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The FDA should require clinical trials in perioperative therapy for non-small cell lung cancer (NSCLC) to address the individual contributions of neoadjuvant and adjuvant treatment to outcomes, an advisory committee unanimously recommended.

By an 11-0 vote, the Oncologic Drugs Advisory Committee (ODAC) agreed with the FDA staff position that standard two-arm trials do not adequately sort out the benefits attributable to the two phases of therapy in the current era of immunotherapy and emerging treatments that have add-on potential for resectable NSCLC. The issue has come into sharper focus in light of recent studies that have called into question benefits of the adjuvant component of perioperative treatment.

New trial designs are needed, said ODAC acting-chair Daniel Spratt, MD, of Seidman Cancer Center and Case Western Reserve in Cleveland. "I think the panel generally agrees that this is something, ideally, that can be addressed up front [and] that is harder to address after the fact. There were comments that this probably extends beyond sequence or phase, as well as duration of therapy."

Several panelists noted that mandating such trials will likely increase the cost of drug development, potentially the time required, and possibly its complexity.

"Overall the value may be substantial, especially to patients, and 'less may be more,'" Spratt continued. "If we're only focused on lung cancer, which is a common disease, it may be something far more feasible. Especially if this extends outside to other solid tumors and rare diseases, that becomes its own separate challenge."

"There was strong consensus that this is an important thing to mandate or figure out how best to incorporate into future trial designs," he added.

The panel also discussed at length whether the requirement should be applied to a pending supplemental application for perioperative durvalumab (Imfinzi) in resectable NSCLC. The phase III AEGEAN trial showed significant improvement in event-free survival (EFS) with the addition of durvalumab to neoadjuvant chemotherapy followed by adjuvant single-agent durvalumab for a year. Panelists expressed strong opinions about the implications of requiring a new trial to address both treatment phases, but FDA did not ask ODAC to vote on the issue.

The overarching issue is potential for overtreatment, said Erin Larkins, MD, acting director of Division of Oncology 2 at the FDA, during opening remarks.

"In a two-arm trial, the relative contribution of each phase -- the neoadjuvant phase and the adjuvant phase -- cannot be established, making it unclear if patients need both phases of therapy," she said. "In the past, FDA has granted approval to perioperative ICI [immune checkpoint inhibitor] regimens based on two-arm trial designs, one in breast cancer and one in non-small cell lung cancer. However, emerging data in non-small cell lung cancer has heightened uncertainty around the need for both phases of treatment."

The agency approved pembrolizumab (Keytruda) for perioperative treatment of resectable NSCLC based on the KEYNOTE 671 trial, which demonstrated a statistically significant improvement in EFS and overall survival. In that trial, patients received neoadjuvant therapy with pembrolizumab and chemotherapy, followed by adjuvant therapy with pembrolizumab alone, a design identical to that of the AEGEAN trial.

Supporting the FDA's concern about potential overtreatment with perioperative regimens, Larkins showed results from randomized trials of ICI therapy for resectable NSCLC: three perioperative trials -- Keynote 671, AEGEAN, and CheckMate 77T with nivolumab (Opdivo); CheckMate 816 with neoadjuvant nivolumab; and two studies of adjuvant ICI therapy -- IMpower010 with atezolizumab (Tecentriq) and KEYNOTE 091 with pembrolizumab.

Acknowledging the hazards and limitations of cross-trial comparisons, Larkins pointed to similar reductions in hazard ratios (0.58 to 0.73), regardless of whether patients received neoadjuvant, adjuvant, or perioperative therapy.

"Rather than support the need for the addition of adjuvant treatment to neoadjuvant chemoimmunotherapy, the observation of similar treatment effect sizes across trials raises concerns for the possibility of overtreatment when using a regimen approach incorporating ICI in both phases of treatment and challenges the notion that the perioperative regimen approach is needed for all patients," she said.

Adding to the FDA position, AstraZeneca recently announced that the phase III of adjuvant durvalumab for resected NSCLC failed to meet the primary endpoint of EFS in patients with PD-L1 expression of at least 25%.

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