By Alice Goodman
May 10, 2023
Patients with Treatment-naive resectable non-small cell lung cancer (NSCLC) treated with neoadjuvant durvalumab plus chemotherapy and durvalumab monotherapy in the adjuvant showed improved event-free survival and pathologic complete response rates compared with those who received neoadjuvant chemotherapy alone, according to an interim analysis of resectable non-small cell lung cancer (NSCLC) survival and a final analysis of complete pathological response in the AEGEAN phase III study reported at the 2023 American Association for Cancer Research (AACR) annual meeting.1 Data were presented by the lead author John V. Heymach, MD, PhDChair of Thoracic/Head and Neck Medical Oncology at the MD Anderson Cancer Center at the University of Texas, Houston.
John V. Heymach, MD, PhD
At a median follow-up of 11.7 months, the interim analysis found that the median event-free survival was not achieved in the durvalumab-containing arm compared with 25.9 months in the chemotherapy-only arm, reflecting a reduction in the 32% risk of disease progression and death with the addition of durvalumab to chemotherapy. In the final pathological complete response analysis, the rate was 17.2% in the durvalumab arm versus 4.3% in the placebo arm, representing a 13% absolute difference in favor of adding 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 benefits of perioperative immunotherapy and adjuvant immunotherapy in NSCLC. Perioperative durvalumab plus neoadjuvant chemotherapy significantly improved both complete pathologic response and event-free survival among patients with resectable NSCLC compared with neoadjuvant chemotherapy alone. This improvement was observed regardless of the platinum agent used [cisplatin or carboplatin]. Adding durvalumab did not impact completion of chemotherapy or surgery, 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 undergoing resection experience a recurrence. Recent phase III trials have demonstrated the clinical benefit of checkpoint inhibitors as neoadjuvant or adjuvant therapy for resectable NSCLC. As a result, some checkpoint inhibitors are approved in this space. Anything we can do to increase cure rates for these patients could be a huge step forward, she said.
Study details
AEGEAN was conducted at 222 centers in 28 countries between January 2019 and April 2022. The study randomly assigned 802 treatment-naive patients with stage II to IIIB NSCLC in a 1:1 ratio to receive durvalumab or placebo plus chemotherapy a platinum base every 3 weeks for four cycles before surgery. After surgery, patients received additional durvalumab or placebo for up to 12 cycles.
A total of 62 patients with EGFR extension AND ALK the mutations were excluded from the intent-to-treat analysis for efficacy after it became apparent that these patients do not benefit from checkpoint inhibitor therapy. This left a total of 740 patients for the efficacy analysis.
At baseline, both treatment arms were well matched for demographic and disease characteristics. The mean age of the patients was 65 years and more than two-thirds of the patients were male with an Eastern Cooperative Oncology Performance Score of 0. Approximately 40% were Asian. About 60% were former smokers and about 25% were current smokers. More than 70% had stage III NSCLC. Approximately half of the tumors had squamous histology and the rest were non-squamous. Approximately 30% had at least 50% PD-L1 expression. About 70% had lymph node involvement.
In both arms, approximately 81% underwent surgery and more than 60% started adjuvant therapy. At the time of the data freeze, 23% of patients were receiving ongoing therapy with durvalumab or placebo.
Primary endpoints
As noted previously, at the first planned interim analysis, there was a 32% reduction for the durvalumab group in the probability of an event-free survival event (defined as the 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 compared with 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 analyzes showed that the benefit of neoadjuvant and adjuvant durvalumab extended broadly across all subgroups, including current smokers and disease stages. The benefit was greatest in patients with stage IIIA NSCLC, but benefits were also seen in those with stage IIB and IIIB disease. The benefit of durvalumab was observed at all PD-L1 levels and was greatest in those whose tumors expressed 50% PD-L1. The benefit of durvalumab was observed whether patients received cisplatin- or carboplatin-based chemotherapy.
The pathological complete response rate was 17.2% for durvalumab-treated patients versus 4.3% for the placebo group, an absolute difference of 13%. Major pathologic response was observed in 33.3% vs 12.3%, respectively, for an absolute difference of 21% in favor of durvalumab.
The rate of grade 3 or 4 adverse events regardless of causality was similar in both treatment arms, approximately 42%. Grade 3 or 4 treatment-related adverse events were observed in approximately 32% of both groups. Deaths were rare, occurring in 1.8% and 0.5% of the two groups, respectively.
Immune-mediated adverse events were reported in 23.5% of the durvalumab-treated group and 9.8% of the placebo-treated patients. These events were largely Grade 1, Dr. Heymach noted. Grade 3 or 4 immune-mediated adverse event rates were 4% and 2.5%, respectively. All grade pneumonia was reported in 3.8% vs 1.8%, respectively.
Dr. Heymach told listeners that AEGEAN was conducted during the pandemic and approximately 10% of patients had a COVID-19 infection during the study.
DISCLOSURE: AEGEAN was funded by AstraZeneca. Doctor Heymach He has advised 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 other products pharmaceuticals Chugai; he has received research support from AstraZeneca, Boehringer Ingelheim, Spectrum, Mirati, Bristol Myers Squibb and Takeda; and received license fees or royalties from Spectrum.
REFERENCE
1. Heymach JV, Harpole D, Mitsudomi T, et al: AEGEAN: A phase 3 study of neoadjuvant duvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. AACR Annual Meeting 2023. Excerpt CT005. Presented on April 16, 2023.
Expert Viewpoint: Roy S. Herbst, MD, PhD
Roy S. Herbst, MD, PhD
Invited interlocutorRoy S. Herbst, MD, PhDdeputy director of Yale Cancer Center, New Haven, Connecticut, called this abstract exploration very exciting when surgery meets immunotherapy.
He commented: NSCLC is a major disease, affecting 2 million or more people…
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