PD-L1 Inhibitors for the Treatment of Extensive-Stage Small Cell Lung Cancer

Millie Das, MD, is a clinical associate professor of medicine-oncology at Stanford University and chief of oncology at the Veterans Affairs (VA) Palo Alto Health Care System, Palo Alto, California. She has a strong interest in clinical research, serving as co-investigator on all lung cancer trials at Stanford and as principal investigator for multiple clinical and translational studies at VA Palo Alto.

What is the recommended first-line standard of care for patients with extensive-stage SCLC?

The first-line standard of care for patients with extensive-stage SCLC is chemotherapy plus immunotherapy, usually platinum-etoposide with a PD-L1 inhibitor, either durvalumab or atezolizumab. Typically, we give that therapy for 4 cycles and then continue with the immunotherapeutic agent alone as maintenance therapy until the disease progresses.

Can you comment on the results of the 2 clinical trials that led to the approval of the PD-L1 inhibitors atezolizumab and durvalumab in extensive-stage SCLC?

A: Atezolizumab was approved first by the US Food and Drug Administration (FDA) in March 2019, based on the results of the IMpower133 trial (ClinicalTrials.gov Identifier: NCT02763579), which evaluated first-line atezolizumab plus chemotherapy in patients with extensive-stage SCLC. This was a randomized, controlled, phase 3 trial in which patients received carboplatin-etoposide plus placebo or carboplatin-etoposide plus atezolizumab.¹ FDA approval was based on an overall survival benefit of about 2 months seen with the addition of atezolizumab compared with placebo. This was really the first trial that showed benefit with the addition of immunotherapy to platinum-etoposide as part of frontline therapy. These data and FDA approval were practice-changing and led us to use atezolizumab as part of frontline therapy for patients with extensive-stage SCLC.
 
About 1 year later, data from the phase 3 CASPIAN trial (ClinicalTrials.gov Identifier: NCT03043872) were released, and the FDA approved durvalumab in March of 2020. In CASPIAN, patients with extensive-stage SCLC were randomly assigned to receive either platinum-etoposide or platinum-etoposide plus durvalumab in the frontline setting. Once again, an approximately 2-month overall survival benefit was noted with the addition of durvalumab to standard platinum-etoposide.²

How did the outlook for patients with extensive-stage SCLC change with the approval of immunotherapies?

A: Before approval of these agents, the standard of care for the past several decades was typically platinum-etoposide. Usually, we would give platinum-etoposide for 4 to 6 cycles, stop therapy, observe for progression, and consider second-line therapy at the time of disease progression. It’s exciting that we have had new drug approvals for these immunotherapeutic agents in the past few years, in the context of multiple prior negative SCLC trials that tried to improve upon results seen with platinum-etoposide alone.
 
Initial FDA approvals of immunotherapy in SCLC were granted in 2018 and 2019 in patients who had experienced disease progression after at least 1 prior line of therapy, with the programmed cell death protein 1 (PD-1) inhibitors nivolumab and pembrolizumab. It is important to note that the patients with SCLC who received a PD-1 inhibitor in the relapsed or progressed setting had not received immunotherapy as part of their first-line treatment. When the PD-L1 inhibitors atezolizumab and durvalumab were subsequently approved as part of frontline treatment, the treatment landscape changed. The potential relevance and efficacy of immunotherapy in the second-line setting, and beyond, have really diminished. 
 
Despite progress in administering a PD-L1 inhibitor in combination with platinum-etoposide as part of frontline treatment, the benefit that we see with immunotherapy in SCLC is not necessarily the same as the benefit seen in non-small cell lung cancer (NSCLC). We see a benefit with the addition of immunotherapy but, regrettably, that benefit appears small. Most of these patients still experience disease progression after their frontline and/or maintenance therapy that includes immunotherapy. It is rare to see patients (with SCLC) who have a complete response and remain in remission for an extended period of time.

What constitutes follow-up care after frontline therapy in this patient population?

A: These patients are closely monitored and usually undergo surveillance imaging every 2 or 3 months, given the aggressive nature of the disease. They undergo either computed tomographic (CT) imaging or positron-emission tomographic imaging plus CT imaging every 2 months to evaluate for disease progression. Importantly, patients with extensive-stage SCLC also undergo frequent brain surveillance because the brain is often the site of metastasis in SCLC patients. I typically perform brain surveillance every 3 months with magnetic resonance imaging.

You mentioned that there is a long way to go in improving treatment for patients with SCLC. What are unmet needs in SCLC?

A: Unfortunately, SCLC remains an aggressive disease. Many of the advances that we have seen in NSCLC have come about due to the identification of molecular targets and associated targeted therapies, which is the kind of success that has just not happened in SCLC. We’re performing next-generation sequencing to look for genetic variability in tumor samples from patients with SCLC and frequently see alterations in TP53 and retinoblastoma (RB) genes, but we don’t have specific drugs that target those pathways. Our standard approach remains chemotherapy, now in combination with immunotherapy.
 
We consider patients who experience relapse or progression within 6 months of receiving frontline therapy to be platinum-resistant; for them, we want to forge ahead with second-line therapy, assuming that they remain fit enough to receive additional treatment. We have a new drug, lurbinectedin, which was approved by the FDA in June 2020 and is a potential second-line treatment for patients with platinum-resistant, relapsed SCLC.³ Prior to the approval of lurbinectedin, we were typically using topotecan or irinotecan in the second line.
 
It is important to point out that all of these drugs are considered cytotoxic chemotherapy. They pose significant risk, including lower blood counts, infection, and bleeding. Often these patients are just very sick and symptomatic when their disease progresses, which makes administering chemotherapy even more challenging. The hope moving forward is to come up with better-tolerated, targeted drugs that have higher efficacy and less toxicity — similar to advancements that we have seen in the NSCLC space.

Are there promising agents under investigation?

Work is underway that is looking at biomarkers and trying to identify patients who are most likely to benefit from the addition of immunotherapy or PARP inhibitors. Trials so far suggest that PARP inhibitors have potential efficacy in patients with SCLC, most often in combination with chemotherapy or immunotherapy. Trying to identify patients up front who are going to benefit from the addition of a PARP inhibitor is a hot area of investigation. Clinical trials related to PARP inhibitors in SCLC are ongoing (ClinicalTrials.gov Identifiers: NCT03672773 and NCT04209595).
 
It is important to mention the KEYNOTE-604 trial (ClinicalTrials.gov Identifier: NCT03066778), the results of which were presented at the 2020 American Society of Clinical Oncology Annual Meeting. This phase 3 randomized trial was designed similarly to IMpower133 and CASPIAN, whereby patients received platinum-etoposide with or without pembrolizumab. The final analysis showed longer survival in the pembrolizumab group, although the significance threshold was not met.⁴ To date, pembrolizumab has not been approved by the FDA but, overall, data from KEYNOTE-604 provide additional support for the use of immunotherapy in combination with platinum-etoposide as frontline treatment in patients with extensive-stage SCLC.

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