An FDA Oncologic Drugs Advisory Committee meeting resulted in continued approval for 4 of 6 indications that were discussed, although all 6 indications did not demonstrate clinical benefit in confirmatory studies. The meeting, held April 27-29, evaluated anti–PD-1/PD-L1 drugs that received accelerated approvals through the FDA’s accelerated approval program, a nearly 30-year-old initiative to expedite the approval process.
An FDA Oncologic Drugs Advisory Committee (ODAC) meeting resulted in continued approval for 4 of 6 indications that were discussed, although all 6 indications did not demonstrate clinical benefit in confirmatory studies. The meeting, held April 27-29, evaluated anti–PD-1/PD-L1 drugs that received accelerated approvals through the FDA’s accelerated approval program, a nearly 30-year-old initiative to expedite the approval process.1
Prior to the meeting, 4 drugs were withdrawn or in the process of being withdrawn, with 6 indications on the docket for discussion during the meeting. Those first 4 were nivolumab (Opdivo) for its indication in small cell lung cancer (SCLC), durvalumab (Imfinzi) for its indication in urothelial cancer, pembrolizumab (Keytruda) for its indication in metastatic SCLC, and atezolizumab (Tecentriq) for its indication in urothelial carcinoma.
Results from confirmatory studies were reviewed for agents in breast cancer (atezolizumab), urothelial cancer (pembrolizumab and atezolizumab), gastric cancer (pembrolizumab), and hepatocellular carcinoma (pembrolizumab and nivolumab).
ODAC voted 7 to 2 in favor of the continued approval of atezolizumab in combination with nab-paclitaxel (Abraxane) for the treatment of patients with advanced or metastatic triple-negative breast cancer (TNBC) with tumors positive for PD-L1 expression.
The agent had received accelerated approval in March 2019 after improvement in progression-free survival in patients with met-astatic TNBC was observed in the phase 3 IMpassion130 trial (NCT02425891). The multicenter, double-blind study randomized 651 patients 2:1 to receive either atezolizumab in combination with paclitaxel or placebo.
For atezolizumab’s indication in urothelial cancer, the committee voted 10 to 1 to maintain its approval of atezolizumab for first-line treatment for patients with urothelial carcinoma who are not eligible for cisplatin.
Final data for the drug’s confirmatory trial, IMvigor130 (NCT02807636), are expected in 2022; the committee decided to delay its decision until those data are available.
The committee voted 5 to 4 against continued accelerated approval of nivolumab for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib.
In September 2017, the FDA granted accelerated approval to nivolumab as a mono-therapy for the treatment of hepatocellular carcinoma in patients previously treated with sorafenib. Approval was based on a 154-patient subgroup of the CheckMate 040 study (NCT01658878), which evaluated nivolumab as a monotherapy for patients with HCC and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib. The overall response rate was 14.3%, which included 3 complete responses and 19 partial responses. Duration of response ranged from 3.2 months to 38.2 months and longer. Of those who responded, 91% had a response lasting 6 months or longer and 55% had a response lasting 12 months or longer.2
Continued approval of the agent was based on CheckMate 459 (NCT02576509). The phase 3, randomized study enrolled 743 participants. The primary outcomes of the study were over-all survival (OS) objective response rate (ORR), progression-free survival (PFS), and efficacy based on PD-L1 expression.
Investigators reported that the OS benefit of nivolumab over sorafenib was not statistically significant.
The median OS for the nivolumab group was 16.4% versus 14.7% for the sorafenib group. In the nivolumab arm, 12-month and 24-month OS rate was 59.7% and 36.8%, respectively. In the sorafenib arm, the 12-month and 24-month OS was 55.1% and 22.1%, respectively. The median PFS was 3.7 months for nivolumab and 3.8 months for sorafenib. The ORR was 57% for nivolumab and 26% for sorafenib. The study did not meet its primary end point.3
In a reversal of its initial approval, ODAC voted 6 to 2 to pull the approval of pembrolizumab for patients with PD-L1–positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received 2 or more lines of therapy.
The initial approval for the agent was granted in September 2017 based on findings from the phase 2 KEYNOTE-059 trial (NCT02335411). In that trial, responses were observed in patients with gastric/GEJ adenocarcinoma treated with pembrolizumab in the third-line setting or beyond.
“Often there is a tail of the curve, and it would be terribly devastating for a patient [not to] receive the therapy," ODAC committee member Diane Reidy-Lagunes, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, said. “Recognizing there are access programs with disparities of health care and differences in the way that patients are treated throughout our country, I was nervous that they may not be able to get that.” Reidy-Lagunes continued, “Having said that… [KEYNOTE]-061 and [KEYNOTE]-062 did prove that single-agent therapy did not seem to pan out as compared to [the combination with chemotherapy].”
For pembrolizumab’s other indications, the committee voted to maintain the drug’s indication in metastatic urothelial carcinoma and in advanced HCC.
Regarding the urothelial carcinoma indication, panelists voted 5 to 3 to maintain approval. Accelerated approval was granted based on the results of the KEYNOTE-052 study (NCT02335424), which found pembrolizumab demonstrated antitumor activity in patients with urothelial cancer who are cisplatin ineligible.
“The patients that fit the accelerated approval label have few options, which include best supportive care, palliative endoscopic resection, radiation, and systemic treatments that include gemcitabine and carboplatin in combination or monotherapy with a cytotoxic agent such as gemcitabine; and more recently [we] can consider pembrolizumab in patients who are platinum ineligible or for those who are PD-L1 positive and have significant disease-related symptoms and/or medical comorbid conditions that wouldn’t meet inclusion criteria for the trial cohorts,” said ODAC panelist Christopher J. Hoimes, DO, of Duke University School of Medicine in Durham, North Carolina.
However, the KEYNOTE-361 trial (NCT02853305) failed to confirm the drug’s benefit. In addition, the OS benefit of avelumab (Bavencio), another checkpoint inhibitor, has further clouded the treatment landscape.
The ODAC committee delivered a unanimous decision, 8 to 0, to keep the pembrolizumab indication for patients with advanced HCC who were previously treated with sorafenib (Nexavar).
“The accelerated approval for pembrolizumab in the second-line setting was appropriate based on a modest response rate seen in KEYNOTE-224 and a clear unmet need in a patient population that needs more effective therapies,” ODAC panelist Christopher Lieu, MD, of University of Colorado Medicine, told Targeted Oncology in an interview.
“I believe the key issue for this approval is that the landscape for HCC treatment has changed dramatically, and there is now an approval for immunotherapy in an earlier-line setting, which brings into question the continued need for this approval in the refractory setting,” Lieu said.
“In the refractory setting, patients are now highly likely to have received some form of immune checkpoint therapy previously, Lieu continued. “However, if we assume 15% to 20% of patients cannot receive bevacizumab [Avastin] in the first-line setting, is it reasonable to continue an indication in an immunotherapy-naive population in the second-line setting [in which] an overall survival benefit may exist? I believe this answer to be yes, until we have final results from the KEYNOTE-394 study.”
Pembrolizumab was granted accelerated approval for this indication in November 2018 in the phase 3 KEYNOTE-224 trial (NCT02702414) of 104 patients with HCC who had disease progression on or after sorafenib or were intolerant to sorafenib. KEYNOTE-224 was a single-arm, multinational trial that assessed ORR per central review as its primary end points. Secondary end points were duration of responses, disease control rate, time to progression, PFS, and OS.4
The FDA created its accelerated approval program in 1992 after the development of treatments for HIV/AIDS was outmatched by the high number of deaths. Under the program, the agency can give early approval to drugs that fill medical needs for serious conditions based on a surrogate end point, such as a laboratory measurement or physical sign, with the potential to predict clinical benefit. The drug manufacturer is then required to confirm the benefit through current or potentially additional clinical trials. In the past 10 years, 85% of the FDA’s accelerated approvals have been granted for oncology treatments.
The recommendations now go to acting FDA Commissioner Janet Woodcock, MD, who will make the final decision on these 6 indications. In the meantime, the accelerated approvals will stay in place as the agency consults with the drug manufacturers.
1. Accelerated approval. FDA. Updated January 4, 2018. Accessed March 22, 2021. https://bit.ly/3vO6hCZ
2. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. FDA. Updated September 25, 2017. Accessed April 29, 2021. https://bit.ly/3aOKRgg
3. Yau T, Park JW, Finn RS, et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30(suppl 5):v874-v875. doi:10.1093/annonc/ mdz394.029
4. FDA approves Merck’s Keytruda (pembrolizumab) for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. News release. Merck. November 9, 2018. Accessed April 29, 2021. https://bit.ly/32XjbS0