Dabrafenib (D) and trametinib (T) plus spartalizumab (S) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: Three-year overall survival (OS) data from the randomized part 3 of the phase III COMBI-i trial.

Abstract

9527 Background: Combination of immune checkpoint inhibitors and targeted therapy may produce durable and deep response in a higher proportion of pts with BRAF V600–mutant unresectable or metastatic melanoma. A recent report from the randomized, double-blind, placebo (PBO)-controlled Part 3 of the Phase 3 COMBI-i trial (NCT02967692) failed to show a statistically significant progression-free survival (PFS) benefit (hazard ratio (HR) of 0.82 (95% CI, 0.66‒1.03, p=.042)). Here, we report 3-year OS data from COMBI-i part 3. Methods: Eligible pts were randomized 1:1 to receive either S+D+T (n = 267; S 400 mg IV Q4W + D 150 mg orally BID + T 2 mg orally QD) or PBO+D+T (n = 265), until progression or unacceptable toxicity. Although the primary endpoint of PFS was not met, exploratory OS and safety analyses were performed. OS was summarized descriptively using Kaplan–Meier methods and HR was estimated using a stratified cox regression model. Results: As of October 19, 2021 (median follow-up, 42.8 months), the median OS was not reached in S+D+T arm and was 40.4 months with PBO+D+T (HR 0.796; 95% CI, 0.615‒1.029). There were 113 (42.3%) deaths in the S+D+T and 126 (47.5%) in the PBO+D+T. Estimated 2-year and 3-year OS rates were 67.7% (95% CI 61.6‒73.1) and 60.1% (95% CI 53.8‒65.8) with S+D+T vs 61.9% (95% CI 55.6‒67.5) and 52.9% (95% CI 46.6‒58.9) with PBO+D+T, respectively. An OS benefit was observed with S+D+T in these prespecified subgroups – Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 (HR 0.50; 95% CI, 0.32‒0.8), age ≥65 years (HR 0.58; 95% CI, 0.36‒0.94), PD-L1 negative ( < 1%) (HR 0.62; 95% CI, 0.42‒0.91), sum of lesion diameters ≥ 66 mm at baseline (HR 0.63; 95% CI, 0.43‒0.91) and metastatic sites ≥ 3 (HR 0.66; 95% CI, 0.47‒0.94). Adverse events (AEs) irrespective of study treatment relationship were observed in 99.3% of pts in S+D+T vs 97.3% in PBO+D+T. The most common AEs (in > 30%; all grades) were pyrexia, diarrhea, and nausea. Grade ≥3 treatment-related AEs (TRAEs) occurred in 56.9% vs 35.2% of pts treated with S+D+T vs PBO+D+T, respectively. Dose reductions of D and T due to AEs were more frequent in the S+D+T arm than PBO+D+T arm (47.2% vs 25.4% and 45.7% vs 25.4%, respectively), contributing to a lower relative dose intensity; the TRAEs leading to discontinuation of all 3 study drugs occurred in 13.5% vs 8% of pts, respectively. Conclusions: Results from this landmark 3-year OS analysis from COMBI-i- part 3 was consistent with the primary analysis, while the PBO+D+T showed a higher OS rate than previously observed for D+T alone in COMBI D/V studies, with a longer median follow-up. Subgroup analyses showed that ECOG PS 1, age ≥65 years, negative PD-L1 status and high tumor burden were associated with better OS in S+D+T in terms of HR. Clinical trial information: NCT02967692.

The role of triple therapy and therapy sequence in treatment of BRAF-mutant metastatic melanoma. Response to overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study

“…In the landmark analysis of 3-year OS with a mFU of 42.8 months, the median OS (mOS) was still not reached in the triple arm, but demonstrated mOS of 40.4 months in the double arm with HR for death of 0.79 (95% CI 0.62–1.03). Similarly to the other studies, the subgroup analysis suggested that patients with ECOG PS 1, age ≥ 65 years, negative PD-L1 status, sum of lesion diameters ≥ 66 mm at baseline and metastatic sites ≥ 3 benefit more from the triple therapy with a prolonged OS, compared to double therapy [ 12 ].…”

Triple Combination of Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors in BRAFV600 Melanoma: Current Status and Future Perspectives

“…In the results from the landmark 3-year OS with a prolonged mFU of 42.8 months, the median overall survival (mOS) was not reached in the triple group, whereas in the double group, the mOS was 40.4 months (HR 0.79; 95% CI 0.62–1.03). The subgroup analysis showed an association of clinical factors, such as ECOG PS 1, age ≥ 65 years, negative PD-L1 status, sum of lesion diameters ≥ 66 mm at baseline and metastatic sites ≥ 3, with a prolonged OS in the triple group [ 34 ].…”

Lessons from clinical trials on triple combination of immune checkpoint inhibitors and BRAF/MEK inhibitors in BRAF-mutant melanoma

“…The latest subgroup analysis of the COMBI-i study presented in 2022 showed that clinical characteristics, such as ECOG PS 1, age ≥65 years, negative PD-L1 status, sum of lesion diameters ≥66 mm at baseline, and metastatic sites ≥3 were associated with prolonged OS for the triple-therapy arm ( 15 ). The COMBI-i trial has consistently shown a higher frequency of dose reductions and discontinuations due to treatment-related adverse events (AEs) in the triple-therapy group than in the control group.…”

“…The dose reduction rates of dabrafenib and trametinib due to AEs were 47.2% and 45.7% in the triple-therapy arm vs. 25.4% and 25.4% in the control arm. The discontinuation rate of all trial drugs due to treatment-related AEs was 13.5% in the triple-therapy arm and 8% in the control arm ( 15 ). Even so, it is noteworthy that there may be a group of patients for whom triple therapy is more effective.…”

“…In fact, although simple numerical comparisons are impossible because these clinical trials are different, the COMBI-i and COMBI-d/v trials showed that patients treated with the combination of dabrafenib and trametinib had a median PFS of 12.0 and 11.1 months, and a 2-year PFS rate of 36% and 31%, respectively ( 2 , 13 ). Furthermore, although the impact of the dramatic evolution of second-line therapies for advanced malignant melanoma should be taken into account, a comparison of the two trials shows a 2-year OS rate of 61.9% vs. 44%, and a 3-year OS rate of 52.9% vs. 37% for patients treated with dabrafenib plus trametinib ( 13 , 15 ).…”