ODAC Votes Against Duvelisib for Relapsed or Refractory CLL/SLL

In an 8 to 4 vote, the FDA’s Oncologic Drug Advisory Committee (ODAC) decided that the benefit/risk profile of duvelisib (Copiktra) is unfavorable for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least 2 prior therapies.¹

The PI3K inhibitor was granted approval in September of 2018 based on results from the phase 3 DUO trial (NCT02004522). At the time of the approval, duvelisib had demonstrated a 60% reduction in the risk of disease progression or death versus ofatumumab (Arzerra) in patients with relapsed/refractory CLL/SLL who had received at least 2 prior lines of therapy. The median progression-free survival observed was 13.3 months with duvelisib versus 9.9 months with ofatumumab (HR = 0.52; P < .0001).²

Notably, extended PFS was also shown in the population of patients with high-risk chromosome 17p13.1 deletions and/or TP53 mutations (HR = 0.40; P = .0002) with duvelisib compared with ofatumumab. The overall response rate observed with duvelisib was also significantly higher vs ofatumumab (74% vs 45%; P < .0001) regardless of patients’ del(17p) status.

Safety results from DUO showed that the most common adverse events in the duvelisib treatment arm were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough. In the ofatumumab arm, the most common AEs were neutropenia and infusion reactions.

Although the DUO trial results were positive and supported the use of duvelisib in CLL/SLL, the FDA issued a warning about duvelisib in July 2022 stating that the agent may lead to an increase in the risk of death in comparison with other agents. In addition, the FDA warned that duvelisib is associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood.

The FDA’s Claim

On day 2 of the September 22/23 ODAC Meeting, the FDA led by Nicholas Richardson, DO, MPH, Division of Hematologic Malignancies II, Office of Oncologic Diseases, FDA, discussed the OS detriment shown in the 5-year OS analysis of the DUO trial, toxicity and tolerability concerns, issues regarding the selected dose, safety concerns with the PI3K inhibitor drug class, the risk/benefit evaluation of duvelisib.¹

Richardson noted during the meeting that concerns about PI3K inhibitors were discussed during the April 21st Meeting of the ODAC, and the committee voted the randomized data are needed to support future approval of PI3K inhibitors like duvelisib.

“At the time of the initial approval, overall survival was immature with a median of 24 months of OS follow-up. At the time of the initial approval, several measures were included to mitigate risks. Development labeling included a box warning for fatal or serious infections, diarrhea or colitis, rash, and pneumonitis. Additionally, the toxicities of neutropenia and hepatic toxicity were included as warnings and precautions. A risk evaluation and mitigation strategy or rounds were also included with the initial approval of developments to ensure its safe and effective use and that its benefits outweigh its risk, explained Richardson, during the ODAC meeting.

“Importantly, to post-marketing requirements were issued because of the concerns with fatal and serious toxicity with develop. One was to characterize longer-term safety and the other was to provide updated over Are all survival data with five years of OS follow-up in the duo trial. The 5-year OS data from the duo trial demonstrate the potential detriment in overall survival in patients treated with the relative in the intent-to-treat [ITT] population,” Richardson added.

The FDA believes that the OS detriment observed in the 5-year analysis is a direct result of unfavorable safety. The FDA’s presentations also highlight the significant number of patients who crossover to subsequent therapy after disease progression on duvelisib.

“The FDA acknowledges that the presence of crossover can make the assessment of overall survival challenging. However, in this case, we have a substantial amount of crossover to feed subsequent therapy with developing a drug with serious and fatal toxicity, potentially causing harm to the control group, and may mask a difference between the treatment arms that would have favored the control arm. But another way, despite crossover, we are still seeing a signal for the potential detriment in overall survival, and the potential for harm was developed. The updated overall survival data are further reinforced by the safety data in the duo trial,” said Richardson.

The safety and OS detriment observed in the long-term follow-up data brought up further concern about the dosage of duvelisib used in the study. Moreover, a positive 5-year analysis was one of the post-marketing requirements from the FDA for the approval of duvelisib in relapsed/refractory CLL/SLL.

Deepti Telaraja, MD clinical reviewer, Department of Hematologic Malgnanicies II at the FDA, noted that the toxicities observed with duvelisib are consistent with common toxicities observed with PI3K inhibitors. This led to multiple drug withdrawals from the United States market earlier in 2022.

“There are 3 major areas of concern with the data were developed from the DUO trial; overall survival, increased toxicity, and inadequate dose optimization. With respect to overall survival, the DUO trial demonstrated a higher rate of deaths, and deaths due to adverse effects on the duvelisib arm. The potential detriment in overall survival occurred in the setting of a benefit in PFS and overall response rate was developed in indicating a primary safety concern. With respect to increased toxicity, the duvelisib arm demonstrated a higher rate of grade 3 or greater adverse events, serious adverse events, and treatment modifications, all of which were driven by infections and immune-mediated toxicity, said Telaraja. “Finally, with respect to dosing, the increased toxicity with DUO listed is correlated with several exposure-response relationships for safety and a lack of clear exposure-response relationships for efficacy. There was also limited dose exploration and dose optimization, which calls into question the acceptability of the selected dose in light of the updated OS data.”

The Applicant’s Response

According to duvelisib developer, SecureBio clinical advisor, and professor of Oncology at Johns Hopkins University, David Sidransky, MD, the applicant discounts the FDA’s claims of negative 5-year analysis results and intolerable toxicity.

The company asserts that the initial results DUO trial had a statistically significant, clinically meaningful PFS benefit as well as an acceptable and manageable safety profile with a positive benefit/risk profile. With longer follow-up, Sidransky said that “OS data at final analysis in the indicated population does not support the conclusion of detriment.” Comparing duvelisib in the long-term analysis to the initial results, Sidransky concluded that the OS was comparable, and the safety profile had not changed since 2018 when duvelisib was granted approval.

A review of the DUO trial data and results from 2 other studies were presented by Matthew Davids, MD, MMSc, director, Clinical Research Division of Lymphoma at Dana-Farber Cancer Institute. Davids stated “Duvelisib monotherapy resulted in a statistically significant and clinically meaningful improvement, PFS and ORR compared to ofatumumab in patients with relapsed/refractory CLL or SLL, including those with high-risk disease. This treatment effect was consistent across all pre-specified subgroups.”

Davids added “A high proportion of patients responded to duvelisib treatment after crossover

and the safety profile of people lifted as well characterized, manageable and reflected in the prescribing information. Importantly, there is no new safety evidence to support a change in the favorable benefit/risk profile since approval.”

SecureBio also noted that 2 other PI3K inhibitors remain approved for CLL/SLL, and no warnings have been issued regarding those agents.

“There is no new evidence to support a change in benefit/risk of duvelisib since approval. The totality of data demonstrates the favorable benefit to risk profile, which is also consistent with that of other pediatric areaa that are approved and refractory we have relapsed CLL deliberative, which remains on the market indicating that this benefit/risk profile is acceptable for patients with relapsed and refractory CLL. To our knowledge, the agency has not issued public safety alerts or taking other actions against the only other two approved agents in the class at this time. There is, therefore, no new evidence that demonstrates the drug is not safe or effective under conditions of use,” said Sidransky.

ODAC’s View

The ODAC discussed the benefit-risk profile of duvelisib for the currently indicated patient populations with consideration of the updated data from the DUO trial.

The discussion started with conflicting information about OS from the sponsor and the FDA. On one side (SecureBio) the detriment in OS was said to be related to crossover. On the FDA’s end, the OS detriment was said to be related to safety.

“The estimated detriment in survival is not something that we can rely on. We really don't know what the long-term effect of survival is for this agent compared to ofatumumab, because that comparison is confounded,” said David Harrington, MA, PhD, professor of Biostatistics (Emeritus) Harvard T.H. Chan School of Public Health and Dana-Farber Cancer Institute, during the meeting.

Overall, the ODAC members decided that the PFS data were compelling, but the safety data were concerning. Although 4 members voted 'yes', the majority who voted against duvelisib said their decision was based on safety.

"I voted yes. I think the drug reduces the burden of CLL in many patients. I do want to compliment the FDA and ODAC for all the work they've done, to bring them to life potential toxicity, this agent have done a great job issuing warnings on its use. Some physicians and patients will determine that the data is insufficient to justify use of the drug. Others will think it's the right drug for the right situation. And ultimately, I trust the decision making of physicians and patients to make informed decisions and would like to see this drug available, said Jorge Garcia, MD, FACP, chairperson of the ODAC.

"I voted no. I think that with this drug and this class of drugs, we are playing with fire. This drug had modest activity with significant toxicity, as did other members of this class and was compared to a drug that we would no longer use in the setting. This drug itself we would no longer use in this setting as patients receive other drugs, such as BTK inhibitors and BCL2 inhibitors, for which they would have been disqualified from the study. So, we're left with a drug that has substantial toxicity and questionable indication today, said Mikkael A. Sekeres, MD, MS, professor of Medicine Sylvester Cancer Center University of Miami, and a temporary voting member of the ODAC.

_REFERENCES:

_{1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA website. September 22, 2022. Accessed September 22, 2022. https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-22-23-2022-meeting-oncologic-drugs-advisory-committee-meeting-announcement-09222022}

_{2. Finn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018; 132 (23): 2446–2455. doi: 10.1182/blood-2018-05-850461}