The Future of Immunotherapy in the Treatment of Small Cell Lung Cancer

Abstract

Small cell lung cancer (SCLC), which accounts for 10%-15% of lung cancer cases, is an aggressive disease characterized by rapid growth and early widespread metastasis. Although up to 80% of patients respond to first-line chemotherapy, most eventually relapse, and there are no approved agents beyond the second line. Despite the high incidence of mutations in SCLC, to date no targeted therapy has shown a benefit for this patient population, and systemic treatment has not changed significantly during the past 3 decades. Given that extensive-stage SCLC has a 5-year survival rate of only 1%-2%, novel therapies are desperately needed. Recent evidence shows that the immune system is capable of generating antitumor responses against various tumors, including lung cancer, suggesting that immunotherapy may be a viable therapeutic approach to the treatment of patients with SCLC. Of the immunotherapies being investigated for patients with SCLC, antibodies that target the programmed cell death protein-1 (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte antigen-4 (ipilimumab) immune checkpoint pathways are perhaps the most promising. Because these immune checkpoint pathways, which under normal circumstances function to protect healthy tissues from damage during inflammatory responses and maintain self-tolerance, can help tumor cells evade elimination by the immune system, they represent potential therapeutic targets.This review discusses the rationale for immunotherapy and the early clinical results of immunotherapeutic agents being investigated in SCLC. The Oncologist 2016;21:910-921 Implications for Practice: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype. Despite sensitivity to first-line chemotherapy, SCLC has high recurrence rates, and responses to second-line treatments are poor. Recent evidence shows that the immune system is capable of generating responses against various tumors, including lung cancer, suggesting that immunotherapy may be a viable approach for patients with SCLC. Of several immunotherapies being investigated, antibodies that target the programmed cell death protein-1 (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte antigen-4 (ipilimumab) immune checkpoint pathways are among the most promising for patients with SCLC and are the focus of this review.

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“…Best response was stable disease in a patient with carcinoid and a patient with pancreatic NET (Patnaik et al 2015), and it remains unclear which NET patient subgroups might potentially benefit from this therapy. In light of the activity of pembrolizumab in small-cell lung cancer and Merkel cell carcinoma (Horn et al 2016, Nghiem et al 2016, the role of immunotherapy might be particularly relevant in high-grade NEC.…”

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“…Recently, immune checkpoint inhibitors emerged in early phase clinical trials, with pembrolizumab, nivolumab and ipilimumab (the antibody blocking the cytotoxic T‐lymphocyte‐associated protein 4—CTLA‐4), showing promising results . Angiogenesis has a crucial role in SCLC as it is involved in metastasis.…”

“…57 In another study targeting by qPCR the human telomerase reverse transcriptase (hTERT) gene in nine MPEs from SCLC, detection of amplification was possible in all nine samples. 60 Recently, immune checkpoint inhibitors emerged in early phase clinical trials, 61 with pembrolizumab, nivolumab and ipilimumab (the antibody blocking the cytotoxic T-lymphocyte-associated protein 4-CTLA-4), showing promising results. 62,63 Angiogenesis has a crucial role in SCLC as it is involved in metastasis.…”

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“…Nonetheless, SCLC patients experience relapse, and there is no approved targeted drug as a second line therapy for these tumors. 30 However, this scenario may change since many promising advances with immune checkpoint inhibitors have emerged in the last few years. 31,32 Genomic analyses have identified driver mutations in SCLC, leading to a better understanding about cellular features and molecular mechanisms involved in initiation, progression, metastasis and resistance.…”

“…Patients with SCLC have carcinomas which display a high growth fraction, rapid doubling time and early establishment of widespread metastatic lesions and response to first‐line chemotherapy. Nonetheless, SCLC patients experience relapse, and there is no approved targeted drug as a second line therapy for these tumors . However, this scenario may change since many promising advances with immune checkpoint inhibitors have emerged in the last few years …”