Dive Insight:

Over the past several years, immunotherapy has changed how multiple tumor types are treated. Drugs like Keytruda, Bristol Myers Squibb’s Opdivo and Roche’s Tecentriq are now standard for many patients with cancers of the lung, skin, and more.

But as with many new cancer medicines, immunotherapies gained their first approvals for people whose disease had spread despite multiple treatments. There’s since been a concerted push to test their use earlier in a patient’s disease course, both after surgery to remove a tumor (the adjuvant setting) and before the procedure (neoadjuvant). Dozens of trials are underway, for instance, in the neoadjuvant setting in melanoma, lung and breast cancers.

The interest is based on the long-lasting survival benefit immunotherapies can provide when they work. The hope is that using them before surgery either with or instead of chemotherapy immunotherapies will help keep cancers from returning for longer than they would otherwise.

But the risk-benefit calculation is different in early disease, when surgery and chemotherapy might put cancer into a lengthy remission on their own and adding an immunotherapy might cause more harm than good. What’s more, using pricey immunotherapies alongside a mix of cheaper, generic drugs could significantly drive up the cost of care.

Those were all considerations when an FDA panel convened in February to discuss Merck’s application for Keytruda in triple-negative breast cancer, an aggressive form of the disease accounting for some 10% to 15% of cases.

Immunotherapy has only recently been cleared for use in breast cancer, specifically the triple-negative form which appears more immunologically “hot” and therefore susceptible to such drugs. Both Keytruda and Tecentriq are approved for use in patients with advanced disease. Merck’s application marked the first time a neoadjuvant immunotherapy regimen was considered for approval in any cancer type.

Merck’s submission was primarily based on a statistically significant improvement in pathological complete responses, or results from tissue samples, for Keytruda and chemotherapy over chemotherapy alone. The drug combo hasn’t yet been proven to stop cancers from recurring. That statistic, known as “event-free” survival, can take time to measure given it’s reliant on disease complications and deaths occurring.

What’s more, Keytruda-treated patients had more side effects and autoimmune problems, FDA scientists noted in briefing documents.

The panel voted 10-0 to defer a decision until Keytruda can be shown to have an EFS benefit and the agency has now followed suit with a rejection letter. (Past approvals for Opdivo and Keytruda in adjuvant melanoma used a similar measure of recurrence-free survival.)

Merck plans to conduct another interim analysis of the Keynote-522 study in the third quarter.

In the meantime, the agency’s decision could be a signal for other developers seeking to win approval for neoadjuvant immunotherapy use. Roche’s Tecentriq and chemotherapy combination, for instance, also improved pathological complete responses, but hasn’t yet been proven to delay breast cancer recurrence. Such is the case with Bristol Myers’ Opdivo in neoadjuvant lung cancer, too

Neither company has publicly disclosed approval applications.

The FDA’s decision doesn’t impact Keytruda’s existing approval in metastatic triple-negative breast cancer.