Immunotherapy for the treatment of metastatic small cell lung cancer: Focus on pembrolizumab

ABSTRACT

The evolving therapeutic landscape of metastatic small-cell lung cancer (SCLC) includes the increasing implementation of immunotherapy. The current  approach for first-line therapy of extensive SCLC consists of a combination of chemotherapy and an immune checkpoint inhibitor (ICI).

Areas Covered

The current evidence on the role of pembrolizumab for patients with extensive SCLC is reviewed in this article. Particularly, preclinical and clinical data from phase I/II and III clinical trials, which evaluate the efficacy and toxicity of pembrolizumab for these patients, are summarized based on PubMed/MEDLINE search and relevant articles. In addition, future perspectives on the emerging role of immunotherapy for SCLC are highlighted in light of potentially useful biomarkers.

Expert commentary

Pembrolizumab shows an excellent toxicity profile in recent studies, and significantly prolonged progression-free survival (PFS) but not overall survival (OS) in the phase III clinical trial KN604, in contrast to atezolizumab and durvalumab. The latter two agents have already been approved and incorporated in the daily clinical practice. Further research should be conducted so that phase III clinical trials can validate the potential clinical benefit of this checkpoint inhibitor in combination with other active agents and establish its role in the metastatic setting of SCLC.

KEYWORDS:

• Immune checkpoint inhibitors
• immunotherapy
• lung cancer
• pembrolizumab
• PD-1
• small-cell lung cancer

Article highlights

• SCLC is highly associated with heavy smoking habits and its prognosis is extremely poor.

• The doublet of platinum-etoposide is still considered the cornerstone of the treatment of SCLC.

• Pembrolizumab has already been approved for the first- and second-line treatment of metastatic NSCLC under certain circumstances.

• There are very few immune biomarkers incorporated in daily clinical practice.

• Currently, PD-L1 constitutes the most widely used predictive and prognostic biomarker, given that positive PD-L1 expression has been shown to be associated with both longer survival and higher responses to immunotherapy in patients with SCLC.

• The highly immunogenic profile of SCLC has led to the development of various immune-related therapeutic strategies, which have been tested in order to improve the OS of these patients.

• The major immune agents that have been evaluated in SCLC include besides pembrolizumab, ipilimumab, nivolumab, atezolizumab, and the combination of durvalumab with either tremelimumab or olaparib. Of them, the anti-PD-L1 monoclonal antibodies atezolizumab and durvalumab have shown a significant survival benefit of approximately 2 months, as compared to chemotherapy alone, in randomized phase III trials (IMPower 133 and CASPIAN, respectively).

• Pembrolizumab is a highly selective, IgG4-kappa humanized monoclonal antibody against PD-1 which has been extensively tested in SCLC at present and its function includes the inhibition of PD-1 binding with PD-L1 and PD-L2.

• Seven studies evaluating pembrolizumab in SCLC have hitherto been published, of which three were phase II trials, two were phase I clinical trials, and one was the exploratory pooled analysis of two prior clinical trials. Recently, the phase 3 keynote-604 study was also published.

• Pembrolizumab has already been evaluated in patients with extensive-stage SCLC as a first-line treatment in combination with chemotherapy, as a maintenance treatment and in combination with radiotherapy after induction chemotherapy, as well as in the setting of refractory or relapsed disease in combination with paclitaxel.

• Six of the aforementioned seven studies have shown a favorable clinical efficacy in terms of objective response rate and an acceptable safety profile, whereas a significant PFS benefit has been demonstrated in the recent phase III KeyNote-604 study regarding patients who received a combination of pembrolizumab plus chemotherapy.

• Further investigation is needed in order to assess the magnitude of clinical benefit of pembrolizumab in extensive-stage SCLC

Declaration of interest

G. Mountzios has declared Honoraria, Consultancy and/or Travel fees from Roche, AstraZeneca, Amgen, Novartis, BMS, MSD, Takeda, Pfizer, and Ipsen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded