In an 8 to 0 vote, the FDA’s Oncologic Drugs Advisory Committee voted to support the accelerated approval of pembrolizumab monotherapy for patients with advanced hepatocellular carcinoma who received prior treatment with sorafenib.
In an 8 to 0 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted to support the accelerated approval of pembrolizumab (Keytruda) monotherapy for patients with advanced hepatocellular carcinoma (HCC) who received prior treatment with sorafenib (Nexavar).
“We are pleased with the positive outcome of today’s discussion. Since the approval of [pembrolizumab] for the second-line treatment of hepatocellular carcinoma, the most common type of liver cancer, [pembrolizumab] has provided an important option for these patients. We look forward to providing updates to the FDA from ongoing trials investigating the use of [pembrolizumab] in liver cancer. We thank all of the patients, advocates and health care providers who participated in today’s discussion,” said Scot Ebbinghaus, MD, Therapeutic Area Head of Oncology at Merck & Co., Inc.
In explaining his decision, Colin D. Weekes, MD, PhD, FASCO, said, “I voted yes because although the results [of KEYNOTE-240] are not statistically significant, I believe they are clinically significant, bore out by the persistent benefit demonstrated in the overall survival curves. In addition, with the results of the KEYNOTE-394 study that are to be reported within the next 6 months, we will be able to have a definitive answer as to whether there is truly a benefit or not of single-agent pembrolizumab in the second-line setting.”
The meeting roster comprised ODAC members, Susan Halabi, PhD; Philip C. Hoffman, MD; Christopher H. Lieu, MD; and David E. Mitchell, as well as temporary voting members Karen R. Hoyt; Pamela L. Kunz, MD; Mark A. Lewis, MD; and Colin D. Weekes, MD, PhD, FASCO.
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 pembrolizumab, the PD-1 inhibitor demonstrated an objective response rate (ORR) per RECIST criteria of 17% (n = 104; 95% CI, 11%-26%) in patients who had progressed on or were intolerant to prior sorafenib in the phase 2 KEYNOTE-224 trial. Responses were 6 months or longer in 89% of patients and 12 months or longer in 56% of patients.
Primary findings from the trial served as the basis for the November 2018 accelerated approval of the agent for the treatment of patients who received prior sorafenib.
The continued approval of the agent was contingent on positive data from the phase 3 KEYNOTE-240 trial, but the study failed to meet its co-primary end points of overall survival (OS) and progression-free survival (PFS), with 1-sided alphas of .023 and .002, respectively.
In the trial, patients who had progressed on or were intolerant to sorafenib were randomized to 200 mg of pembrolizumab every 3 weeks plus best supportive care (n = 278) or placebo plus best supportive care (n = 135).
The median PFS was 3 months in the pembrolizumab arm vs 2.8 months in the placebo arm (HR, 0.775; 95% CI, 609-987; P = .0186). The median OS was 13.9 months and 10.6 months, respectively (HR, 0.781; 95% CI, 0.611-0.998; P = .0238). Long-term follow-up demonstrated a median PFS of 3.3 months with pembrolizumab vs 2.8 months with placebo (HR, 0.70; 95% CI, 0.56-0.89; P = .0011). The median OS was 13.9 months vs 10.6 months (HR, 0.77; 95% CI, 0.62-0.96; P = .0112).
However, the ORR was 18.3% (95% CI, 14.0%-23.4%) in the pembrolizumab arm vs 4.4% (95% CI, 1.6%-9.4%) in the placebo arm, mirroring the favorable response rate reported in KEYNOTE-224.
“Although KEYNOTE-240 did not meet its primary end point, it confirmed the activity of pembrolizumab that was seen in the phase 1b KEYNOTE-224 study that supported its accelerated approval. When coupled with the differences in safety profile compared with the [available] TKIs, this makes keeping pembrolizumab approved a priority because it’s an important option for our patients,” said Richard S. Finn, MD, lead study author of KEYNOTE-240, during the hearing.
Key concerns that the FDA expressed in upholding the accelerated approval included the low response rate of single-agent pembrolizumab in the post-sorafenib setting, the changed treatment landscape that came with the approval of atezolizumab (Tecentriq) plus bevacizumab (Avastin) in the frontline setting, and the fact that the benefit of pembrolizumab was not confirmed in the same post-sorafenib setting in the KEYNOTE-240 trial.
However, approximately 15% to 20% of patients with advanced HCC are not eligible or have a contraindication to bevacizumab in the frontline setting, precluding them from receiving the combination of atezolizumab/bevacizumab as first-line therapy, said Finn.
In the open public hearing, medical oncologists, Cathy Eng, MD, FACP, FASCO, and Milind Javle, MD, asserted that rescinding the accelerated approval of pembrolizumab as second-line therapy in advanced HCC would not be in the best interest of patients.
In conclusion, Merck stated that ongoing phase 3 trials that the FDA has accepted as a way of fulfilling the post-market requirement for pembrolizumab include the KEYNOTE-394 and LEAP-002 trials.
Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. April 28, 2021. Accessed April 28, 2021. https://collaboration.fda.gov/ODAC04282021?disclaimer-consent=true&proto=true.