Early switch from run-in with targeted to immunotherapy in advanced BRAFV600-positive melanoma: final results of the randomised phase II ImmunoCobiVem trial

Abstract

Background: Optimal sequencing of immune checkpoint inhibitors (ICIs) and targeted therapies (TTs) in BRAF^V600-positive advanced melanoma should achieve rapid tumour control and durable progression-free survival (PFS), translating into prolonged overall survival (OS).

Patients and methods: The 1 : 1 randomised phase II ImmunoCobiVem trial compared-after a 3-month run-in phase with vemurafenib (VEM, 960 mg twice daily) and cobimetinib (COB, 60 mg daily days 21-28, q4w)-continuous VEM + COB until disease progression (PD1) and second-line atezolizumab (ATEZO, 1200 mg, q3w) in arm A versus early switch to ATEZO after run-in, followed by crossover to VEM + COB at PD1, in arm B. PFS from the start of run-in until PD1 was the primary endpoint (PFS1); secondary efficacy endpoints were OS, overall PFS (PFS2) and PFS3 (time from PD1 to PD after crossover, i.e. PD2) and best overall response rates (BORRs).

Results: The final analysis (median follow-up 57.0 months, interquartile range 22.7-63.0 months) confirmed longer PFS1 for continuous TT [arm A (69 patients) versus arm B (early switch, 66 patients); hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.41-0.91, P = 0.006], but early switch to ICIs resulted in better long-term OS [4- and 5-year landmark OS 42% (95% CI 29% to 55%) and 40% (95% CI 27% to 53%) for arm A, and 53% (95% CI 38% to 65%) and 45% (95% CI 31% to 58%) for arm B; descriptive HR 1.17, 95% CI 0.71-1.91]. Absolute BORRs were 81% and 89%, respectively, with 15 (22%) and 19 (29%) patients achieving a complete response at least once along each sequence. At crossover, TT retreatment (arm B) resulted in higher PFS3 than second-line ICI (arm A).

Conclusions: Early switch to ICIs after TT run-in (arm B) led to an improved, although not statistically significant, 4- and 5-year landmark OS compared with arm A. No subgroups were identified for which a TT run-in provided clinical benefit. The number of patients developing brain metastasis and the time to brain metastasis were not improved by an early TT to ICI switch.

Keywords: crossover design; immunotherapy; melanoma; sequential therapy; targeted therapy.

Figure 1

Study design. Study design (A) and selected patient characteristics (B) after randomisation and after crossover (arms A and B, ITT population). LDH status, metastatic stage (M1c yes/no) and prior adjuvant therapy were stratification factors resulting in equal distribution at the time of randomisation. Reasons for treatment discontinuation before PD1 included adverse events (n = 12/n = 4), patient or investigator decision (n = 13/n = 6) or death (n = 2/n = 2) in arms A and B, respectively (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2025.105053). For patients with brain metastases at PD1, crossover was restricted to patients with asymptomatic brain metastases only. ATEZO, atezolizumab; BM, brain metastasis; COB, cobimetinib; ECOG, Eastern Cooperative Oncology Group; ITT, intention-to-treat; i.v., intravenous; LDH, lactate dehydrogenase; OS, overall survival; PD1, first documented disease progression; PFS, progression-free survival; VEM, vemurafenib. ^aMedian, at the time of enrolment. ^bEligible: 0 or 1. ^cAt the time of PD1.

Figure 2

Kaplan–Meier curves. For PFS1 (A, primary endpoint population) and OS (B, ITT population). The primary endpoint population excluded two patients (133 of 135 only): one patient each in arm A and arm B due to confirmed disease progression in the brain; both patients had brain metastases as the only site of progression, but continued study treatment due to anticipated ongoing clinical benefit as per investigator assessment. CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; NE, not evaluable; OS, overall survival; PFS, progression-free survival.

Figure 3

Kaplan–Meier curves. For crossover patients: PFS3 (A) and PFS2 (total PFS, B). PFS3 is the time from first progression to second progression after crossover. PFS2 is the time from enrolment to second progression in patients who crossed over (total PFS). A, atezolizumab; C, cobimetinib; CI, confidence interval; HR, hazard ratio; V, vemurafenib.

Figure 4

Patterns of disease progression. Shown are the patterns of PD according to BOR in part 1 of the trial (combined BOR of run-in phase plus randomised phase, with early switch to atezolizumab in arm B) with emphasis on the development of BM. While the overall probability of progression correlates with the depth of prior tumour response, no clear correlation was seen for the development of BM. Seven patients in arm A and 11 patients in arm B who developed asymptomatic BM during the randomised phase were allowed to cross over, as the trial excluded the crossover of patients with multiple and/or symptomatic BM and/or leptomeningeal disease. The development of multiple/symptomatic brain or leptomeningeal metastasis was the predominant cause preventing crossover in both arms. ^aTwo patients with small and asymptomatic BM as the only site of progression were allowed to continue trial treatment, but are not depicted further as they entered the randomised phase with BM. aBM, asymptomatic brain metastasis; BM, brain metastasis; BOR, best overall response; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 5

Explorative analysis of crossover outcomes: Kaplan–Meier estimates for patients with or without brain metastasis before crossover. PFS3 (A) and OS (B) show rapid progression and a general lack of activity for second-line atezolizumab after TT failure. For arm B, re-challenge with TT demonstrates some late-line activity in terms of PFS3 (A, right panel) with high OS rates in patients without brain metastases at the time of crossover and poor OS outcome in patients with brain metastases (B, right panel). Reported are the log-rank P values. CI, confidence interval; HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival; TT, targeted therapy.