The FDA Oncologic Drugs Advisory Committee voted down three problematic indications of cancer drugs, two of which got on the market under the agency’s accelerated approval program.
All three indications nixed at ODAC’s Sept. 22-23 meeting had one thing in common: there were no data confirming that the doses were optimized before pivotal clinical trials began. Two of the three indications presented to the committee had apparent survival deficits on the experimental arms.
The indications represent three different classes of drugs, which likely means that the FDA position and the ODAC recommendations are generalizable across the board.
The committee voted down the following agents:
- Poziotinib, a pan-epidermal growth factor receptor inhibitor, which was granted an accelerated approval for NSCLC patients with HER2 exon 20 insertion mutations. The agent is sponsored by Spectrum Pharmaceuticals.
- Melphalan flufenamide, a peptide-drug conjugate of melphalan, which was granted an accelerated approval in combination with dexamethasone for relapsed or refractory multiple myeloma patients who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD-38 directed monoclonal antibody. The agent is sponsored by Oncopeptides AB.
- Duvelisib, a PI3K inhibitor, which received a regular approval in 2018 for relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma who have received at least two prior therapies. The committee was asked to weigh in on updated 5-year overall survival data, which the FDA required as a postmarketing requirement due to initial toxicity concerns. The agent is sponsored by Secura Bio Inc.
Last week, in a perspective paper in The New England Journal of Medicine and in a conversation with this publication (The Cancer Letter, Sept. 23, 2022), FDA officials said that for the best chance at a successful accelerated approval, “a comprehensive development plan, for both the initial accelerated approval and the confirmatory trial, should be prospectively discussed and agreed upon with FDA.”
FDA officials recommended that the agent’s dose be nailed down early in the development plan and that confirmatory trials be ongoing at the time when accelerated approval is granted. Issues to be agreed upon in consultation with the agency should include the study population, trial design, the endpoints for both accelerated approval and for verification of benefit—and the timelines for getting the answers.
The agency also published a complete list of oncology accelerated approval indications that have been granted since 1992, when the program began. The just-published data include time to withdrawal or conversion to regular approval for each indication.
A successful development program must begin with dose optimization, Richard Pazdur, director of the FDA’s Oncology Center of Excellence, said at the ODAC meeting. “I’ve said this before, and I’ll say it again, proceeding with a drug development program when you don’t have a well-founded dose is literally building a house on quicksand,” Pazdur said.
ODAC votes concur with FDA analyses
On Sept. 22, ODAC voted 9:4 against the poziotinib for NSCLC indication.
The agency’s question was:
Discuss the overall risk:benefit of poziotinib 16 mg once daily given its limited response rate with poor durability, high rate of toxicity, inadequate dosage optimization, and delayed confirmatory trial.
“It will take a long while before we know the true dose and the true efficacy of the agent,” Jorge A. Garcia, ODAC chair, director of the GU Medical Oncology clinical and research programs at University Hospitals Seidman Cancer Center, and professor of Medicine and Urology at Case Western Reserve University School of Medicine, said after the vote.
There’s been, certainly, a need for better drugs—we all feel that—but we shouldn’t be using drugs that might actually be harming patients.
Christopher Lieu
“So, [there is] definitely an unmet need for a subgroup that was probably first identified probably more than a decade ago now. The drug poziotinib seems to be active and there are patients who definitely benefit from this agent, but for the overall population of HER2 exon 20 insertion patients, and in the specific setting where this accelerated approval is sought, there’s several open questions,” Anish Thomas, an ODAC temporary voting member, and a medical oncologist and Lasker Clinical Research Scholar in the Developmental Therapeutics Branch at NCI, said at the meeting.
“As an oncologist, I would love to see more options for these patients. A big advantage seems to be that it is an oral administration over available therapies, but it is somewhat offset by toxicities as well as uncertainties around the dose itself,” Thomas said. “While I recognize that this is a rare patient population and that the dose and schedule is not always straightforward, I feel like it needs to be looked at, and it has not been so far in its extended development course, and I think that would benefit the patients in the long run. And I also feel like given the low therapeutic index, better predictors of response should be sought.”
Later that day, ODAC voted 14:2 against melphalan flufenamide for the multiple myeloma indication.
The agency’s question was:
Given the potential detriment in overall survival, failure to demonstrate a progression-free survival benefit, and lack of an appropriate dose, is the benefit-risk profile of melphalan flufenamide favorable for the currently indicated patient population?
“We all embrace new treatment for MM, and we encourage you to work with the FDA to see if you can actually identify the right patient population, for the right clinical trial, with the right statistical design, if you really believe this agent has promise in MM,” Garcia said in his wrap-up remarks.
“The post-hoc analysis should be used for hypothesis generation, as opposed to labeling and indication for use,” Christopher Lieu, ODAC member and co-director of Gastrointestinal Medical Oncology at University of Colorado Hospital, said at the meeting. “There’s been, certainly, a need for better drugs—we all feel that—but we shouldn’t be using drugs that might actually be harming patients.
“To me, the answer is pretty simple. You have an analysis which may support the use in a specified patient population that could show a benefit, and a confirmatory study should be performed in this population, but the data do not support the use of this agent at this time,” Lieu, who is also associate director for Clinical Research at University of Colorado Hospital, said.
On Sept. 23, ODAC voted 8:4 thumbs-down on duvelisib for the chronic lymphocytic leukemia and small lymphocytic lymphoma indications.
The agency’s question was:
Given the potential detriment in overall survival, duvelisib-associated toxicity, concerns with the selected dose, and the safety issues with the PI3K inhibitor class, is the benefit-risk profile of duvelisib favorable in patients with relapsed or refractory CLL or SLL after at least two prior therapies?
“There is no clear data that this agent, at least prospectively, would have any true benefit for this patient population in the contemporary setting,” Garcia said during the meeting, particularly considering that patients already have effective treatment options with known efficacy and safety.
Duvelisib is one of six PI3K inhibitors indicated for chronic lymphocytic leukemia or non-Hodgkin’s lymphoma which have shown initial benefit in efficacy outcomes, but demonstrate potential detriment in overall survival in subsequent confirmatory trials.
“The consistent pattern of a potential detriment in OS in multiple randomized trials within a class of drugs is unprecedented in oncology, and gives credence to the fact that this is unlikely to be a finding that is due to chance,” Nicholas Richardson, pediatric hematologist/oncologist in the division of Hematological Malignancies II, said at the meeting on behalf of the FDA.
“I think that with this drug, and this class of drugs, we are playing with fire,” Mikkael A. Sekeres, an ODAC temporary voting member and professor and chief in the Division of Hematology at Sylvester Comprehensive Cancer Center, said at the meeting.
“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 this setting,” Sekeres said.
“This drug itself we would no longer use in this setting, as patients receive other drugs, such as BTK inhibitor 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 a questionable indication today.”
HHS OIG report adds to scrutiny of accelerated approvals
Previously, FDA focused on the “dangling indications” of PD-1 and PD-L1 inhibitors that received accelerated approvals but their benefits were not validated in confirmatory trials (The Cancer Letter, March 5, March 12, April 30, June 25, October 15, 2021).
I think that with this drug, and this class of drugs, we are playing with fire.
Mikkael A. Sekeres
FDA’s Oncology Center of Excellence has conducted a systematic review of accelerated approvals and found that if the confirmatory trial was ongoing at the time of accelerated approval, the median time to converting the approval to traditional approval was 3.0 years, compared to 5.0 years if this trial was not yet started.
Meanwhile, the median time to withdrawal was 3.8 years if the confirmatory trial was ongoing at the time of accelerated approval, compared to 7.3 years if this trial was not yet started.
“The goal of a comprehensive approach would be to prevent a delay in obtaining the confirmatory evidence and therefore minimize the potential risk to patients of having an ineffective drug on the market,” FDA officials said in a conversation with The Cancer Letter.
In a related development, the HHS Office of the Inspector General has released a “data snapshot” report on the accelerated approval program. The report, titled “Delays in Confirmatory Trials for Drug Applications Granted FDA’s Accelerated Approval Raise Concerns,” was conveyed to FDA Commissioner Robert M. Califf. The report, which contains no recommendations, is posted here.
“More than one-third of accelerated approval drug applications with incomplete confirmatory trials are past their trials’ original planned completion dates, including four that are more than 5 years past those dates,” the report states.
“Of all 278 drug applications granted accelerated approval from the start of this approval pathway, 104 have incomplete confirmatory trials,” the report continues. “The 139 applications with completed trials took on average 48 months from when FDA granted them accelerated approval to when FDA deemed their trials to be completed.
Also, according to OIG, Medicare and Medicaid spent more than $18 billion from 2018 to 2021 for accelerated approval drugs with confirmatory trials that continue past their planned completion dates.
“These estimates demonstrate that Medicare and Medicaid are spending billions of dollars on drugs that have yet to verify a clinical benefit,” the report states.
