Overall survival (OS) with first-line atezolizumab (A) or placebo (P) in combination with vemurafenib (V) and cobimetinib (C) in BRAF^V600 mutation-positive advanced melanoma: Second interim OS analysis of the phase 3 IMspire150 study.

Abstract

9547 Background: Primary analysis of the phase 3 IMspire150 study (NCT02908672) demonstrated improved investigator-assessed progression-free survival (PFS) with first-line A + V + C vs P + V + C in patients (pts) with BRAFV600 mutation–positive advanced melanoma (hazard ratio [HR] 0.78; 95% CI, 0.63-0.97; P= 0.025). With median follow-up of 18.9 months at primary analysis, OS data were immature; interim analysis of OS at the time of the primary analysis demonstrated a trend in favor of A + V + C over P + V + C (estimated 2-year OS rate, 60.4% vs 53.1%) (Gutzmer et al. Lancet 2020;395:1835-1844). Herein, we present results from the second interim OS analysis of the IMspire150 study. Methods: IMspire150 enrolled previously untreated pts with stage IV or unresectable stage IIIc BRAFV600 mutation-positive melanoma (n = 514). Pts were randomized 1:1 to receive 28-day cycles of A + V + C (n = 256) or P + V + C (n = 258). Pts received V + C in cycle 1; A or P was added on days 1 and 15 from cycle 2 onwards. The second interim OS analysis was planned after ̃270 OS events were recorded, and was projected to have a minimally detectable difference of HR of 0.74 with a P value boundary of 0.0140. OS was estimated using the Kaplan-Meier method. Results: At data cutoff (Sept 8, 2021), 273 OS events had occurred. Median follow-up was 29.1 months (range, 1-54) for A + V + C and 22.8 months (range, 0-54) for P + V + C. A continued trend toward OS benefit in favor of A + V + C over P + V + C was observed with median OS of 39.0 vs 25.8 months, but the difference did not reach statistical significance (HR, 0.84; 95% CI, 0.66-1.06; P= 0.1432). A delayed treatment effect was observed, with landmark OS rates for A + V + C vs P + V + C of 76.1% vs 76.5% at 12 months and 61.5% vs 53.3% at 24 months. With additional follow-up, A + V + C continued to show PFS benefit over P + V + C (HR, 0.79; 95% CI, 0.64-0.97; P= 0.0224); overall response rates (66.7% vs 65.0%) and median duration of response (21.0 vs 12.6 months) remained consistent with those reported at primary analysis. No new safety signals were observed with additional follow-up. Conclusions: With further follow-up, A + V + C demonstrated a consistent, but not statistically significant, improvement in OS and continued benefit in duration of response versus P + V + C in previously untreated pts with BRAFV600 mutation–positive advanced melanoma. Clinical trial information: NCT02908672.

Neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma: NEO-TIM, a phase II randomized non-comparative study

“…Triple therapy in the first line obtained encouraging results in ongoing phase III trials in advanced resectable melanoma. Pembrolizumab + dabrafenib + trametinib improved PFS, duration of response (DOR), and OS compared with placebo + dabrafenib + trametinib ( 29 ), and atezolizumab + vemurafenib + cobimetinib prolonged PFS and provided a clinically meaningful benefit in median DOR compared with placebo + vemurafenib + cobimetinib ( 30 ) in patients with BRAF V600E/K-mutant melanoma. Based on such results, this study will evaluate the neoadjuvant treatment with ICB and targeted therapy followed by adjuvant treatment with atezolizumab (an anti-PD-L1).…”

“…NeoTrio found that concurrent dabrafenib/trametinib/pembrolizumab had higher pCR and pathological response rate compared with dabrafenib/trametinib with sequence pembrolizumab and with pembrolizumab alone, but it had a high toxicity ( 31 ). Our study, differently from NeoTrio study, will use the triple combination with vemurafenib/cobimetinib/atezolizumab which gave positive results in the phase III study in patients with metastatic melanoma ( 18 , 30 ) and is currently approved by FDA. Data from the BRAF wild-type arm of our study will also be useful to understand whether MEK inhibitors have immune-stimulating or immune-suppressor effect in advanced melanoma.…”

Diagnosing and Managing Uveitis Associated with Immune Checkpoint Inhibitors: A Review

“…Reported Adverse Events Cardiovascular Arrhythmia [21] Cardiac failure [22] Hypertension [23] Myocardial infarction [22] Myocarditis [24,25] Stroke [22] Endocrine Hypothyroidism, hyperthyroidism [26,27] Hypophysitis [28,29] Hyperglycemia [30] Loss of appetite [26,31] Gastrointestinal/renal Colitis/Diarrhea [32] Constipation [26] Esophageal achalasia [33] Hepatitis [34] Nausea [26] Nephritis [35] Pancreatitis [26] General Fatigue [31] Pyrexia [31] Table 1. Cont.…”

“…Inflammatory myopathy [36] Arthropathy [37] Nervous Encephalopathy [20] Facial palsy [38] Hearing loss, vertigo [39,40] Neuropathy [23] Dermatological Alopecia [23] Dermatitis [14] Rash [26] Pruritus [26] Photosensitivity [26] Vitiligo [26,41] Respiratory Cough [31] Dyspnea [31] Pneumonitis [26] Other Sarcoidosis [42,43] Hematological disturbances Note: common side effects (those affecting between 1 in 10 and 1 in 100 people) are in bold [14,20].…”

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

“…The OS was not reported due to the short mFU. Updated results from a second interim analysis with a longer mFU did not show any statistical significance with regards to the OS [ 31 ]. Based on these results, triple therapy with atezolizumab, cobimetinib and vemurafenib received FDA approval; this combination is currently the only approved triple therapy.…”