1. Fuerst, Mark L.

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ATLANTA-Pembrolizumab shows promising antitumor activity with durable responses in patients with pretreated, advanced small cell lung cancer (SCLC), according to results from a pooled analysis of two clinical trials.

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Up to 70 percent of patients with SCLC have advanced disease at diagnosis, and less than 2 percent of patients are still alive 5 years after diagnosis. SCLC comprises around 15 percent of diagnosed lung cancers and is strongly associated with smoking.


"Current treatment guidelines specify a variety of first- and second-line treatment options; however, for patients who require third-line therapy, there are no specific recommendations and prognosis is very poor," said lead author Hyun Cheol Chung, MD, PhD, Professor at Yonsei Cancer Center, Yonsei University College of Medicine in Seoul, Republic of Korea, at the American Association for Cancer Research annual meeting (Abstract CT073). "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."


Based on these findings, the FDA granted a priority review designation to a supplemental biologics license application for pembrolizumab as a treatment for patients with advanced SCLC whose disease has progressed following two or more prior lines of therapy. The FDA will likely make a decision on this application in June.



The researchers evaluated the safety and efficacy of the anti-PD-1 agent pembrolizumab as monotherapy in a pooled analysis of the SCLC cohorts from the KEYNOTE-028 and KEYNOTE-158 multicohort basket trials. All patients included in the analysis received at least two lines of prior therapy for advanced disease.


In the phase II KEYNOTE-158 basket study, patients with 10 tumor types plus microsatellite instability-high cancers, including advanced SCLC, were enrolled regardless of biomarker status. Patients were treated with pembrolizumab at 200 mg intravenously every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or study withdrawal. Patients were followed up for survival.


The international, nonrandomized, multi-arm, phase Ib KEYNOTE-028 basket trial evaluated the safety and efficacy of pembrolizumab in patients with advanced solid tumors. Patients received 10 mg/kg of pembrolizumab every 2 weeks for 24 months or until progression, intolerable toxicity, physician decision to discontinue, or withdrawal of consent occurred.


Patients from KEYNOTE-028 were required to have PD-L1-positive tumors, but this was not the case for those in KEYNOTE-158.


Of 131 SCLC patients included in the two trials, Chung presented the results of 83 patients, median age 62 years, who were eligible for efficacy analyses. More than one-third (36%) of patients had received three or more lines of therapy.


In the pooled analysis, the objective response rate was 19.3 percent, which included two complete responses and 14 partial responses. The median duration of response was not reached at the time of analysis. Of the 16 responders, nine had responses lasting for at least 18 months.


After a median of 7.7 months of follow-up, the median progression-free survival (PFS) was 2 months and median overall survival (OS) was 7.7 months. At 12 months, PFS and OS were 17 percent and 34 percent, respectively, and at 24 months, PFS and OS were 13 and 21 percent, respectively.


"Our findings are particularly noteworthy given that data show that, historically, patients with SCLC in the third-line treatment setting have limited survival benefit, with a median duration of response of less than 2 months and median survival of around 2-3 months," Chung said. "Our study shows that pembrolizumab monotherapy can provide durable clinical benefit with manageable toxicity in this hard-to-treat patient population."


Fourteen of the 16 responders had PD-L1-positive tumors. "Given that the two studies differed slightly in their methods for assessing PD-L1-positivity, we did not seek to evaluate the role of PD-L1 in patient selection in this pooled analysis," said Chung.


Overall, the adverse events noted were consistent with the safety profile of pembrolizumab and no new safety signals were identified. Chung added that 13 patients (10%) had a grade 3 treatment-related adverse event. Three patients had grade 5 treatment-related adverse events (intestinal ischemia, pneumonia, encephalopathy), and 21 percent of patients experienced an immune-related adverse event or infusion reaction. However, there were no grade 5 immune-related adverse events or infusion reactions.


In conclusion, Chung stated: "Pembrolizumab demonstrated promising antitumor activity in patients with advanced SCLC who had received two or more lines of prior therapy. Responses were durable, with the majority of patients estimated to have response duration of at least 18 months. No unexpected toxicities from pembrolizumab were observed."


Limitations of the study include that it is a retrospective, exploratory, pooled analysis, and that the two trials were single-arm studies, Chung noted.


Pembrolizumab is also being explored in combination with etoposide and platinum-based chemotherapy in patients with newly diagnosed, extensive-stage SCLC in the ongoing phase III KEYNOTE-604 study.


Mark L. Fuerst is a contributing writer.