Emerging Treatments in SCLC: Impact of Targeted Therapy

Hossein Borghaei, DO, MS: Wade, what do you think about DLL3 bispecifics? Where do you think they’re going? Do you think these are promising data we’re beginning to see? How do you put it in context?

Wade Iams, MD: I’d place it along similar lines of a subset of patients having a notable benefit. I hope more patients can be enrolled and treated with these DLL3 bispecific T-cell engagers and that we have meaningful identification of patients with durable response. Treating everybody with it is going to be a hard sell in relapsed small cell lung cancer [SCLC], just because of the performance status and comorbidities of most of the patients.

Hossein Borghaei, DO, MS: Vivek, do you think molecular targets are going to have any meaningful role in small cell lung cancer?

Vivek Subbiah, MD: Absolutely. Thank you for that question. As lung cancer doctors and oncologists, we all know that non–small cell lung cancer has become the poster child for precision oncology. As a field, small cell lung cancer is about 15 years behind non–small cell lung cancer. Hopefully there’s going to be a renaissance of biomarkers and personalized therapies. One of the first steps is defining the population. Everyone here mentioned the recent subclassification. Although the previous studies identified 3 possible subtypes of small cell lung cancer based on transcription factors, which indicate whether a particular gene is turned on or off, a large number of patients with small cell lung cancer don’t fit into 1 of these 3 groups.

Rather than trying to apply a hypothesis to the many tumors, Lauren Byers looked into an unbiased bioinformatics approach, letting the data speak for itself. This led to 1300-gene signature that comes from the previous subgroups, SCLC-A, SCLC-N, and SCLC-P. Interestingly, they came up with another unrecognized fourth group with a unique new landscape, as Steve Liu mentioned. What are the 3 subgroups? The first group is SCLC-A, which is activation of ASCL1. The second group is SCLC-N, which is activated by NEUROD1. The third group is SCLC-P, which is activated by POU2F3. The fourth and most important type is the SCLC-I group, or the SCLC-inflamed group, which is categorized by an inflamed gene signature with high expression of multiple immune genes, including significantly greater levels of genes, indicating the presence of CD83-positive cytotoxic T cells.

This shows that the inflamed group has a distinct biology and a tumor microenvironment that tends to be more responsive to immunotherapy. Interestingly, they also suggested the SCLC-I group was sensitive to immune checkpoint blockade; the SCLC-A group, the ones with activation of the ASCL1 pathway, responded better to the BCL2 inhibitors; the SCLC-N group responded preclinically to Aurora kinase inhibitors; and the SCLC-P group responded to the PARP inhibitors. This and other studies give us hope that the field of small cell lung cancer is looking to the field of non–small cell lung cancer and that in the near future, we can identify subsets of patients who will benefit from therapy. We’re all hopeful that small cell lung cancer is going to be defined by precision oncology.

Transcript Edited for Clarity