Atezolizumab (Tecentriq), the first in class anti-PD-L1 antibody was the first immunotherapy given accelerated approval for metastatic TNBC (mTNBC) in March 2019. This was the first immune checkpoint inhibitor approved for breast cancer, and rapidly changed the standard of care for management of newly diagnosed mTNBC that expressed PD-L1 (~40%). On Friday we learned that Genentech had voluntarily withdrawn its accelerated approval based on the emerging results from other trials and “changes in the treatment landscape”. What does that mean?
Part of the agreement with the FDA when a company gets accelerated approval is to perform confirmatory post-marketing trials since the strength of data needed to get the accelerated approval is less than a regular approval. Accelerated approvals exist to provide patients earlier access to promising drugs, if they have diseases with high unmet needs. mTNBC certainly met that criteria when Genentech submitted their application with the Impassion130 data of Atezolizumab and Abraxane. Unfortunately since then we have learned that their confirmatory trial, Impassion131 did not show the same results – which is the main problem for Genentech if they wanted to convert the accelerated approval into a full approval.
Since this approval, Merck have also had multiple positive studies with a sister drug, Pembrolizumab (Keytruda) that is now not only approved in the same setting as Atezolizumab (first-line treatment of PD-L1 positive metastatic TNBC) but also more recently, the KEYNOTE-522 data showed an impressive benefit in the early stage setting regardless of PD-L1 status. This means that now the standard of care for early stage TNBC is the use of Pembrolizumab (“Pembro”) + chemo, followed by adjuvant Pembro after surgery in patients who are candidates for immunotherapy. This adds to the reason why Genentech made the decision not to Pursue Atezolizumab + Abraxane in the metastatic setting – they would not be able to do any further confirmatory trial in the US any more since the vast majority of patients would receive it in the early stage setting, making them ineligible to receive if if the cancer recurs. Currently in breast cancer, once the cancer recurs after immunotherapy, we generally don’t give it again, unless on a trial of a novel combination. Switching between PD-1 and PD-L1 agents after progression on one, has not proven to be effective in other cancers either. We still have a lot of research to do to understand the mechanisms of immunotherapy resistance in breast cancer to understand how to tailor treatments after progression on a PD-1/PD-L1 inhibitor. Genentech therefore has made a smart business decision to move on.
As the study manager for an ongoing Genentech supported trial of an Atezolizumab combination in metastatic IBC, a thought came to my mind – have they given up on breast cancer altogether and seceded the market to Merck? Surely not. I read their press release from Friday closely and don’t think so. “We remain dedicated to finding meaningful treatments for people living with this aggressive disease and will continue to study Tecentriq in mTNBC.” Phew! With 2 large trials of Atezo-treated TNBC patients and tissue available, I’m quite sure their biomarker team are actively looking for how to position Atezo in the resistant setting, so I’m quite excited to see the future trials that will come out of those studies, whether led by Genentech or designed by academic institutions.
Is this loss of approval bad news overall for patients in the short term?
My opinion is no. The data has led us to believe the earlier we give immunotherapy the more likely patients will benefit, so now it is the standard to give it for early stage TNBC. For the small portion of de novo metastatic TNBC patients, oncologists can still get PD-L1 testing and give Pembrolizumab along with their choice of chemo (Abraxane, Paclitaxel or Gemcitabine-Carboplatin) if the PD-L1 status is positive – therefore all immunotherapy options are not lost. I also read that the approvals overseas are not impacted at this time by the decision – however I wouldn’t be surprised if countries with national healthcare review the data and change funding choices. My hope is that Pembro approvals catch up quickly so that the same options are available for international patients similar to the US now that the data supporting full approval of Pembro is available.
