Expert Examines Immunotherapy Potential in Small Cell Lung Cancer

David P. Carbone, MD, PhD

Several ongoing clinical trials are examining the efficacy and safety of immunotherapy agents in patients with small cell lung cancer (SCLC), explains David P. Carbone, MD, PhD.

Two early phase studies have already shown encouraging results. In the phase I/II CheckMate-032 trial,¹ pretreated patients with SCLC received monotherapy with the PD-1 inhibitor nivolumab (Opdivo) or the combination of nivolumab plus the CTLA-4 inhibitor ipilimumab (Yervoy). Data showed that the median progression-free survival (PFS) was 3.35 months with the combination and 1.38 months with nivolumab alone. Median OS was 7.75 months with the combination and 3.55 months with single-agent therapy. The objective response rate (ORR) with the combination was 31.1%.

In the phase Ib KEYNOTE-028 trial,² the PD-1 inhibitor pembrolizumab (Keytruda) had an ORR of 29.2% (95% CI, 12.6-51.1) in patients with SCLC who had prior chemotherapy.

Additionally, results of a phase I study, which examined the antibody-drug conjugate rovalpituzumab tesirine (Rova-T), demonstrated that patients with relapsed/refractory SCLC who were sensitive to first-line combination chemotherapy and were positive for delta-like 3 (DLL3) gene expression experienced an ORR of 64% with Rova-T.³

OncLive: Is there potential for immunotherapy in lung cancer subtypes other than non—small cell lung cancer?

What immunotherapy trials are on the horizon in SCLC?

In an interview with OncLive, Carbone, the Barbara J. Bonner Chair in Lung Cancer Research and director of the James Thoracic Center at The Ohio State University Comprehensive Cancer Center, shares insight on some of these ongoing trials and others that are exploring immunotherapy in patients with SCLC.Carbone: Absolutely. There is a huge potential for it in a small subset of patients. Therefore, we have to figure out who that subset is. There are early hints that immunotherapy is active in small cell lung cancer and mesothelioma. Both of those diseases are areas of great need.There have been 2 small cohorts in other studies that have been reported. They showed reasonable response rates in SCLC that have been independent of PD-L1 status with both single-agent PD-1 and also PD-1 plus CTLA-4 antibodies.

One of the drawbacks is that it seems that these patients have a higher risk of devastating toxicities. Therefore, there are ongoing studies looking at that. We are participating in a study of the first-line setting of SCLC of chemotherapy with maintenance PD-1 versus PD-1 plus CTLA-4 versus placebo, and that will be an interesting study, as well.

Can you elaborate on the rovalpituzumab research?

In SCLC, another immunotherapy agent—in a sense—is the antibody-drug conjugate therapy rovalpituzumab (Rova-T). That is an exciting study.DLL3 is a molecule that is expressed on about two-thirds of SCLCs, and it is actually a functionally active molecule. It’s a NOTCHED ligand that inhibits NOTCH1. That activates CO1, which is a main driver of SCLC. Therefore, Stemcentrx linked a drug to an antibody against DLL3 with a chemotherapy drug and showed that there was a high response rate in the second- and third-line setting of SCLC.

It was higher than what we have seen by far, and what we have seen with single-agent chemotherapy, which is the standard. I am excited to see how those read out, but we don’t have data yet.

As more of these immunotherapy agents get approved and are utilized, is there a learning curve for oncologists to best manage the toxicities that are associated with them?

Definitely. There is a learning curve among oncologists transitioning from chemotherapy to targeted therapies and managing a totally different spectrum of side effects and different features of patients and side effects. It’s the same things with immunotherapy. I don’t think oncologists are universally managing patients with TKIs effectively—even today.

Immunotherapy agents are, again, a completely different sphere of knowledge. Oncologists are not used to looking closely for hyperthyroidism or other autoimmune effects. Patients can have devastating pneumonitis or colitis, especially with the combination regimens. Thoracic medical oncologists are not used to dealing with this. There will be a learning curve, in that patients should probably go to oncologists who are experienced in giving those drugs, as they come out and are approved in different regions of the world.

References

1. Calvo E, Lopez-Marin, JA, Bendell J, et al. Nivolumab (NIVO) monotherapy or in combination with ipilimumab (IPI) for treatment of recurrent small cell lung cancer (SCLC). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 3098.
2. Ott PA, Elez E, Hiret S, et al. Pembrolizumab for ED SCLC: Efficacy and Relationship with PD-L1 Expression. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 3285.
3. Pietanza MC, Spigel D, Bauer TM, et al. Safety, activity, and response durability assessment of single agent rovalpituzumab tesirine, a delta-like protein 3 (DLL3)-targeted antibody drug conjugate (ADC), in small cell lung cancer (SCLC). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. 7LBA.