FDA Questions Clinical Trial Data of Multiple Oncology Drugs from Janssen, Pfizer, Roche, and UroGen Ahead of ODAC Review

According toFiercePharma reported that Johnson & Johnson, Pfizer, and Roche and other pharmaceutical companies have been questioned whether they have provided reliable clinical data for their anticancer drugs targeting the right patient population.FDA to Hold Special Meeting of the Oncologic Drugs Advisory Committee for Discussion.

FDA Questions Johnson & Johnson’s Bid to Expand Darzalex Faspro Use in High-Risk Smoldering Multiple Myeloma

In Pfizer's case, the company is attempting to expand the indication of its PARP inhibitor Talzenna to include first-line treatment for metastatic castration-resistant prostate cancer (mCRPC) patients without homologous recombination repair (HRR) gene mutations. However, the FDA pointed out that in the Talapro-2 trial, which did not involve biomarker screening, Pfizer failed to predefine a formal analysis plan for the substantial population of HRR-negative patients.

FDA Raises Two Concerns Over Roche’s Application for Columvi Combination Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Patients Ineligible for Stem Cell Transplant: First, the underrepresentation of U.S. patients in the Phase III Starglo trial; Second, the positive data from the study appears to be entirely driven by patient populations outside the U.S. and Europe.

In addition to the applications from the three major pharmaceutical companies, the FDA has also requested the expert committee to evaluate UroGen's application for the marketing of its chemotherapy drug Jelmyto bladder instillation therapy for recurrent low-risk/intermediate-risk non-muscle-invasive bladder cancer (NMIBC). As there are currently no approved drugs for this indication, the FDA seeks opinions on the following: whether durable complete response data evaluated in a single-arm trial can establish drug efficacy, and whether the data provided by UroGen truly confirms the durability of the efficacy.

Despite the FDA's cautious stance setting obstacles for these companies, the issues raised by the agency are not entirely unprecedented overall. This, in fact, provides an important assurance to industry observers—the review policies of the FDA's oncology drug division maintain continuity.

This two-day meeting, scheduled for May 20-21, is the first oncology drug review meeting chaired by newly appointed FDA Commissioner Dr. Marty Makary.

An in-depth study of the documents prepared by the FDA for the meeting reveals that the core issue faced by Johnson & Johnson, Pfizer, and Roche is the patient selection problem.

SMM: To Treat or Not to Treat

FDA Points Out That When Johnson & Johnson's Talapro-2 Trial Was Initiated, Two Guidelines for Risk Stratification of Smoldering Multiple Myeloma (SMM) Patients Had Not Been Updated. According to the New Criteria, Only 41% of the Participants in the Study Were Classified as High-Risk Population. Therefore, the FDA Naturally Questions Whether the Study Results Can Be Applied to the High-Risk Patient Group in the Real World Who Progress to Multiple Myeloma.

Johnson & Johnson stated in a filing before the meeting that the specific criteria for high-risk SMM are still evolving, and the design of the Aquila trial in 2015 was based on the understanding at that time. The company emphasized: "However, the risk of disease progression to multiple myeloma appears to be consistent across different risk models."

Since SMM is typically asymptomatic, the current standard treatment is merely monitoring. Therefore, the FDA raised the question: the clinical significance of early treatment before the actual onset of multiple myeloma (rather than treating after the disease has developed) remains unclear.

The best way to confirm this significance is to demonstrate an improvement in the gold standard endpoint of overall survival (OS). However, the FDA pointed out that although OS was a key secondary endpoint in the Aquila trial, the statistical power of the trial was insufficient to show a significant survival benefit. At five years, the absolute survival difference between the two groups was only about 5 percentage points.

Although the trial reached the primary endpoint of progression-free survival (PFS), due to the high incidence of adverse events and the unproven correlation between PFS and OS improvement, the FDA is uncertain whether this indicator is sufficient to support approval.

Johnson & Johnson argues that high-risk SMM patients can benefit from proactive treatment, whereas mere monitoring is not an ideal option due to the lack of approved therapies. The National Comprehensive Cancer Network guidelines currently recommend that high-risk patients prioritize participation in clinical trials.

Pfizer's "Suboptimal Design"

Pfizer's issue lies in what the FDA calls the "suboptimal design" of the Talapro-2 trial. The trial evaluates Talzenna in combination with Xtandi versus Xtandi alone, aiming to achieve both PFS and OS endpoints in first-line mCRPC patients (regardless of HRR status). However, the FDA questioned its analysis of the non-HRR mutant subgroup.

FDA Criticizes Pfizer for Failing to Preset Statistical Tests in Biomarker-Negative Population (the Majority of mCRPC Patients). The Trial Was Designed Only for the HRR Mutation Group and the Entire Population, Potentially Leading to Incorrect Conclusions for the HRR-Negative Population. Exploratory Subgroup Analysis Showed That the Talzenna Regimen Reduced Mortality Risk by Only 12% in Patients with HRR-Negative/Unknown Tumors. Additionally, Multiple Crossovers and Overlaps Between the Survival Curves of the Two Groups Further Complicated Efficacy Interpretation.

FDA reviewers considered the trial OS results unconvincing, as only 9% of BRCA-mutated patients in the control group subsequently received PARP inhibitors (which have been proven to extend survival). BRCA is the main subtype of HRR mutations. The FDA questioned whether the OS benefit of Talzenna in the mutated group might be overestimated, leading to misleading extrapolations when applying the overall population data to HRR-negative populations.

The reviewers also pointed out that neither AstraZeneca/MSD's Lynparza nor Johnson & Johnson's Akeega, two PARP inhibitor regimens, had shown benefits in this subgroup. Pfizer argued that the other two regimens were both combined with Johnson & Johnson's Zytiga (mechanism different from Xtandi), and preclinical models suggested that Xtandi and PARP inhibition might have a more synergistic effect.

Roche's Data Divergence

By contrast, Roche's issue is more straightforward. Although the Phase III Starglo trial demonstrated that Columvi combined with chemotherapy significantly improved OS by 38% in second-line DLBCL patients, a pre-specified subgroup analysis suggested that European, American, and white patients might experience a survival disadvantage.

Due to nearly half of the patients in the trial coming from Asia, the FDA's reanalysis found significant regional differences: the risk of death in the Asian group was reduced by 61%, while in the non-Asian group it was 6% higher than the control group. The difference may be due to the highly effective CAR-T therapy in Europe and America improving survival as a later-line treatment, and the FDA has already approved CAR-T for second-line treatment.

Roche countered in the briefing that only a small number of patients can access CAR-T therapy at large academic medical centers, emphasizing "a significant unmet need for rapid control of this aggressive disease."

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