Final results from the phase 2 ImmunoCobiVem trial indicate a trend towards improved overall survival (OS) in patients with BRAF V600–positive melanoma who switched to atezolizumab (Tecentriq) after an initial run-in period with vemurafenib (Zelboraf) plus cobimetinib (Cotellic). However, this OS benefit was not statistically significant. The findings, presented at the 2024 ESMO Congress, highlight the complexities of sequencing targeted therapies and immunotherapies in melanoma treatment.
ImmunoCobiVem Trial Details
The ImmunoCobiVem trial enrolled patients with previously untreated unresectable or metastatic BRAF V600–mutated melanoma. Following a 3-month run-in phase of vemurafenib (960 mg twice daily) plus cobimetinib (60 mg once daily), patients without progressive disease (PD) were randomized to either continue vemurafenib/cobimetinib (Arm A, n = 69) or switch to atezolizumab (1200 mg every 3 weeks; Arm B, n = 66) until PD. The primary endpoint was progression-free survival (PFS1), defined as PFS from the start of the run-in phase to first PD. Secondary endpoints included OS, overall PFS2, PFS3, best overall response rate, duration of response, and safety.
Dirk Schadendorf, MD, of the University of Essen, noted that a significant number of patients experienced rapid progression after switching from targeted therapy to immune checkpoint inhibition (ICI). He stated, "The better early tumor control—PFS1—with continuous targeted therapy in arm A and treatment options outside the trial influence the overall effect size for early switch from targeted therapy to ICI within this trial."
Survival Outcomes
At a median follow-up of 57 months, the median OS was 40.2 months (95% CI, 18.9-NE) in Arm A versus 49.6 months (95% CI, 26.1-NE) in Arm B (HR, 1.17; 95% CI, 0.71-1.91; stratified P = .94). The 60-month OS rates were 40% and 45%, respectively. While the atezolizumab arm showed a numerical advantage, the difference did not reach statistical significance.
Final PFS1 data showed a median PFS1 of 13.0 months (95% CI, 9.9-15.6) in Arm A versus 5.9 months (95% CI, 5.5-8.3) in Arm B (HR, 0.61; 95% CI, 0.41-0.91; stratified P = .006). The 60-month PFS1 rates were 19% and 15%, respectively, indicating that continuous targeted therapy provided better initial tumor control.
Sequencing and Subsequent Therapies
In patients who crossed over to receive the alternative treatment upon progression, the time to second progression (PFS3) was 2.8 months (95% CI, 2.1-3.3) in those initially on vemurafenib/cobimetinib followed by atezolizumab (n = 21) compared to 6.0 months (95% CI, 2.1-8.8) in those initially on atezolizumab followed by vemurafenib/cobimetinib (n = 35; HR, 1.72; 95% CI, 0.93-3.20). The 48-month PFS3 rates were 10% and 17%, respectively. The total PFS (PFS2) was 12.6 months (95% CI, 8.3-17.0) in arm A versus 14.6 months (95% CI, 8.6-25.6) in arm B (HR, 1.29; 95% CI, 0.70-2.38; P = .41); 60-month PFS2 rates were 10% and 21%, respectively.
Lack of Subgroup Benefit
Schadendorf concluded that "No subgroups were identified for which a targeted therapy run in provided clinical benefit," suggesting that the early switch strategy may not be universally advantageous.
