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Immuno-combination therapy in metastatic melanoma

ESMO 2020
Both immune checkpoint inhibitors and targeted therapy have improved the treatment outcomes for patients with unresectable or metastatic melanoma. However, many patients experience disease progression and, therefore, new treatment strategies are needed. Several combinations of targeted therapy and immunotherapy are tested.

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%).

  1. 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.
  2. 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.
  3. Fukumura D, et al. Nat Rev Clin Oncol 2018;15:325-340.
  4. 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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