Meeting NewsPerspective

Pembrolizumab shows durable benefit as third-line treatment of advanced small cell lung cancer

Photo of Hyun Cheol Chung
Hyun Cheol Chung

ATLANTA — Pembrolizumab demonstrated antitumor activity and induced durable responses in patients with advanced small cell lung cancer who had received two or more previous lines of therapy, according to pooled data from two KEYNOTE trials presented at American Association for Cancer Research Annual Meeting.

“Up to 70 percent of patients with small cell lung cancer have advanced disease at diagnosis,” Hyun Cheol Chung, MD, PhD, professor at Yonsei Cancer Center of Yonsei University College of Medicine in Seoul, South Korea, said in a press release. “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.”

Chung and colleagues presented data on outcomes of 83 patients (median age, 62 years; range, 24-84; 64% men) who received pembrolizumab (Keytruda, Merck), an anti-PD-1 monoclonal antibody, as monotherapy in the phase 1b KEYNOTE-028 (n = 19) and the phase 2 KEYNOTE-158 (n = 64) basket studies.

Eligible patients had histologically/cytologically confirmed, incurable advanced small cell lung cancer, an ECOG performance status of 0 or 1, were immunotherapy naïve, and had received two or more previous lines of systemic therapy (36% three or more lines). Patients in KEYNOTE-028 also were required to have tumors expressing PD-L1, whereas PD-L1 positivity was not required for KEYNOTE-158.

Participants in KEYNOTE-028 received 10 mg/kg pembrolizumab every 2 weeks, whereas those in KEYNOTE-158 received 200 mg pembrolizumab every 3 weeks. Patients remained on these regimens for 2 years or until unacceptable toxicity.

Objective response rate evaluated by RECIST 1.1 criteria served as the primary endpoint of both studies. Duration of response, PFS and OS served as secondary endpoints and were determined by the Kaplan-Meier method. Independent central review evaluated response.

At the time of data cutoff, median follow-up was 7.7 months (range, 0.5-48.7).

The ORR was 19.3% (95% CI, 11.4-29.4), including two patients with complete response and 14 patients with partial response. Of these 16 responders, 14 were PD-L1 positive.

Fifteen patients (18%) had stable disease, 45 (54%) had progressive disease, six (7%) had no assessment and one patient (1%) had incomplete response.

Median duration of response was not reached (range, 4.1-35.8+ months). Nine of the 16 responses (61%) lasted for 18 months or longer.

Median PFS rates were 16.9% at 12 months and 13.1% at 24 months, and OS rates were 34% at 12 months and 21% at 24 months.

Among all 131 patients in the two KEYNOTE studies, including those with one or more prior lines of therapy, 8% (n = 10) experienced grade 3 treatment-related adverse events, none experienced a grade 4 adverse event and 2% (n = 3) had grade 5 treatment-related adverse events, including intestinal ischemia, pneumonia and encephalopathy.

Twenty-seven patients (21%) experienced immune-mediated adverse events or reactions to infusion, however, none was grade 5.

Chung acknowledged that the pooled analysis was limited by its retrospective, exploratory nature and the fact that the two trials were single-arm studies.

“Our findings are particularly noteworthy, given that data show that historically, patients with small cell lung cancer in the third-line treatment setting have limited survival benefit, with a duration of response of less than 2 months and a median survival of around 2 to 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.” – by Jennifer Byrne

Reference:

Chung HC, et al. Abstract CTPL03. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.

Disclosures: Merck Sharp & Dohme Corp. provided funding for this research. Chung reports grant/research support from Bristol-Myers Squibb/Ono, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Merck-Serono and Taiho; honoraria from Eli Lilly/Foundation Medicine and Merck Serono, and a consultant role with Bristol-Myers Squibb, Celltrion, Eli Lilly, Merck-Serono and Quintiles.

Photo of Hyun Cheol Chung
Hyun Cheol Chung

ATLANTA — Pembrolizumab demonstrated antitumor activity and induced durable responses in patients with advanced small cell lung cancer who had received two or more previous lines of therapy, according to pooled data from two KEYNOTE trials presented at American Association for Cancer Research Annual Meeting.

“Up to 70 percent of patients with small cell lung cancer have advanced disease at diagnosis,” Hyun Cheol Chung, MD, PhD, professor at Yonsei Cancer Center of Yonsei University College of Medicine in Seoul, South Korea, said in a press release. “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.”

Chung and colleagues presented data on outcomes of 83 patients (median age, 62 years; range, 24-84; 64% men) who received pembrolizumab (Keytruda, Merck), an anti-PD-1 monoclonal antibody, as monotherapy in the phase 1b KEYNOTE-028 (n = 19) and the phase 2 KEYNOTE-158 (n = 64) basket studies.

Eligible patients had histologically/cytologically confirmed, incurable advanced small cell lung cancer, an ECOG performance status of 0 or 1, were immunotherapy naïve, and had received two or more previous lines of systemic therapy (36% three or more lines). Patients in KEYNOTE-028 also were required to have tumors expressing PD-L1, whereas PD-L1 positivity was not required for KEYNOTE-158.

Participants in KEYNOTE-028 received 10 mg/kg pembrolizumab every 2 weeks, whereas those in KEYNOTE-158 received 200 mg pembrolizumab every 3 weeks. Patients remained on these regimens for 2 years or until unacceptable toxicity.

Objective response rate evaluated by RECIST 1.1 criteria served as the primary endpoint of both studies. Duration of response, PFS and OS served as secondary endpoints and were determined by the Kaplan-Meier method. Independent central review evaluated response.

At the time of data cutoff, median follow-up was 7.7 months (range, 0.5-48.7).

The ORR was 19.3% (95% CI, 11.4-29.4), including two patients with complete response and 14 patients with partial response. Of these 16 responders, 14 were PD-L1 positive.

Fifteen patients (18%) had stable disease, 45 (54%) had progressive disease, six (7%) had no assessment and one patient (1%) had incomplete response.

Median duration of response was not reached (range, 4.1-35.8+ months). Nine of the 16 responses (61%) lasted for 18 months or longer.

Median PFS rates were 16.9% at 12 months and 13.1% at 24 months, and OS rates were 34% at 12 months and 21% at 24 months.

Among all 131 patients in the two KEYNOTE studies, including those with one or more prior lines of therapy, 8% (n = 10) experienced grade 3 treatment-related adverse events, none experienced a grade 4 adverse event and 2% (n = 3) had grade 5 treatment-related adverse events, including intestinal ischemia, pneumonia and encephalopathy.

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Twenty-seven patients (21%) experienced immune-mediated adverse events or reactions to infusion, however, none was grade 5.

Chung acknowledged that the pooled analysis was limited by its retrospective, exploratory nature and the fact that the two trials were single-arm studies.

“Our findings are particularly noteworthy, given that data show that historically, patients with small cell lung cancer in the third-line treatment setting have limited survival benefit, with a duration of response of less than 2 months and a median survival of around 2 to 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.” – by Jennifer Byrne

Reference:

Chung HC, et al. Abstract CTPL03. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.

Disclosures: Merck Sharp & Dohme Corp. provided funding for this research. Chung reports grant/research support from Bristol-Myers Squibb/Ono, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Merck-Serono and Taiho; honoraria from Eli Lilly/Foundation Medicine and Merck Serono, and a consultant role with Bristol-Myers Squibb, Celltrion, Eli Lilly, Merck-Serono and Quintiles.

    Perspective
    Jorge Nieva

    Jorge Nieva

    The CHECKMATE and IMpower trials have shown that checkpoint inhibition is an effective strategy in small cell lung cancer. What is most exciting about the current KEYNOTE studies is that it a rare example of third-line efficacy in small cell lung cancer, which is a marvelous achievement. We know that small cell lung cancer is associated with relatively high tumor mutational burden, and it is a disease that is immune-responsive. So, having the pooled analysis available in this study was quite useful to confirm that the strategy works. A 20% response rate in the third-line setting is wonderful and provides hope to patients who haven’t had the kind of response to chemotherapy they had hoped for. There is the question, though, given the advancement of checkpoint inhibition into the first-line setting in combination with chemotherapy, of how widely adopted this strategy will be, as most pretreated patients will now be checkpoint inhibitor experienced. It will be interesting to see the results of future studies that utilize pembrolizumab in the first-line setting.

    • Jorge Nieva, MD
    • USC Norris Comprehensive Cancer Center

    Disclosures: Nieva reports research funding from Merck and consultant fees from AstraZeneca, Genentech and Takeda.

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