Immunotherapy Research Key to Moving SCLC Field Forward

Ramsey N. Asmar, MD

The addition of atezolizumab (Tecentriq) to chemotherapy for the frontline treatment of patients with extensive-stage small cell lung cancer (SCLC) significantly prolonged progression-free (PFS) and overall survival (OS) compared with chemotherapy alone, according to phase III data of the IMpower133 trial.

In the study, 403 patients with treatment-naïve SCLC were randomized to receive atezolizumab (n = 201) or placebo (n = 202). At a median follow-up of 13.9 months, the median OS in the atezolizumab group was 12.3 months versus 10.3 months for chemotherapy alone (HR, 0.70; 95% CI, 0.54-0.91; P = .007). Moreover, median PFS was 5.2 months for patients treated with the combination and 4.3 months in the placebo group.

Patients received carboplatin and etoposide with either atezolizumab or placebo for 4 induction cycles of 21 days, followed by a maintenance phase of the PD-L1 inhibitor or placebo.

According to Ramsey N. Asmar, MD, the paradigm of SCLC has finally started to shift in the right direction; however, more work with immunotherapy is needed. For example, the development of effective biomarkers is a necessary area of research.

Yet, some studies show mixed findings with immunotherapy. For example, single-agent nivolumab (Opdivo) did not improve OS versus standard topotecan or amrubicin, where approved, in patients with SCLC who relapsed following platinum-based chemotherapy, according to topline findings from the phase III CheckMate-331 trial.

The FDA granted an accelerated approval to nivolumab in August 2018 for the treatment of patients with metastatic SCLC who have progressed on platinum-based chemotherapy and at least 1 other line of therapy.

OncLive: How would you describe the state of SCLC treatment?

Can you elaborate on some of the immunotherapy studies we have seen?

What are your thoughts on the findings from the IMpower133 trial?

What other recent studies in this space should be highlighted?

In an interview at the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Asmar, a thoracic oncologist at Atlantic Health System, discussed recent advances and next steps in SCLC.Asmar: This disease has very much lagged behind NSCLC in terms of clinical progress. We are hopefully about to turn a corner with exciting new developments, particularly with some immunotherapy results that have recently been published.Nivolumab is a checkpoint inhibitor that was FDA approved in August 2018 for use in extensive-stage SCLC in patients who have progressed on 2 prior lines of therapy. This was based on data from the CheckMate-032 trial. It looked at nivolumab as monotherapy and nivolumab plus ipilimumab (Yervoy). These agents have shown good, durable responses in heavily pretreated patients. These are now viable options for patients following chemotherapy.This was a frontline study looking at atezolizumab combined with carboplatin and etoposide chemotherapy. This was a randomized, placebo-controlled trial. Patients receiving the triplet had improved OS and PFS compared with those receiving the chemotherapy regimen with placebo. This is a landmark study, in that atezolizumab is the first agent to improve survival in the frontline setting in many decades. I believe this triplet will be the new standard of care.There were data presented at the 2018 ASCO Annual Meeting for a novel antibody-drug conjugate called rovalpituzumab tesirine (Rova-T). It has an interesting mechanism of action, targeting a protein called DLL3, which is expressed on 80% of SCLC cells. Upon binding to that target, the agent releases a cytotoxic payload that damages DNA. It ultimately kills the cell.

What are the selection criteria for second-line treatment?

There were phase I data showing that this agent was active in heavily pretreated patients with SCLC. The phase II data was presented at the 2018 ASCO Annual Meeting. There is a lot more work that needs to be done here, particularly with its toxicity profile; some people are concerned about that. We need larger phase III studies.As of right now, nivolumab has been FDA approved technically in the third-line setting. However, if you look at the NCCN guidelines, they suggest second-line treatment with nivolumab plus or minus ipilimumab. This combination is largely available. In terms of how to select patients, it's an interesting question.

Does the future of SCLC treatment lie in immunotherapy?

What is an area of SCLC you would like to see addressed in research?

Is there anything you else that you would like to add?

There's a lot of ongoing investigation looking at biomarkers. We know PD-L1 expression is a biomarker in NSCLC, but it's not a reliable biomarker in SCLC. Tumor mutational burden (TMB) could potentially be used in this disease. The idea is that the higher the TMB, the better the response would be to immunotherapy.The future of all cancer treatment lies in immunotherapy. SCLC will be part of that paradigm shift. We learned that this disease is a highly immunogenic tumor. Modulation of the immune system can lead to responses. Where we are headed now is fine-tuning the immunotherapy arsenal and finding new agents with more potency specifically in SCLC.One very interesting area of this disease that is currently being explored is epigenetics. SCLC tumors are heavily methylated, and there have been interesting science showing that the use of HDAC inhibitors can be of therapeutic value in SCLC. Epigenetics is an area of great interest in the coming years.SCLC is one of the most devastating cancers. It's very lethal and very aggressive. The last 20 to 30 years has been somewhat of a dark age for this disease. However, we are now finally starting to see some movement in terms of new treatment and new ideas. I'm optimistic that in the near future, we'll turn a corner.

Horn L, Mansfield A, Havel L, et al. First-line atezolizumab plus chemotherapy in extensive-stage small cell lung cancer [published online September 25, 2018]. N Eng J Med. doi: 10.1056/NEJMoa1809064.