Sequential Treatment With Immunotherapy and Targeted Therapy Denotes OS Benefit in BRAF-Mutant Melanoma

Paolo A, Ascierto, MD

Immunotherapy in the form of ipilimumab (Yervoy) plus nivolumab (Opdivo) followed by the targeted therapy combination encorafenib (Braftovi) plus binimetinib (Mektovi) elicited an overall survival (OS) benefit in patients with untreated BRAF-mutated metastatic melanoma, according to findings from the phase 2 SECOMBIT trial (NCT02631447).

SECOMBIT enrolled patients to 3 arms, where they received targeted therapy followed by immunotherapy (arm A), immunotherapy followed by targeted therapy (arm B), or a sandwich approach of targeted therapy followed by immunotherapy followed by additional targeted therapy (arm C).

The 2-year OS rates were 65% (95% CI, 54%-76%) in arm A, 73% (95% CI, 62%-84%) in arm B, and 69% (95% CI, 59%-80%) in arm C. Additionally, at a median follow-up of 32.2 months (interquartile range, 27.9-41.6), the median OS was not reached in any arm, and the lower bounds of the 95% CI were not estimable. Furthermore, over 30 patients were alive in each arm. Assuming a null hypothesis of median OS of 15 months, all arms met the OS end point.

“Our study supports the fact that eligible patients with BRAF V600–mutant melanoma obtain clinical benefit with combination immunotherapy as the first line of treatment,” lead study authors Paolo A, Ascierto, MD, of National Tumor Institute Fondazione G. Pascale, and Mario Mandalà, MD, of Papa Giovanni XXIII Cancer Center Hospital, and colleagues, wrote.

BRAF and MEK inhibition can regulate some of the immunosuppression that occurs in BRAF V600–mutant melanoma, and response to BRAF and MEK inhibition is partially immune-mediated, with the emergence of immune-related adverse effects (AEs) during targeted therapy associated with prolonged clinical benefit. This randomized, open-label, noncomparative trial evaluated survival outcomes of sequential treatment with targeted therapy and immunotherapy combinations in patients with BRAF V600–mutant metastatic melanoma.

Patients were eligible if they were at least 18 years of age, with an ECOG performance status of 0 or 1, histologically confirmed unresectable stage III or IV melanoma with measurable disease by computed tomography or magnetic resonance imaging (MRI) per RECIST v1.1 criteria, and tumors harboring a BRAF V600 mutation. Patients who had received prior adjuvant treatment, such as with CTLA-4, PD-1, or PD-L1 checkpoint inhibitors, were eligible if they completed these therapies more than 6 weeks before randomization. Patients with brain metastases were eligible if MRI showed no evidence of progression for more than 4 weeks after local treatment and within 28 days of receiving the first dose of study drug, and if they did not require immunosuppressive doses of systemic corticosteroids for more than 2 weeks before beginning study treatment.

Patients were ineligible if they had received previous adjuvant treatment with BRAF inhibitors. Other ineligible patients included those with autoimmune disease, conditions requiring systemic treatment with immunosuppressive medications within 14 days of treatment, prior treatment with checkpoint inhibitors for metastatic disease, severe or uncontrolled systemic disease, a history of uncontrolled cardiovascular or interstitial lung disease with evidence or risk of central serous retinopathy or retinal vein occlusion, and hepatitis B virus surface antigen or hepatitis C virus ribonucleic acid indicating acute or chronic infection. Patients who were pregnant, had previously tested positive for HIV or known AIDS, or had a history of severe or life-threatening skin AEs or other reactions to drugs were also excluded.

From November 2016 to May 2019, 209 patients from 37 sites across 9 countries were randomly assigned to encorafenib plus binimetinib until progressive disease (PD) followed by ipilimumab plus nivolumab until second PD (arm A, n = 69), ipilimumab plus nivolumab until PD followed by encorafenib plus binimetinib until second PD (arm B, n = 71), or encorafenib plus binimetinib for 8 weeks followed by ipilimumab plus nivolumab until PD followed by encorafenib plus binimetinib until second PD (arm C, n = 69).

One patient each in arms B and C had brain metastases. All patients who had received prior adjuvant therapy completed the full treatment course: 14 in arm A, 10 in arm B, and 11 in arm C.

Encorafenib was administered at 450 mg orally once daily, binimetinib at 45 mg orally twice daily, ipilimumab at 3 mg/kg once every 3 weeks, and nivolumab at 1 mg/kg once every 3 weeks for 4 cycles and 3 mg/kg every 2 weeks thereafter.

The primary end point of this trial was 2-year OS. Secondary end points included total progression-free survival (PFS), defined as time from randomization to first or second PD or death; 3-year OS; best overall response rate (ORR); duration of response, defined as time from complete response (CR) or partial response (PR) to progression or death from underlying cancer; and evaluation of biomarkers in the intention-to-treat population.

At a data cutoff of May 2021, 69, 69, and 68 patients in arms A, B, and C, respectively, had received the first treatment, and 36, 36, and 35 patients in arms A, B, and C, respectively, had received the second treatment. In total, 2 patients in arm B withdrew before beginning treatment, and 1 patient in arm C never began treatment. In total, 14, 12, and 17 patients in arms A, B, and C completed the sequence. At this data cutoff, 23 patients were still receiving treatment in arm A (targeted therapy, n = 16; immunotherapy, n = 7), 26 patients were still receiving treatment in arm B (immunotherapy, n = 15; targeted therapy, n = 11), and 28 patients were still receiving treatment in arm C (immunotherapy, n = 19; targeted therapy, n = 9).

Of the patients included in follow-up, 32 were from arm A, 32 were from arm B, and 35 were from arm C.

The 3-year OS rates were 54% (95% CI, 41%-67%) in arm A, 62% (95% CI, 48%-76%) in arm B, and 60% (95% CI, 58%-72%) in arm C. Although this trial was not designed to compare the arms, exploratory analyses defined OS hazard ratios (HRs) of 0.73 (95% CI, 0.42-1.26) for arm B vs arm A and 0.81 (95% CI, 0.48-1.37) for arm C vs arm A.

The 1-year total PFS rates were 77% (95% CI, 67%-87%), 72% (95% CI, 61%-83%), and 78% (95% CI, 68%-88%) in arms A, B, and C, respectively. The 2-year total PFS rates were 46% (95% CI, 34%-58%), 65% (95% CI, 54%-76%), and 57% (95% CI, 45%-69%) in arms A, B, and C, respectively. The 3-year total PFS rates were 41% (95% CI, 29%-53%), 53% (95% CI, 43%-63%), and 54% (95% CI, 42%-66%) in arms A, B, and C, respectively. The exploratory total PFS HRs were 0.71 (95% CI, 0.44-1.14) for arm B vs arm A and 0.74 (95% CI, 0.46-1.18) for arm C vs arm A.

Best ORRs for the first treatment were 87.0% in arm A, 44.9% in arm B, and 82.4% in arm C. Best ORRs for the second treatment were 25.7% (n = 35) in arm A, 57.9% (n = 38) in arm B, and 62.2% (n = 37) in arm C.

Best responses with the second treatment, ipilimumab plus nivolumab, in arm A included 2 CRs, 7 PRs, and 3 cases of stable disease (SD). In the other 2 arms, the best responses with the second treatment, encorafenib plus binimetinib, were 4 CRs, 18 PRs, and 9 cases of SD in arm B, and 9 CRs, 14 PRs, and 3 cases of SD in arm C.

Investigators analyzed safety during sequential treatment in all patients who received at least 1 dose of study treatment. They observed no new safety signals during the full course of sequential treatment during this trial.

The most common AEs of any grade in arm A were fever (43%; n = 30), creatine kinase increase (38%; n = 26), and diarrhea (32%; n = 22). The most common AEs of any grade in arm B were diarrhea (41%; n = 28), pruritis (27%; n = 19), and hypothyroidism (26%; n = 18). The most common AEs of any grade in arm C were fever (29%; n = 20), diarrhea (29%; n = 20), and rash (28%; n = 19).

Grade 3/4 AEs were reported in 39% (n = 27; 95% CI, 28%-51%), 59% (n = 41; 95% CI, 48%-71%), and 38% (n = 26; 95% CI, 27%-50%) of patients in arms A, B, and C, respectively. Creatine kinase increase (9%; n = 6) was the most common grade 3/4 AE, followed by transaminase increase (14%; n = 10) and lipase increase (12%; n = 8).

Treatment-related AEs leading to discontinuation occurred in 10% (n = 7) of patients in arm A, 10% (n = 7) of patients in arm B, and 9% (n = 6) of patients in arm C. No AEs leading to withdrawal from the study or death were associated with the study treatment. This trial will continue to follow patients for safety.

“Although not formally compared, the ORR for ipilimumab plus nivolumab was numerically higher when given first in the sequence. [Additionally,] the sandwich approach, [arm C], warrants further investigation, as there is likely no one-size-fits-all strategy for patients with BRAF-mutant melanoma,” the study authors concluded.

Reference

Ascierto PA, Mandalà M, Ferrucci PF, et al. Sequencing of ipilimumab plus nivolumab and encorafenib plus binimetinib for untreated BRAF-mutated metastatic melanoma (SECOMBIT): a randomized, three-arm, open-label phase II trial. J Clin Oncol. Published online, September 1, 2022. doi:10.1200/JCO.21.02961