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Checkpoint inhibitor shows efficacy in third line for SCLC

By Neil Osterweil
MDedge News

The immune checkpoint inhibitor pembrolizumab produced durable objective responses in some patients with extensive-stage small-cell lung cancer (SCLC) who had disease progression on two or more prior lines of therapy, data from two clinical trials showed.

An exploratory analysis of pooled data on patients with SCLC enrolled in the KEYNOTE-028 trial, a phase 1b study of pembrolizumab in patients with locally advanced and/or metastatic tumors positive for the programmed death protein ligand-1 (PD-L1), and the KEYNOTE-158 trial, a phase 2 trial in patients with advanced solid tumors that have progressed on prior therapy, regardless of PD-L1 status, showed an objective response in 16 of 83 patients (19.3%) with heavily pretreated SCLC, reported Hyun Cheol Chung, MD, PhD, of Yonsei Cancer Center at Yonsei University College of Medicine in Seoul, Republic of Korea.

“Our findings show that pembrolizumab monotherapy can provide promising antitumor activity with durable clinical benefit and manageable toxicity in patients whose disease has progressed after two or more lines of prior therapy for advanced SCLC,” he said at the 2019 annual meeting of the American Association for Cancer Research (AACR).

A total of 131 patients with SCLC were enrolled in the two trials, and of this group, 83 had data for efficacy analyses. The patients included 19 enrolled in KEYNOTE-028 (PD-L1-positive) and 64 enrolled in KEYNOTE-158. All patients had received at least two prior lines of therapy for SCLC.

Hyun Cheol Chung, MD, PhD

Of the 83 patients, two had a complete response and 14 had a partial response. An additional 15 patients had stable disease

The patients had a median age of 62 years (range 24 to 84), 64% were male, and 16% had brain metastases. In all, 53 patients had received two prior lines of therapy, and 30 had received three or more prior lines. Slightly more than half of the patients (47) had tumors positive for PD-L1.

Of the 83 patients, two had a complete response and 14 had a partial response. An additional 15 patients had stable disease, 1 had persistence of one or more nontargeted lesions, 45 had disease progression. Six did not have post-baseline assessments.

The median duration of response had not been reached at the time of the data cutoff. Of the 16 patients with responses, nine had an estimated duration of response of at least 18 months, Dr. Hyun said.

After a median follow-up of 7.7 months, median progression-free survival (PFS) was 2 months, and median overall survival was 7.7 months.

The 12-month and 24-month PFS rates were 17% and 13%, respectively, and the 12- and 24-month month over overall survival rates were 34% and 21%.

There were no new safety signals seen in the pooled analysis. Treatment-related grade 3 adverse events occurred in 7% of patients in this analysis, compared with 8% of all 131 patients with SCLC in the two trials. There were three treatment-related deaths among the 131 patients: one from pneumonia, one from intestinal ischemia, and one from encephalopathy in a patient who was not included in the pooled analysis. Adverse events leading to discontinuation occurred in 6% of patients in the pooled analysis (7% overall). There were no deaths related to immune-mediated causes.

“This pooled analysis supports the use of pembrolizumab monotherapy for patients with extensive-stage SCLC as third-line or later therapy,” Dr. Hyun said.

“I would say this study reproduced the efficacy of checkpoint blockade for relapsed small-cell in the third line and beyond,” said invited discussant Taofeek Owonikoko, MD, PhD, of Emory University, Atlanta. “It showed very prolonged durability of response in those who responded. It offers an alternative strategy beyond cytotoxic chemotherapy going forward.”

He noted, however, that the single-arm design of the trials make it difficult to draw definitive conclusions and that there is a possible “survivor bias” effect. In addition, the strategy may have limited benefits because only about 20% of patients with SCLC survive to third-line therapy.

“Despite the changing treatment landscape, I still think there will be opportunities for immune checkpoint blockade post frontline,” Dr. Owonikoko concluded.

The KEYNOTE trials are sponsored by Merck Sharp & Dohme. Dr. Hyun Cheol Chung disclosed grants/research support, fees, and consulting for Merck-Serono and others. Dr. Taofeek Owonikoko is on the advisory board for and has received research support from several companies, not including Merck.

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