Patients with treatment-naive resectable non–small cell lung cancer (NSCLC) treated with neoadjuvant durvalumab plus chemotherapy and adjuvant durvalumab monotherapy had improved event-free survival and pathologic complete response rates compared with those who received neoadjuvant chemotherapy alone, according to an interim analysis of event-free survival and a final analysis of pathologic complete response in the phase III AEGEAN trial reported at the American Association for Cancer Research (AACR) 2023 Annual Meeting.1 The data were presented by lead author John V. Heymach, MD, PhD, Chair of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston.
John V. Heymach, MD, PhD
At a median follow-up of 11.7 months, the interim analysis found that median event-free survival was not reached in the durvalumab-containing arm vs 25.9 months in the chemotherapy-alone arm, reflecting a 32% reduction in the risk of disease progression and death with the addition of durvalumab to chemotherapy. In the final analysis of pathologic complete response, the rate was 17.2% in the durvalumab arm vs 4.3% in the placebo arm, representing a 13% absolute difference favoring the addition of durvalumab to chemotherapy. Perioperative durvalumab plus neoadjuvant chemotherapy was associated with a manageable safety profile.
“AEGEAN is the first phase III study to describe the benefit of perioperative immunotherapy and adjuvant immunotherapy in NSCLC. Perioperative durvalumab plus neoadjuvant chemotherapy significantly improved both pathologic complete response and event-free survival among patients with resectable NSCLC vs neoadjuvant chemotherapy alone. This improvement was observed regardless of the platinum agent used [cisplatin or carboplatin]. The addition of durvalumab did not impact completion of chemotherapy or surgery,” explained Dr. Heymach.
“Non–small cell lung cancer remains the leading cause of cancer mortality. Surgery remains the standard of care with curative intent for early-stage NSCLC. Historically, about half of patients who undergo resection experience recurrence. Recent phase III trials have demonstrated the clinical benefit of checkpoint inhibitors as either neoadjuvant or adjuvant therapy for resectable NSCLC. Consequently, some checkpoint inhibitors are approved in this space. Anything we can do to increase cure rates for these patients could be a tremendous advance,” he said.
AEGEAN was conducted across 222 sites in 28 countries between January 2019, and April 2022. The study randomly assigned 802 patients with treatment-naive NSCLC stage II to IIIB in a 1:1 ratio to receive durvalumab or placebo plus platinum-based chemotherapy every 3 weeks for four cycles before surgery. After surgery, patients received further durvalumab or placebo for up to 12 cycles.
A total of 62 patients with EGFR and ALK mutations were excluded from the intent-to-treat analysis for efficacy after it became evident that these patients do not benefit from checkpoint inhibitor therapy. This left a total 740 patients for the efficacy analysis.
At baseline, both treatment arms were well balanced for demographic and disease characteristics. Median patient age was 65 years, and more than two-thirds of patients were male with an Eastern Cooperative Oncology Performance performance score of 0. About 40% were Asian. About 60% were former smokers, and about 25% were current smokers. More than 70% had stage III NSCLC. About half the tumors had a squamous histology, and the others were nonsquamous. About 30% had PD-L1 expression of at least 50%. About 70% had nodal involvement.
In both arms, about 81% underwent surgery, and more than 60% started adjuvant therapy. At the time of the data lock, 23% of patients were receiving ongoing therapy with durvalumab or placebo.
As previously noted, at the first planned interim analysis, there was a 32% reduction for the durvalumab-treated group in the likelihood of an event-free survival event (defined as the length of time from randomization to an event such as disease progression precluding definitive surgery, disease recurrence, or death). Median event-free survival was not reached in the durvalumab arm vs 29.5 months in the placebo arm. The 12-month event-free survival rate was 73.4% vs 64.5%, respectively; the 24-month rate was 63.3% vs 52.4%, respectively.
Subgroup analysis showed that the benefit of neoadjuvant and adjuvant durvalumab extended broadly across all subgroups, including current smokers and disease stages. The benefit was greater in patients with stage IIIA NSCLC, but benefits were also observed in those with stages IIB and IIIB disease. The benefit of durvalumab was seen across all PD-L1 levels and was highest in those whose tumors expressed PD-L1 ≥ 50%. Durvalumab’s benefit was observed regardless of whether patients received cisplatin-based or carboplatin-based chemotherapy.
The rate of pathologic complete response was 17.2% for durvalumab-treated patients vs 4.3% for the placebo group—an absolute difference of 13%. A major pathologic response was seen in 33.3% vs 12.3%, respectively, for an absolute difference of 21% favoring durvalumab.
The rate of grade 3 or 4 adverse events regardless of causality was similar in both treatment arms, about 42%. Treatment-related adverse events of grade 3 or 4 were observed in about 32% of both groups. Deaths were uncommon and occurred in 1.8% and 0.5% of the two groups, respectively.
Immune-mediated adverse events were reported in 23.5% of the durvalumab group and 9.8% of placebo-treated patients. These events were largely grade 1, Dr. Heymach noted. The rates of grade 3 or 4 immune-mediated adverse events were 4% and 2.5%, respectively. Pneumonitis of any grade was reported in 3.8% vs 1.8%, respectively.
Dr. Heymach told listeners that AEGEAN was conducted during the pandemic, and about 10% of patients had COVID-19 infection during the study.
DISCLOSURE: AEGEAN was funded by AstraZeneca. Dr. Heymach has served as an advisor to Genentech, Mirati Therapeutics, Eli Lilly and Co, Janssen, Boehringer Ingelheim, Regeneron, Takeda, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca, BioAtla, Sanofi, Spectrum, GlaxoSmithKline, EMD Serono, Blueprint Medicines, and Chugai Pharmaceuticals; has received research support from AstraZeneca, Boehringer Ingelheim, Spectrum, Mirati, Bristol Myers Squibb, and Takeda; and has received licensing fees or royalties from Spectrum.
1. Heymach JV, Harpole D, Mitsudomi T, et al: AEGEAN: A phase 3 trial of neoadjuvant duvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. AACR Annual Meeting 2023. Abstract CT005. Presented April 16, 2023.
Roy S. Herbst, MD, PhD
Invited discussant Roy S. Herbst, MD, PhD, Deputy Director of the Yale Cancer Center, New Haven, Connecticut, called this “a very exciting abstract exploring when surgery meets immunotherapy.”
He commented: “NSCLC is a big disease, affecting 2 million or more people...