Ramalingam Reflects on Recent Advances in SCLC

Suresh S. Ramalingam, MD

The small cell lung cancer (SCLC) landscape is experiencing a wave of new clinical trials, many of which are proving the activity of novel targeted agents and immunotherapy. Suresh A. Ramalingam, MD, explained that the field is anxiously awaiting phase III data to confirm the promise that these agents have shown so far.

Single-agent lurbinectedin showed compelling activity as a second-line treatment for patients with SCLC, according to results of a phase II trial presented at the 2018 ASCO Annual Meeting.¹ Of the 61 patients treated with lurbinectedin, 24 (39.3%) had a partial response, and the median progression-free survival (PFS) and overall survival (OS) was 4.1 months and 11.8 months, respectively. Additionally, the agent was deemed to have an acceptable tolerability and safety profile.

This agent is currently being studied in the global, randomized, phase III ATLANTIS study with doxorubicin versus investigator’s choice of either cyclophosphamide, doxorubicin and vincristine or topotecan (NCT02566993). ATLANTIS is actively recruiting for patients with SCLC who have failed 1 prior platinum-containing line of therapy.

In findings also presented at the 2018 ASCO Annual Meeting, the DLL3-targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) achieved a best overall response rate (ORR) of 29% (95% CI, 22-36) as a third-line treatment for DLL3-high biomarker-selected patients with relapsed/refractory SCLC in the phase II TRINITY trial.²

In June 2018, Genentech (Roche) reported in a press release that the combination of their agent atezolizumab (Tecentriq) with chemotherapy improved OS and PFS in patients with extensive-stage SCLC when compared with chemotherapy alone. This met the coprimary endpoints of the phase III IMpower133 trial, but data have yet to be presented.

OncLive: What are your thoughts on the phase II data with lurbinectedin?

In light of the results presented at the 2018 ASCO Annual Meeting, do you have any further thoughts on Rova-T?

In an interview with OncLive^®, Ramalingam, deputy director of Winship Cancer Institute of Emory University, reflected on recent data and what is on the horizon for SCLC.Ramalingam: It was a small study of about 60 patients, but it showed activity in both the platinum-sensitive and platinum-refractory patients. The median PFS was very promising. I came out of [the 2018 ASCO Annual Meeting] thinking it could be something helpful for our patients. There is a phase III clinical trial with lurbinectedin that is currently underway, and this only makes it more exciting to see what the results of that phase III trial will be. [The ATLANTIS study] is a randomized phase III trial that has been ongoing for about 1.5 years.The presentation at the 2018 ASCO Annual Meeting showed a low response rate with Rova-T, even in the biomarker-positive patients. That is lower than the 40% response rate reported from the first cohort of patients. In the broader experience, it looks like the drug may not be as active as we had previously thought.

Atezolizumab is showing promise. Can you share your insight on that agent in SCLC?

There are also concerns about some of the adverse events (AEs) that we have seen, including photosensitivity and fusions. Based on all of these things, Rova-T, at this point, would not be something that I would anticipate entering clinical practice in 2018. Hopefully, ongoing studies will further stratify the efficacy of this drug, and [address] how to manage the AEs.We just learned that in SCLC, a randomized phase III trial of chemotherapy with or without atezolizumab was positive for PFS and OS through a press release. The press release that Genentech put out indicated that the trial met its primary endpoint of improving efficacy. We eagerly anticipate the results to be reported at one of the upcoming meetings. If the results are clinically meaningful, atezolizumab is going to be the first immune checkpoint inhibitor to enter the SCLC space. It will be in combination with chemotherapy in the frontline setting.

Are there any other immunotherapy agents showing promise in SCLC?

This has gotten a lot of people excited, including myself. For the first time, we have seen a survival trial in the frontline setting be positive for a survival endpoint-driven trial.In SCLC, the nivolumab (Opdivo) plus ipilimumab (Yervoy) combination was shown to be associated with response rates of approximately 25%. That is now in the NCCN guidelines for second-line therapy. There are ongoing randomized trials with that combination. At this point, we are awaiting the results of those trials, and we have not seen any data from these trials yet.

Is there anything else going on in the SCLC space that you would like to highlight?

There is a trial of nivolumab versus topotecan, as well as a study of nivolumab plus ipilimumab in the maintenance setting of SCLC after patients have received chemotherapy. The results of both of these trials, which have completed accrual, will help us understand the role of nivolumab in the nivolumab/ipilimumab combination. My feeling is that immune checkpoint inhibition with PD-1/PD-L1 as monotherapy is unlikely to be of substantial benefit in SCLC. The combination with chemotherapy or CTLA-4 inhibition might be a more appealing strategy.In SCLC now, the main strategy is figuring out how to incorporate immunotherapy with all of the excitement that we have seen. Immunotherapy in combination with chemoradiotherapy in limited-stage SCLC is going to be studied in a large trial. The use of immunotherapy as maintenance is going to be studied, and we already have a positive trial for immunotherapy in combination with chemotherapy.

The other question will be biomarkers for immunotherapy in SCLC. Is it going to be the same as what we use for non—small cell lung cancer? Is PD-L1 expression a good marker? How is tumor mutation burden involved? These are all going to be important questions.

References

1. Perez JMT, Leary A, Besse B, et al. Efficacy and safety of lurbinectedin (PM1183) in small cell lung cancer (SCLC): Results from a phase 2 study. J Clin Oncol. 2018;36 (suppl; abstr 8570).
2. Carbone DP, Morgensztern D, Moulec SL, et al. Efficacy and safety of rovalpituzumab tesirine in patients With DLL3-expressing, ≥ 3rd line small cell lung cancer: Results from the phase 2 TRINITY study. J Clin Oncol. 2018;36 (suppl; abstr 8507).