As Imbruvica stumbles, BeiGene's Brukinsa steps up with FDA nod in follicular lymphoma

With a new FDA nod, BeiGene has filled the follicular lymphoma approval gap for BTK inhibitors.

Thursday, the FDA doled out an accelerated approval for BeiGene’s Brukinsa to be used alongside Roche’s anti-CD20 antibody Gazyva to treat follicular lymphoma after at least two prior lines of systemic therapy.

Brukinsa is now the first BTK inhibitor approved to treat follicular lymphoma in the U.S., and it boasts the broadest label within the drug class across various hematology indications, Mehrdad Mobasher, M.D., BeiGene’s chief medical officer of hematology, noted in an interview.

Nevertheless, in late-line follicular lymphoma, the Brukinsa combo will face competition from much-touted CAR-T therapies and bispecific antibodies.

Brukinsa’s approval in this use is based on tumor shrinkage data from the phase 2 ROSEWOOD trial. After a median follow-up of about 20 months, the Brukinsa-Gazyva combo triggered a response in 69% of patients, significantly better than the 46% overall response rate seen in the Gazyva monotherapy arm. After 18 months, 69% of patients who took the doublet remained in remission, versus 42% among those who took Gazyva alone.

On a secondary endpoint, patients on the doublet also went longer without disease progression. Median disease-free progression came in at 28 months for the combo, compared with about 10 months for the control arm. The combo also showed a 38% reduction in the risk of death, although that analysis didn't bear statistical significance.

In terms of efficacy, Brukinsa faces tough competition in follicular lymphoma. Novartis’ CD19 CAR-T Kymriah and Gilead Sciences’ rival cell therapy Yescarta got their accelerated approvals in the same third-line follicular lymphoma setting based on overall response rates of 86% and 91%, respectively. Further, the FDA recently put Bristol Myers Squibb’s application for its Breyanzi in third-line follicular lymphoma under priority review. In the primary analysis of the phase 2 TRANSCEND FL trial, Breyanzi elicited an objective response rate of 97%.

As for complete responses, the CAR-Ts each delivered rates at or above 60%—94% in the case of Breyanzi—versus 39% for the Brukinsa-Gazyva regimen.

In December 2022, the FDA offered the same third-line follicular lymphoma nod to Roche’s CD20xCD3 bispecific Lunsumio, an off-the-shelf therapy that has posted an 80% tumor response rate, including a 60% rate of complete responses. And the agency recently granted a priority review to AbbVie’s subcutaneous bispecific Epkinly in third-line follicular lymphoma based on a reported 82% overall response rate and a 63% complete response rate. 

Despite the rivals' strong efficacy, the Brukinsa-Gazyva pairing offers physicians another treatment option, Mobasher said.

Both CAR-T and bispecifics require patient monitoring for the potentially dangerous side effect of cytokine release syndrome. By comparison, the BeiGene regimen combines an oral drug with an infused monoclonal antibody.

Follicular lymphoma is an indolent disease, and patients will need another treatment when they progress, the BeiGene exec added.

Currently, BeiGene doesn’t have data on whether the Brukinsa-Gazyva combo still works following treatment with a CAR-T or bispecific. Doctors will decide on the appropriate third-line regimen based on the patient’s health, the availability of other medicines and the capabilities of each treatment facility, Mobasher argued.

Brukinsa’s approval in follicular lymphoma comes about a year after AbbVie and Johnson & Johnson’s first-in-class BTK inhibitor Imbruvica failed in a phase 3 trial. In April 2023, AbbVie and J&J pulled an accelerated approval for Imbruvica in marginal zone lymphoma, citing the failure of the phase 3 SELENE study.

Data unveiled in June showed that adding Imbruvica to chemoimmunotherapy cut the risk of progression or death by 19% in patients with previously treated follicular lymphoma or marginal zone lymphoma. The number didn’t meet statistical significance.

As part of the accelerated approval, Brukinsa is on the hook to further prove itself in a confirmatory study, which is now set to be the phase 3 MAHOGANY trial, per an agreement between BeiGene and the FDA. The trial is testing Brukinsa and Gazyva against the combination of BMS’ Revlimid and Roche’s Rituxan in follicular or marginal zone lymphoma patients who’ve tried at least one prior therapy.

Thanks to an approval in front-line chronic lymphocytic leukemia, Brukinsa is on a fast growth trajectory. The drug reached blockbuster status last year after more than doubling sales to $1.3 billion. In contrast, AbbVie’s reported revenues for Imbruvica dropped 21% year over year to $3.6 billion.

Looking to further bolster Brukinsa in its clash with Imbruvica and AstraZeneca’s Calquence in the BTK class, BeiGene is evaluating combining Brukinsa with its second-generation BCL-2 inhibitor sonrotoclax, a potential competitor to AbbVie and Roche’s Venclexta.

While the BeiGene, AbbVie/J&J and AZ meds are each covalent BTK inhibitors, Eli Lilly recently introduced a noncovalent BTK option, Jaypirca, which can be used after a covalent peer.

While Lilly is also targeting the first-line follicular lymphoma setting, Mobasher argued that doctors will prefer to keep Jaypirca in the second line so they have a salvage therapy available in case patients relapse on a covalent drug.

BeiGene’s proposal for the post-covalent setting, he noted, is a BTK degrader, which has also shown some early clinical activity in heavily pretreated patients.