Rudin Reflects on Recent Data in SCLC

Charles M. Rudin, MD, PhD

The field of small cell lung cancer (SCLC) is experiencing an outpouring of new data. Much of the excitement surrounds immunotherapy, particularly following recent findings with atezolizumab (Tecentriq).

In findings from the IMpower133 trial presented at the 19th World Conference on Lung Cancer, the addition of atezolizumab to standard carboplatin and etoposide significantly prolonged survival in patients with extensive-stage SCLC compared with the standard of care alone. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab arm (95% CI, 10.8-15.9) compared with 10.3 months (95% CI, 9.3-11.3) in the placebo arm (HR, 0.70; 95% CI, 0.54-0.91; P = .0069).^1,2

Although these results are promising, Charles M. Rudin, MD, PhD, said that there are other targets in SCLC worth exploring. This includes DLL3, a target of interest for several trials that are in process.

Agents under investigation targeting DLL3 include rovalpituzumab tesirine (Rova-T). Although preliminary reports showed disappointing activity in the third-line setting for patients with relapsed/refractory SCLC with high expression of DLL3, Rudin explained that DLL3 remains a target of interest.

OncLive: Could you share your thoughts on some of the recent immunotherapy data reported in SCLC?

In an interview with OncLive, Rudin, chief, Thoracic Oncology Service, co-director, Druckenmiller Center for Lung Cancer Research, Sylvia Hassenfeld Chair in Lung Cancer Research, Memorial Sloan Kettering Cancer Center, reflected on the latest developments in SCLC.Rudin: This is an exciting time for SCLC; a lot of new targets are emerging and a lot of new strategies are now being deployed in the clinic. One of the recent success stories was the initial trial bringing the PD-L1 inhibitor atezolizumab into first-line treatment for patients with SCLC. This was a trial randomizing patients between carboplatin and etoposide, which is a standard of care, versus the same standard of care plus atezolizumab. This was positive for both progression-fee survival and OS.

I would say that although this was a positive study, there was some disappointment with the extent of the benefit. It ended up being a 2-month improvement in median survival, which is certainly good, but there is still a lot of work to be done. There are a lot of other targets that are being actively explored for SCLC now.

Are there any other targets of interest being studied in SCLC?

What is the understanding of SCLC genomics?

This trial really showed us that this can be an immune-responsive disease, and it opens the opportunity to build on that. There are a number of strategies that may play out in this realm.We are particularly interested in a target called DLL3. There is an antibody-drug conjugate in active development now, called Rova-T, targeting DLL3. There are a number of DLL3-targeted agents coming forward, including a bispecific that will link DLL3-positive tumor cells to CD3-positive T cells. The idea is that if you can recruit these cells into the tumor specifically, you might get better responses. We have no data with that strategy yet, but it is an interesting one and we will see how it plays out.The investigators that are focused on SCLC are beginning to recognize that there are different subsets of the disease defined by different transcription factors. There are 2 transcription factors in particular that differentiate SCLC subsets. They look identical under the microscope, but they behave very differently and have different wiring and biology. These transcription factors are ASCL1 and NEUROD1.

Where should research focus moving forward?

The subset of tumors that are high for ASCL1 are sort of classic SCLCs, and those are the tumors that express high levels of DLL3. The other subset, NEUROD1, tends to be high in c-MYC, a protein that we do not currently have a good drug for. However, it gives us a handle on what we might try in that space.There are multiple strategies being deployed, both in SCLC and non—small cell cancer, that are very interesting. Incorporating targeted therapy with immunotherapy has been a struggle. There have been some initial trials that have shown unexpected toxicities with the combinations. Learning how to combine these strategies to get optimal response with targeted agents and optimal durability of response with immunotherapy is something that we are still learning about, but that will play out in the next several years.

References

1. Liu S, Mansfield A, Szczesna S, et al. IMpower 133: primary PFS, OS and safety in a ph1/3 study of 1L atezolizumab + carboplatin + etoposide in extensive-stage SCLC. In: Proceedings from the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract PL02.07.
2. Liu S, Mansfield A, Szczesna S, et al. First-Line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer [published online ahead of print September 25, 2018]. N Eng J Med. doi:10.1056/NEJMoa1809064.