Patients who discontinued induction immunotherapy for advanced melanoma because of adverse events did just as well as those who continued treatment uninterrupted, a pooled analysis of randomized trials showed.
Patients who discontinued had an objective response rate of almost 60% compared with about 50% for those who finished induction therapy. Median progression-free survival (PFS) did not differ significantly between patients who discontinued and those who did not; median overall survival had yet to be reached in either group.
“Most patients who discontinued the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) did so before receiving all four doses of the combination,” Michael A. Postow, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues concluded in the Journal of Clinical Oncology.
“Efficacy of nivolumab plus ipilimumab seemed to be similar for those who did and did not discontinue because of adverse events. This suggests that patients may continue to derive benefit from combination therapy even after treatment is stopped because of adverse events.”
Despite the preliminary nature of the data, the findings raised “thought-provoking questions about the possible impact of early treatment cessation in the setting of toxicity on the durability of response,” two Australian oncologists wrote in an accompanying editorial.
“Several key messages ave arisen from this work,” said Matteo S. Carlino, MD, of the University of Sydney, and Shaneen Sandhu, MD, of Peter MacCallum Cancer Center and the University of Melbourne, in the editorial. “The response rate, depth of response, and overall survival do not seem to be diminished for patients who discontinue treatment as a result of immune-related adverse events at induction.
“In addition, the use of immunomodulatory agents to manage checkpoint inhibitor-related toxicities does not seem to hinder responses or durability of responses in the majority of patients who discontinue treatment because of immune-related adverse events at induction. The merits, liability, and optimal duration of ongoing anti-PD-1 therapy after discontinuing induction therapy because of immune-related adverse events will require prospective evaluation.”
The predictive utility of early-onset immune-related adverse events also requires further study, Carlino and Sandhu added.
Clinical trials of combined nivolumab-ipilimumab therapy for advanced melanoma showed that about 40% of patients discontinued induction therapy with the combination because of therapy-related adverse events. Most patients stopped before receiving the recommended four doses of therapy. The impact of early discontinuation on clinical outcomes remained unclear.
To investigate the impact of early discontinuation on outcomes, Postow and colleagues pooled data from randomized phase II and III trials involving a total of 409 patients with advanced melanoma treated with the combination of nivolumab and ipilimumab. Investigators compared treatment efficacy in 96 patients who discontinued treatment during the induction phase of therapy because of adverse events and in 233 patients who did not discontinue because of adverse events.
Investigators evaluated the safety of the combination in patients who discontinued treatment at any time because of adverse events versus those who who did not.
After a minimum follow-up for efficacy of 18 months, median PFS was 8.4 months (95% CI 5.8-16.7) in patients who discontinued induction therapy because of adverse events and 10.8 months (95% CI 5.9-23.0) in those who did not discontinue during induction therapy (P=0.97). The 18-month PFS was 38% in the patients who discontinued and 49% for those who did not. Median PFS had yet to be reached in either group (HR 0.79, 95% CI 0.54-1.17, P=0.2344).
The 18-month overall survival was 67% for patients who discontinued induction therapy because of adverse events and 62% for those who did not.
The objective response rate also did not differ significantly between patients who discontinued because of adverse events (58.3%) and patients who did not (50.2%).
The safety analysis showed that 156 of 407 (38%) patients discontinued treatment at any time because of adverse events, most of which were grade 3/4 severity. Colitis was the most common adverse event leading to discontinuation (10%), followed by elevated liver enzymes (4% to 5%). Colitis also was the most common serious adverse event leading to hospitalization (21% of all patients who discontinued treatment because of adverse events).
The most frequent grade 3/4 treatment-related adverse events associated with discontinuation at any time were gastrointestinal (especially diarrhea and colitis, 20% each). For patients who did not discontinue because of adverse events, the most common grade 3/4 adverse events were hepatic (10%).
Systemic corticosteroids were the most frequently used immunosuppressive therapy for management of adverse events, administered to 91% of patients who discontinued nivolumab-ipilimumab combination therapy because of adverse events and 55% of those who did not discontinue.
The study was supported by Bristol-Myers Squibb and the National Cancer Institute.
Postow disclosed relationships with Bristol-Myers Squibb, Marck, Amgen, Novartis, Array BioPharma, Infinity Pharmaceuticals, and RGenix. All of the coauthors disclosed relationships with one or more healthcare industry company.
Carlino disclosed relationships with Bristol-Myers Squibb, Merck, Amgen, Novartis, and Pierre Fabre. Sandhu disclosed relationships with Merck, Bristol-Myers Squibb, Amgen, and Janssen.