ABSTRACT
Background: Durable clinical benefit has been achieved with nivolumab (NIVO) + ipilimumab (IPI), including an overall survival (OS) of 49% and a melanoma-specific survival (MSS) of 56%, with median MSS not reached (NR) at 6.5-y minimum follow-up. Here we report sustained efficacy outcomes at 7.5 y. Methods: Patients (pts) with previously untreated, unresectable stage III/IV melanoma were randomly assigned 1:1:1 and stratified by PD-L1 status, BRAF mutation status, and metastasis stage to receive NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W, followed by NIVO 3 mg/kg Q2W (n = 314);NIVO 3 mg/kg Q2W + placebo (n = 316);or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were progression-free survival (PFS) and OS with NIVO + IPI or NIVO alone versus IPI. Results: With a minimum follow-up of 7.5 y, median OS remained stable at 72.1 mo (NIVO + IPI), 36.9 mo (NIVO), and 19.9 mo (IPI);median MSS was NR, 49.4 mo, and 21.9 mo, respectively (Table). While the objective response rate remained stable at 58% (NIVO + IPI), 45% (NIVO), and 19% (IPI), median duration of response had now been reached for NIVO at 90.8 mo and remains NR and 19.2 mo for NIVO + IPI and IPI, respectively. Subsequent systemic therapy was received by 36%, 49%, and 66% of NIVO + IPI-, NIVO-, and IPI-treated patients, respectively, and median time to that therapy was NR (95% CI, 45.9-NR), 24.7 mo (16.0-38.7), and 8.0 mo (6.5-8.7). Of patients alive at 7.5 y, 106/138 (77%, NIVO + IPI), 80/115 (70%, NIVO), and 27/60 (45%, IPI) were off treatment and had never received subsequent systemic therapy. No change to the safety summary was observed with additional follow-up;updated health-related quality of life data will be reported. Of the 10 new deaths since the 6.5-y follow-up (ie, 5 NIVO + IPI;3 NIVO;2 IPI), none were treatment-related;4 were due to melanoma progression;1 was due to an unknown cause;and 5 were due to other causes, but not associated with a COVID diagnosis. Conclusions: The 7.5-y follow-up continues to demonstrate the durability of responses with NIVO + IPI and an ongoing survival plateau. A substantial difference in median OS and MSS between patients treated with NIVO + IPI or NIVO was observed in descriptive analyses.
Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/diagnosis , Exanthema/complications , Fever/complications , Pneumonia, Viral/diagnosis , Adult , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/virology , Humans , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , SARS-CoV-2ABSTRACT
Background: The long-term benefit of adjuvant dab + tram in pts with resected stage III BRAFV600E/K-mutant melanoma was demonstrated in COMBI-AD where AEs led to permanent discontinuation of dab + tram in 26% of pts, most often due to pyrexia (9%). The COMBIAPlus trial (NCT03551626) is designed to evaluate whether an adapted pyrexia management algorithm could reduce high-grade pyrexia and other pyrexia-related adverse outcomes, such as treatment cessation and hospitalization. Methods: COMBI-APlus is an open-label, Phase IIIb trial evaluating an adapted pyrexia management algorithm in pts with high-risk resected stage III BRAF V600E/K-mutant melanoma treated with 12 mo of adjuvant dab + tram. In the adapted algorithm, both dab and tram were interrupted promptly at the onset of pyrexia (temperature ≥ 38°C). In the event of suspected recurrent pyrexia, treatment may be interrupted in the presence of pyrexia syndrome (ie, chills, rigors, night sweats, or influenza-like symptoms without temperature ≥ 38°C) at investigator discretion. Treatment with dab + tram was restarted at the same dose level once pts were symptom free for ≥ 24 hours. The primary endpoint is the composite rate of grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent discontinuation due to pyrexia vs a historical control from COMBI-AD (20%;95% CI, 16.3%-24.1%). Secondary endpoints include relapse-free survival (RFS) and safety. Results: A total of 552 pts were enrolled. At the data cutoff (5 Oct 2020), all pts had completed 12 mo of treatment;median duration of follow-up was 18.4 mo. COMBI-APlus met its primary endpoint of significant improvement in composite rate of pyrexia. The composite rate was 8.0% (95% CI, 5.9%-10.6%), with rates of 3.8% for grade 3/4 pyrexia, 4.3% for hospitalization due to pyrexia, and 2.4% for discontinuation due to pyrexia. The estimated 12-mo RFS rate was 91.8% (95% CI, 89.0%-93.9%). The most common AEs (≥ 20%) were pyrexia (67.8%), headache (31.7%), blood creatine phosphokinase increase (27.9%), diarrhoea (27.0%), chills (26.4%), fatigue (25.7%), asthenia (23.6%), nausea (23.4%), rash (21.4%), and arthralgia (21.0%). AEs of any type led to permanent dab + tram discontinuation in 14.7% of pts. Conclusions: This primary analysis suggests the new adapted pyrexia management algorithm is effective in reducing grade 3/4 pyrexia, pyrexiarelated hospitalization, and treatment discontinuation in pts receiving adjuvant dab + tram. The early efficacy appears consistent with that observed in COMBI-AD. The growing experience of oncologists in managing pyrexia with this simple algorithm may reduce the need for hospitalization or visits to a healthcare provider, which is highly desirable during the current COVID- 19 pandemic. Thus, more pts can remain on treatment and derive benefit.