 3+ sites) and location (brain, lung, liver, bone) of baseline metastasis. Treatment sequence from 1L to 2L (i.e. IO/TT vs TT/IO) were also compared for PFS and OS outcomes. Results: A total of 1,961 patients were included, with 620 patients (32%) on IO monotherapy, 501 patients (26%) on IO combo therapy, and 840 patients (43%) on TT in the 1L. When adjusted for sex, age, ECOG, and Charlson Comorbidity Index, there was no difference in PFS or OS between 1L IO mono, IO combo and TT therapies in patients who had 1, 2, or 3+ baseline metastases. For patients who had either baseline brain, liver, lung, or bone metastasis, there was no difference in PFS and OS between IO mono, IO combo, and TT combo therapies. Of the 521 patients included in the sequencing analysis (only patients who received 2L therapy), 239 patients (46%) had 1L IO/2L TT. There was no difference in PFS or OS between treatment sequences for patients with any number or location of baseline metastasis. Conclusions: In this real-world retrospective cohort study, there is no difference in survival between 1L TT and IO for BRAF+ MM patients. Outcomes are comparable regardless of number and location of metastases, including brain metastasis. Whether switching from 1L TT to IO before progression may account for differences compared to trial data will be explored further.[Table: see text]

Meta-analysis of randomized phase II-III trials evaluating triplet combinations of immunotherapy and targeted therapy for BRAF V600-mutant unresectable or metastatic melanoma.

9541 Background: Immune-checkpoint inhibitors (ICI) and targeted-therapies (TT) have become standard options for BRAF -V600 metastatic melanoma (B-mut MM) patients. However, still more than 50% of those patients do not respond or relapse to these current strategies. Preclinical and translational data suggest that ICI plus TT may improve treatment outcomes in patients with B-mut MM, but with conflicting results in the clinical setting. Methods: We performed a systematic review and meta-analysis of randomized phase II-III studies published until January 2022 comparing first-line ICI+TT vs TT alone in B-mut MM. We obtained summary estimates through random-effects models. Overall survival (OS) and progression-free survival (PFS) were the main outcomes retrieved but we look also at difference in responses and adverse events. Results: We summarized data from 3 independent trials and we showed a significant advantage in terms of PFS and OS for the experimental arms in B-mut MM patients treated with ICI+TT rather than TT alone. The summary estimate indicates a significant 23% decrease in risk of progression (SHR = 0.77, 95%CI: 0.66-0.89, with no between-study heterogeneity I2= 0%) and a significant 21% reduction in risk of death (SHR = 0.79, 95%CI: 0.66-0.96, with no heterogeneity I2= 0%). However, no difference was shown (p-value = 0.56) between arms in terms of summary Objective Response Rate (ORR) estimates (Summary ORR doublet = 65.4% [61.5%; 69.2%] and Summary ORR triplet = 67% [63%; 70.9%], respectively). From the subgroup analysis on PFS risk estimates, no significant differences were observed in summary HRs by age ( &lt; 65 vs ≥65 years, p-value = 0.11), sex (female vs male, p-value = 0.58), ECOG PS (0 vs 1, p-value = 0.36), LDH levels (lower vs upper, p-value = 0.59) and PDL1 status (positive vs negative, p-value = 0.89). Significant differences were found in frequencies of grade 3 or more adverse events with higher number of events occurring in B-mut MM vs TT alone (Summary Odd Ratio = 2.01, 95%CI: 1.16-3.47, I2= 74%), whereas no significant differences were found in terms of any adverse event between arms (SOR = 1.83, 95%CI: 0.70-4.78, I2= 0%). Conclusions: This study supports and extend the discussion on first-line available combinations to be offered to B-mut MM patients. Combining ICI with TT demonstrated an effective advantage on both PFS and OS, although augmenting toxicities. Further biomarker-driven investigation may identify patient subpopulations who could benefit from ICI+TT combinations in order to expand their window of therapeutic opportunities.

Progression and mortality post-immunotherapy discontinuation among patients with BRAFV600-mutant (BRAF+) metastatic melanoma.

9531 Background: Immunotherapy (IO) is commonly used to treat BRAF+ metastatic melanoma (MM) patients in the first line (1L) setting and has demonstrated durable outcomes in clinical trials. However, most patients discontinue IO therapy for toxicity, disease progression, or other reasons. To date, no multi-center or nationwide US-based study has examined treatment patterns and outcomes for patients with BRAF+ MM post discontinuation of 1L IO. The aim of this study is to describe real-world treatment patterns and outcomes among patients who discontinued 1L IO. Methods: This retrospective cohort study used the Novartis BRAF+ meLanoma patients ObsErvational (NOBLE) database, the harmonized customized data from Flatiron and ConcertAI. Patients were ≥18 years old, had a diagnosis of BRAF+ MM, were treated with pembrolizumab, nivolumab, or ipilimumab + nivolumab on or after 9/1/2014, and then discontinued 1L therapy. Reason for discontinuation was extracted from medical records. Descriptive statistics were used to describe baseline characteristics and treatment patterns. Kaplan–Meier curves were used to analyze time to progression or death (TTPD) and time to death (TTD). Results: Of the 898 included patients (mean age: 61 years; male: 65%); 46% initiated ipilimumab + nivolumab, 24% nivolumab, and 30% pembrolizumab. The most common reasons for 1L discontinuation were toxicity (26%) and progression (25%). Medical records noted 5.3% completed therapy on discontinuation and 34.5% provided no reason of discontinuation with median duration of therapy (MDOT) of 379 and 138 days respectively. At 6 months, 34 % (n = 303) remain on IL IO. MDOT for patients who discontinued IO due to toxicity and those who discontinued due to progression were 54 and 63.5 days respectively. Patients who discontinued due to toxicity had a median time of 142 days to next treatment. TTPD was best for patients who discontinued therapy due to completion or toxicity (6-month progression rate: 13% and 20%). Patients who discontinued due to progression did especially poorly (6-month progression rate: 59%). About 33% of patients (n = 296) needed second line (2L) therapy, and the majority (80.7%) received combination BRAF+ targeted therapy. Overall, 38% and 50% of patients died post IO discontinuation for any reason at 1 and 2 years, respectively. 31% of patients had brain metastases and a greater proportion (56%) died within a 2-year period compared with those without brain metastases (56% vs 49%, p = 0.0036). Conclusions: IO, although effective, is not curative for all patients. A significant number of patients discontinue therapy due to progression. Patients with BRAF+ MM who progress early on 1L IO therapy have a high risk of death and should be considered for other therapy options, including targeted therapy.

The Role of Treatment Sequencing with Immune-Checkpoint Inhibitors and BRAF/MEK Inhibitors for Response and Survival of Patients with BRAFV600-Mutant Metastatic Melanoma-A Retrospective, Real-World Cohort Study.

Simple SummaryThe clinical application of kinase inhibitors and immune-checkpoint inhibitors (CPI) has substantially improved the treatment landscape of melanoma. While BRAF/MEK inhibitors allow for rapid disease control, and CPI can evoke durable tumor responses, primary and secondary resistance frequently limit treatment efficacy. Observations from preclinical trials suggest that treatment with BRAF/MEK inhibitors may enhance susceptibility towards CPI therapy and thus improve long-term tumor control. To date, little prospective data is available for the optimal sequencing of these agents in melanoma patients. In this retrospective, real-world analysis, we analyzed the role of sequential treatment with BRAF/MEK inhibitors and CPI in 135 BRAF-mutant, metastatic melanoma patients. Our results demonstrate that front-line treatment with CPI is associated with favorable tumor control and overall survival in patients with BRAF-mutant melanoma. Further, our data indicate that patients who are refractory to front-line BRAF/MEKi therapy are at higher risk of rapid disease progression compared to patients with front-line CPI treatment.The advent of immune-checkpoint inhibitors (CPI) and BRAF/MEK-directed targeted therapy (TT) has improved the treatment landscape of patients with BRAFV600-mutant metastatic melanoma. While TT allows for rapid disease control, the development of secondary TT resistance limits the duration of responses. Responses to CPI have a slower onset but can be durable in a subset of patients. To date, little prospective data is available for the optimal sequencing of these agents in melanoma patients. In this retrospective, single-center, real-world analysis, we identified 135 patients with BRAF-mutated, metastatic melanoma who received consecutive treatment with TT followed by CPI, or vice versa, as first and second-line therapy, respectively. We collected data on clinical-pathological factors, treatment duration, best overall response, progression-free survival and overall survival (OS). Our data revealed that front-line treatment with CPI, followed by TT, showed a non-significant trend towards better OS compared to front-line TT (median OS: 35.0 vs. 18.0 months, p = 0.070). This association was confirmed in a subgroup of patients without systemic pre-treatments (median OS: 41.0 vs. 14.0 months, p = 0.02). Further, we observed significantly better objective response rates to second-line treatments for patients receiving front-line CPI (18.4 vs. 37.8%, p = 0.024). Last, our results indicated that rapid disease progression was less common in patients treated with front-line CPI (27.6% vs. 16.2%) and that subsequent treatment with TT resulted in favorable survival outcomes. Our real-world data indicate that sequential treatment with front-line CPI is associated with favorable tumor control and overall survival in a subgroup of previously untreated BRAF-mutant metastatic melanoma patients.

Theragnostic significance of tumor-infiltrating lymphocytes and Ki67 in BRAFV600-mutant metastatic melanoma (BRIM-3 trial)

We conducted a retrospective tumor tissue analysis as part of the BRIM3 trial to evaluate the theragnostic significance of tumor-infiltrating lymphocytes (TILs) and melanoma cell proliferation. Using manual semi-quantitative analyses, we assessed the density of TILs by pathology review of tissue sections stained with hematoxylin and eosin (H&E TIL score) and by immunohistochemistry (IHC) with an anti–CD8 antibody (CD8 TIL score); also, the melanoma cell proliferation by IHC with an anti–Ki67 antibody. Three hundred and fifty-three, 280, and 172 patients’ tumor tissue samples were available for H&E, CD8, and Ki67 IHC analysis, respectively. There was no association between high (2+, 3+) peritumoral and intratumoral H&E and/or TIL CD8 score or high Ki67 proliferation index (>15%) with serum LDH level and stage IV melanoma. Neither high Ki67 proliferation, nor high peritumoral and/or intratumoral TIL score was significantly associated with objective antitumor response in any treatment arm. High intratumoral and high peritumoral CD8 TIL score was significantly associated with progression-free survival (PFS) only in DTIC-treated patients (P = 0.002 and 0.037, respectively); in vemurafenib-treated patients, high intratumoral and/or peritumoral CD8 TIL score was not significant (log-rank P = 0.053 and 0.062, respectively). Nevertheless, a high peritumoral CD8 TIL score was a significant predictor of PFS and overall survival after adjustment for age, sex, serum LDH, ECOG performance status, and treatment arm in a Cox regression model. Vemurafenib does not only benefit patients bearing brisk TILs; even vemurafenib-treated patients with absent and/or non–brisk TILs tend to have longer PFS compared to DTIC-treated patients with brisk TILs. High peritumoral CD8 TIL score is a favorable prognostic factor independent of well-established AJCC staging factors.

STARBOARD: encorafenib+binimetinib+ pembrolizumab for first-line metastatic/unresectable BRAF V600-mutant melanoma.

Despite the significant progress in the treatment of unresectable or metastatic BRAF V600-mutant melanoma, there remains two primary treatment options: targeted therapy and immunotherapy. Targeted therapy or immunotherapy alone is associated with efficacy limitations including efficacy limited to select patient subsets. With separate mechanisms of action and different response patterns, the combination of targeted agents and immunotherapy to treat patients with BRAF V600-mutant melanoma may further improve patient outcomes. Current treatment guidelines recommend treatment with targeted agents alone, immunotherapy, or the combination of targeted agents and immunotherapy. The randomized, double-blind STARBOARD trial aims to evaluate efficacy and safety of encorafenib, binimetinib and pembrolizumab in treatment-naive patients with metastatic or unresectable locally advanced BRAF V600-mutant melanoma in comparison to pembrolizumab.