Sequential Immunotherapy and Targeted Therapy Shows OS Benefit in BRAF+ Melanoma

Three different sequencing schemas for immunotherapy followed by targeted therapy in patients with BRAF V600-mutant melanoma have shown positive survival outcomes and safety consistent with results from prior studies.

Findings from the phase 2 SECOMBIT trial (NCT02631447) show sequential immunotherapy of ipilimumab (Yervoy) plus nivolumab (Opdivo) followed by the targeted therapy combination of encorafenib (Braftovi) plus binimetinib (Mektovi) provides overall survival (OS) benefit in patients with untreated BRAF-mutated metastatic melanoma.1

The randomized, 3-arm, phase 2 SECOMBIT trial enrolled patients to arm A where they were treated with targeted therapy followed by immunotherapy, arm B consisting of immunotherapy followed by targeted therapy, or arm C which gave patients targeted therapy, then immunotherapy, followed by additional targeted therapy.

According to findings published in the Journal of Clinical Oncology, at a median follow-up of 32.2 months (interquartile range, 27.9-41.6) all arms failed to reach the median OS, and the lower bounds of the 95% CI were not estimable. Then at 2 years, the 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.

“SECOMBIT describes clinical benefit after 3 different sequencing schemas for targeted therapy and immunotherapy for the treatment of BRAF V600-mutant melanoma, with survival outcomes and safety consistent with the results of other studies,” wrote the study authors led by Paolo A, Ascierto, MD, of National Tumor Institute Fondazione G. Pascale, and Mario Mandalà, MD, of Papa Giovanni XXIII Cancer Center Hospital.

This open-label, noncomparative trial examined the survival outcomes of patients with BRAF V600–mutant metastatic melanoma given sequential treatment consisting of targeted therapy and immunotherapy combinations.

Enrollment in the trial was open to patients aged 18 years and older who had 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.

Those who had received previous adjuvant treatment, including CTLA-4, PD-1, or PD-L1 checkpoint inhibitors, could be included if they had completed their therapy longer than 6 weeks before the time of randomization. If a patient had brain metastases, they were eligible for enrollment if the 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. These patients also must not require immunosuppressive doses of systemic corticosteroids for more than 2 weeks prior to the start of the study.

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 was 2-year OS with the secondary end points of total progression-free survival (PFS), 3-year OS, best overall response rate (ORR), duration of response, and evaluation of biomarkers in the intention-to-treat population.

A total of 209 patients from 37 sites across 9 countries were enrolled in the trial between November 2016 to May 2019. Patients were then randomly assigned to receive encorafenib plus binimetinib until progressive disease (PD), then 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).

The median age of patients enrolled in arm A and B was 55 years (range, 19-77; 18-81) and 51 (range, 28-80) in arm C. In this intent-to-treat population, 60.9%, 47.9%, and 60.9% patients were male, 82.6%, 87.3%, and 89.9% had an ECOG performance status of 0, and 59.4%, 52.1%, and 63.8% had 1.00 or lower upper limits of normal in arms A, B, and C.

In both arm B and C, 1 patient had brain metastases. Among patients who had received prior adjuvant therapy, all completed the full course of treatment, including 14 in arm A, 10 in arm B, and 11 in arm C.

By May 2021, the time of the data cutoff, 206 patients, including 69 patients in arm A, 69 in arm B, and 68 in arm C, had received the first treatment while 107, 36, 36, and 35 patients, received the second treatment. In arm B, 2 patients withdrew from the study prior to the start of treatment, and 1 patient in arm C never started treatment. In arms A, B, and C, a total of 14, 12, and 17 patients completed the sequence.

As of the data cutoff date, 23 patients continued to receive treatment in arm A with 16 receiving targeted therapy and 7 with immunotherapy. In arm B, 26 patients were still receiving treatment with immunotherapy (n = 15) and targeted therapy (n = 11), and in arm C, 28 patients were receiving treatment with immunotherapy (n = 19) and targeted therapy (n = 9). Then included in the follow-up were 32 patients from arm A, 32 from arm B, and 35 from arm C.

Findings revealed that the median OS was not reached in any of the treatment arms at a median follow-up of 32.2 months. However, assuming a null hypothesis of median OS of 15 months (ie, 33% of patients surviving at 24 months), the study did meet its primary end point for all treatment arms.

The OS rates at 3 years 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. While the trial was not designed to compare the arms, an exploratory analysis defined the OS hazard ratios (HRs) as 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.

Total PFS rates were 77% (95% CI, 67%-87%) in arm A, 72% (95% CI, 61%-83%) in arm B, and 78% (95% CI, 68%-88%) in arms C, respectively.

The 2-year total PFS rates in arms A, B, and C were 46% (95% CI, 34%-58%), 65% (95% CI, 54%-76%), and 57% (95% CI, 45%-69%) 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. Further, the exploratory total PFS HR for arm B vs arm A was 0.71 (95% CI, 0.44-1.14) and 0.74 (95% CI, 0.46-1.18) for arm C vs arm A.

For the first treatment, the best ORRs were 87.0%, 44.9%, and 82.4% in arms A, B, and 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. With the second treatment of ipilimumab plus nivolumab, the best responses in arm A consisted of 2 CRs, 7 PRs, and 3 cases of stable disease (SD) vs the best responses with the second treatment in the other 2 arms of encorafenib plus binimetinib being 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.

There were no new safety signals observed during the full course of sequential treatment during this trial and none of the AEs which led to death or withdrawal from the study were found to be associated with the trial regimen.

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

Grade 3/4 AEs were observed in 39% of patients in arm A (n = 27; 95% CI, 28%-51%), 59% in arm B (n = 41; 95% CI, 48%-71%), and 38% in arm C (n = 26; 95% CI, 27%-50%), respectively. The most common grade 3/4 AE was creatine kinase increase (9%; n = 6), then transaminase increase (14%; n = 10) and lipase increase (12%; n = 8). Seven patients (10%) in arm A discontinued treatment due to treatment-related AEs compared with 10% (n = 7) of patients in arm B, and 9% (n = 6) of patients in arm C. This trial will continue to follow patients for safety.

“Importantly, no new safety signals were observed in any arms, and the incidences of TRAEs were similar in the sandwich arm (arm C) compared with other arms. Patients will continue to be followed for safety,” concluded the study authors.

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
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