Roche pulls a Gavreto approval before Blueprint severance, citing unfeasible trial

Another FDA accelerated approval has run its course, with Roche giving up on a niche indication for cancer drug Gavreto.

After speaking with the FDA, Roche’s Genentech unit has decided to withdraw Gavreto for the treatment of advanced RET-mutant medullary thyroid cancer. Blueprint Medicines, the drug’s original developer, revealed the news in a securities filing Friday.

Gavreto earned this approval back in 2020 under the FDA’s accelerated approval pathway based on tumor shrinkage data from the phase 1/2 ARROW trial. Now, Roche figures the phase 3 trial AcceleRET-MTC, which is designed to convert the nod into a full approval, is no longer feasible, according to the Blueprint filing.

Despite the retreat from RET-mutant disease, Gavreto maintains an approval in RET fusion-positive thyroid cancer. For that indication, the FDA's postmarketing requirements call for additional data from patients in the ARROW trial and the basket TAPISTRY trial, a Blueprint spokesperson told Fierce Pharma.

The company remains on track to deliver on that commitment, the spokesperson added.

Medullary thyroid cancer only makes up a small fraction of Gavreto’s meager sales. The RET inhibitor only generated altogether CHF 26 million last year.

Meanwhile, Roche in February decided to terminate the Blueprint partnership and will return Gavreto to the Massachusetts biotech. The two companies are in a transition period and will officially untie the knot in February.

Blueprint is currently searching for a new partner for Gavreto and the biotech doesn’t expect the withdrawal to affect that process, the company spokesperson said. In fact, the termination of the AcceleRET-MTC trial reduces future development costs for any potential partner, the spokesperson added. 

Besides thyroid cancer, Gavreto’s initial indication is in RET fusion-positive non-small cell lung cancer. In that use, which is also an accelerated approval, Roche is investigating Gavreto in a phase 3 trial. The AcceleRET-Lung trial is pitting Gavreto against chemo with or without Merck’s Keytruda in newly diagnosed RET-positive metastatic NSCLC.

The drug was once part of an umbrella phase 3 trial comparing RET-, ALK- and ROS-targeted therapies against AstraZeneca’s Imfinzi in stage 3 NSCLC, but a Genentech spokesperson said the Gavreto arm has been closed.

For the NSCLC indication, the FDA wants to see more data from patients in the original ARROW trial as confirmatory evidence for a full nod, the Blueprint spokesperson said. 

In the past, drugmakers have pulled accelerated approvals because confirmatory trials became difficult to run. In one recent example, Viatris withdrew the antimicrobial powder Sulfamylon because new clinical practice has made it impossible for the company to enroll patients in a controlled phase 4 trial for its product.

A Genentech spokesperson said Gavreto’s AcceleRET-MTC trial was not activated “due to changes to the evolving treatment landscape over time." The study was set to study Gavreto against either Exelixis’ Cabometyx or Sanofi’s Caprelsa in previously treated RET-mutant thyroid cancer. It’s possible that given the availability of RET inhibitors, doctors no longer want to treat patients with traditional, less precise multikinase inhibitors.

But Eli Lilly is running a similar phase 3 trial for its rival RET inhibitor Retevmo. Coded LIBRETTO-531, that phase 3 is also using Cabometyx or Caprelsa in the control arm. In response to Fierce Pharma’s inquiry, a Lilly spokesperson said its trial “remains on track.”

Gavreto’s withdrawal comes against a backdrop of increased scrutiny by the FDA’s oncology department on accelerated approvals that don’t meet confirmatory trial requirements. The agency has pushed for market withdrawals of certain PD-1/L1 inhibitors, PI3K inhibitors, PARP inhibitors, and other meds.