Charles M. Rudin, MD, PhD, Hassenfeld Professor and Chief of the Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, commented that although ATLANTIS1 “unfortunately joins the ranks of negative phase III studies in patients with recurrent small cell lung cancer,” there are “some positive outcomes and silver linings.”
As background, Dr. Rudin emphasized the aggressive nature of small cell lung cancer and noted that although recent treatment advances, especially immunotherapy, have helped “flatten the [survival] curve,” at least 90% of patients still experience disease recurrence (usually soon) and have few treatment options.
The recent approval of lurbinectedin offers an alternative to older standard treatments, such as topotecan. Lurbinectedin produces responses in about 35% of patients and a median overall survival of about 9.5 months. But its major advantage over topotecan has been better tolerability, particularly less myelosuppression, according to data derived from a single-arm phase II trial in 105 patients.2
Charles M. Rudin, MD, PhD
“Was ATLANTIS even the right trial?” Dr. Rudin asked. As a follow-up to the single-agent study, 2 he said his preference would have been a phase III study that validated the previous findings. “Instead, we got this one, although I do understand the rationale,” he said. “When ATLANTIS was designed, we thought we would need a combination for substantial activity, but, in fact, I think doxorubicin added toxicity and required lowering the doses of lurbinectedin. We also saw the response rate was not higher—and, in fact, was numerically lower—than with single-agent lurbinectedin.”
“But this is the trial we have, and I think there are positive outcomes from a negative trial,” he commented. “We see hints of durable benefit in terms of progression-free survival and response rate, relative to control. And, again, the real win is on the toxicity side. Even with the addition of doxorubicin, we see substantial advantages over control arms in terms of hematologic toxicity.”
Practical Implications
ATLANTIS offers support for the continued study of lurbinectedin, especially as a “new platform on which to form better combinations for small cell lung cancer,” such as lurbinectedin plus irinotecan, he added. In a phase Ib/II study presented at the 2020 World Conference on Lung Cancer, lurbinectedin plus irinotecan yielded a response rate of 62% and a median progression-free survival of 6.2 months in previously treated patients.3
“It’s easy for me to be a Monday morning quarterback and say this was the wrong trial. But the data forthcoming with irinotecan will be very important. I think that is the right trial.”
Meanwhile, Dr. Rudin said: “This agent does appear to have efficacy. It only has accelerated approval, so we need confirmatory data, but meanwhile it does offer something for our patients.”
Finally, he advised: “For now, when we use it, I’d stick with the single agent. It demonstrates comparable outcomes, with a superior safety profile, to current standards of care.”
DISCLOSURE: Dr. Rudin has served as a consultant for AbbVie, Amgen, AstraZeneca, Epizyme, Genentech/Roche, Ipsen, Jazz, Lilly, and Syros and has served on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics.
REFERENCES
1. Paz-Ares L, Ciuleanu TE, Navarro A, et al: Lurbinectedin/doxorubicin versus CAV or topotecan in relapsed SCLC patients: Phase III randomized ATLANTIS trial. 2021 World Conference on Lung Cancer. Abstract PL02.03. Presented September 9, 2021.
2. Trigo J, Subbiah V, Besse B, et al: Lurbinectedin as second-line treatment for patients with small cell lung cancer: A single-arm, open-label, phase 2 trial. Lancet Oncol 21:645-654, 2020.
3. Ponce-Aix S, Coté G, Falcón A, et al: Lurbinectedin with irinotecan in relapsed small cell lung cancer: Results from the expansion stage of a phase I-II trial. J Thorac Oncol 16(suppl):S127 (Abstract OA11.04), 2021.
