Amid Advances, Obstacles Remain in Small Cell Lung Cancer

Aaron S. Mansfield, MD

The emergence of chemoimmunotherapy in the frontline setting of extensive-stage small cell lung cancer (SCLC) offered a potential new standard of care to a previously stagnant space, said Aaron S. Mansfield, MD. However, he added, there is still work remaining to improve the outlook for this disease.

In March 2019, the FDA approved the combination of atezolizumab (Tecentriq) plus carboplatin and etoposide for the frontline treatment of this patient population. The regulatory decision was based on findings from the phase III IMpower133 study, which showed a significant improvement in overall survival (OS) with the combination compared with chemotherapy alone.

At a median follow-up of 13.9 months, median OS was 12.3 months with the addition of atezolizumab compared with 10.3 months in those who received chemotherapy alone, translating to a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.54-0.91; P = .0069) with atezolizumab.¹ Moreover, the chemoimmunotherapy combination resulted in an increased median progression-free survival at 5.2 months versus 4.3 months in the control arm.

Updated data from the trial, which were presented at the 2019 AACR Annual Meeting, confirmed the survival benefit with the combination and did not reveal any new safety signals. Grade 3/4 treatment-related adverse events (AEs) were observed in 57% of patients in the atezolizumab arm compared with 56% of those in the placebo arm. The most common CNS-related AEs were headache (34.8% in atezolizumab arm vs 19.0% in placebo arm), asthenia (21.7% vs 9.5%), dizziness (8.7% vs 0%), insomnia (8.7% vs 4.8%), and fall (8.7% vs 4.8%).²

In an interview with OncLive, Mansfield, an associate professor of oncology and a consultant in the Division of Medical Oncology at Mayo Clinic, discussed recent progress in SCLC and remaining challenges in the field.

OncLive: What is the current treatment paradigm for patients with extensive-stage SCLC?

Mansfield: For decades, our standard of care has been a platinum doublet, either cisplatin or carboplatin with etoposide. We have not been that successful at improving upon that. This treatment is actually fairly effective in terms of shrinking tumors; there is a very high response rate. The problem is that those responses are not durable. After an initial response, the tumor often progresses very soon after. This is a disease with a poor survival—medians have always been under 1 year.

Could you expand on the challenges with developing effective treatments in this space?

There are many challenges with developing drugs for SCLC. One of them is the lack of tissue we have to study. A lot of the time, patients are diagnosed from cytology or from a pleural effusion because they present with advanced disease and many symptoms. They are often hospitalized or come through the emergency department, and we don't have the luxury of time to obtain adequate tissue samples. Also, it is very rare that these patients go to surgery to have their disease removed, whereas in non—small cell lung cancer (NSCLC), several of those patients can go to surgery. [In NSCLC], we have tissue repositories and we are able to study them in more detail. That's why we've seen a proliferation of targeted therapies in that disease, but SCLC has been much more difficult to study.

What are some of recent advances that have been made in this area?

There are several ongoing trials looking at different therapeutic approaches. The one we presented at the 2019 AACR Annual Meeting was an update on a chemoimmunotherapy combination. Other studies have looked at temozolomide (Temodar) and PARP inhibitors. There are proteins expressed in SCLC that researchers are trying to target with antibody-drug conjugates. Most of these endeavors have not been successful, but that isn’t due to a lack of effort.

What is the rationale for the field shifting toward chemoimmunotherapy combinations?

The exact mechanism to how this works is elusive, but when certain drugs make it into the second- or third-line setting, we sometimes see them combined with the frontline [agents]. First, we have seen that chemotherapy and immunotherapy can be safely combined together in NSCLC. In the trial we presented here, we saw that giving the drugs led to no increase in adverse events. In the lab, we do find that some chemotherapies upregulate PD-L1 expression, so that does provide rationale for blocking PD-1/PD-L1 from interacting with one another.

Could you discuss the research that you presented from IMpower133?

IMpower133 is a randomized clinical trial of patients with extensive-stage SCLC who were randomized to receive either carboplatin and etoposide with placebo or atezolizumab. They were randomized 1:1, and there were over 400 patients randomized to each arm. The major finding [that we presented at the 2019 AACR Annual Meeting] was survival; this has been presented before and updated today. There is an improvement in survival when atezolizumab is added to chemotherapy compared with when it is not. The hazard ratio was 0.7 and the median survival improved by 2 months. For one of the first times ever, we saw survival beat 1 year in this disease.

Could you expand on the implications of these findings?

It is now an FDA-approved regimen we can use in clinic in the United States. The results are convincing enough for regulatory approval, and it seems like many are adopting this regimen for the treatment of their patients. This is one of the first approvals in decades in SCLC. It is really exciting to have something where we are seeing meaningful improvements in survival. I do think this regimen will be adopted by many upfront, but this still leaves a big hole as to what we do after this regimen. It’s not a cure. It does help patients live longer, but there's still a lot of work to do.

These data have been presented before, but [the take-home message is that] we don't see an increase in toxicity by adding the immunotherapy to chemotherapy. This is a relatively effective regimen with no added safety findings.

Are there any other novel approaches under investigation in SCLC that have potential?

Some of my colleagues identified that a new molecule may predict sensitivity to some other agents. That molecule wouldn't be for everyone with SCLC, but a subgroup. We looked at tumor mutational burden in this population as part of IMpower133, but we didn't quite see that it helped predict response, at least with the blood-based test.

References

1. Liu S, Mansfield A, Szczęsna S, et al. PL02.07 IMpower 133: primary PFS, OS and safety in a ph1/3 study of 1L atezolizumab + carboplatin + etoposide in extensive-stage SCLC. J Thorac Oncol. 2018;13(10):S185-S186. doi: 10.1016/j.jtho.2018.08.013.
2. Mansfield A, Liu SV, Szczęsna A, et al. CT199/13-IMpower133: primary efficacy and safety + CNS-related adverse events in a ph1/3 study of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Presented at: 2019 AACR Annual Meeting; March 29-April 3, 2019; Atlanta, GA. Abstract CT199/13.