Committee members felt the data on overall survival for patients treated with Copiktra was difficult to interpret, and the therapy was associated with a higher risk of serious side effects and deaths compared with Kesimpta.
The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 8 to 4 on Sept. 23, 2022, against Secura Bio’s Copiktra (duvelisib) against whether the benefit-risk profile of Copiktra for patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
Before the voting, Christopher H. Lieu, M.D., associate professor of Medicine, Associate Director for Clinical Research, University of Colorado Cancer Center Aurora, Colorado, expressed concern that there are not only have deaths from disease but also from the treatment. He pointed out that in disease where survival is measured in weeks to months, the bar that that is set for toxicity is pretty low.
“If you have an indolent disease, what is the cost to our patient that we are going to expect out of a therapy in a setting that we are not sure that it improves overall survival,” he asked. “I’m sure there are patients who are alive and well today because of this treatment but the flipside is true as well and that’s what makes this decision so difficult. There are people who have passed away because of this medication. It is not just about offering treatment options but also the costs in terms of toxicity and in this situation death.”
Lieu mentioned that he has concerns about this class of medication. “If we are not clearly not improving overall survival in these patients but we are increasing toxicities and treatment associated death, I’m not sure we are truly helping patients.”
The FDA had granted regular approval of Copiktra in September 2018 for adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies. At that time, the DUO trial showed that Copiktra demonstrated a median progression free survival of 13.1 months, and an advantage in overall response rate 73.8% was seen.
But toxicities were seen in the trial, including serious or fatal infections, diarrhea or colitis, rash, pneumonitis, hepatotoxicity, and neutropenia. Because of this, the FDA issued a postmarketing requirement and required the submission of overall survival from the DUO study with five years of follow up data.
In June 2022, the FDA released a warning about an increased risk of serious adverse events, including death, seen in the five-yeard data. In materials released ahead of the advisory committee meeting, agency officials expressed concern about potential harm to patients based on the follow up data and that benefit-risk of duvelisib in patients with relapsed or refractory CLL or SLL is not favorable. At a median follow-up of 63 months in the intent-to-treat population, the overall survival of patients treated with Copiktra was 52.3 months compared with 63.3 months for patients treated with Novartis’ monoclonal antibody Kesimpta (ofatumumab). There were 80 deaths (50%) in the Copiktra arm vs. 70 deaths (44%) in the Kesimpta arm. The estimated hazard ratio for Copikta was 1.09. (A hazard ratio above 1 means there is a higher risk of harm.)
In patients who had two or more prior treatments, the median overall survival at 63 months was 43.9 in the Copikta arm vs. 46.8 in the Kesimpa arm with a hazard ratio of 1.06. There were 53 deaths (56%) in the Copikta arm and 49 deaths in the Kesimpa arm. In the Copikta arm, adverse events leading to treatment discontinuation occurred in 70 patients (44%), dose reduction in 48 patients (30%), and dose interruption in 112 patients (71%).
One committee member who voted yes was Jorge J. Nieva, M.D., associate professor of Clinical Medicine, Section Head, Solid Tumors, University of Southern California (USC), Keck School of Medicine in Los Angeles. “I think the drug reduces the burden of CLL in many patients. I want to compliment the FDA in the effort they’ve made to bring to the light the potential toxicities of this agent. Some patients and physicians will determine the data is insufficient to justify use of the drug. Others will think it is the right drug for the right situation. Ultimately, I trust the decision making of physicians and patients to make informed decisions and would like to see this drug available.”