“Retreatment is feasible, but patients need to be selected for retreatment on a case-by-case basis.”— Fernando C. Santini, MD
INCREASING NUMBERS of patients are being treated with checkpoint inhibitors, and about one-quarter to one-third will develop immune-related adverse events. One question on the minds of oncologists is can these patients be safely re-treated once their adverse events resolve?
One of the first studies to address this gap in knowledge says “maybe”: retreatment is feasible and safe in selected patients with non–small cell lung cancer (NSCLC) treated with anti–programmed cell death protein 1 (PD-1) and anti–programmed cell death ligand 1 (PD-L1) checkpoint inhibitors, with some caveats. The study was presented at the 2017 ASCO Annual Meeting.1
“This is the largest retrospective data set in NSCLC. The take-home message from our series is that retreatment is feasible, but patients need to be selected for retreatment on a case-by-case basis. Our data suggest we may not need to re-treat early responders who develop an immune-related adverse event,” said Fernando C. Santini, MD, of the Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York.
“There is no standard protocol for how long to treat patients with NSCLC using checkpoint inhibitors. Typically, treatment is discontinued for grade 3/4 toxicity. Until now, we have had only case reports on retreatment after toxicity resolves,” he explained.
THE RETROSPECTIVE STUDY was based on 482 patients with NSCLC treated with immune checkpoint inhibitors (including anti– PD-1, anti–PD-L1, plus or minus anti–cytotoxic T-lymphocyte–associated protein 4 [CTLA-4]) at Memorial Sloan Kettering between April 2011 and May 2016. For the retrospective study, two cohorts were compared: 38 patients who had a treatment delay due to an immune-related reaction and were later re-treated when the reaction resolved and 32 patients with no treatment delay but treatment discontinuation due to definite immune-related reactions adverse events.
There were several important differences between patients who were re-treated compared to those who discontinued treatment. Those who were re-treated tended to have less severe immune-related adverse events (grade 3–4 = 37% vs 66%, P = .01); more easily treatable immune-related adverse events (hospitalization rate = 22% vs 56%, P = .003); use of intravenous corticosteroids (10% vs 40%, P = .01); steroid taper longer than 4 weeks (34% vs 67%, P = .02); and more likely to be receiving first-line treatment (66% vs 25%, P = .001). There were no significant differences in the type of immune-related adverse events between the two cohorts. These differences are important to keep in mind when considering the types of patients who were re-treated in this study—they tended to have milder immune-related adverse events, which ultimately resolved prior to patients being re-treated.
Of the re-treated patients, 50% had no subsequent immune-related adverse event after the first event resolved, but 24% developed the same immune-related adverse event, and 26% developed a different immune-related adverse event following retreatment.
Two features were associated with recurrent/new toxicity following retreatment: hospitalization during the first immune-related adverse event and duration of less than 3 months of treatment before the first immune-related adverse event.
“It is noteworthy that patients with either low-grade or high-grade toxicities as their first toxicity were equally likely to have recurrent or new immune-related adverse events or no subsequent immune-related adverse events, Dr. Santini continued.
The immune-related adverse events that developed after retreatment were largely manageable. “Nearly all of the recurrent immune-related adverse events in the re-treated group were manageable, with 16 of 19 [84%] improving to grade 0/1 with treatment,” Dr. Santini said.
However, there were two deaths that occurred as well, despite the use of high-dose corticosteroids, anti–tumor necrosis factor treatment, and other immunosuppressants: one due to pneumonitis and one due to colitis.
In addition to examining the safety and feasibility of re-treatment, Dr. Santini also investigated the degree of benefit that patients who were re-treated experienced. Three (8%) of all re-treated patients developed the onset of objective response following retreatment.
“They did, however, have two deaths, which tempers re-treating everyone.”— Lawrence Fong, MD
Interestingly, however, some patients may not need retreatment. Among patients who developed a complete or partial response on initial checkpoint inhibitor treatment prior to the onset of immune-related adverse events, progression-free and overall survival were similar in the retreatment and discontinued treatment cohorts. According to Dr. Santini, this finding suggests early responders may not need retreatment.
“THIS IS A VERY IMPORTANT ABSTRACT in providing outcomes in patients re-treated with checkpoint inhibition after developing an immune-related adverse event. Clinical trials studying checkpoint inhibitors typically take these patients off trial, said Lawrence Fong, MD, Leader of the Cancer Immunotherapy Program at the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco. “This abstract demonstrates you can re-treat these patients, with about 50% not developing new events. They did however, have two deaths, which tempers retreating everyone.” ■
DISCLOSURE: Drs. Santini and Fong reported no conflicts of interest.
1. Santini FC, Rizvi H, Wilkins O, et al: Safety of retreatment with immunotherapy after immune-related toxicity in patients with lung cancers treated with anti-PD(L)-1 therapy. 2017 ASCO Annual Meeting. Abstract 9012. Presented June 3, 2017.