Consolidation therapy with the PD-L1 antibody durvalumab after chemoradiotherapy extended survival in patients with limited-stage small cell lung cancer (SCLC) compared with standard-of-care chemoradiotherapy alone, according to the first planned interim analysis of the phase III ADRIATIC trial presented at the 2024 ASCO Annual Meeting by David R. Spigel, MD, FASCO, Chief Scientific Officer, Sarah Cannon Research Institute, Nashville.1 These positive results are the first for limited-stage SCLC in several decades, said experts, and the results were hailed as “groundbreaking” and greeted with loud applause at the Plenary Session.
David R. Spigel, MD, FASCO
At the 3-year follow-up, median overall survival was 55.9 months in the durvalumab-treated group vs 33.4 months in the placebo group, reflecting an absolute difference of almost 2 years and a 27% reduction in the risk of death (P = .0104). At a median follow-up of 27.6 months, median progression-free survival was 16.6 months with durvalumab vs 9.2 months with placebo, reflecting a 24% reduction in the risk of disease progression or death (P = .0161).
“Durvalumab as consolidation treatment after chemoradiotherapy demonstrated a statistically significant and clinically meaningful improvement in overall survival and progression-free survival compared with placebo in limited-stage SCLC in the ADRIATIC trial. The treatment benefit was consistent across all predefined patient subgroups for both overall survival and progression-free survival. These data suggest that durvalumab will become the new standard of care,” said Dr. Spigel.
“We have seen advances with immunotherapy in locally advanced unresectable and metastatic non–small cell lung cancer. We’ve also seen advances in extensive or metastatic SCLC. This is the first trial to show that immunotherapy helps patients with limited-stage or nonmetastatic SCLC,” he added.
There have been no major advances in limited-stage SCLC for decades. The current standard of care is concurrent chemotherapy and radiotherapy, but most patients will relapse within 2 years of treatment, and median overall survival is about 25 to 30 months. Five-year survival ranges from 29% to 34%. Thus, better treatments are sorely needed.
Study Details
The phase III, randomized, double-blind, placebo-controlled, multicenter international ADRIATIC study was designed to evaluate the role of durvalumab with or without the CTLA-4 antibody tremelimumab as consolidation therapy after concurrent chemoradiation in patients with stage I to III limited-stage SCLC, including those with unresectable stage I to III disease. Prior to randomization, patients had no sign of disease progression. They were randomly assigned to one of three arms, receiving either durvalumab, placebo, or durvalumab plus tremelimumab, and treatment was continued until disease progression or unacceptable toxicity for up to 2 years.
Concurrent chemoradiotherapy consisted of four cycles of platinum/etoposide with radiation begun before the end of the second chemotherapy cycle. Some patients received prophylactic cranial irradiation.
At the ASCO meeting, Dr. Spigel reported results of the first planned interim analysis of the comparison between the durvalumab arm (n = 264) and the placebo arm (n=266). The data regarding the combination of durvalumab plus tremelimumab are still blinded and will be presented in the future.
Baseline characteristics were well balanced between the durvalumab and placebo arms. Most patients had stage III disease and were treated with cisplatin/etoposide chemotherapy plus once-daily radiation. About one-third of the durvalumab group and one-quarter of the placebo recipients remained on treatment for 2 years. The most common reason for not completing treatment was disease progression.
The 3-year overall survival rate was 56.5% for the durvalumab arm vs 47.6% for the placebo arm. Subgroup analysis of overall survival showed a consistent benefit for durvalumab across all predefined subgroups, including age, gender, race, type of chemotherapy, and use of prophylactic cranial irradiation.
At a median follow-up of more than 2 years, median progression-free survival was about 17 months for the durvalumab group vs 9 months for the placebo group, a 24% reduction in risk of disease progression or death (P = .0160). Subgroup analysis of progression-free survival showed a consistent benefit for durvalumab across all subgroups.
Safety Profile
Durvalumab had an acceptable safety profile, according to Dr. Spigel. The rate of grade 3 or 4 adverse events was similar in both groups—about 24%. Serious adverse events were reported in 29.8% of the durvalumab group vs 24.2% of the placebo group.
Treatment was stopped due to adverse events in about 16% of the durvalumab group compared to 11% of the placebo group. Radiation pneumonitis developed in 38% of durvalumab recipients vs 30% of the placebo group. The rate of severe pneumonitis (grade 3 or 4) was 3% in the durvalumab group and 2.6% in the placebo group. Deaths were reported in 2.7% and 1.9% of patients, respectively. Specifically, two patients on the durvalumab arm experienced fatal encephalopathy and pneumonitis.
The study is ongoing, and future results will determine whether outcomes are improved in the group of patients treated with the combination of durvalumab and tremelimumab. The researchers plan to analyze subsets of patients to determine if specific groups will have greater benefit from these immunotherapies.
Expert Point of View
“SCLC is the most aggressive type of lung cancer. Treatment of limited-stage SCLC with intent to cure has not changed since the 1980s. The key takeaway point from the groundbreaking ADRIATIC trial is that durvalumab consolidation is a new standard for care for patients with limited-stage SCLC who have not had disease progression on chemoradiation,” said formal discussant of this trial, ASCO Expert Lauren Byers, MD, of The University of Texas MD Anderson Cancer Center, Houston.
Lauren Byers, MD
“This is important because the magnitude of the survival benefit is about 2 years with durvalumab consolidation, whereas in other trials in SCLC, survival benefit is measured in months. The subgroup analysis suggests that starting durvalumab early after chemoradiotherapy may increase the benefit,” she continued.
Follow-up trials will address the optimal sequencing of immunotherapy and combinations. The next step will be to identify which patients benefit the most from immunotherapies and to develop further personalized treatment for SCLC. “We know one size does not fit all,” said Dr. Byers. She suggested that the explanation for the greater magnitude of benefit of durvalumab in limited-stage disease compared to extensive-stage disease may be due to intrinsic differences in four distinct molecular subtypes of SCLC that have been recently defined. “Two inflammatory subtypes appear more frequently in limited-stage disease than in extensive-stage SCLC and may explain the benefit of durvalumab,” she said.
DISCLOSURE: The study was funded by AstraZeneca. Dr. Spigel has a leadership role with ASCO and a consulting or advisory role with AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Ipsen, Jazz Pharmaceuticals, Lyell Immunopharma, MedImmune, Monte Rosa Therapeutics, Novartis, Novocure, and Sanofi/Aventis; has received institutional research funding from AbbVie, Aeglea Biotherapeutics, Agios, Amgen, AnHeart Therapeutics, Apollomics, Arcus Biosciences, Arrys Therapeutics, Ascendis Pharma, Asher Biotherapeutics, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Celgene, Celldex, Cyteir, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Ellipses Pharma, EMD Serono, Endeavor BioMedicines, Erasca, Evelo Biosciences, Faeth Therapeutics, Foundation Bio, Fujifilm, G1 Therapeutics, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Immunogen, Incyte, Ipsen, Janssen Oncology, Janux Therapeutics, Jazz Pharmaceuticals, Kronos Bio, Lilly, Loxo, Lyell Immunopharma, MacroGenics, MedImmune, Merck, Millennium, Moderna Therapeutics, Monte Rosa Therapeutics, Nektar, Neon Therapeutics, Novartis, Novocure, Oncologie, Peloton Therapeutics, Pfizer, Phanes Therapeutics, PTC Therapeutics, PureTech, Razor Genomics, Repare Therapeutics, Rgenix, Seagen, Shenzhen Chipscreen Biosciences, Stemline Therapeutics, Strata Oncology, Synthekine, Taiho Oncology, Takeda, Tango Therapeutics, Tarveda Therapeutics, Tesaro, Tizona Therapeutics, Transgene, The University of Texas Southwestern Medical Center–Simmons Cancer Center, Verastem, and Zai Lab; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Genentech, and Novartis. Dr. Byers has received honoraria from Clinical Care Options and UpToDate; has served in a consulting or advisory role for AbbVie, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Genentech, Jazz Pharmaceuticals, Merck Sharp & Dohme, Novartis, and Puma Biotechnology; has received institutional research funding from Amgen, AstraZeneca, and Jazz Pharmaceuticals; and holds patents or receives royalties related to molecular subtyping of small cell lung cancer to predict therapeutic responses, as well as methods and systems for diagnosis, classification, and treatment of small cell lung cancer and other high grade neuroendocrine carcinomas.
REFERENCE
1. Spigel DR, Cheng Y, Cho BC, et al: ADRIATIC: Durvalumab as consolidation treatment for patients with limited-stage small-cell lung cancer. 2024 ASCO Annual Meeting. Abstract LBA5. Presented June 2, 2024.
