A potential first-ever FDA-approved treatment for smoldering myeloma received a positive review from an advisory committee, but not without reservations, even from panelists who voted in favor.
By a 6-2 vote, the Oncologic Drugs Advisory Committee (ODAC) agreed that a randomized trial of subcutaneous daratumumab (Darzalex Faspro) provided sufficient evidence of a favorable risk-benefit profile for daratumumab in high-risk smoldering myeloma. The FDA is not bound by advisory committee recommendations but usually follows the advice.
Throughout the discussion that preceded the vote, ODAC panelists' comments reflected ambivalence about the trial -- which showed a clear reduction in the risk of progression to frank myeloma -- about the definition of smoldering myeloma, the need to treat the condition, and the risks to patients.
"Make no mistake about it, this is going to lead to overtreatment for a population of patients, and those patients will experience toxicity, particularly infection," said Christopher Lieu, MD, of the University of Colorado Cancer Center in Aurora. "But two things weighed on me. Number one, I really want patients and providers to have the option to discuss this, to have the benefit-risk discussion, and I think that's a very nuanced conversation."
"The second thing is that this can't be the end of the story," he continued. "This is going to lead to overtreatment and there has to be a predictive biomarker or some type of risk stratification to refine this group [that requires treatment]. I don't think we have a lot of interest in just adding more agents and getting a marginal increase in progression-free survival with significant added toxicity."
Despite his concerns, Lieu said the randomized phase III AQUILA trial demonstrated a positive risk-benefit profile, albeit marginal.
In a separate session, the panel decided by an 8-1 vote that results of a randomized trial of a glofitamab (Columvi) combination do not apply to a U.S. population of transplant-ineligible patients with relapsed/refractory lymphoma. The STARGLO trial included only 25 patients from the U.S., 9% of the intention-to-treat population of 274. Europe accounted for 32% of the patients, Australia for 11%, and Asia for 48%.
Moving forward, the FDA will prioritize enrollment of U.S. patients in clinical trials, said Richard Pazdur, MD, of the agency's Oncology Center of Excellence, following the STARGLO vote.
"Unfortunately, if you take a look at all the oncology trials that come to us, only about 20% of the population is derived from the United States," said Pazdur. "We'd like to understand the reasons why sites are not enrolling in the United States ... . The Oncology Center of Excellence is looking quite closely to ensure that control arms [of clinical trials] are applicable to the United States and represent current standards here, not just the weakest control arm that we have."
"People are developing drugs or marketing in the United States, so they should address our interests here in the United States, and I just want to make sure that is clearly delineated," he added.
AQUILA Trial
As reported late last year, the AQUILA trial showed that treatment with daratumumab reduced the risk of progression to multiple myeloma or death (PFS) at 5 years by 50% in patients with high-risk smoldering myeloma as compared with active monitoring. The daratumumab arm also had significantly better 5-year overall survival (OS), 93.0% versus 86.9%.
In a report prepared for ODAC, FDA staff did not question the results so much as the patient selection criteria and the definition of high risk.
"The criteria used in the protocol did not completely align with any of the available models, but instead incorporated criteria from multiple models and additional criteria," said FDA reviewer Payal Aggarwal, DO.
Three-fourths of the study population met the protocol-defined criteria for high risk, she continued, but "more than half of the trial participants were assessed as intermediate or low risk by any risk model. The AQUILA trial therefore enrolled a heterogeneous patient population of high-, intermediate-, and low-risk patients based on the currently used risk models."
The heterogeneity of the patient population created uncertainty as to whether the AQUILA results actually apply to high-risk patients, Aggarwal concluded.
Speaking on behalf of Johnson & Johnson/Janssen, Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota, said smoldering myeloma is a malignant condition, in contrast to monoclonal gammopathy of uncertain significance (MGUS). The risk of progression from smoldering myeloma to myeloma is 10% per year, 10 times higher than the risk associated with MGUS, he said.
AQUILA used risk criteria outlined in a 2015 consensus report. In the control arm, the highest-risk patients had a median time to progression of 21 months.
"Patients with high-risk smoldering myeloma have a median time to progression of only 2 to 3 years," said Rajkumar. "This is the group of patients best suited for early intervention to delay end-organ damage, to delay the need for full-blown myeloma therapy, and to improve overall survival."
Despite reservations about overtreatment, the panel was persuaded by the PFS and OS data.
"We may be overtreating some patients for 3 years [the treatment duration in AQUILA] and we may have some real pre-myeloma patients we are undertreating," said Toni Choueiri, MD, of Dana-Farber Cancer Institute in Boston. "The thing is, we do not have today an ideal classification of who to treat for sure, with high certainty. What sealed the deal for me, that I could not ignore, was the trend in OS."
STARGLO Trial
STARGLO was a confirmatory trial to support accelerated approval of glofitamab plus gemcitabine-oxaliplatin chemotherapy as second-line therapy for transplant-ineligible patients with relapsed/refractory lymphoma (diffuse large B-cell not otherwise specified or large B-cell arising from follicular lymphoma). Patients assigned to the comparator arm received rituximab (Rituxan) plus the same chemotherapy.
According to the FDA staff report, an interim analysis showed a statistically significant 41% reduction in the survival hazard for the glofitamab arm. However, the overall results appeared driven by Asian patient populations, as the hazard ratios for non-Asian patients actually trended in favor of the control arm. Noting a difference in follow-up time as a potential contributing factor (8.7 months in non-Asian countries vs 14.6 in Asian regions), Genentech officials opted to continue follow-up.
An updated analysis after a median follow-up over 20.7 months showed a median OS of 25.5 months for the glofitamab arm versus 12.9 months for the rituximab arm. However, a subgroup analysis still showed regional variation, reflected in a hazard ratio of 2.62 for North American patients, 1.09 for European patients, and 0.41 for the rest of the world.
Genentech representatives emphasized the consistency of the overall results in favor of glofitamab for the primary and key secondary outcomes, which they said supported transition of the regimen to full approval. They also noted differences in use of subsequent therapies (new anti-lymphoma therapy; NALT), particularly highly effective NALT, explained at least some of the regional variation in outcomes.
Ultimately, the ODAC panel did not find the arguments sufficiently compelling to support the conversion to full approval.
"We're sitting here at the U.S. FDA and there were 25 patients in this trial from the United States," said Daniel Spratt, MD, of University Hospitals Seidman Cancer Center in Cleveland. "I think it's imperative -- and the company sounds as if it is willing to do so -- to ensure there are a sufficient number of patients from the United States, just as they did so for China."
Acting ODAC Chair Neil Vasan, MD, PhD, of Columbia University Medical Center in New York City, said, "I kept coming back to this question: Is this a multi-regional clinical trial that adheres to the properties of ICH 17? I don't believe this to be the case."
"Another word that I kept coming back to was 'sufficient,' that sponsors should plan to enroll a sufficient number of U.S. participants. I don't think we can define that as a number or a percent but certainly, if there is a low percentage of patients enrolled in a trial, and we see this directionality in multiple endpoints, we have to call it into question."
https://www.medpagetoday.com/hematologyoncology/hematology/115702
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