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Head of the Thorax Institute Curie-Montsouris
Nicolas Girard, MD, PhD, has disclosed that he has received consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche, Sanofi, and Teva, and funds for research support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche.
The current standard of care for patients with newly diagnosed extensive-stage small-cell lung cancer (ES-SCLC) combines immune checkpoint inhibitors with chemotherapy. In this setting, the PD-L1 inhibitors atezolizumab (with carboplatin plus etoposide) and durvalumab (with carboplatin/cisplatin plus etoposide) are approved for use, yielding a survival benefit for patients with ES-SCLC over chemotherapy alone. Now that we have chemotherapy plus immuno-oncology regimens in the first-line setting, there is an unmet need for new therapies in the setting of relapsed disease since the efficacy of available chemotherapy options, including topotecan, is low. In this commentary, I review some of the key clinical data in the treatment of patients with refractory ES-SCLC from the 2020 World Conference on Lung Cancer (WCLC) that will hopefully change the treatment landscape for relapsed SCLC in the near future.
Lurbinectedin Plus Irinotecan in Relapsed ES-SCLC
In 2020, lurbinectedin, a selective inhibitor of oncogenic transcription, received accelerated approval by the FDA for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy based on results from the PM1183-B-005-14 trial. The trial met its primary endpoints with an ORR, as determined by RECIST 1.1, of 35% and a median duration of response of 5.3 months (95% CI: 4.1-6.4).
At WCLC 2020, safety and efficacy data from a phase Ib/II study of lurbinectedin in combination with irinotecan was reported (NCT02611024). Evaluation of the combination was pursued based on preclinical data suggesting synergistic/additive antitumor activity when lurbinectedin was combined with the topoisomerase I inhibitor irinotecan. In the phase II expansion cohort, 21 patients with relapsed advanced ES-SCLC who received up to 2 previous lines of treatment received lurbinectedin, irinotecan, and G-CSF. The endpoints in this study included defining the maximum tolerated dose, safety, and efficacy.
In the current study, patients were pretreated with 38% having 2 lines of previous treatment. The ORR was 62%, with 81% having a stable disease response, and the median PFS was 6.2 months (95% CI: 4.3-8.5). The most common grade 3/4 treatment-related adverse events were neutropenia (62%), diarrhea (29%), and fatigue (24%). Because neutropenia is an expected adverse event, G-CSF support was included in the trial. Oncologists are familiar with prevention and management of neutropenia, so the combination of lurbinectedin and irinotecan could be of interest in relapsed advanced SCLC. Even though the phase III ATLANTIS trial, a landmark study that compared the combination of lurbinectedin and doxorubicin with the standard of care (topotecan or cyclophosphamide/doxorubicin/vincristine), failed to meet its primary endpoint of OS, I think the current results suggest that further investigation of lurbinectedin in combination of irinotecan is warranted.
In addition, lurbinectedin is also being evaluated in combination with pembrolizumab in the ongoing phase I/II LUPER trial (NCT04358237), which includes patients with relapsed ES-SCLC whose disease has progressed after first-line chemotherapy.
AMG 757 in Relapsed/Refractory ES-SCLC
DLL3 is an atypical Notch ligand that is highly expressed in SCLC and other neuroendocrine tumors, but not in normal tissues. Targeting DLL3 has been an investigational focus in the management of SCLC, including with the antibody–drug conjugate rovalpituzumab tesirine (Rova-T). Although early-stage trials showed promising results with Rova-T in the second-line and third-line settings, it was eventually shown that it had no clinically meaningful OS benefit when compared with control treatments as well as had significant toxicity. Therefore, its development was halted.
Another promising strategy targeting DLL3 that is currently under development is AMG 757, a bispecific antibody. A phase I trial (NCT03319940) is evaluating the safety of AMG 757 in 52 patients with refractory tumors after ≥ 1 line of platinum-based chemotherapy treatment and ≥ 1 line of systemic treatment. The primary endpoints for this study include safety, tolerability, and maximum tolerated dose and secondary endpoints include antitumor activity.
The report on this AMG 727 study at WCLC 2020 showed a confirmed PR of 14% in this cohort of patients, which is high compared with existing options in this setting. Moreover, in preliminary results that require additional follow-up, AMG 757 showed prolonged efficacy, with 20% for patients completing ≥ 6 months of treatment and a median duration of response of 6.2 months among patients with a confirmed response. A longer duration of response is an unmet need in patients with relapsed/refractory SCLC, and for me, these results are the most striking result with this agent.
Cytokine-release syndrome was observed with AMG 727 in 23 of 52 patients (44%), but it was manageable with supportive care and corticosteroids. This adverse event is part of the mechanism of action of bispecific antibodies and is probably associated with the efficacy, so was promising to see.
The results of both these trials are promising and, in the future, may provide much needed treatment options for patients with relapsed ES-SCLC, but we will need to wait for more data. Meanwhile, expanded access programs for the access to lurbinectedin are ongoing in several countries, and enrollment of patients in trials is more than ever recommended.
What are your thoughts on the new data on relapsed ES-SCLC reported at WCLC 2020? I encourage you to answer the polling question and post your questions and thoughts in the comments box below.