Oncology Data Advisor: Currently, what is the survival rate for patients with extensive-stage small cell lung cancer? How has this number changed in recent years?

Anne Chiang, MD, PhD: The survival rate for patients with extensive-stage small cell lung cancer has improved in recent years, and this is due to the two frontline FDA approvals of immunotherapy combined with chemotherapy. These approvals were based on the results of the IMpower133 trial and the CASPIAN trial, combining chemotherapy with atezolizumab and durvalumab, respectively. The updated analysis for CASPIAN was recently presented with a median follow-up of 39.4 months; this showed a three-year overall survival of 17.6% for extensive-stage small cell patients treated with chemotherapy plus immunotherapy versus 5.8% for patients just treated on the chemo arm. The two-year overall survival data for the CASPIAN was 22.9% versus 13.9%. The last reported update from the IMpower133 trial with median follow-up of 22.9 months showed similar two-year overall survival of 22% versus 17%. It's amazing to me that the three-year CASPIAN data show that overall survival rates for patients treated with chemotherapy and durvalumab is three times that of patients treated with chemotherapy alone. I am hopeful that these patients will continue to do well over time.

Oncology Data Advisor: How does tumor mutational burden (TMB) impact response to therapy and outcomes for patients with extensive-stage small cell lung cancer?

Dr. Chiang: We were very excited about tumor mutational burden as a biomarker because we knew that programmed death ligand 1 (PD-L1) staining is rare in SCLC tumors, and PD-L1 status is not prognostic in the same way as in non–small cell lung cancer (NSCLC). Initially, there were signals that patients who had high TMB had a better response to immunotherapy, for example in the Checkmate-032 trial. That being said, TMB was not prognostic in the initial IMpower133 data, although the more recent data may show a slight trend for better outcomes for patients with 16 or more mutations/megabase. Right now, TMB status does not impact clinical decisions.

Oncology Data Advisor: That's good to know. Thank you. What are some of the most recent advancements in the treatment of patients with extensive-stage small cell lung cancer?

Dr. Chiang: Important clinical advancements include the incorporation of immunotherapy into the frontline regimen with chemotherapy, as I mentioned, and the approval of lurbinectedin for use in the relapsed setting.What I think is tremendously exciting right now are recent insights into small cell lung cancer biology, specifically the understanding that there may be subtypes of small call, based on molecular profiling and overexpression of certain transcriptional regulators, that may have therapeutic vulnerabilities.

Using samples from the IMpower133 trial, a recent study showed that SCLC patients could be divided into subtypes, such as "A, N, P", according to the overexpression of transcriptional activators ASCL1, NEUROD1, and POU2F3, respectively. Another subtype, "I," did not show overexpression of the aforementioned transcriptional regulators; rather, it is an "inflamed "signature characterized by upregulation of inflammatory genes.Notably, patients with subtype I treated on the chemotherapy/atezolizumab arm of the trial exhibited better survivalthan those in the placebo arm. These results are still preliminary but indicate there may be a way to identify patients that are going to do particularly well with immunotherapy. It would be amazing if we could ultimately treat our SCLC patients with targeted therapy based on their particular subtype.

There are lots of really exciting clinical trials ongoing, using approaches with new classes of drugs such as antibody-drug conjugates, bispecific antibodies, poly–adenosine ribose polymerase (PARP) inhibitors, and other therapeutics that exploit aspects of small cell such as high mitotic activity and proliferation.

Oncology Data Advisor: Wow. That really sounds like a lot of exciting developments going on there. Thank you. Do you have any words of advice for community oncologists in optimizing outcomes for patients with extensive-stage small cell lung cancer?

Dr. Chiang: My words of advice are to consider clinical trials early, to develop new and better tools for these patients. Also, work with your interventional pulmonologists and radiologists to get adequate tumor biopsies, which will be important going forward. Most importantly, don't give up hope. I think there are lots of reasons for optimism, even in this population of patients.

For more expert perspectives from Dr. Chiang, check out her free CME/NCPD-approved activity on extensive-stage small cell lung cancer. 

For More Information

Horn L, Mansfield AS, Szczęsna A, et al (2018). First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med, 379(23):2220-2229. DOI:10.1056/NEJMoa1809064

Paz-Ares L, Dvorkin M, Chen Y, et al (2019). Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet, 394(10212):1929-1939. DOI:10.1016/S0140-6736(19)32222-6

Gay CM, Stewart CA, Park EM, et al (2021). Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell, 39(3):346-360.e7. DOI:10.1016/j.ccell.2020.12.014

US Food & Drug Administration (2019). FDA approves atezolizumab for extensive-stage small cell lung cancer. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-extensive-stage-small-cell-lung-cancer

US Food & Drug Administration (2020). FDA approves durvalumab for extensive-stage small cell lung cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-extensive-stage-small-cell-lung-cancer

About Dr. Chiang

Anne Chiang, MD, PhD, is the Chief Integration Officer and Deputy Chief Medical Officer of Smilow Cancer Hospital and Associate Professor of Medicine in the Section of Medical Oncology at Yale University. Additionally, she is an Executive Officer of the Southwest Oncology Group (SWOG) Cancer Research Network, overseeing clinical trials in lung and breast cancers. Dr. Chiang specializes in thoracic oncology, and her research focuses on the development of novel therapeutic agents and combinations of immune checkpoint inhibitors for patients with lung cancer. She has particular expertise in quality measurement and improvement initiatives regarding patient-centered cancer services, and she was integral in achieving the American Society of Clinical Oncology (ASCO) Quality Oncology Practice Initiative (QOPI) Certification for the Smilow academic and network clinical practice. She has authored or coauthored numerous peer-reviewed publications focused on the treatment and management of patients with lung cancer.

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.