FDA staff unimpressed by Merck & Co. data for adjuvant Keytruda in high-risk, early TNBC

In briefing documents posted to the FDA website ahead of an advisory panel meeting on February 9, agency staff cast doubt on data from the Phase III KEYNOTE-522 trial submitted by Merck & Co. to support an expanded label for its anti-PD-1 therapy Keytruda (pembrolizumab) in triple-negative breast cancer (TNBC). FDA reviewers characterised some key KEYNOTE-522 findings as "questionable" and indicated that both the study's design and results do not support approval.

Keytruda received FDA clearance for its first breast cancer indication last November, when the agency granted accelerated approval for use in combination with chemotherapy to treat patients with locally recurrent, unresectable or metastatic TNBC whose tumours express PD-L1 with a combined positive score of 10 or greater. Merck is looking to broaden the label to include treating patients with high-risk, early-stage TNBC, in combination with chemotherapy in the neoadjuvant setting, then as a single agent as adjuvant treatment after surgery.

The randomised KEYNOTE-522 study compared Keytruda to placebo in combination with chemotherapy in the neoadjuvant setting, and as monotherapy in the adjuvant setting, in 1174 patients with high-risk, early-stage TNBC. The co-primary endpoints are pathologic complete response (pCR) rate and event-free survival (EFS), while overall survival (OS) was assessed as a key secondary goal. Data from the first interim analysis of KEYNOTE-522 unveiled in 2019, showed that a significantly higher number of TNBC patients achieved pCR when Keytruda was added to chemotherapy, compared to chemotherapy alone, with rates of 64.8% and 51.2%, respectively, for a treatment difference of 13.6%.

FDA discouraged Merck from filing

FDA staff noted that at the most recent interim analysis, the pCR rates were 63% for Keytruda-treated patients and 55.5% in the placebo group, for a rate difference of "only 7.5%" based on all randomised patients. They suggested that this "small improvement" in pCR for neoadjuvant Keytruda is of "questionable clinical meaningfulness," regardless of tumour PD-L1 status. Moreover, the EFS endpoint had not met its pre-specified threshold for statistical significance and remained immature, with 53% of targeted EFS events having occurred. Agency staff said that as a result, the OS endpoint could not be formally tested and is also immature, with 32% of the targeted OS events having occurred.

"The FDA has repeatedly expressed concerns about the KEYNOTE-522 trial design and results to [Merck] and discouraged submission of this marketing application," reviewers said, noting that at a meeting in 2016, the agency had "stated that the proposed target of 15% improvement in pCR rate may not be adequate to predict improvement in long-term outcomes in patients with early-stage TNBC."

Evidence of greater toxicity

Meanwhile, the FDA staff also pointed out that more patients who received Keytruda compared to placebo experienced immune-mediated adverse events (AEs) or infusion reactions. Further, there were four deaths in patients who received Merck's drug that reviewers said were potentially due to immune-mediated AEs. "The addition of [Keytruda] is associated with increased toxicity due to increased immune-mediated AEs, some of which may be severe, irreversible, and/or require life-long medication in potentially curable and otherwise healthy patients," the FDA report said.

Roche's Tecentriq (atezolizumab) was approved by the FDA in 2019 in combination with chemotherapy for use in adults with PD-L1-positive unresectable, locally advanced or metastatic TNBC. The Swiss drugmaker reported that Tecentriq generated sales of CHF 723 million ($801 million) in the fourth quarter of 2020, up 25% from the year-ago period.

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