AACR 2023 | AEGEAN Trial: New Data on Neoadjuvant Chemotherapy/Immunotherapy + Adjuvant Immunotherapy Released
According to the preliminary results of the phase III AEGEAN trial (NCT03800134) interim analysis presented at the AACR Annual Meeting in 2023, in patients with resectable non-small cell lung cancer (NSCLC), the perioperative durvalumab combined with platinum-based neoadjuvant chemotherapy showed statistically significant improvements in pathological complete response (pCR) and event-free survival (EFS) compared to placebo combined with chemotherapy. [1,2]
John V. Heymach reported the results of the AEGEAN trial at AACR 2023. For eligible early-stage NSCLC patients, surgery is the primary curative intervention. Recent phase III trials [including CheckMate 816 (NCT02998528), IMpower010 (NCT02486718), and KEYNOTE-091 (NCT02504372)] have shown benefits from using PD-1/PD-L1 inhibitors in the neoadjuvant or adjuvant treatment of resectable NSCLC. [3-5] Therefore, the FDA has approved nivolumab and atezolizumab for the neoadjuvant and adjuvant treatments, respectively, for resectable NSCLC. [6,7] However, combining neoadjuvant and adjuvant immunotherapies in the perioperative regimen can eradicate micrometastases and enhance long-term therapeutic effects.
This treatment strategy was evaluated in the global, randomized, double-blind, placebo-controlled AEGEAN trial. The study population consisted of untreated, resectable stage IIA-IIIB NSCLC patients (according to the AJCC 8th edition), scheduled for lobectomy, sleeve resection, or bilobectomy. Apart from requiring an ECOG performance status score of 0 or 1, patients also had to confirm their PD-L1 status and show no EGFR or ALK mutations.
Between January 2, 2019, and April 19, 2022, researchers randomized 802 patients at a 1:1 ratio to receive either the neoadjuvant regimen of "durvalumab 1,500 mg IV + platinum-based chemotherapy (every 3 weeks, 4 cycles)" or the same regimen of placebo IV + platinum-based chemotherapy. After surgery, based on randomization, patients received 12 cycles of either durvalumab or placebo treatment every 4 weeks. Postoperative radiation therapy was allowed. The primary endpoints were pCR confirmed by the central laboratory (based on the IASLC 2020 standards) and EFS assessed by blinded independent central review (BICR) following the RECIST v1.1 criteria. Secondary endpoints included major pathological response (MPR), BICR-assessed disease-free survival (DFS), and overall survival (OS).
Research Protocol
The minimum follow-up time was 6.7 months. Baseline characteristics between the two groups were well balanced. Most patients were male, with a diagnosis of stage IIIA, histological type of non-squamous NSCLC, and PD-L1 expression levels between 1% and 49%. Regarding tumor, lymph nodes, and metastasis classifications, most patients were at T3 and N2 stages. Additionally, over 70% of the patients planned to receive carboplatin-based neoadjuvant chemotherapy.
Baseline Characteristics
In the neoadjuvant treatment phase, the majority of patients in the trial group completed 4 cycles of chemotherapy (84.7%) and durvalumab (86.9%). In the control group, 87.2% of the patients finished 4 cycles of chemotherapy, and 88.5% completed 4 cycles of placebo. In general, 77.6% of patients in the trial group and 76.7% in the placebo group underwent surgery after neoadjuvant treatment. In the adjuvant treatment phase, 65.8% and 63.4% of patients in the two groups, respectively, received durvalumab adjuvant therapy, and around 23% of patients in both groups were still undergoing adjuvant therapy as of the data cutoff.
Research Results
The pCR rate for the durvalumab group (n=366) was 17.2%, and for the placebo group, it was 4.3% (n=374), showing an absolute difference of 12.9% (95% CI: 8.7%-17.6%; P=0.000036). The MPR for the durvalumab and placebo groups was 33.3% and 12.3%, respectively, presenting an absolute difference of 21.0% (95% CI: 15.1%-26.9%; P=0.000002).
With a median follow-up of 11.7 months (range: 0.0-46.1 months) and a maturity of 31.9%, the median Event-Free Survival (EFS) was not reached (NR; 95% CI: 31.9-NR) in the durvalumab monotherapy group vs. 25.9 months (95% CI: 18.9-NR) for the placebo. The stratified Hazard Ratio (HR) was 0.68 (95% CI: 0.53~0.88; P=0.003902). The 12-month and 24-month EFS rates for the durvalumab monotherapy group were 73.4% and 63.3%, respectively, while for the placebo group, they were 64.5% and 52.4%, respectively.
EFS: Median EFS (EFS stands for Event-Free Survival),EFS: 12-month EFS, EFS: 24-month EFS
Results
Other results indicated that the benefits in pCR (pathological complete response) and EFS (Event-Free Survival) were generally consistent across all predefined subgroups. Additionally, regardless of whether neoadjuvant chemotherapy uses cisplatin (HR=0.59; 95% CI: 0.35~1.00) or carboplatin (HR=0.73; 95% CI: 0.54~0.98), the durvalumab monotherapy regimen improved EFS.
Safety Profile
During the entire study period, 96.5% of patients in the durvalumab monotherapy group experienced adverse events (AE) of any grade, compared to 94.7% in the placebo group. In each group, 42.3% and 43.4% of patients experienced grade 3 or 4 AEs. 12.0% and 6.0% of patients discontinued durvalumab monotherapy or placebo treatment, respectively. Furthermore, 1.8% and 1.0% of patients canceled surgery. The mortality rate from all causes of adverse events was 5.8% and 3.8%, respectively.
86.5% of patients in the durvalumab monotherapy group and 80.7% in the placebo group experienced AEs believed to be related to durvalumab, placebo, or chemotherapy of any grade. The incidence of grade 3 or 4 events was 32.3% and 33.1%, respectively. 1.8% and 0.5% of patients died from adverse events potentially related to the treatment.
23.5% of patients in the durvalumab monotherapy group reported any grade of immune-mediated adverse reactions (irAE), compared to 9.8% in the placebo group. Each group saw 4.0% and 2.5% of patients experience grade 3 or 4 irAEs. The incidence of pneumonia of any grade was 3.8% and 1.8%, respectively.
Researchers' Statement
"NSCLC remains a leading cause of cancer mortality. Historically, about half of the patients relapse after undergoing surgery," said the chief research author, John V. Heymach, the head of thoracic/head and neck oncology at MD Anderson Cancer Center, in a press release. "Anything we can do to improve the cure rate for these patients can be a significant advancement. AEGEAN is the first phase III study describing the benefits of perioperative immunotherapy combined with neoadjuvant chemotherapy, bringing potential new treatment regimens for resectable NSCLC patients."
John V. Heymach, MD, PhD
"Before the study commenced, there were concerns that administering neoadjuvant immunotherapy might make surgery more challenging for some patients. However, in reality, an almost identical number of patients in both groups were able to undergo surgery, indicating that including neoadjuvant immunotherapy did not reduce the number of patients who could continue with surgery," Heymach stated.
"We are delighted to see that the trial met its primary endpoint of increasing pCR and significantly reducing the likelihood of disease progression, relapse, or death. For NSCLC patients, the good news is that multiple treatment options are now showing improved effectiveness. This research lays the foundation for designing new combination regimens. It's a new treatment paradigm that requires multidisciplinary team involvement—integrating oncology, molecular pathology, and surgical oncology teams more extensively to collectively strive for better clinical outcomes," Heymach added.
Researchers will continue to monitor long-term EFS, DFS (Disease-Free Survival), and OS (Overall Survival) data.
References
1. Heymach JV, Harpole D, Mitsudomi T, et al. AEGEAN: a phase 3 trial of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT005.
2. Durvalumab-based treatment before and after surgery improved outcomes for patients with resectable non-small cell lung cancer. Press release. AACR. April 16, 2023. Accessed April 16, 2023. https://aacr.ent.box.com/
3. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170
4. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomized, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344-1357. doi:10.1016/S0140-6736(21)02098-5
5. O’Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022;23(10):1274-1286. doi:10.1016/S1470-2045(22)00518-6
6. FDA approves neoadjuvant nivolumab and platinum-doublet chemotherapy for early-stage non-small cell lung cancer. News release. FDA. March 4, 2022. Accessed April 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
7. FDA approves atezolizumab as adjuvant treatment for non-small cell lung cancer. News release. FDA. October 15, 2021. Accessed April 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/