FDA Panel Opposes Nivolumab for Second-line Advanced HCC

In a 5 to 4 vote, the FDA’s Oncologic Drugs Advisory Committee voted to oppose maintaining the accelerated approval of nivolumab monotherapy for patients with advanced hepatocellular carcinoma who received prior treatment with sorafenib.

In a 5 to 4 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted to oppose maintaining the accelerated approval of nivolumab (Opdivo) monotherapy for patients with advanced hepatocellular carcinoma (HCC) who received prior treatment with sorafenib (Nexavar).

In explaining his decision, Anthony D. Sung, MD, said, “I voted no because of the negative randomized [CheckMate-459] trial. The data are not there, and it does not sound like there is a trial that is currently planned that will help yield more data. I do think there are patients who benefit from nivolumab monotherapy, but the data show that the benefit is not there for the population as a whole. I would encourage Bristol Myers Squibb [BMS] or other members of the pharmaceutical industry to dig deeper to try to identify biomarkers that could identify which patients may benefit from these drugs.”

The meeting roster comprised ODAC members, Susan Halabi, PhD; Philip C. Hoffman, MD; Christopher H. Lieu, MD; David E. Mitchell; and Anthony D. Sung, MD; temporary voting members, Karen R. Hoyt; Pamela L. Kunz, MD; Mark A. Lewis, MD; and Colin D. Weekes, MD, PhD, FASCO.

Voting members Susan Halabi, PhD; Anthony D. Sung, MD; Pamela L. Kunz, MD; Mark A. Lewis, MD; and Colin D. Weekes, MD, PhD, FASCO voted against the continued accelerated approval of nivolumab.

Non-voting members included acting designated federal officer of ODAC, Takyiah Stevenson, PharmD, acting industry representative to the committee, Albert L. Kraus, PhD, and FDA participants, Richard Pazdur, MD, Julia Beaver, MD, and Steven Lemery, MD, MHS.

The meeting represents the final day of a 3-day public review of 6 indications for checkpoint inhibitors granted under the agency’s accelerated approval process that later failed to reach thresholds for statistical significance for key end points in confirmatory clinical trials.

With regard to nivolumab, the PD-1 inhibitor demonstrated an objective response rate (ORR) of 14.3% (95% CI, 9.2%-20.8%) by RECIST criteria in patients who had progressed on, or were intolerant to, prior sorafenib in the phase 1/2 CheckMate-040 trial (n = 154). The median duration of response was 16.6 months (95% CI, 3.2-38.2+). Responses were 6 months or longer in 91% of patients and 12 months or longer in 55% of patients.

Primary findings from the trial served as the basis for the September 2017 accelerated approval of the agent for the treatment of patients with HCC who received prior sorafenib.

The continued approval of the agent was contingent on positive data from the frontline phase 3 CheckMate-459 trial, but the study failed to meet its primary end point of overall survival, with a 2-sided alpha of 0.05.

In the trial, patients were randomized to receive either 240 mg of nivolumab every 2 weeks (n = 371) or 400 mg of sorafenib daily (n = 372).

Primary findings showed that the median OS was 16.4 months with nivolumab vs 14.7 months with sorafenib (HR, 0.85; 95% CI, 0.72-1.02; P =.075), failing to demonstrate statistical significance. In the updated analysis, the median OS was 16.4 months and 14.8 months, respectively (HR, 0.85; 95% CI, 0.72-1.00).

The ORR was 15% in the sorafenib arm vs 7% in the sorafenib arm, which was consistent with that reported response rate data from the CheckMate-040 trial.

“Despite the evolving landscape of HCC therapy, a subset of patients will still be treated with a TKI in the first-line setting due to contraindications to the combination of atezolizumab [Tecentriq] and bevacizumab [Avastin]. The majority of the patients treated with sorafenib will eventually discontinue treatment due to progression or intolerance, making nivolumab monotherapy a valuable option in these patients,” Anthony El-Khoueiry, MD, an associate professor of medicine at the Keck School of Medicine, said during the hearing.

“In addition, patients with intolerance to sorafenib may not be good candidates for treatment with another TKI in the second-line setting. Approximately 35% of patients receive nivolumab in the second-line setting currently. Nivolumab has been studied and shown to be efficacious independent of etiology. It has also shown benefit in Child-Pugh B and elderly patients. Given the favorable safety profile and the potential for durable response translating into meaningful clinical benefit, all immunotherapy-naïve patients going into second-line treatment should have the option to use nivolumab,” added El-Khoueiry.

However, key concerns that the FDA expressed in upholding the accelerated approval included the low response rate of nivolumab monotherapy in the post-sorafenib setting, the changed treatment landscape that came with the approval of atezolizumab plus bevacizumab in the frontline setting, the negative confirmatory trial, and the fact that the response rate of nivolumab plus ipilimumab (Yervoy) is higher than nivolumab monotherapy in the second-line setting.

Moreover, the accelerated approval of the combination of nivolumab and ipilimumab for the treatment of patients with HCC who have received prior therapy with sorafenib would be maintained pending confirmatory data, irrespective of the decision of the biologics license application for nivolumab monotherapy.

During the hearing, the panel questioned why the accelerated approval of nivolumab should be maintained when the accelerated approval for the combination would stand pending further review.

Thomas Abrams, MD, a medical oncologist at Dana-Farber Cancer Institute, explained that each regimen is reserved for distinct patient populations in practice. Abrams added that the combination is generally given to fitter patients who progressed on a frontline TKI, whereas nivolumab is typically given to less fit patients in the second-line setting.

In conclusion, BMS stated that they are committed to completing several ongoing phase 3 trials that could demonstrate the clinical benefit of nivolumab, including CheckMate-9DX, CheckMate-9DW, and CheckMate-74W.


Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. April 29, 2021. Accessed April 29, 2021. https://collaboration.fda.gov/ODAC04292021?disclaimer-consent=true&proto=true.