Roche has detailed Tecentriq’s performance in early-stage liver cancer from a positive phase 3 trial. But a negative sign of patient deaths might raise some eyebrows, and it could force the company to delay a potential FDA filing.
The combination of Tecentriq and Avastin reduced the risk of disease recurrence or death by 28% compared with active surveillance when adopted after surgery as an adjuvant treatment for hepatocellular carcinoma (HCC) patients who were at high risk of recurrence. Investigators shared the results from the phase 3 IMBrave050 trial at the American Association for Cancer Research's 2023 annual meeting.
But in an early evaluation of patients’ life expectancy, the Tecentriq-Avastin combo was linked to a 42% increased risk of death at an interim analysis, according to a press presentation by Pierce Chow, Ph.D., from the Duke-NUS Medical School.
Chow noted the overall survival analysis is “highly immature,” given that only 47 patients, or 7% of the entire trial population, had died.
Also calling the survival data “extremely immature,” Tim Eisen, Roche’s genitourinary oncology franchise head, said in an interview that “it would be wrong to attribute anything to these data, because it’s just the very first data to come through.” Most patients in the trial were still alive, he noted.
Of the 27 deaths in the Tecentriq-Avastin arm, three COVID-19-related deaths occurred within one year of randomization. None of the 20 deaths in the control arm were related to COVID-19 in the first year.
The number of deaths caused by liver cancer recurrence was similar between the two arms, according to Chow. But two patients’ deaths (0.6%) were deemed related to the treatment of Tecentriq or Avastin.
More broadly, investigators recorded a 24.1% rate of serious side effects for the Tecentriq-Avastin combo, including 13.3% related to treatment. In contrast, the surveillance group logged a 10.3% rate of serious side effects.
Despite the side effect profile, Chow touted IMbrave050 as a landmark study because it was the first to show any efficacy for an adjuvant treatment in liver cancer.
“These results have established a benchmark in adjuvant therapy for HCC and have the potential to be practice-changing,” he said.
In addition, Chow struck a positive note because the Tecentriq-Avastin combo’s safety profile appeared at least on par with—or even better than—its showing in the phase 3 IMbrave150 trial, which got the regimen an FDA approval in metastatic liver cancer in 2020.
In that metastatic cancer trial, six treatment-related deaths (1.8%) occurred for Tecentriq and Avastin. The study tracked a 38% rate of serious side effects from the combo, including 17% related to treatment.
But in that earlier study, the Tecentriq-Avastin pairing showed a 42% reduction in the risk of death versus Bayer’s old standard Nexavar in front-line liver cancer.
The unfavorable overall survival trend in the new IMbrave050 study could make life difficult for Roche in its interactions with the FDA. The preliminary signal will likely prompt the agency to demand more follow-up data to make sure the Tecentriq regimen doesn’t hurt patients’ chances at survival.
“I think it’s clear from the policies that have been in place for some time that we will be needing to wait for more data,” Eisen said in an interview. The exact timing of when those data will be available is driven by death events in the trial, he added.
The FDA has become increasingly cautious about the potential detrimental effect adverse events may have on overall survival, and Roche knows the agency's stance all too well.
Following an FDA request, the Swiss pharma last year had to delay an application for Polivy in front-line large B-cell lymphoma to accrue more survival data. And when the company did provide those data, the FDA raised concerns about the drug’s lack of a life extension showing in a phase 3 trial despite a tumor progression benefit. The FDA has yet to make a decision on that Polivy application after an advisory committee overwhelmingly backed its use.
Besides, having a similar safety profile between uses in early-stage and metastatic diseases may simply not be good enough for the Tecentriq-Avastin combo, especially given the overall survival red flag. During a recent advisory committee meeting on GSK’s fellow checkpoint inhibitor Jemperli, FDA’s oncology chief Richard Pazdur, M.D., noted that the regulatory bar for an early-stage disease setting “has to be higher” than in late-stage metastatic disease.
IMbrave050’s trial design could also make it difficult for Tecentriq to eventually show an overall survival advantage. Patients in the control arm are allowed to cross over to receive Tecentriq and Avastin after recurrence. Of the 133 patients whose cancer did return, 61% have gone on to receive the combo so far.
In addition to the safety concern, the adjuvant trial was conducted mainly in Asia. Patients who are identified as Asian make up nearly 82% of the entire trial population, and about 62% of participants have hepatitis B, which, according to the Centers for Disease Control and Prevention, accounts for just about 15% of liver cancer cases in the U.S. Liver cancer does disproportionally affect Asians in part because of viral hepatitis.
Liver cancer appears to respond to immunotherapy differently with or without viral infection. In the metastatic setting, the earlier IMbrave150 trial found a very small 9% death risk reduction for Tecentriq and Avastin in nonviral cancer cases.
For Roche, the good news this time is that the event-free survival benefit was comparable between patients whose tumors had no PD-L1 expression and those with PD-L1-positive disease, according to Eisen. The FDA previously left out PD-L1-negative disease from its approval for Tecentriq in adjuvant non-small cell lung cancer because of a lack of showing for those patients.