PATIENTS WITH advanced non–small cell lung cancer (NSCLC) may no longer have to come to the clinic every 2 weeks for treatment. According to a descriptive analysis of the phase IIIb/IV CheckMate 384 study, a more convenient dosing option of nivolumab has demonstrated convincing short-term safety data with suggested noninferiority.¹

Data presented at the 2019 ASCO–Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Symposium showed that nivolumab at 480 mg every 4 weeks provided similar efficacy and safety to nivolumab at 240 mg every 2 weeks in patients with advanced NSCLC. Treatment-related adverse events and postrandomization progression-free survival at 6 months were similar in both treatment arms, researchers reported.

Edward B. Garon, MD

“Overall, the clinical data are in agreement with the pharmacokinetic modeling and provide further evidence for this 480-mg every-4-week nivolumab dosing option,” said Edward B. Garon, MD, Director of Thoracic Oncology at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. “This study offers support for the use of nivolumab every 4 weeks as a more convenient option for patients with advanced NSCLC.”

As Dr. Garon explained, nivolumab is approved at a fixed dose of 240 mg every 2 weeks in many countries across multiple different tumor types, but it’s also been approved at a dose of 480 mg every 4 weeks in the United States and Canada. Nevertheless, said Dr. Garon, there are limited safety data regarding the 480-mg dose, which was approved based on pharmacokinetic modeling predicting that the exposure, safety, and efficacy of the dose would be similar to those of the body weight–based dose of 3 mg/kg every 2 weeks.

“In many respects, extending the dosing frequency of nivolumab fulfills some of the promise of immunotherapy—the idea that we would be able to decrease the medicalization of the lives of our patients,” said Dr. Garon. “For some people, this would lead to them being able to resume a more normal work schedule. For other people, it may allow them to do things for fun, like travel on trips that would take longer than a couple of weeks.”

Study Design

IN THE CHECKMATE 384 trial, patients with previously treated NSCLC were randomly assigned to 1 of 2 nivolumab regimens: 240 mg every 2 weeks vs 480 mg every 4 weeks. Patients were eligible if they had been on nivolumab for up to 12 months and had undergone two scans demonstrating evidence of disease control. Patients were treated until disease progression, unacceptable toxicity, or until they had been treated for 2 additional years. The study’s co-primary endpoints were the rates of progression-free survival at 6 and 12 months, respectively. Secondary endpoints included safety.

“Overall, the clinical data are in agreement with the pharmacokinetic modeling and provide further evidence for this 480-mg every-4-week nivolumab dosing option.”

— Edward B. Garon, MD

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A database lock was performed on June 4, 2018, for patients enrolled as of April 3, 2018 (n = 329). That group had a minimum follow-up of 2.2 months. The median follow-up for the entire group was approximately 10 months.

As Dr. Garon reported, CheckMate 384 was originally designed to show noninferiority of nivolumab at 480 mg every 4 weeks with a 10% margin and a one-sided 95% confidence interval. However, the study had to be amended due to changes in the treatment landscape. The administration of immune checkpoint inhibitors in the first-line setting and the subsequent approval of the nivolumab 480-mg every-4-weeks dose in the United States and other countries made it more difficult to enroll patients on the study. With the reduction in the sample size to 363, there is now insufficient power to conduct the original noninferiority analysis, said Dr. Garon. However, the one-sided 95% confidence interval was maintained to be consistent with the study’s original intent.

Similar Safety and Efficacy

AT THE ASCO-SITC symposium, Dr. Garon presented a descriptive analysis of data from 329 patients, demonstrating similar rates of postrandomization progression-free survival at 6 months between treatment arms. The median progression-free survival was 12.1 months with the 480-mg regimen vs 12.2 months with the 240-mg dose, and these similarities were consistent across the subgroups analyzed, Dr. Garon reported.

Safety analysis showed a slightly higher rate of treatment-related adverse events in the lower-dose, higher-frequency regimen (61%) as opposed to the higher-dose lower-frequency regimen (48%). However, serious treatment-related adverse events and treatment-related adverse events leading to treatment discontinuation were similarly low in both treatment arms. The most common treatment-related adverse events were skin, endocrine, and gastrointestinal toxicities for both regimens, said Dr. Garon. He noted that the discrepancy in low-grade toxicity may be biased by the fact that patients receiving the 240-mg dose are coming in for more frequent visits and thus have more opportunities to discuss the adverse events they may be experiencing. No patients died as a result of toxicity in either treatment arm.

The final analysis will occur after all 363 patients have had a minimum of 12 months of follow-up, the authors reported. ■

DISCLOSURE: Dr. Garon has received institutional research funding from AstraZeneca, Bristol-Myers Squibb, Dynavax, Genentech, Iovance Biotherapeutics, Lilly, Merck, Mirati Therapeutics, Neon Therapeutics, and Novartis; and has received honoraria from Dracen.

REFERENCE

1. Garon EB, Reinmuth N, Falchero L, et al. CheckMate 384: Phase IIIb/IV trial of nivolumab (nivo) 480 mg Q4W versus 240 mg Q2W after ≤ 12 months of nivo in previously treated advanced NSCLC. 2019 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 100. Presented February 28, 2019.