J&J's Balversa gets mixed approval in bladder cancer as FDA ratchets up scrutiny on subgroup data, patient survival

When the FDA converts an accelerated approval into a full nod, it’s typically associated with a wider label for the drug at hand.

But in the case of Johnson & Johnson’s Balversa, the FDA narrowed the use of the first-in-class bladder cancer drug in two ways and expanded it in another.

A full FDA approval now allows Balversa (erdafitinib) to treat locally advanced or metastatic urothelial carcinoma in patients with susceptible FGFR3 genetic alterations following at least one line of prior therapy. In a Friday announcement about the drug’s updated label, the FDA specified that Balversa shouldn’t be used in patients who are eligible for and have not received a prior PD-1/L1 therapy.

Compared with Balversa’s accelerated approval from 2019, the full nod is narrower on two fronts. Under the original go-ahead, Balversa was also able to reach patients with FGFR2 alterations, and it could target post-chemo patients regardless of their eligibility for PD-1/L1 therapy.

In one positive label change for J&J, while the previous nod only allowed Balversa after prior treatment with platinum-based chemotherapy, the updated approval now covers second-line patients regardless of their prior systemic therapy. That means patients who’ve progressed on standard PD-1 treatment can also get Balversa.

The way J&J approached the full approval—and the way the FDA ruled—tell a cautionary tale about the FDA's close attention to patient subgroup data and overall survival findings.

For the full green light, J&J only pursued the approval of Balversa in patients with FGFR3 alterations, a company spokesperson told Fierce Pharma.

To support a full approval, J&J conducted the phase 3 THOR study, also known as Study BLC3001. In cohort 1 of the trial, Balversa cut the risk of death by 36% compared with chemotherapy in previously treated patients, including those treated with a PD-1/L1 inhibitor. Those who got Balversa lived a median 12.1 months versus 7.8 months for the control group.

The trial was designed to enroll patients with FGFR2 and FGFR3 alterations, but it eventually didn’t have any FGFR2 representation. The real-world frequency of this disease subtype is extremely low, the J&J spokesperson said.

In a statement, Daniel Suzman, M.D., a deputy director at the FDA’s oncology division, said the approval was “limited to patients with FGFR3-altered tumors only because of a lack of data confirming clinical benefit in the extremely rare population of patients with FGFR2-altered tumors.”

The developments come amid a growing trend at the FDA to exclude patient subgroups in approvals, either because of low representation in clinical trials or unconvincing efficacy data. In June 2023, the FDA left out patients with high-grade B-cell lymphoma in an approval for Roche’s large B-cell lymphoma therapy Columvi, citing a “limited number of patients” in a study.

As for Balversa, cohort 1 was only a part of the THOR trial. For years, Merck & Co.’s Keytruda has had a second-line bladder cancer nod and a limited first-line approval. So in cohort 2 of THOR, J&J pitted Balversa directly against Keytruda in previously treated patients who had not received a PD-1/L1 drug. And the updated Balversa label suggests the FDA was not happy with the results.

In cohort 2, Balversa failed to beat Keytruda in extending patients’ lives. In fact, the J&J drug was linked to an 18% increased risk of death. “Similar” overall survival was the word investigators used when presenting the data at the 2023 European Society of Medical Oncology annual congress in October. But a small improvement on progression-free survival and a negative overall survival showing have become a precarious combination at the FDA, and Balversa was clearly no exception.

J&J is looking on the bright side, stressing that patients who are eligible to receive PD-1/L1s are increasingly receiving those treatments up front. The company seems to be positioning its medicine as an option for those who still need treatment after a PD-1/L1 inhibitor.

After Balversa’s accelerated approval in 2019, Merck KGaA and its former partner Pfizer won an FDA nod for their PD-L1 therapy Bavencio as a first-line maintenance therapy in bladder cancer patients who’ve responded to an initial round of chemo. And the combination of Keytruda and Astellas and Pfizer’s Padcev just won approval as a first-line treatment for bladder cancer after showing a major overall survival benefit against chemo.

“Due to emerging treatment landscape, anti-PD-1s are used more and more in the earlier line setting […] and therefore, there is an unmet need for patients after progressing on anti-PD-1,” the J&J spokesperson said.