Limited-Stage SCLC Gets a New Standard of Care With Consolidation Durvalumab

CHICAGO — Consolidation treatment with durvalumab (Imfinzi) following concurrent chemoradiotherapy significantly improved both overall survival (OS) and progression-free survival (PFS) in patients with limited-stage small cell lung cancer (SCLC), the phase III randomized ADRIATIC trial showed.

Median OS was 55.9 months in the durvalumab group compared with 33.4 months in the placebo group (HR 0.73, 95% CI 0.57-0.93, P=0.0104), with 3-year landmark OS rates of 56.5% and 47.6%, respectively, reported David Spigel, MD, chief scientific officer at the Sarah Cannon Research Institute in Nashville, Tennessee, during a plenary session at the American Society of Clinical Oncology (ASCO) annual meeting.

Median PFS was 16.6 months with the anti-PD-L1 monoclonal antibody versus 9.2 months with placebo (HR 0.76, 95% CI 0.61-0.95, P=0.0161), with 2-year landmark PFS rates of 46.2% and 34.2%, respectively.

“Consolidation durvalumab will become the new standard of care for patients with limited-stage small cell lung cancer following chemoradiotherapy,” said Spigel, whose presentation of ADRIATIC’s results was met with a prolonged ovation from the plenary audience.

ASCO discussant Lauren A. Byers, MD, of the University of Texas MD Anderson Cancer Center in Houston, noted that standard treatment for limited-stage SCLC has been largely unchanged since the 1980s. ADRIATIC is the first positive global phase III trial of immunotherapy for limited-stage SCLC, she added.

She agreed with Spigel that the “groundbreaking” trial sets a new standard of care with consolidative durvalumab after concurrent chemoradiotherapy, and noted that the next step will be to move beyond a “one-size-fits-all” approach and “towards personalized, biomarker-driven approaches for patients with small cell lung cancer.”

These results are important because of “the magnitude of benefit that patients received with the addition of durvalumab consolidation,” she said.

She pointed out that the CASPIAN trial, which evaluated durvalumab plus etoposide versus etoposide as first-line treatment of extensive-stage SCLC, and the IMpower133 study, which evaluated atezolizumab (Tecentriq) plus carboplatin and etoposide versus carboplatin and etoposide in the same setting, both reported an OS improvement of only about 2 months.

“This looks very different in the limited-stage patients where there was almost a 2-year improvement in overall survival at the interim analysis of ADRIATIC,” she said. “Why is the value of durvalumab benefit that much greater for limited-stage disease as compared to extensive-stage disease?”

She suggested a possible reason could be biologic differences in SCLC, pointing to a study she and her colleagues at MD Anderson conducted in which they identified four distinct molecular subtypes of SCLC.

“These subtypes have distinct therapeutic vulnerabilities, including a subtype called the ‘inflamed’ group and the POU2F3 group that are relatively more inflamed, and seem to get relatively more benefit from the addition of anti-PD-L1 in extensive-stage patients, based on retrospective analysis of the CASPIAN and Impower133 trials,” Byers said.

“Interestingly, in limited-stage small cell lung cancer, those subtypes — the POU2F3 and inflamed subtypes — are more frequent than what we see in extensive-stage small cell lung cancer, and that may be part of the reason we are seeing greater benefit in patients with limited-stage disease,” she added.

In the double-blind, multicenter ADRIATIC trial, eligible patients had stage I to III limited-stage SCLC (stage I/II inoperable), a WHO performance status of 0/1, and had not progressed after concurrent platinum-based chemoradiotherapy. Prophylactic cranial irradiation was allowed before randomization. The study population had a median age of 62 years, about two-thirds were men, and most had stage III disease.

Patients were randomized to either durvalumab 1,500 mg IV monthly (n=264), placebo (n=266), or a third arm that combined durvalumab and tremelimumab (Imjudo). This interim analysis included only the comparison between durvalumab and placebo. The chemotherapy used was platinum and etoposide for four cycles, while the radiation therapy could either be given once daily at up to 66 Gy, or twice daily at up to 45 Gy, over 3 weeks.

Incidence of grade 3 and 4 adverse events (AEs) were similar in the durvalumab and placebo arms (24.4% and 24.2%, respectively), while there were more serious AEs reported in the durvalumab arm (29.8% vs 24.2%). Any-grade immune-mediated AEs were reported in 32.1% of patients in the durvalumab arm and 10.2% in the placebo arm, while rates of pneumonitis or radiation pneumonitis were 38.2% and 30.2% in the two groups, respectively.

AEs leading to treatment discontinuation occurred in 16.4% of patients in the durvalumab arm and 10.6% in the placebo arm.

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