ODAC Recommends Enhanced Trial Designs for Perioperative NSCLC Regimens Following Durvalumab Approval
核心洞察
The FDA's ODAC voted 11-0 in favor of requiring new trial designs for perioperative NSCLC (搜索) regimens to include within-trial assessment of treatment phase contribution.
This recommendation follows the FDA's approval of durvalumab plus chemotherapy as neoadjuvant treatment and durvalumab as adjuvant treatment for resectable NSCLC (搜索), based on the AEGEAN trial.
Concerns were raised about potential overtreatment and the need to determine the individual contributions of neoadjuvant and adjuvant phases in perioperative immune checkpoint inhibitor regimens.
The FDA's Oncologic Drugs Advisory Committee (ODAC) has recommended that future clinical trial designs for perioperative regimens in resectable non-small cell lung cancer (搜索) (NSCLC (搜索)) include adequate within-trial assessment of the contribution of each treatment phase. This decision follows the recent FDA approval of durvalumab (Imfinzi) in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by durvalumab monotherapy as adjuvant treatment, for adult patients with resectable NSCLC without known EGFR (搜索) mutations or ALK (搜索) rearrangements.
The approval, granted on August 15, 2024, was based on findings from the phase 3 AEGEAN trial (NCT03800134). However, the trial design did not clearly delineate whether the event-free survival (EFS) benefits observed with neoadjuvant durvalumab plus chemotherapy followed by adjuvant durvalumab were attributable to the neoadjuvant phase, the adjuvant phase, or both. The ODAC meeting, held on July 25, 2024, addressed these concerns, particularly the potential for overtreatment and the need to understand the individual contributions of each treatment phase.
AEGEAN Trial Data and ODAC Concerns
The AEGEAN trial demonstrated a statistically significant and clinically meaningful improvement in EFS, with a median EFS not reached (NR; 95% CI, 31.9-NR) in the durvalumab plus chemotherapy arm compared to 25.9 months (95% CI, 18.9-NR) in the chemotherapy alone arm (HR, 0.68; 95% CI, 0.53-0.88; P=.0039). Despite these positive results, the FDA noted that the trial's design did not allow for a within-trial assessment of the individual contributions of durvalumab in combination with chemotherapy in the neoadjuvant phase and durvalumab in the adjuvant phase.
"It’s important to note that the FDA’s question that was voted [on during the meeting] was specifically for future trials. They explicitly said this doesn’t apply to AEGEAN or current studies. There was a separate nonvoting question about whether additional studies were needed [regarding] AEGEAN, and the consensus of the panel was that additional studies were not needed," said John V. Heymach, MD, PhD, in an interview with OncologyLive.
Implications for Future Trial Designs
The ODAC vote highlights the need for more sophisticated trial designs that can discern the specific benefits of each treatment phase in perioperative regimens. This may involve separate trials or multi-arm trial designs to evaluate neoadjuvant and adjuvant therapies independently. According to Heymach, the FDA raised concerns that mandating studies to understand the contribution of each phase of treatment could potentially slow down the trial process. Perioperative studies may take 5 to 8 years to read data out, and pros and cons should be weighed when designing future trials.
Alternative Approaches and Biomarkers
To mitigate potential delays, experts suggest exploring novel trial designs and incorporating biomarkers, such as pathologic complete response, as potential endpoints. Marina Chiara Garassino, MD, emphasized the importance of leveraging liquid biopsies, radiomics, and patient-specific conditions to personalize the adjuvant component of therapy. Such approaches could help identify patients who would benefit most from adjuvant therapy, potentially reducing overtreatment and associated toxicities.
Durvalumab in the Context of Existing Therapies
Durvalumab is now one of two FDA-approved perioperative regimens for resectable NSCLC (搜索). The other is pembrolizumab (Keytruda) plus platinum-containing chemotherapy as neoadjuvant treatment followed by adjuvant single-agent pembrolizumab. Data from the KEYNOTE-671 trial showed a median overall survival (OS) not reached (95% CI, NR-NR) in the pembrolizumab arm versus 52.4 months (95% CI, 45.7-NR) in the chemotherapy/placebo arm (HR, 0.72; 95% CI, 0.56-0.93; 1-sided P = .00517).