I-O Strategies in Relapsed/Refractory SCLC


Charles Rudin, MD, PhD: Small cell lung cancer is initially quite sensitive to chemotherapy. The real problem with small cell lung cancer is that it rapidly evolves from that chemotherapy-sensitive state to being quite chemotherapy resistant, and that happens quite quickly. When the tumor comes back in a chemotherapy-resistant form, we’re left with fewer options for treatment of those tumors. Until quite recently, the only standard option there was a drug called topotecan, which offers limited benefit, frankly, for those patients. More recently, there was an approval of an immunotherapy drug, nivolumab, for a third-line treatment of patients with recurrent small cell lung cancer. It’s interesting to think about how we’re going to apply that now that the standard of care in the first line has changed to actually incorporate immunotherapy. In my opinion, it’s unlikely that patients are going to respond to an immunotherapy of a similar class in recurrent disease if they’ve progressed on immunotherapy as part of their first-line regimen.

For patients who have relapsed or refractory small-cell lung cancer, we have seen evidence of activity of immunotherapy drugs in that context. There have been trials that have suggested a benefit, both for nivolumab and pembrolizumab. These are 2 PD-1 [programmed cell death protein 1] inhibitors, as well as the combination of nivolumab with ipilimumab, a drug directed against a target called CTLA4.

We’re now very interested in trying to define subsets of small cell lung cancer and to use that as a way to help define biomarkers that may optimize therapies for patients with recurrent small cell lung cancer. This is really an area of active investigation on both the laboratory and the clinical side. We believe there are subsets of small cell lung cancer that can be defined by different expression of certain key transcription factors. These include factors like ASCL1, NEUROD1, and a third factor, POU2F3, the most recently identified, defining a third subset of small cell lung cancer. There’s a fourth subset that lacks all 3 of those transcription factors, and we think these subsets may have differential sensitivity to certain drugs that are in development now.

Transcript Edited for Clarity

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