Posted: August 14, 2019
Shirish Gadgeel, MBBS, is the Mary Lou Kennedy Research Professor in Thoracic Oncology and a professor in the Division of Hematology/Oncology at the University of Michigan Rogel Cancer Center. He is the co-leader of the Thoracic Oncology Research Program and associate director for cancer care at Networking and Affiliated Centers. In an interview with the IASLC Lung Cancer News, Dr. Gadgeel explained the purpose of maintenance trials in SCLC and the challenges of enrolling patients on clinical trials at the time of an SCLC diagnosis. He also discussed a few pivotal maintenance trials and their implications for further research and daily care.
Q: Is the maintenance setting a viable venue for drug development and exploration in SCLC?
A: As a general matter, I do think maintenance trials have value. SCLC is a unique tumor in that patients can be very symptomatic at the time of diagnosis; therefore, systemic chemotherapy must be initiated relatively quickly. The current recommended chemotherapy regimen does, at least initially, produce responses quite quickly in a good proportion of patients; however, this benefit is not sustained in a substantial number of patients. Unfortunately, as of now, second-line therapies have not shown significant or durable benefit. Therefore, if there is a survival benefit in a maintenance trial, which is a clear and clean endpoint, there is a pretty good chance that the maintenance therapy led to the improvement.
Q: Do the positive results from IMpower1331 make further studies of maintenance therapy problematic? Or does the overall survival (OS) advantage seen in this study re-invigorate such efforts?
A: I think that maintenance trials still have relevance despite the new positive dataset from IMpower133, in which atezolizumab plus chemotherapy improved survival compared with chemotherapy alone. Although we see improvement, the median survival is still only a little more than 12 months, so there is further room for improvement. IMpower133 results don’t change my opinion because an improvement in survival may actually be a reason to consider other drugs in addition to maintenance atezolizumab.
Q: CheckMate 4511 did not show an OS benefit for ipilimumab and nivolumab in combination versus placebo as maintenance therapy in extensive-stage SCLC. Please comment on the study design and objective endpoints.
A: CheckMate 451 was a pretty large trial of 800 patients that failed to meet the primary endpoint of OS. Although disappointing, I don’t think the results are necessarily surprising because when you examine the existing data for checkpoint inhibitors in extensive-stage SCLC, it is clear that the drugs work but only for a minority of patients. In that minority, however, the benefit can be sustained. It would make sense that this benefit does not translate to a very large study population. I think that with these immunotherapy agents, particularly in SCLC, biomarkers are even more relevant. It would be interesting to see if the investigators of CheckMate 451 assessed whether patients with specific biomarkers in their tumors did derive more benefit with the combination of nivolumab and ipilimumab as maintenance therapy. Current data suggest two biomarkers that might be relevant with regard to efficacy of immunotherapy: tumor mutation burden and PD-L1 expression.
CheckMate 0323 showed that the benefit from immunotherapy agents, particularly the combination of nivolumab and ipilimumab, was restricted to patients who had high tumor mutation burden. Likewise, patients with PD-L1–positive tumors appeared to derive benefit in a phase II trial of pembrolizumab. Of note, PD-L1 expression was not only assessed within tumor cells but also in stromal cells, such as tumor-associated macrophages or tumor-associated lymphocytes, so positivity was based on a composite score for PD-L1 expression in the tumor and in the surrounding microenvironment. If the tumor had positive PD-L1 expression, then patients appeared to do well on the treatment. I think that a maintenance trial evaluating these checkpoint inhibitors, but restricted to patients with these biomarkers, may show a survival advantage.
Q:What are your thoughts on the ongoing MERU trial (NCT03033511) testing rovalpituzumab tesirine (Rova-T) in this setting? Given the track record in TRINITY,4 are there concerns regarding toxicity?
A: Based on the available data—particularly the TRINITY trial—and some personal experience, I continue to have some concerns about the toxicity of Rova-T. All of the toxicities associated with the agent are manageable, but my concern is that the toxicities can be sustained and could potentially affect the ability to initiate subsequent therapies. Even if the drug does wind up providing clinical benefit, my concern is that when disease eventually progresses, patients will have a more difficult time tolerating the next treatment because of the toxicities they experienced receiving Rova-T. However, I am awaiting the results of MERU before making a final decision about the clinical value of this drug in the maintenance setting. ✦
References:
1. Horn L, Mansfield AS, Reck M, et al. Phase I/III trial of atezolizumab with carboplatin and etoposide in ES-SCLC in first-line setting (IMpower133). J Clin Oncol. 2017;35:15_ suppl, TPS8584.
2. Ready N, Owonikoko TK, Postmus PE, et al. CheckMate 451: A randomized, double-blind, phase III trial of nivolumab (nivo), nivo plus ipilimumab (ipi), or placebo as maintenance therapy in patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC) after first-line platinum-based doublet chemotherapy (PT-DC). J Clin Oncol. 2016;34:15_suppl, TPS8579.
3. Ready N, Farago AF, de Braud F, et al. Third-Line Nivolumab Monotherapy in Recurrent SCLC: CheckMate 032. J Thorac Oncol. 2019;14(2):237- 244.
4. Carbone DP, Morgensztern D, Le Moulec S, 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;36:15_suppl, 8507.
