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A bid for another expansion of indications for the blockbuster oncology drug pembrolizumab (Keytruda) could face a hard sell during an FDA advisory committee hearing.

An FDA pointed to concerns dating back almost 5 years about the adequacy of data to support an indication for pembrolizumab as neoadjuvant therapy for triple-negative breast cancer (TNBC). According to the staff-prepared document, submitted to the Oncologic Drugs Advisory Committee (ODAC), the FDA expressed concern in 2016 that a proposed 15% improvement in pCR (pathologic complete response) in the planned "may not be adequate to predict improvement in long-term outcomes of patients with early-stage TNBC."

Subsequently, the FDA "discouraged submission of this sBLA (supplemental Biologics License Application) given the demonstrated small improvement in pCR rate which had questionable clinical meaningfulness and the immaturity of the EFS (event-free survival) and OS (overall survival) data."

Results reported in 2019 showed a 13.6% absolute difference in pCR in favor of neoadjuvant chemotherapy plus pembrolizumab followed by adjuvant pembrolizumab as compared with chemotherapy plus placebo followed by placebo in the adjuvant setting. According to the FDA document, the most recent analysis showed an absolute difference of 7.5%.

Follow-up continues for the co-primary endpoint of EFS and for the key secondary endpoint of OS, for which data remain immature for definitive analysis. ODAC will meet virtually on Tuesday to recommend whether the FDA should make a decision about the sBLA at this point or wait for more data from future analyses of KEYNOTE-522.

Currently, no PD-1/L1-targeted agent has an indication for early breast cancer. Pembrolizumab won accelerated approval last November for metastatic or recurrent unresectable triple-negative breast cancer -- its astonishing 18th indication overall -- and atezolizumab (Tecentriq) has a similar indication. The latter's approval was based on the IMpassion130 trial, which showed a modest but statistically significant improvement in median progression-free survival (PFS) with the combination of atezolizumab and nab-paclitaxel (Abraxane). The success in the metastatic setting led to optimism that checkpoint inhibition might have a role in early breast cancer.

The KEYNOTE-522 trial involved 1,174 patients with untreated, operable, high-risk TNBC. They were randomized 2:1 to receive carboplatin-paclitaxel chemotherapy plus pembrolizumab or placebo, followed by adjuvant pembrolizumab or placebo. The co-primary endpoints were pCR and EFS. The trial identified no new safety signals for any of the drugs.

In their submission to ODAC, Merck representatives stated that the KEYNOTE-522 results made a case for a favorable risk-benefit conclusion.

"The observed statistically significant increase in pCR, the clinically meaningful absolute pCR rate for pembrolizumab + NAC (neoadjuvant chemotherapy), the clinically meaningful improvement and durable trend in EFS in all participants regardless of initial response to neoadjuvant therapy and surgical outcome, and trend for improvement in OS outweigh the incremental toxicity from adding pembrolizumab to chemotherapy, which is generally manageable with standard clinical practice."

"KEYNOTE-522 provides a new therapeutic regimen that resulted in promising long-term outcomes in patients with high-risk, early-stage TNBC, which is a population with a high unmet medical need," they added.

The FDA noted that pembrolizumab's approval in November for metastatic TNBC also included PD-L1 expression ≥10%, not an unselected population as proposed for the neoadjuvant indication. The status was granted on the basis of data showing a PFS benefit after a protocol amendment, and an OS benefit has yet to be demonstrated. As a result, confirmation of a benefit with pembrolizumab is still needed in the metastatic setting.

"Data for pembrolizumab from the metastatic TNBC setting are not supportive of clinical benefit in the neoadjuvant setting," FDA staff concluded.

The ODAC virtual meeting begins at 10 a.m. ET Tuesday. The meeting will be available to the public via .

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