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An advisory panel recommended the FDA not revoke the accelerated approval for atezolizumab (Tecentriq) in combination with nab-paclitaxel (Abraxane) for treating metastatic, PD-L1-positive triple-negative breast cancer (TNBC).

In a 7-2 vote, the Oncologic Drugs Advisory Committee (ODAC) affirmed the accelerated approval, with members clearly conflicted over the decision.

"This was a difficult decision in a very difficult disease to treat," said Harold Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston, who voted yes on the proposition. "I have spent decades caring for these patients, and we all wish we had fundamentally better options."

ODAC's meeting was the first of a three-day review of accelerated approvals with confirmatory trials that missed their primary endpoints.

FDA initially granted atezolizumab, a PD-L1 immune checkpoint inhibitor, accelerated approval in 2019 in combination with nab-paclitaxel for patients with untreated metastatic or locally advanced unresectable TNBC whose tumors express PD-L1, based on findings from the IMpassion130 trial, which showed a significant improvement in progression-free survival (PFS) over nab-paclitaxel alone.

But the agency issued a safety alert the following year, when atezolizumab plus paclitaxel as first-line treatment in metastatic TNBC failed to improve PFS over paclitaxel and placebo in PD-L1-positive patients in the phase III IMpassion131 trial. Additionally, overall survival was numerically worse in the investigational arm for both the PD-L1-positive subgroup and the total population.

In presentations during the meeting, FDA staff explained the agency's apprehension, noting that the observed PFS improvement in the IMpassion130 trial was modest, and the overall survival benefit in the PD-L1-positive subgroup did not reach statistical significance.

"The observed 7.5-month [overall survival] difference may be due to chance alone," said Laleh Amiri-Kordestani, MD, of the Division of Oncology at the FDA's Center for Drug Evaluation and Research. "Additionally, the benefit was not confirmed in the confirmatory IMpassion131 trial that enrolled a very similar population. And the apparent possible detriment to overall survival in this trial is concerning."

Stanley Lipkowitz, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, voted to maintain the accelerated approval and noted that the treatment landscape for metastatic TNBC has not changed, and that no therapies have demonstrated a significant survival benefit to date. "While the overall survival figures in IMpassion130 may not have reached statistical significance," he said, "there is a hint of it in the study."

"It's hard to discount the overall survival benefit observed in IMpassion130," agreed Alberto Montero, MD, of Case Western Reserve University in Cleveland, Ohio, explaining his yes vote by pointing out the need to maximize the therapeutic options in patients with such an aggressive terminal illness. "Most patients with stage IV triple-negative breast cancer live less than 2 years," he said.

In explaining his yes vote, ODAC chair Philip Hoffman, MD, of the University of Chicago, said there could be a number of reasons, other than lack of efficacy, for the failure of IMpassion131 to show benefit. "I don't feel there's enough evidence to say no to this," he added.

With the vote reaffirming the accelerated approval for atezolizumab plus nab-paclitaxel combination, the question now becomes what kind of confirmatory study sponsor Genentech can pursue in order to achieve regular approval.

"The most rigorous approach would be to repeat the original pivotal clinical trial," said Stephen Chui, MD, Genentech's Group Medical Director. "Enroll patients with PD-L1 positive metastatic TNBC, otherwise identical to those in IMpassion130, and randomize them to receive either nab-paclitaxel plus atezolizumab or nab-paclitaxel plus placebo."

"However," he added, "after the positive data readout from IMpassion130, we see that it could be challenging to randomize patients to receive nab-paclitaxel without cancer immunotherapy."

Genentech suggested that other possibilities of confirmatory trials include the ongoing , as well as the and trials which are studies in early-stage TNBC.

Matthew Ellis, MD, PhD, of Baylor College of Medicine in Houston, one of the two committee members voting no, agreed it will be difficult to perform the correct validation study, "which is taking the PD-L1-positive population and randomizing them between nab-paclitaxel versus nab-paclitaxel plus atezolizumab. No other study makes any sense at all."

"The science will not progress with continued approval," Ellis added. "It's not that I don't feel the tragedy of these women every day. I've done that for the last 30 years. I just think the data are the data and you can choose to interpret it in different ways. But, in the end the only correct interpretation is the statistics presented by the biostatisticians."

The FDA is not bound by ODAC's decisions but usually follows its advice.

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