A phase 3 randomized clinical trial published in the New England Journal of Medicine on November 2, 2023 has found that adding the immunotherapy drug durvalumab to neoadjuvant chemotherapy significantly improves outcomes for patients with resectable non-small cell lung cancer (NSCLC).
The AEGEAN trial, funded by AstraZeneca, enrolled 802 patients with stage II-IIIB NSCLC across 28 countries between January 2019 and April 2022. Patients were randomized 1:1 to receive either durvalumab or placebo in addition to platinum-based chemotherapy before surgery, followed by adjuvant durvalumab or placebo for up to 12 months.
The study's primary endpoints were event-free survival and pathological complete response. At the first interim analysis, with a median follow-up of 11.7 months, the durvalumab group showed significantly improved event-free survival compared to placebo (hazard ratio 0.68, p=0.004). The 12-month event-free survival rate was 73.4% with durvalumab vs 64.5% with placebo.
Pathological complete response rates were also significantly higher in the durvalumab group (17.2% vs 4.3%, p<0.001). Importantly, these benefits were observed across most subgroups, including patients with PD-L1 expression <1%.
To be eligible, patients had to have newly diagnosed, previously untreated, histologically confirmed resectable stage IIA-IIIB NSCLC. Key exclusion criteria included previous exposure to immunotherapy, active autoimmune disorders, and planned sublobar resections. The protocol was amended during enrollment to exclude patients with EGFR mutations or ALK translocations.
The study population was representative of the global NSCLC patient population, with a median age of 65 years, 71.6% male, and 85.5% current or former smokers. Over 70% had stage III disease and about half had N2 nodal involvement. Histology was roughly evenly split between squamous and non-squamous subtypes.
Safety profiles were generally consistent with known effects of durvalumab and chemotherapy. Grade 3-4 adverse events occurred in 42.4% of durvalumab patients vs 43.2% of placebo patients. Immune-mediated adverse events were more common with durvalumab (23.7% vs 9.3%) but were mostly grade 1-2.
A key strength of this study is its robust design as a large, international, randomized phase 3 trial. The perioperative approach, combining neoadjuvant and adjuvant immunotherapy, is also notable and may provide synergistic benefits. However, there are some limitations to consider.
The follow-up duration is still relatively short at a median of 11.7 months. Longer-term data will be important to assess durability of benefit and any late toxicities. The exclusion of EGFR/ALK-positive patients partway through the trial, while clinically appropriate, does limit generalizability to that population.
Additionally, the trial design does not allow for direct assessment of the relative contributions of the neoadjuvant vs adjuvant components. Future studies comparing different sequencing approaches may help clarify this.
The authors conclude that perioperative durvalumab plus neoadjuvant chemotherapy significantly improves outcomes for patients with resectable NSCLC, with a manageable safety profile. They suggest this regimen should be considered as a potential new standard of care for this patient population.
The potential clinical impact of these findings is substantial. If widely adopted, this approach could significantly reduce recurrence rates and improve survival for early-stage NSCLC patients. The benefit seen even in PD-L1 low expressors is particularly noteworthy and could expand the population of patients considered for immunotherapy.
However, implementation may face some challenges. The perioperative approach requires close coordination between medical oncology, thoracic surgery, and other specialties. Careful patient selection and monitoring for immune-related adverse events will be crucial. Additionally, the cost implications of adding immunotherapy in the early-stage setting will need to be considered.
This study adds to a growing body of evidence supporting the use of immunotherapy in earlier stages of NSCLC. It aligns with recent positive results from other trials like CheckMate-816 (neoadjuvant nivolumab), IMpower010 (adjuvant atezolizumab), and KEYNOTE-091 (adjuvant pembrolizumab).
An interesting aspect of this trial is the perioperative approach, which theoretically combines the benefits of priming anti-tumor immunity before surgery while also addressing micrometastatic disease afterward. While cross-trial comparisons should be made cautiously, the authors note that regimens including neoadjuvant immunotherapy appear to show at least similar, if not greater, benefit compared to adjuvant-only approaches.
The pathological complete response rates seen in this trial are also noteworthy. While the correlation between pathological response and long-term outcomes in NSCLC is still being established, high pCR rates are generally considered a positive prognostic indicator.
One question that arises from this study is how to optimally sequence and combine different treatment modalities in early-stage NSCLC. Future research may explore tailoring perioperative approaches based on individual patient and tumor characteristics, potentially incorporating biomarkers beyond PD-L1 expression.
The safety profile observed in this trial is reassuring, with no new signals identified. However, the increased rate of immune-related adverse events with durvalumab underscores the need for vigilant monitoring and management, particularly in the perioperative setting where such events could potentially delay surgery or adjuvant therapy.
It's worth noting that this trial excluded patients with EGFR mutations or ALK translocations, a decision made in light of emerging data suggesting limited benefit from immunotherapy in these populations. The subgroup analysis showing no clear benefit in EGFR-mutated patients enrolled before this exclusion supports this approach. This highlights the importance of molecular testing in treatment selection, even in early-stage disease.
In conclusion, the AEGEAN trial represents a significant advancement in the treatment of early-stage NSCLC. By demonstrating substantial improvements in event-free survival and pathological complete response rates with the addition of durvalumab to standard chemotherapy, it establishes a new potential standard of care for patients with resectable disease. As with any practice-changing study, careful consideration of patient selection, potential toxicities, and resource implications will be crucial as these findings are translated into clinical practice. Ongoing follow-up from this trial and further studies building on these results will help refine our approach to treating early-stage NSCLC in the era of immunotherapy.
References
Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023;389(18):1672-1684. doi:10.1056/NEJMoa2304875
