Ramalingam Weaves Through Expanding SCLC Landscape

Suresh S. Ramalingam, MD

The treatment of patients with small cell lung cancer (SCLC) has changed very little in the last few decades. However, the introduction of checkpoint inhibitors may change the prognosis for a number of patients with this disease, said Suresh S. Ramalingam, MD.

In April 2018, the FDA granted a priority review to a supplemental biologics license application for nivolumab (Opdivo) for the treatment of patients with SCLC with disease progression following 2 or more lines of therapy. Findings from the phase I/II CheckMate-032 trial showed a median overall survival (OS) of 4.4 months and a 1-year OS rate of 33% with single-agent nivolumab in patients with progressive SCLC following ≥1 prior line of therapy.^1,2

Additionally, an exploratory analysis from this trial investigated the combination of nivolumab and ipilimumab (Yervoy) in patients with recurrent SCLC with a high tumor mutational burden (TMB). In this high-TMB subgroup, the combination demonstrated an objective response rate (ORR) of 46%. Additionally, nivolumab/ipilimumab had a superior ORR versus nivolumab monotherapy (21%) in this population, which Ramalingam said supports the idea that combinations may be more beneficial than monotherapy in SCLC.³

Pembrolizumab (Keytruda) has also demonstrated encouraging response rates in patients with SCLC. Findings from the phase Ib KEYNOTE-028 trial showed that pembrolizumab induced an ORR of 33% in patients with extensive-stage SCLC.⁴

Although there have been early signals with other agents, such as PARP inhibitors and lurbinectedin, immunotherapy remains the most promising option that is emerging for this disease, Ramalingam said. More data on novel agents will be released at the 2018 ASCO Annual Meeting, such as the full results with rovalpituzumab tesirine (Rova-T), which thus far has demonstrated underwhelming preliminary results in the third-line setting of relapsed/refractory SCLC treatment.

OncLive: What is the prognosis of patients with newly diagnosed SCLC?

The FDA recently granted a priority review to single-agent nivolumab for the treatment of patients with SCLC. Could you share some insight on the efficacy of this agent in this disease?

In an interview with OncLive, Ramalingam, deputy director of Winship Cancer Institute of Emory University, shed light on the recent data with these agents in SCLC.Ramalingam: We divide SCLC into 2 broad subgroups. There is what we call limited-stage SCLC, which is an earlier stage of lung cancer, and then there is extensive-stage SCLC, which is the typical metastatic SCLC. The prognosis is different for these 2 groups. If someone has limited-stage SCLC, we see a 5-year survival rate of approximately 25%. There is a subset of those patients whom we can cure with chemotherapy and radiation. We cannot cure patients with extensive-stage disease. Presently, the median survival is around 10 months. Their prognosis is considerably worse than those with limited stage SCLC. PD-1/PD-L1 inhibition seems to be a rational strategy in SCLC. These tumors have a high TMB, which can predict who might benefit from agents like nivolumab and pembrolizumab. There will be some phase II studies done with nivolumab and pembrolizumab. [These agents] have shown response rates of 10% to 15%. These are used in patients who have already had standard chemotherapy in the frontline setting, and then go on to get immunotherapy in the second-line setting. The median progression-free survival is relatively modest with the immune checkpoint inhibitors. At first look, one could say that there is some promise here, but we need to better understand who responds to these agents and how we can personalize therapy based on biomarkers.

There was another clinical trial in which patients either received nivolumab alone, or they got nivolumab with ipilimumab. In this experience, the combination seemed to do better than nivolumab alone. The NCCN has now included the combination of nivolumab and ipilimumab in their guidelines for second-line SCLC treatment.

If selection for PD-1/PD-L1 agents is improved, could immunotherapy have a bigger impact in this disease?

Is there an effort toward developing biomarkers for immunotherapy in SCLC?

Findings with lurbinectedin in the SCLC landscape came out late last year. Have any further data been released?

Is there any promise for PARP inhibitors in this disease?

What is the outlook for Rova-T?

There are ongoing trials comparing nivolumab to topotecan, combining nivolumab with chemotherapy, and combining PD-1 inhibitors with CTLA-4 inhibitors. These are active compounds. Monotherapy with PD-1 inhibition has been relatively low to modest. The randomized trials that are ongoing will help us understand if they are better than the current standard of care in this setting, which is topotecan.We remain hopeful and optimistic that immunotherapy will be able to improve the outcomes for patients with SCLC. The need is fairly high, simply because what we currently use in the second-line setting—topotecan—has relatively low response rates. Topotecan has been around for a very long time, and we haven't seen anything that exceeds the very low bar it has set. The availability of immune checkpoint inhibition in this space would be a substantial step forward in the treatment of patients with SCLC. There is a great deal of interest and anticipation that these ongoing trials in SCLC with immune checkpoint inhibitors will be fruitful.Very much so. The things that we have in non—small cell lung cancer (NSCLC), such as PD-L1 expression and TMB, are being studied in SCLC. Obviously, there are other exploratory studies to look at other markers, as well. We do not have a whole lot of information on these 2 markers, or any marker besides PD-L1 expression in SCLC at this point.There are a number of other strategies that are being studied, with lurbinectedin being one of them. At this point, we do not have any phase III data to show how it will fit in the landscape. There are ongoing trials that people are eagerly awaiting the results of. We have conducted a study with the PARP inhibitor veliparib in combination with chemotherapy, and it showed some modest signals. Our main interest is now looking to see if there is a biomarker that can be used to select patients [for PARP inhibitors]. There is another PARP inhibitor that has shown single-agent activity in SCLC called talazoparib; I believe that is also being studied in a larger group of patients. PARP inhibitors may be beneficial. Again, the key would be to select patients based on biomarkers. There was a lot of enthusiasm after the initial reports came out with Rova-T for patients who had high DLL3 expression. The response rate in the initial experience was about 40%. Now, there is a larger data set that will be reported at the 2018 ASCO Annual Meeting, and there is also a press release that indicated that the company will delay the submission for Rova-T for FDA approval. This raises the notion that perhaps the drug did not prove as active in subsequent follow-up studies as it had in the first study.

Are there any other early-stage or emerging agents in SCLC?

As I glance through the abstracts for the 2018 ASCO Annual Meeting that are now available for public view, it is clear that response rates are lower with Rova-T in this group of patients compared with the initial report. There is now an ongoing conversation about what level of activity would be necessary to have this drug in the clinic. There are some toxicity concerns with Rova-T, such as skin toxicities and pleural effusions. How those are managed can determine what level of efficacy is sufficient for Rova-T to be used in the clinic.I must say that immunotherapy is by far the most anticipated area. Combinations of immunotherapy with other immune-based agents is one strategy. Then based on the recent success in NSCLC with combining chemotherapy with immunotherapy, trials are pursuing a similar approach in SCLC.

The outcomes for SCLC have not changed in many decades. There is a critical unmet need to have effective therapies, and immune checkpoint inhibition is definitely one approach that we hope will help us move the needle.

References

1. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Checkmate 032: nivolumab (N) alone or in combination with ipilimumab (I) for the treatment of recurrent small cell lung cancer (SCLC). J Clin Oncol. 2016;34(suppl; abstr 100).
2. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883-895. doi: 10.1016/S1470-2045(16)30098-5.
3. Antonia S. Impact of tumor mutation burden on the efficacy of nivolumab or nivolumab + ipilimumab in small cell lung cancer: an exploratory analysis of CheckMate 032. In: Proceedings from the 2017 World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract OA 07.03a.
4. Ott PA, Elez E, Hiret S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2017;35(34): 3823-3829. doi: 10.1200/JCO.2017.72.5069.