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iStock, leolintang Roche and Genentech were unable to sufficiently demonstrate the benefit of using Columvi in an earlier treatment setting for DLBCL in a U.S. population, according to the FDA. The FDA has rejected Roche and subsidiary Genentech’s proposal to use the bispecific antibody Columvi as part of a second-line treatment regimen in patients with diffuse large B cell lymphoma. In its complete response letter, the regulator cited insufficient evidence to support the use of Columvi in this indication in the U.S. patient population, according to Roche’s news release on Friday. Columvi is approved as a third-line treatment option for diffuse large B cell lymphoma (DLBCL) under the FDA’s accelerated pathway program. Despite Friday’s rejection, Columvi “remains under accelerated approval for people with third-line or later DLBCL,” as per the company’s news release. Delivered intravenously, Columvi is a bispecific antibody that targets both CD20, found on the surface of B cells, and CD3, expressed by T cells. This mechanism of action allows the drug to activate cancer-killing T cells and bring them closer to the malignant B cells. In 2021, Roche and Genentech kicked off the Phase III STARGLO study, combining Columvi with gemcitabine and oxaliplatin to treat patients with relapsed or refractory DLBCL. STARGLO formed the foundation of the Columvi application, and results showed that patients treated with the Columvi combo saw a 41% drop in the risk of death compared with those who received rituximab, gemcitabine and oxaliplatin. The Columvi-based regimen likewise hit secondary endpoints, including progression-free survival. Despite these results, the FDA’s Oncologic Drugs Advisory Committee (ODAC) in May voted 8–1 against Columvi’s expansion, raising concerns about the applicability of the drug’s efficacy data in the U.S. In STARGLO’s intention-to-treat population, only 25 of more than 270 participants were from North America. Ravi Madan, a “no” vote who heads Prostate Cancer Clinical Research at the National Cancer Institute, said at the time of the ODAC meeting that drug sponsors should make “deliberate decisions” to make sure that their studies “apply to the U.S. population.” Trial demography appears to be an increasingly pressing concern at the FDA. At another ODAC meeting last week to assess GSK’s application for its antibody-drug conjugate Blenrep for multiple myeloma, committee member Daniel Spratt of Western Reserve University brought up enrollment issues. GSK’s “clinical development program enrolled almost no patients in the United States,” he said. “This is the United States FDA, so the proposed patient population [are] the United States patients,” Spratt noted. Poor enrollment from a U.S. population “precludes any assessment of the [drug’s] benefit-risk pro the U.S.” Aside from STARGLO, Roche and Genentech are also testing Columvi in the Phase III SKYGLO study , which combines the bispecific with Polivy, Rituxan, cyclophosphamide, doxorubicin and prednisone for the treatment of patients with large B cell lymphoma. The companies are in discussions with the FDA to use SKYGLO as the new postmarketing requirement for Columvi, as per Friday’s release.

The denial for Columvi comes amid a fresh push at the FDA to increase U.S. representation in oncology clinical trials. The other shoe has dropped for Roche’s bid to move Columvi into earlier treatment of diffuse large B-cell lymphoma (DLBCL) in the U.S.The FDA has declined to approve Columvi, in combination with the chemo regimen GemOx, for the treatment of second-line DLBCL patients who are not eligible for autologous stem cell transplant, Roche and its subsidiary Genentech said Friday.In a complete response letter, the FDA suggested the phase 3 Starglo data do not provide enough evidence to support the proposed indication in a U.S. population, according to Roche.The rejection mirrors the outcome of a recent FDA advisory committee meeting, at which an external panel of experts voted 8 to 1 that results from the Starglo trial are not applicable to the U.S. The decision diverges from a green light that European regulators recently granted to Roche in the same indication.Starglo was also intended to serve as a confirmatory study to convert Columvi’s U.S. accelerated approval in the third-line setting into a full approval. With the negative review, Roche is in discussions with the FDA to potentially use the phase 3 Skyglo study to fulfill its confirmatory trial requirement instead. That study is testing Columvi in combination with Roche’s Polivy-R-CHP regimen in patients with previously untreated CD20-positive large B-cell lymphoma.For now, Columvi remains under accelerated approval, Roche said, indicating that the FDA does not intend to pull the CD20xCD3 T-cell engager off the market.“While we are disappointed with this outcome, we remain confident in the data supporting the value of Columvi for U.S. patients who have relapsed following initial treatment, and its key role as monotherapy in the third-line setting,” Levi Garraway, M.D., Ph.D., Roche’s chief medical officer and head of global product development, said in a July 18 released. “We are committed to bringing Columvi to more people living with lymphoma and are actively exploring its potential in additional treatment settings, including as frontline therapy.” The FDA recently shared more than 200 past complete response letters sent to since-approved drugs and consolidated them at a single online portal. The database does not yet include some of the most recent rejections, and the Columvi one was not uploaded as of publication time.The FDA scrutinized Starglo despite its overall positive readout, spotlighting an imbalance in patient survival data between Asian and non-Asian regions.While Columvi-GemOx significantly reduced the risk of death by 41% over Rituxan-GemOx in the entire Starglo trial population, the risk of death was 6% higher for the Columvi regimen in non-Asian countries, according to an FDA subgroup analysis. In addition, the fact that Starglo only enrolled 9% of its patients from the U.S. also caught the FDA’s attention.Roche offered several explanations, including broader access to more efficient subsequent therapy in Western countries and slow U.S. enrollment thanks to COVID. But the FDA and its advisory panel were clearly unconvinced.The denial for Columvi comes amid a fresh push at the FDA to increase U.S. representation in oncology clinical trials.“Unfortunately, if you take a look at all the oncology trials that come to us, only about 20% of the population is derived from the United States,” the FDA’s oncology leader Richard Pazdur, M.D., said during the advisory committee meeting. “We’d like to see robust increased enrollment in the United States.” This topic was brought up again Thursday during another advisory committee meeting focused on GSK’s application for Blenrep in second-line multiple myeloma. Despite two positive phase 3 trials, the FDA’s advisors voted against both Blenrep combination regimens proposed by GSK.While eye toxicity and dose selection were the main underlying issues, experts also spotted low U.S. patient enrollment—below 5% in each study—as a key shortfall.Considering that GSK enrolled “almost no” U.S. patients, the study effectively “precludes any assessment of the benefit/risk profile in the U.S.,” one committee member said during the Blenrep discussion.