Patients with advanced small cell lung cancer (SCLC) often present with extensive disease at diagnosis and are resistant to treatment.1 A pooled analysis of phase 1b KEYNOTE-028 and phase 2 KEYNOTE-158 trials investigated the effects of the anti-programmed cell death protein 1 (anti-PD-1) checkpoint inhibitor pembrolizumab in a cohort of SCLC patients who had already received 2 or more prior lines of therapy.2 The duration of survival response was extended up to 18 months by third-line or more pembrolizumab monotherapy.2 The study was presented at the 2019 Annual Meeting of the American Association for Cancer Research (AACR), Atlanta, USA.
The burden of advanced SCLC
Extensive-stage SCLC occurs almost exclusively in heavy smokers and accounts for approximately 15% of all lung cancers.3 Generally, the prognosis is poor with a median overall survival (OS) of 8-12 months and a 2-year OS rate of 5%.1 Although the response rate to first-line treatment with platinum and etoposide chemotherapy reaches 50-80%, disease progression occurs universally, and the outcomes with second line treatment are poor.4
A promising anti-tumor activity and a safety profile
The KEYNOTE-028 and KEYNOTE-158 trials were designed to determine the efficacy and safety of pembrolizumab in SCLC cohorts.5,6 Patients eligible for inclusion in the analysis had histologically or cytologically confirmed incurable and advanced SCLC, were immunotherapy-naïve, and have progressed despite therapy or failed standard therapy. In both trials, the median duration of pembrolizumab administration was 2 years.
Radiographic imaging was performed every 8 weeks in KEYNOTE-028 compared with every 9 weeks in KEYNOTE-158, and every 12 weeks after 6 months in KEYNOTE-028 and after 1 year in KEYNOTE-158. Dosage of the agent varied between the trials as well. Pembrolizumab was given at 10mg/kg every 2 weeks in KEYNOTE-028, versus a dose of 200mg given every 3 weeks in KEYNOTE-158. Overall response rate (ORR) was the primary endpoint for both studies. Duration of response (DOR), progression-free survival (PFS), and OS served as secondary endpoints in both trials, and were estimated using the Kaplan-Meier method.
Data from KEYNOTE-028 showed an ORR of 33.3% (95% CI: 0.16-0.55) and a DOR of 19.4 months. Increased survival benefit was observed with pembrolizumab and resulted in a median PFS of 1.9 months and a median OS of 9.7 months. In comparison, the ORR observed in the KEYNOTE-158 trial was 18.7% (95% CI: 0.12-0.27), while the DOR ranged from 2.1 months to 18.7 months. Median PFS and OS in this trial were reported to be 2.0 months and 8.7 months respectively (Figure 1).
In KEYNOTE-028, pembrolizumab achieved clinically meaningful anti-tumor activity against SCLC. It was well tolerated, and the safety was consistent with the reported safety profiles of pembrolizumab with other types of tumors. Changes in tumor burden from baseline for individual patients are shown in Figure 2, where 1 patient (4.2%) experienced a complete response, 7 patients (29.2%) had partial responses, and 1 patient (4.2%) had stable disease for less than 6 months. Data from KEYNOTE-158 showed promising anti-tumor activity and durable responses in advanced SCLC, especially in patients with PD-L1-positive tumors.6
Pembrolizumab as the third-line treatment option for SCLC
A total of 131 patients with SCLC enrolled in the both KEYNOTE-028 and KEYNOTE-158 clinical trials. Among them, 83 patients had received ≥2 prior lines of therapy and determined to be eligible for the efficacy analysis of pembrolizumab. The median age of the selected population was 62 years, 64% of patients were men, and 36% had received ≥3 lines of systemic therapy. Although patients who participated in the KEYNOTE-028 trial were required to have PD-L1-positive tumors (combined positive score ≥1), this was not necessary for the enrollment in KEYNOTE-158.2 Therefore, the pooled analysis was not able to assess the role of PD-L1 positivity in the outcome.
In a press briefing of the meeting, the lead investigator of the study, Prof. Hyun Cheol Chung, at Yonsei Cancer Center, Yonsei University College of Medicine, Korea commented “In this pooled analysis, pembrolizumab had antitumor activity among patients with extensive-stage SCLC who had received 2 or more previous lines of therapy”. He further commended on the durability of events by saying “Responses were durable, and most responses lasted throughout 18 months. Median OS and PFS in this analysis were similar to the SCLC populations of KEYNOTE-028 and KEYNOTE-158.”7
Results from the pooled analysis presented at the meeting showed an ORR of 19.3% (95% CI: 0.11-0.29), with 2 patients (2%) achieving a complete response, 14 patients (17%) experiencing a partial response, and 15 patients achieving stable disease (18%). Nine of the responding patients (61%) had an estimated DOR of ≥18 months.2
The median follow-up duration was 7.7 months, and investigators observed a median PFS of 2 months (95% CI: 1.9-3.4) and a median OS of 7.7 months (95% CI: 5.2-10.1) with pembrolizumab. When the follow up was increased to 12 months, the PFS rate was 17%, while the OS rate was 34%. At 24 months, PFS and OS rates were 13% and 21% respectively.
Prof. Chung further explained the significance of these results “Our findings are particularly noteworthy given that the data showed, historically, patients with SCLC on the third-line of treatment setting have limited survival benefit, with a duration of response of less than 2 months and median survival of around 2 to 3 months,” On balancing the durable clinical benefits and adverse events, he said, “Our study showed that pembrolizumab monotherapy can provide durable clinical benefit with manageable toxicity in this hard-to-treat patient population.”8
In light of these findings, Dr. Louis M. Weiner, the moderator of the briefing session and Director of the Georgetown Lombardi Cancer Center, Georgetown, USA, emphasized, “To put this study in perspective, SCLC that is extensive and has relapsed is a disease setting where responses are rare, long-term survival is unheard of, and the duration of response can be measured almost in minutes as opposed to months”.9 Additionally, he mentioned, “These findings are really stunning for anyone who has been in the field for a while, to be able to see a survival curve in the patients who did have the good fortune of responding.”
Moreover, Dr. Weiner added that 9 of the 16 patients who responded to the agent are still surviving without disease progression many months after having received the treatment. “This is something that has never been seen in SCLC. The impact on median OS was, again, unprecedented in this disease,” remarked Dr. Weiner.9
Expressing his opinion on this pooled analysis, Dr Hossein Borghaei, MD, Chief of the Division of Thoracic Medical Oncology, Fox Chase Cancer Center, Philadelphia, USA said, “The results of this pooled analysis indicated 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.”9
The adverse events (AEs) observed in the analysis proved to be consistent with previous reports of the safety profile of pembrolizumab. Of all the patients treated in the 2 clinical trials, 60% experienced a treatment-related AE of any grade, while 61% experienced an event in the pooled analysis of 83 patients.
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 or more therapies. The prognosis for extensive SCLC is poor, with median survival time of approximately 6 months. This pooled analysis supports the use of pembrolizumab monotherapy for patients with advanced and incurable SCLC as third-line or later therapy.
1. Alvarado-Luna G, Morales-Espinosa D. Treatment for small cell lung cancer, where are we now?-a review. Transl Lung Cancer Res. 2016;5(1):26-38.
2. Pembrolizumab after two or more lines of prior therapy in patients with advanced small-cell lung cancer (SCLC): Results from the KEYNOTE-028 and KEYNOTE-158 studies. (Accessed May 24, 2019 at, https://www.abstractsonline.com/pp8/#!/6812/presentation/9832).
3. Pesch B, Kendzia B, Gustavsson P et al. Cigarette smoking and lung cancer–relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer. 2012;131(5):1210-9.
4. Hurwitz J, McCoy F, Scullin P et al. New advances in the second-line treatment of small cell lung cancer. Oncologist. 2009;14(10):986-94.
5. 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. 2017;35(34):3823-3829.
6. Meeting Library | Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158. (Accessed May 24, 2019 at, https://meetinglibrary.asco.org/record/160031/abstract).
7. Pembrolizumab Shows Promising Antitumor Activity in Pretreated Patients With SCLC. OncLive (Accessed May 24, 2019 at, https://www.onclive.com/conference-coverage/aacr-2019/pembrolizumab-shows-promising-antitumor-activity-in-pretreated-patients-with-sclc).
8. AACR 2019: Data Analysis Shows Activity of Pembrolizumab in Pretreated Patients with Advanced Small Cell Lung Cancer – The ASCO Post. (Accessed May 24, 2019 at, https://www.ascopost.com/News/59889).
9. Pembrolizumab as Third-Line Option for Extensive-Stage SCLC – The ASCO Post. (Accessed May 24 2019 at, https://www.ascopost.com/issues/may-10-2019/pembrolizumab-as-third-line-option-for-extensive-stage-sclc/).