Pembrolizumab for small-cell lung cancer: an interview with Hyun Cheol Chung

Photo credit: Scott Wilkinson, Adam Marcus

We recently had the chance to speak with Hyun Cheol Chung from Yonsei University (Seoul, South Korea) about the KEYNOTE-028 and KEYNOTE-158 trial results, which were recently presented at the AACR Annual Meeting (March 29 – April 3, Atlanta, GA, USA). These trials have demonstrated that pembrolizumab induces promising anti-tumor activity in patients with pretreated, advanced small-cell lung cancer (SCLC) according to pooled analysis data. Read the interview below to find out what the next steps are for this study as well as how this trial might affect the clinical practice on the frontline of care.

Could you provide us an overview of the KEYNOTE-028 trial and KEYNOTE-158 trial results that were recently presented at AACR?

The purpose of our study was to evaluate the efficacy and safety of pembrolizumab, an anti–programmed death-1 (PD-1) monoclonal antibody, as monotherapy in a pooled analysis of the SCLC cohorts from the KEYNOTE-028 and KEYNOTE-158 multicohort studies in patients who have received at least two lines of prior therapy for advanced disease.

The most important findings among the 83 patients included in our pooled analysis are the promising antitumor activity observed with pembrolizumab monotherapy (objective response rate of 19.3% [95% confidence interval, 11.4–29.4]) with response lasting at least 18 months in 9 of 16 (61%, per Kaplan-Meier estimate) patients who had a complete response or partial tumor response (median duration of response was not reached).

In addition to the durable antitumor activity, patients who received pembrolizumab monotherapy had a median progression-free survival of 2.0 months (95% confidence interval, 1.9–3.4), and median overall survival of 7.7 months (95% confidence interval, 5.2–10.1). Overall, 34% and 21% of patients, respectively, were estimated to be alive at 12- and 24-month intervals following treatment initiation with pembrolizumab monotherapy. Additionally, 10 patients (8%) had a Grade 3 or higher treatment-related adverse event (AE). Overall, the AEs noted were consistent with the pembrolizumab safety profile and no new safety signals were identified.

The most important findings among the 83 patients included in our pooled analysis are the promising antitumor activity observed with pembrolizumab monotherapy.

How do you hope this trial might affect the clinical practice on the frontline of care?

Up to 70% of patients with small cell lung cancer (SCLC) present with advanced disease. 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. Given these limited treatment options for patients who require third-line or subsequent therapy for SCLC, 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.

What further advances do you hope to see with respect to head and neck cancer, as well as immuno-oncology, in the coming years?

Our findings are particularly noteworthy given that in the third-line setting ORR is typically around 20% with median duration of response <3 months, and median survival around 2–3 months. Our study shows that pembrolizumab monotherapy can provide durable clinical benefit with manageable toxicity in this hard-to-treat patient population.

As we could see the signal of immuno-oncology (IO) agent in this SCLC category with amenable toxicity, this drug can be tested in upfront cancer state such as 2nd line and 1st line treatment with monotherapy, combination with other IO agent, chemotherapy and targeted agents.

For the 2nd line treatment IO agent can be tested in head-to-head comparison with chemotherapy using IO agent monotherapy or IO agent combination to make a chemotherapy-free treatment.

For the 1st line, IO agent can be combined to chemotherapy to prolong the survival, or used as a maintenance treatment after certain period of chemotherapy. We are hoping to prolong the patient survival with maintenance of good performance status of patient’s physical condition from various treatment options.

What further investigations do you have planned?

The limitations of this analysis are typical of those associated with such retrospective, exploratory, pooled analyses. As early phase studies, both KEYNOTE-158 and KEYNOTE-028 were single-arm studies, and were therefore non-comparative. Additionally, as mentioned above, the two studies differed in their eligibility requirements regarding PD-L1 expression, with eligibility for KEYNOTE-028 requiring patients with PD-L1–positive tumors, whereas KEYNOTE-158 enrolled patients regardless of PD-L1 expression.

Even if these limitations we could see 10% of patient showed a long-term survival whereas half of the patients progressed within 3 months of treatment. If we can differentiate or predict these responders and non-responders, that will be good for optimal personalized treatment. For this purpose, many studies to find out the best biomarkers and combination strategy are under investigation.

AACR19: pembrolizumab demonstrates promise in small-cell lung cancer patients