FDA committee calls for more research into lung cancer therapy studied only in China
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The FDA should not make a regulatory decision on sintilimab for advanced lung cancer until additional study demonstrates applicability to U.S. patients, an advisory committee determined.
Results of the randomized phase 3 ORIENT-11 study — conducted exclusively in China — showed the addition of the agent to chemotherapy prolonged PFS among patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.
However, the Oncologic Drugs Advisory Committee (ODAC) voted 14-1 that an additional clinical trial should be conducted before the FDA considers approval for that indication.
Committee members who supported the need for additional study cited several factors for their votes, including the single-country design ORIENT-11, the fact the comparator regimen did not reflect standard therapy in the United States, and the decision by the study sponsors not to use OS as the primary endpoint.
“In my opinion, the value of well-designed multiregional clinical trials and the importance of the charge to have more diverse clinical trials were central to my vote,” said Ibiayi Dagogo-Jack, MD, assistant professor of medicine at Harvard Medical School. “The data presented don’t support the applicability of ORIENT-11 findings to the diverse, more heterogeneous U.S. population, and the primary endpoint of PFS is a step backward.”
The FDA is not required to follow ODAC’s recommendation but often does.
Sintilimab (Innovent Biologics/Eli Lilly), a PD-1 inhibitor, is approved in China for multiple indications but is not approved in the United States.
Innovent Biologics submitted a biologics license application to the FDA seeking approval of the agent in combination with pemetrexed and platinum-based chemotherapy for first-line treatment of patients with stage IIIB, IIIC or IV nonsquamous NSCLC with no EGFR or anaplastic lymphoma kinase genomic tumor aberrations.
The application cited data from the ORIENT-11 study, which included 397 patients in China with previously untreated locally advanced or metastatic nonsquamous NSCLC without EGFR or ALK mutations and an ECOG performance status of 0 or 1.
Researchers randomly assigned patients 2:1 to 200 mg sintilimab (n = 266; median age, 61 years; 76.7% men) or placebo (n = 131; median age, 61 years; 75.6% men) plus 500 mg/m2 pemetrexed and either 75 mg/m2 cisplatin or carboplatin area under the curve 5 every 3 weeks for four cycles. Patients then received maintenance therapy with either sintilimab or placebo with pemetrexed. Treatment continued until disease progression, and participants in the placebo group could cross over to sintilimab.
PFS served as the primary endpoint. Secondary endpoints included OS, overall response rate, time to response, duration of response and safety.
As Healio previously reported, results after median follow-up of 8.9 months (range, 0.6-14.8) showed longer median PFS in the sintilimab group (8.9 months vs. 5 months; HR = 0.48; 95% CI, 0.36-0.64). Researchers reported 6-month PFS rates of 68.3% (95% CI, 62-73.8) for the sintilimab group vs. 42% (95% CI, 32.8-50.9) for the placebo group.
Some ODAC members questioned the inclusion of patients with stage IIIB or IIIC disease, who could have received curative treatment.
Committee member David Mitchell, founder of Patients for Affordable Drugs, contended sintilimab would not address an unmet need.
“We have treatments that are safe and effective and show an improvement in overall survival, rather than this drug that was tested against a primary endpoint of progression-free survival, and not against current standard of care,” Mitchell said. “At a time when the FDA and industry are trying to increase diversity in clinical trials to ensure they are representative of the patient population to be treated, it makes no sense to move in the opposite direction with this application.”
Briefing documents submitted by Innovent suggested that clinical practice standards are similar between China and the United States and that sintilimab had demonstrated a sufficiently favorable risk-benefit profile.
ODAC member Christopher H. Lieu, MD, director of the gastrointestinal medical oncology program at University of Colorado, voted in favor of additional study because the applicability of ORIENT-11 results “is still questionable.”
“However, I’d stress that this already is a known entity. There is a body of evidence available, and I have concerns about forcing a noninferiority, 7-plus year study as a confirmatory study,” Lieu said. “I would hope the FDA and the applicant would be able to work toward a potentially more feasible and efficient solution.”
Jorge J. Nieva, MD — associate professor of clinical medicine and section head of solid tumors at University of Southern California Norris Comprehensive Cancer Center — cast the lone dissenting vote, suggesting an additional trial is not necessary.
“This drug works, adding value over chemotherapy alone in the first-line treatment of [patients with advanced lung cancer],” Nieva said. “We have no evidence that the data presented are unreliable, synthetic or otherwise fraudulent ... and the PFS endpoint is appropriate with a crossover design. ...
“I don’t believe we have an excess number of drugs for lung cancer,” Nieva added. “If we did, we would’ve seen downward pricing pressure by now.”
ODAC members are charged with determining whether drugs are safe and effective, not to determine how many drugs are too many, Nieva said.
“Regarding the need for resolving health equity issues in the U.S., health equity will improve when there are fewer cost barriers to care,” Nieva said. “Having more drugs competing for those same patients will have, I think, greater impact on equity than the need for diversity in clinical trial enrollment, which I believe is important. ...
“I think ‘me-too drugs’ are good things,” he added. “They bring down drug prices and increase access to care for all patients. It seems the chief sin the applicant has committed is not doing things the way the FDA would like it to have been done. They failed to show proper process, not that they failed scientifically. I think the FDA should be in the business of evaluating their science and not the process, unless the process used compromises the science.”
Eli Lilly issued the following statement after the meeting: “[Although] we are disappointed with the outcome of today’s ODAC as it relates to the investigational product sintilimab, we appreciated the opportunity to publicly discuss the application and broader issues related to single-country clinical trials. We had hoped that sintilimab could have played a positive role for patients and the U.S. health care system through an aggressive pricing strategy. We acknowledge that the landscape has changed dramatically on a number of fronts since the ORIENT-11 study was conducted and the sintilimab application was initiated. Lilly wholeheartedly agrees with the importance of ethics in clinical trial conduct and clinical trial diversity. We have long-standing initiatives in place to advance diversity and inclusion in Lilly-conducted clinical trials. Along with Innovent, we will continue to work with the FDA as it completes its review of the sintilimab application.”
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