Adding durvalumab to EP for ES-SCLC improves overall survival

Adding durvalumab immunotherapy to etoposide and platinum (EP) for the first-line treatment for extensive-stage small cell lung cancer (ES-SCLC) significantly improved 18-month overall survival, compared with EP alone, in the phase 3 CASPIAN trial.

The overall survival (OS) rate at a planned interim analysis 18 months after treatment initiation in the open-label trial was 33.9% among 268 patients randomized to receive the programmed death-ligand 1 (PD-L1) inhibitor durvalumab (Imfizi) and EP (D+EP), compared with 24.7% in 269 patients who received only EP, and median OS in the study arms, respectively, was 13.0 vs. 10.3 months (hazard ratio, 0.73), Luis Paz-Ares, MD, PhD, reported at the World Conference on Lung Cancer.

“The overall survival benefit [and] the magnitude of the benefit was very consistent across all the relevant study subgroups; that includes those patients with brain metastases,” said Dr. Paz-Ares, chair of the medical oncology department at the Hospital Doce de Octubre, and associate professor at the Universidad Complutense, and head of the lung cancer unit at the CNIO (National Oncology Research Center), all in Madrid.

The secondary endpoints of progression-free survival (PFS) and objective response rate (ORR) also were improved with D+EP, compared with EP: Median PFS was 5.1 vs. 5.4 months; the 12-month PFS rate was 17.5% vs. 4.7% in the arms, respectively (hazard ratio, 0.78); and investigator-assessed ORR was 79.5% vs. 70.3% (OR, 1.64), he said.

Study subjects were treatment-naive ES-SCLC patients randomized 1:1:1 to receive 1,500 mg of durvalumab + EP either with or without 75 mg of the anti-CTLA-4 agent tremelimumab, or to an EP-only control group. Patients in the immunotherapy arms received up to four cycles of EP followed by maintenance durvalumab until progression, and those in the control arm received up to six EP cycles with optional prophylactic cranial irradiation.

More than half of the patients in the control arm (56.8%) received all six EP cycles, he noted.

The interim analysis looked only at the D+EP and EP groups; the group receiving tremelimumab as well as D+EP will be included in the final CASPIAN analysis, he explained.

The incidence of grade 3/4 adverse events was similar between the D+EP and EP groups (61.5% vs. 62.4%), and the incidence of hematologic toxicities was numerically higher in the EP arm, he noted, adding that no new safety signals were identified.

The findings are intriguing, as ES-SCLC is a recalcitrant disease; initial response rates among EP-treated patients are high, but patients typically relapse within 6 months of starting treatment, and median OS is only about 10 months, Dr. Paz-Ares explained, noting that EP has been the standard first-line treatment for more than 30 years.

“More recently, immune checkpoint inhibitors have shown significant activity in this setting, particularly when combined with platinum-etoposide as first-line treatment,” he said. “The CASPIAN trial has evaluated the role of durvalumab, plus or minus tremelimumab, in combination with EP for [ES-SCLC].”

Of note, this chemoimmunotherapy regimen offers flexibility in platinum choice (carboplatin or cisplatin), reflecting current clinical practice for this challenging disease, and the 27% reduction in the risk of death with the addition of durvalumab was seen despite a robust control arm regimen that permitted up to six cycles of EP and prophylactic cranial irradiation, Dr. Paz-Ares said.

“With all those data, we believe combining durvalumab with either cisplatin- or carboplatin-etoposide in extensive-stage small cell lung cancer provides a new, important treatment option for patients and physicians,” he concluded.

Invited discussant Myung-Ju Ahn, MD, of Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, said the CASPIAN findings confirm the benefit of immune checkpoint inhibition in ES-SCLC as also demonstrated in the IMpower133 study of atezolizumab + EP for ES-SCLC, which was reported at WCLC 2018 and simultaneously published in the New England Journal of Medicine.

Based on these findings, D+EP is a new standard for the treatment of ES-SCLC, Dr. Ahn said, noting, however, that results from the D+EP+tremelimumab arm of CASPIAN, and findings from the ongoing phase 3 KEYNOTE 604 trial of pembrolizumab + EP for ES-SCLC are pending, and that since the efficacy of immunotherapy in SCLC has been observed in only a minority of patients in studies reported to date, predictive biomarker study is warranted for identifying those most likely to benefit.

“There is still a lot of room for investigation to improve small cell lung cancer,” she said. “There is still a long way to go.”

The CASPIAN trial was sponsored by AstraZeneca. Dr. Paz-Ares reported financial relationships with several pharmaceutical companies including AstraZeneca. Dr. Ahn reported receiving honoraria from, and/or serving as a consultant or adviser for AstraZeneca, Bristol-Myers Squibb, Ono, Merck Sharp & Dohme, Takeda, Boehringer Ingelheim, Roche, and Alpha Pharmaceuticals.