FDA Panel Supports Atezolizumab/Nab-Paclitaxel Combo for PD-L1+ Metastatic TNBC

The FDA's Oncologic Drugs Advisory Committee voted 7 to 2 in support of maintaining the indication of atezolizumab in combination with nab-paclitaxel as a treatment for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors are PD-L1 positive.

“People with triple-negative breast cancer have few treatment options, which is why today's committee decision to recognise the importance of this Tecentriq combination is significant,” said Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, the developer of atezolizumab. “We are grateful to the FDA and ODAC for the open dialogue and look forward to continued collaboration to improve the lives of people with breast cancer.”

The meeting roster comprised ODAC members, Susan Halabi, PhD, Philip C. Hoffman, MD, Christopher H. Lieu, MD, temporary voting members, Harold J. Burstein, MD, PhD, Matthew Ellis, MD, PhD, Sandra Finestone, PsyD, Stan Lipkowitz, MD, PhD, Alberto J. Montero, MD, MBA, CPHQ, and Jennifer M. Spotila, JD.

Voting members, Susan Halabi, PhD, and Matthew Ellis, MD, PhD, voted against the continued approval of the combination.

In explaining her decision, Halabi said, “This is a difficult decision for me. I was almost on the fence. I voted no, the main reason is while I do appreciate there is a huge unmet need, my concern is the choice of endpoints. It seems to me that while PFS may be confirmed in another trial, I am not totally convinced that this will translate into a meaningful benefit for the patient.”

Non-voting members included acting designated federal officer of ODAC, Joyce Yu, PharmD, acting industry representative to the committee, Albert L. Kraus, PhD, and FDA participants, Richard Pazdur, MD, Julia Beaver, MD, and Laleh Amiri-Kordestani, MD.

The meeting represents the first day of a 3-day public review of 6 indications for checkpoint inhibitors granted under the agency’s accelerated approval process that later failed to reach thresholds for statistical significance for key end points in confirmatory clinical trials.

With regard to atezolizumab, the PD-L1 inhibitor plus nab-paclitaxel demonstrated a modest improvement in progression-free survival (PFS) and a possible overall survival (OS) benefit in treatment-naïve patients with locally advanced or metastatic PD-L1–positive TNBC in the phase 3 IMpassion130 trial (Table 1).

IMpassion130 trial

Primary findings from the trial served as the basis for the December 2019 accelerated approval of the combination in this indication.

However, the confirmatory phase 3 IMpassion131 trial failed to verify the clinical benefit, instead demonstrating a potential detriment in OS with the combination of atezolizumab and paclitaxel (Table 2).

IMpassion131 trial

In providing evidence in support of the approval, Charles Fuchs, MD, senior vice president and global head of oncology and hematology drug development at Genentech, stated that:

• Patients with metastatic TNBC have the highest unmet need in breast cancer
• The phase 3 IMpassion130 primary analysis supported the accelerated approval in PD-L1–positive metastatic TNBC
• New data since the accelerated approval continues to support the benefit and risk of atezolizumab plus nab-paclitaxel in PD-L1–positive metastatic TNBC
• Multiple options are under discussion for generating data to confirm the clinical benefit of the combination

However, Diana Zuckerman, PhD, president of the National Center for Health Research, stated, “All patients deserve to know if there are meaningful benefits that outweigh meaningful risks for them. It doesn’t help patients to continue to approve a treatment that has not proven to benefit them and is proven to harm many patients, and that’s why we support continued research but not continued approval.”

Despite today’s decision, Genentech is committed to generating additional data to confirm the clinical benefit of atezolizumab in TNBC with trials such as IMpassion132, which is randomizing patients with high-risk metastatic TNBC to atezolizumab plus carboplatin/gemcitabine or capecitabine or placebo plus carboplatin/gemcitabine or capecitabine. OS will serve as the primary end point of the study.

“Randomized controlled trials are the preferred methodology to balance measured and unmeasured cofounders which the FDA considers necessary to provide a reliable assessment of the efficacy of atezolizumab,” wrote the FDA in an addendum to the combined FDA and Applicant ODAC Briefing Document. “Although IMpassion132 is enrolling a different patient population and has a different chemotherapy backbone, FDA agrees that IMpassion132 could confirm the benefit of atezolizumab for patients with TNBC whose tumors express PD-L1.”

Reference

Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. April 27, 2021. Accessed April 27, 2021. https://collaboration.fda.gov/ODAC04272021?disclaimer-consent=true&proto=true.