In COMBI-I, 532 patients with unresectable or metastatic BRAF-mutated melanoma were randomised 1:1 to treatment with the PD-1 inhibitor spartalizumab (440 mg every 4 weeks) plus dabrafenib (150 mg BID) and trametinib (2 mg every 4 weeks) – the “triplet” – or placebo plus dabrafenib and trametinib – the “doublet” [1].
Median progression-free survival (PFS) was 16.2 months in the triplet arm and 12.0 months in the doublet arm (HR 0.82; P=0.042). Estimated PFS rates at 12 months were 58% and 50%, respectively, and 44% and 36% at 24 months. Based on the statistical design of the study, with a significance threshold for PFS at P<0.025 (equivalent HR <0.801), COMBI-i did not meet its primary endpoint.
In the SECOMBIT trial, immunotherapy and targeted therapy were given sequentially. In this phase 2 study, 251 patients with untreated, metastatic BRAF-mutated melanoma, were randomised 1:1:1 to 3 arms [2]:
- Arm A: encorafenib plus binimetinib until progression, followed by ipilimumab plus nivolumab.
- Arm B: ipilimumab plus nivolumab until progression, followed by encorafenib plus binimetinib.
- Arm C: encorafenib plus binimetinib for 8 week, followed by ipilimumab plus nivolumab until progression, followed by encorafenib plus binimetinib.
Dosing regimens for all patients were encorafenib 450 mg daily, binimetinib 45 mg daily, ipilimumab 3 mg/kg every 3 weeks for 4 cycles, and nivolumab 1 mg/kg every 3 weeks. Primary results are listed in the Table. The study is still ongoing for the completion of the main endpoint (overall survival, OS).
Table: Interim results of the SECOMBIT trial [2]

The LEAP-004 trial explored the efficacy of lenvatinib plus pembrolizumab in patients with unresectable stage III/IV melanoma who progressed on anti–PD-1-based therapy. This combination was based on the rationale that combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects [3]. In the open-label, single-arm, phase 2 LEAP-004 study, 103 patients were enrolled to receive lenvatinib (20 mg/ daily) and pembrolizumab (200 mg every 3 weeks up t to 35 cycles) until progression or unacceptable toxicity [4].
At a median follow-up of 12.0 months, objective response rate (ORR) was 21.4% (complete response 1.9%, partial response 19.4%). Median duration of response was 6.3 months. ORR was 31.0% in 29 patients who progressed on prior anti-CTLA4 plus anti-PD-(L)-1 therapy. Median PFS was 4.2 months and median OS was 13.9 months. The safety profile was consistent with prior studies. Most common treatment-related adverse event were hypertension (56.3%) and hypothyroidism (42.7%).
- Nathan P, et al. Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: Results from the randomized part 3 of the phase III COMBI-i trial. ESMO 2020 Virtual Meeting, abstract LBA43.
- Ascierto PA, et al. First report of efficacy and safety from the phase II study SECOMBIT (SEquential COMBo Immuno and Targeted therapy study). ESMO 2020 Virtual Meeting, abstract LBA45.
- Fukumura D, et al. Nat Rev Clin Oncol 2018;15:325-340.
- Arance Fernandez AM, et al. Lenvatinib (len) plus pembrolizumab (pembro) for advanced melanoma (MEL) that progressed on a PD-1 or PD-L1 inhibitor: Initial results of LEAP-004. ESMO 2020 Virtual Meeting, abstract LBA44.
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