USE OF the anti–programmed cell death protein 1 (anti–PD-1) checkpoint inhibitor pembrolizumab after two or more prior lines of therapy led to responses in patients with advanced small cell lung cancer (SCLC) in a pooled analysis of two clinical trials: phase Ib KEYNOTE-028 and phase II KEYNOTE-158.1–3 The responses and durability of response were referred to as outstanding in this difficult-to-treat setting. The study was presented at the 2019 Annual Meeting of the American Association for Cancer Research (AACR).
“Current treatment guidelines for extensive SCLC specify a variety of first- and second-line options. However, there are no specific guidelines for patients who require third-line therapy, and the prognosis is poor, with median survival times of approximately 6 months. This pooled analysis supports the use of pembrolizumab monotherapy for patients with extensive-stage SCLC as third-line or later therapy,” stated lead author Hyun Cheol Chung, MD, PhD, Professor at Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
“This pooled analysis supports the use of pembrolizumab monotherapy for patients with extensive-stage SCLC as third-line or later therapy.”— Hyun Cheol Chung, MD, PhD
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Up to 70% of all patients with SCLC present with extensive-stage disease at diagnosis. Outcomes are poor in patients who experience disease progression after first- and second-line therapies for extensive-stage SCLC. Two multicohort studies—KEYNOTE-028 and KEYNOTE-158—demonstrated antitumor activity with pembrolizumab monotherapy in patients with previously treated extensive-stage SCLC.1–3
KEYNOTE-028 is a phase Ib study in a selected patient population of programmed cell death ligand 1 (PD-L1)-positive tumors alone; KEYNOTE-158 is a phase II trial that enrolled all comers with regard to PD-L1 expression levels. In both trials, patients received pembrolizumab for 2 years or until progression of disease. Objective response rates in the 2 trials were 33.3% and 18.7%, respectively; the duration of response was 19.4 months and not yet reached, respectively; the median progression-free survival was 1.9 months and 2.0 months, respectively; and the median overall survival was 9.7 months and 8.7 months, respectively.1,2
Details of Pooled Analysis
DR. CHUNG presented a pooled analysis of efficacy and safety for a total of 83 patients from the SCLC cohorts in both trials who had received 2 or more prior lines of therapy. Responses were assessed according to Response Evaluation Criteria in Solid Tumors. The efficacy analysis included overall response rate, duration of response, progression-free survival, and overall survival.
At baseline, the median age was 62 years (range, 24–84 years); 64% were male; 16% had brain metastases; 64% had 2 prior lines of therapy; 36% had 3 or more prior lines of therapy; 57% had PD‑L1– positive tumors; and 80% had previous radiation therapy. The median range of follow-up was 7.7 months.
The overall response rate was 19% (2% were complete responses and 17% were partial responses). Another 18% had stable disease. The median duration of response was not reached; a total of 9 patients (61%) had an estimated duration of response of at least 18 months. The median progression-free survival was 2.0 months, and the median overall survival was 7.7 months.
No new safety signals emerged in the pooled analysis. The proportion of patients with at least 1 treatment-related adverse event was similar for patients treated with more than 1 line of prior therapy (n = 131) or 2 or more lines of prior therapy (n = 83): 60% and 61%, respectively. Grade 3 treatment-related adverse events were reported in 8% and 7%, respectively. There were no grade 4 events reported; 2% of patients died due to grade 5 treatment-related adverse events. Adverse events leading to treatment discontinuation were reported in 7% and 6%, respectively. Immune-mediated adverse events and infusion reactions were reported in 21% and 24%, respectively. Grades 3 and 4 immune-related adverse events occurred in 5% and 6%, respectively.
Comments on Study Findings
Louis M. Weiner, MD
“SCLC THAT is extensive and multiply relapsed is a disease for which responses are rare; long-term responses are unheard of; and the duration of response can be measured in minutes, not months,” stated Louis M. Weiner, MD, Director of the Georgetown Lombardi Comprehensive Cancer Center, Washington, DC. “In this pooled analysis, 9 people are surviving 18 months or more without disease progression. This has never been seen before in this setting. Any improvement in median overall survival is an important advance.”
Dr. Weiner continued: “These findings are stunning for anyone who has been in the field a while, to be able to see a survival curve in patients who had the good fortune of responding. This treatment can be effective in nearly 20% of heavily pretreated patients with extensive SCLC. This is a great comfort to our patients in the community.”
Hossein Borghaei, MD
Also commenting on this pooled analysis, Hossein Borghaei, MD, Chief of the Division of Thoracic Medical Oncology, Fox Chase Cancer Center, Philadelphia, said: “SCLC is one of the most aggressive cancers we treat. The treatment landscape has recently been changed with the introduction of atezolizumab plus platinum-doublet chemotherapy, showing an improvement in overall survival from a median of 10 months to 12 months in the metastatic setting.”
Dr. Borghaei continued: “The results of this pooled analysis indicate that for patients with the disease who have not been treated with a checkpoint inhibitor upfront, the use of pembrolizumab in the third-line setting is effective. Other checkpoint inhibitors have been approved in this setting and the current report confirms prior results and provides an additional option for our patients.” ■
DISCLOSURE: The exploratory analysis was funded by Merck Sharp & Dohme. Dr. Chung has received grants from Eli Lilly, GlaxoSmithKline, MSD, Merck-Serono, Bristol-Myers Squibb/Ono, and Taiho; compensation from Merck-Serono and Eli Lilly Foundation Medicine; and consulting fees from Taiho, Celltrion, MSD, Eli Lilly, Quintiles, Bristol-Myers Squibb, and Merck-Serono. Dr. Weiner disclosed financial ties with Jounce Therapeutics, Celldex Pharmaceuticals, Forty Seven Inc, Immunome, BioeXcel Therapeutics, Klus Pharma, Mersana, Origin Commercial Ventures, Tessa Therapeutics, and Samyang. Dr. Borghaei has received research support from Millennium, Merck/Celgene, and BMS/Lilly; is an advisor/consultant for BMS, Lilly, Genentech, Celgene, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, and Takeda; and is on the data and safety monitoring board for the University of Pennsylvania CAR T Program and Takeda.
1. Ott PA, Elez E, Hiret S, et al: Pembrolizumab in patients with extensive-stage small-cell lung cancer: Results from the phase Ib KEYNOTE-028 study. J Clin Oncol 35:3823-3829, 2017.
2. Chung HC, Lopez-Martin JA, Kao SCH, et al: Phase 2 study of pembrolizumab in advanced small-cell lung cancer: KEYNOTE-158. 2018 ASCO Annual Meeting. Abstract 8506. Presented June 4, 2018.
3. Chung HC, Piha-Paul SA, Lopez-Martin J, et al: Pembrolizumab after two or more lines of prior therapy in patients with advanced small-cell lung cancer: Results from the KEYNOTE-028 and KEYNOTE-158 studies. 2019 AACR Annual Meeting. Abstract CT073. Presented April 1, 2019.