For an upcoming oncology advisory committee meeting, the FDA is questioning whether Johnson & Johnson, Pfizer and Roche have provided convincing clinical data for their cancer drugs in the right patient populations.
In J&J’s bid to get Darzalex Faspro into high-risk smoldering multiple myeloma, the FDA argues that patients enrolled in J&J’s phase 3 Aquila trial don’t match the modern-day definition of “high-risk.” Besides, for an asymptomatic precursor condition, the agency also questions whether more mature patient survival data are needed to determine the drug’s benefit-risk profile.
In Pfizer’s case, the New York pharma is trying to expand its PARP inhibitor Talzenna into first-line treatment of metastatic castration-resistant prostate cancer (mCRPC) for patients without homologous recombination repair (HRR) gene mutations. But the FDA noted that the company’s Talapro-2 trial in a biomarker-unselected population didn’t define a prespecified formal analysis for the sizable HRR-negative patient population.
As for Roche’s application for a combination incorporating Columvi in patients with previously treated diffuse large B-cell lymphoma (DLBCL) who are not candidates for stem cell transplant, the FDA voiced concerns around ample representation of U.S. patients in the phase 3 Starglo trial as well how the study’s positive readout appeared to be entirely driven by patients outside the U.S. and Europe.
Besides applications by the three Big Pharma companies, the FDA is also asking its advisors to weigh in on UroGen’s submission for an intravesical solution of the company’s chemotherapy Jelmyto in recurrent low-grade intermediate-risk non-muscle invasive bladder cancer. Because no drugs are currently approved in this disease setting, the agency is looking for input on whether durable complete response data—assessed in a single-arm trial—can establish a drug’s efficacy and whether the data provided by UroGen has even proven durability.
Although the FDA’s hesitance marks a hurdle for the companies, the points raised by the agency are in general not unprecedented, offering industry watchers valuable reassurance of policy continuity at the FDA’s oncology department.
The two-day meeting, which is scheduled to take place May 20 and 21, is the first for oncology drugs under new FDA Commissioner Marty Makary, M.D.
Digging deeper into the FDA’s documents prepared for the meeting, J&J, Pfizer and Roche are basically all dealing with a patient selection problem.
SMM: To treat or not to treat
J&J’s Talapro-2 trial started before two guideline updates for risk stratification of patients with smoldering multiple myeloma (SMM), the FDA noted. By the new standards, only 41% of participants in the study are categorized as high-risk. So, the FDA naturally wondered whether the study’s findings can be applied to a real-world population of patients who are at high risk for developing multiple myeloma.
In its own document ahead of the event, J&J noted that the specific criteria to characterize high-risk SMM continue to evolve and that the company designed Aquila in 2015 based on what was known at the time.
“The risk of progression to multiple myeloma, however, appears to be consistent across the risk models,” J&J pointed out.
Because SMM is usually asymptomatic, the current standard of care is simple monitoring. So, the FDA flagged “uncertain implications of early treatment” before the development of multiple myeloma versus treatment when multiple myeloma actually develops.
One way to be certain of those implications would be to show improvement on the gold-standard overall survival endpoint. However, even though overall survival was a key secondary endpoint, the Aquila trial was not adequately powered to show a statistically significant survival benefit, the FDA noted. At five years, the absolute survival difference between the trial’s two arms was about 5 percentage points.
The trial met its primary endpoint of progression-free survival. But the FDA wasn’t sure whether that measure is adequate for an approval in light of a higher rate of adverse events and a lack of proven correlation with improved overall survival.
J&J, for its part, argues that high-risk SMM patients can benefit from proactive therapy and that mere surveillance is an undesirable alternative because there’s no approved therapy. The National Comprehensive Cancer Network guidelines currently recommend high-risk patients participate in clinical trials as a preferred pathway.
Pfizer’s ‘suboptimal design’
Meanwhile, Pfizer’s issue comes down to what the FDA described as the “suboptimal design” of the Talapro-2 trial.
Talapro-2, which evaluated the combination Talzenna and Xtandi compared with Xtandi alone, met both its progression-free survival and overall survival endpoints in a broad first-line mCRPC patient population regardless of HRR status. However, the FDA is taking issue with the study’s analysis for the non-HRR-mutated subgroup.
The FDA blasted Pfizer for not having a statistically powered test in the biomarker-negative population, which represents the majority of mCRPC patients. The study was only designed to measure the HRR-mutated group and all comers, and, therefore, it opens the possibility of false conclusions in the HRR-negative population, the agency said.
An exploratory subgroup analysis found that the death-risk reduction for patients with HRR-negative or unknown tumors was only 12% for the Talzenna regimen. In addition, the survival curves recording patient death events between the two treatment arms crossed and overlapped multiple times, further challenging the interpretation of the treatment effect, the FDA said in its review document.
The FDA reviewers appeared unpersuaded by the trial’s overall survival findings because only 9% of BRCA-mutated patients in the control arm went on to receive a subsequent PARP inhibitor, even though this approach has proven to prolong patients’ lives. BRCA is a major subtype of HRR mutations.
Therefore, the FDA staffers wondered whether Talzenna’s overall survival benefit was exaggerated in the mutated group, which could make extrapolating the all-comers data to the HRR-negative population more misleading.
The FDA reviewers were also uncertain because previous trials of two other PARP inhibitor regimens, AstraZeneca and Merck’s Lynparza and J&J’s Akeega, have not demonstrated a benefit in this patient subgroup.
In its own document, Pfizer noted that the other two PARP regimens both use J&J’s Zytiga as their combo partner, which has a different mechanism from Xtandi. Preclinical models suggest Xtandi might better synergize with PARP inhibition, according to Pfizer.
Roche’s data divergence
By comparison, Roche’s problem seems more straightforward.
Although the phase 3 Starglo trial linked Roche’s Columvi-chemo combo to a statistically significant 38% improvement in overall survival in second-line DLBCL, prespecified subgroup analyses found potential unfavorable survival outcomes in white patients and in patients enrolled in Europe or North America.
As the trial enrolled roughly half of all patients in Asian countries, the FDA regrouped the analyses and found a marked difference in Asian versus non-Asian regions. Among patients in Asian countries, the Roche regimen cut the risk of death by 61%, whereas its risk of death was 6% higher than the control arm in the non-Asian group.
One possible explanation for the gap is the availability of highly efficacious CAR-T therapies in the U.S. and Europe serving as later-line therapies to improve survival outcomes. The FDA has also approved CAR-T therapies specifically for second-line treatment.
However, Roche argued in the briefing document that only a limited proportion of patients can access CAR-T therapies, which are generally only available at large academic treatment centers.
“There remains a significant unmet need for immediately available, effective treatment options to rapidly control this aggressive disease,” the company said in its briefing document.