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Melanoma immunotherapy trials may not capture all toxicity data
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Common Terminology Criteria for Adverse Events may not appropriately reflect immune-related adverse event severity, duration or timing, according to study results.
Trials also may underreport immunosuppressive use to manage immune-related adverse events.
“Our extensive experience using combination checkpoint blockade led us to believe the adverse events reported in clinical trials did not capture the full extent of the clinically relevant toxic effects,” Alexander N. Shoushtari, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “Trials uniformly emphasize Common Terminology Criteria for Adverse Events [CTCAE] grade 3 to 4 events even though grade 2 events are often serious. Also, trials often miss late toxic effects and do not capture emergency department visits unless they result in admission.”
Shoushtari and colleagues sought to describe toxic effects and time to treatment failure in a prospective cohort of 64 patients (median age, 56 years) with advanced or unresectable melanoma enrolled in an expanded access program from December 2014 through January 2016.
Patients received 1 mg/kg IV with nivolumab (Opdivo, Bristol-Myers Squibb) and 3 mg/kg ipilimumab (Yervoy, Bristol-Myers Squibb) every 3 weeks for four doses, followed by 3 mg/kg nivolumab every 2 weeks or 2 mg/kg pembrolizumab (Keytruda, Merck) every 3 weeks until unacceptable toxicity, disease progression or complete response.
Researchers evaluated any clinically significant immune-related adverse event, defined as any CTCAE grade 2 or higher or any immune-related event that required systemic steroids.
Minimum follow-up after the last nivolumab-ipilimumab treatment was 6.7 months.
Twenty-five patients (39%) received all four doses of nivolumab plus ipilimumab, and 18 went on to maintenance nivolumab. Eleven patients only received three doses, 20 patients received two doses and eight received one dose.
Adverse events served as the most common reason for not receiving all four doses (80%), followed by progression (11%) or death due to another cause (2%). Seventeen patients who could not receive all four doses due to adverse events received anti-PD-1 monotherapy for a median of four doses.
Thirty-one patients (48%) received no maintenance anti-PD-1 therapy.
A majority of patients (n = 58; 91%) had at least one clinically significantly immune-related adverse event — for a median of two (range, 0-7) per patient — and 38 (59%) had a grade 3 or grade 4 event. The most common grade 3 and grade 4 events included diarrhea (44%) and endocrinopathies (42%).
Four of the 31 patients (13%) who stopped treatment early due to toxic effects developed new, clinically significant events more than 16 weeks after discontinuation (range, 22-33 weeks).
Researchers noted these late effects “would not be captured in randomized trials and thus may be underreported.”
“Future clinical trials using checkpoint inhibitors should consider increasing follow-up time to capture delayed toxic effects and standardize the reporting for types, timing and duration of immunosuppressive therapy,” they added.
Forty-six patients (72%) required systemic steroids, 14 (22%) required infliximab for steroid-refractory diarrhea, and two (3%) required mycophenolate for steroid-refractory transaminitis.
Thirty-two patients (50%) visited the ED due to an immune-related adverse event, and 23 (36%) were admitted to the hospital.
After a median follow-up of 14 months, 27 (42%) treatment failures occurred.
Among 50 patients free from treatment failure at 12 weeks, researchers observed no difference in time to treatment failure among those who underwent treatment modification due to toxicity, and those who did not.
“To our knowledge, this is the first landmarked analysis of the impact of toxic effects on efficacy with nivolumab plus ipilimumab in melanoma,” the researchers wrote. “Patients can be reassured that if significant toxic effects arise, further doses of combination therapy can be delayed or omitted without decreasing the likelihood of benefit. Moreover, because half of these patients received no maintenance anti-PD-1 therapy, the need for maintenance anti-PD-1 therapy is unclear and should be assessed in a future randomized study.” – by Alexandra Todak
Disclosures: Shoushtari reports institutional research funding from Bristol-Myers Squibb and Immunocore and advisory roles with Bristol-Myers Squibb, Castle Biosciences, Immuncore and Vaccinex. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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