Tuesday marked the first of 3 days of hearings on whether checkpoint inhibitors should keep indications after follow-up studies failed to show benefits that led to accelerated approval.
An FDA panel voted 7-2 Tuesday to keep atezolizumab (Tecentriq) on the market for certain patients with metastatic triple negative breast cancer (TNBC), but how Genentech will move forward to show the value of the PD-L1 inhibitor in this setting remained unclear.
FDA’s Oncology Drug Advisory Committee (ODAC) grappled with the conundrum it will face for 2 more days, as it reviews 6 indications in checkpoint inhibitors that were granted under the agency’s accelerated approval pathway but failed to show the same benefits in later studies.
The question now, is, what should FDA do? Take the drug off the market, or let more data accumulate, given the fact that, by definition, these approvals were granted because they offered hope to cancer patients without options?
The case of atezolizumab frustrated even those ODAC panelists who voted to keep its indication in metastatic TNBC, with several citing the factor that helped the drug win the indication in the first place: The patients in question still have few ways to treat a disease that strikes many young women carrying genetic mutations. TNBC spreads quickly, with a high recurrence rate in the first 3 years.
Thus, pulling the indication seemed an overreach to some panelists, if trials now in the pipeline might shed light on conflicting results seen thus far. (Of note, FDA just granted regular approval for sacituzumab in metastatic TNBC.)
“People with triple-negative breast cancer have few treatment options, which is why today's committee decision to recognize the importance of this Tecentriq combination is significant,” Levi Garraway, MD, PhD, Genentech's chief medical officer and head of Global Product Development, said in a statement. “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.”
In March 2019, atezolizumab won accelerated approval in combination with nab-paclitaxel for adult patients with metastatic TNBC whose tumors express PD-L1 based on a median progression-free survival (PFS) of 7.4 months, compared with 4.8 months for those on placebo and nab-paclitaxel. At the time, overall survival (OS) results showed a benefit, but the data were not yet mature.
But a subsequent study not only failed to confirm the PFS benefit, it also showed better survival in the placebo group, prompting an FDA safety alert to only use atezolizumab with nab-paclitaxel, not paclitaxel, which was the chemotherapy partner in the later trial.
In presenting their case Tuesday, Genentech officials highlighted the fact that the second trial wasn’t an apples-to-apples comparison to the one that led to accelerated approval. Besides the difference in chemotherapy, patients in the second trial were pretreated with steroids. One ODAC panelist pressed the Genetech team whether they had adequately screened patients in the second trial to ensure they truly had TNBC, given the remarkable results in the placebo arm.
“In the end, it has been challenging for us to point to any single factor that clearly accounts for the difference in efficacy outcomes between the 2 studies,” said Steve Chui, MD, Genentech’s group medical director and Global Development lead for Tecentriq.
He also noted that as the data from the original study matured, an OS benefit of 33% emerged.
The question for ODAC, then, if the indication is to stay in place, is what studies should be used to evaluate it going forward? Genentech pointed to 3 other trials in progress, including one involving higher-risk patients than those in the first 2 trials, and another involving early-stage TNBC.
Trying to replicate the trial that led to accelerated approval presents a problem, Chui said. Today the PD-L1 inhibitor is approved in 89 countries and listed in multiple clinical guidelines—including those for the National Comprehensive Cancer Network. So, trying to recruit patients who would know they might receive only chemotherapy would pose significant challenges, he said.
The FDA’s Laleh Amiri-Kordestani, MD, acknowledged the lack of clear-cut options. The agency still lacks confirmation of the initial PFS finding, and using the current trial studying early-stage TNBC “reduces patient accrual challenges to trials evaluating an indication that has already been approved under accelerated approval.”
Some ODAC members who voted to keep the indication were less convinced that the hurdles of repeating the initial trial could not be overcome. Even representatives from patient advocacy groups were split on how FDA should proceed.
“This is a difficult decision for me. I was almost on the fence,” said panelist Susan Halabi, PhD, of Duke Cancer Institute, who voted against keeping the indication. “While I do appreciate there is a huge unmet need, my concern is the choice of end points. 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.”
Panelist Stanley Lipkowitz, MD, PhD, a senior investigator at the National Cancer Institute, said his yes vote was a tough call. Some concessions are in order, he said, including the possibility of another ODAC hearing in the future when more data are available.
“I didn’t really hear it from Genentech that if they can’t confirm this, [the indication] has to be withdrawn,” Lipkowitz said.