FDA’s ODAC Votes 12 to 0 That MRD Is a Viable End Point in Myeloma Trials

CAR T-cell therapy in multiple myeloma: © Kasloom - stock.adobe.com

In a 12 to 0 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) decided that evidence supported that minimal residual disease (MRD) could be used as an accelerated approval end point in clinical trials of multiple myeloma.

“I think the sets a precedence of actually moving the field forward, not only for the patients to get the drug earlier, but can we stop therapy based on MRD? If the duration of MRD is longer with better treatments, it kind of opens up a whole other way of even maybe treating patients where you don't have this continuously, where you can get treatment gaps like you do in solid tumors,” said Ranjana H. Advani, MD, ODAC member and Saul Rosenberg Professor of Lymphoma, Division of Oncology, Stanford University School of Medicine.

Establishing MRD as an End Point in Multiple Myeloma Trials

Nicole Gormley, MD, associate director of oncology end point development for the FDA’s Oncology Center of Excellence and director of the Division of Hematologic Malignancies II, presented guidance on how clinical end points were established for regulatory decisions.

“Approval is based on demonstration of clinical benefit or an effect on an established surrogate accelerated approval is intended for products that treat serious or life-threatening illnesses, taking into account the condition and availability of alternative treatment options. It should provide a meaningful benefit,” Gormley said. “In order for a biomarker to be a true surrogate for a long-term outcome of interest, it should be in the causal pathway between treatment of the disease and the true clinical end point of interest.”

Gormley noted that most oncology accelerated approvals are based on intermediate clinical end points, including overall response rate (ORR), progression-free survival (PFS), and event-free survival. However, Gormley noted that it is “rare that there are true surrogates in oncology.”

According to Gormley, considerations for how novel end points can be developed in oncology is important, which can include relying on meta-analysis data, including patient-level data from multiple clinical trials to evaluate individual- and trial-level surrogacy.

However, Gormley noted, “There are caveats regarding the use of a surrogate endpoint, even those that are fully clinically validated.” These caveats include that the surrogate may not be appropriate for subpopulations or future trial populations if there are significant differences between the meta-analysis and new trial populations. Further, the therapeutic modalities may have a substantially different mechanism of action than those of the therapeutics included in the meta-analysis.

Bindu Kanapuru, MD, associate director of therapeutic review in the Division of Hematologic Malignancies II, presented additional regulatory considerations. These included assay considerations, like ensuring that the assays used had adequate performance, were appropriately validated for the context of use, and used standardized procedures of sample collection and processing. Kanapuru also highlighted the importance of confirmatory trials to verify clinical benefit and expedited withdrawal for drugs that do not verify benefit from the market.

Bone marrow aspirate cytology of multiple myeloma: ©David A Litman - stock.adobe.com

Applicants’ Perspectives

Representatives of 2 meta-analyses evaluating MRD as a surrogate for PFS and overall survival (OS) were present at the ODAC meeting. C. Ola Landgren, MD, PhD, presented background on the EVIDENCE meta-analysis.

Landgren began with an overview of the MRD initiative in myeloma, noting its beginnings in 2009 with an interagency collaboration with the FDA, National Cancer Institute, and National Heart, Lung, and Blood Institute to establish MRD as a regulatory end point. In 2021, Landgren noted that the FDA approved the initiative’s statistical analysis plan for this evaluation.

“We do not yet have an established curative treatment [for multiple myeloma]. The most effective treatments are in the first line with our current end points, progression-free survival and overall survival. For patients with newly diagnosed multiple myeloma, we're taking a long time to mature. New effective therapies are unavailable to patients for more than 10 years while waiting for studies to mature,” said Landgren, professor of medicine, chief of the Division of Myeloma, and director of the Sylvester Myeloma Institute at the Sylvester Comprehensive Cancer Center, University of Miami.

Based on PFS results in clinical trials, following an average of 2 years for adequate patient recruitment, comparative studies may now require over 8 years to show a statistically significant effect of a new therapy. Landgren also added that 15% to 35% of patients are lost at each line of multiple myeloma therapy and that establishing effective frontline therapies is a primary goal of multiple myeloma treatment.

While ORR has been used as an intermediate end point in myeloma studies, Landgren noted that it is not a good intermediate end point among the newly diagnosed population, as the assessment for ORR only requires a 50% reduction in disease.

“To accelerate the availability of new and effective treatments for patients with multiple myeloma, an objective and reliably measured early end point that is reasonably likely to predict long-term outcomes and clinical benefit is urgently needed,” Landgren said.

Landgren noted that in January 2020, the FDA published guidance on 2 potential uses of MRD in drug development: as a validated surrogate end point for traditional approval, or as a surrogate end point reasonably likely to predict clinical benefit for accelerated approval. The strength of evidence required for a surrogate end point was based on biological plausibility of the relationship, demonstration of the prognostic value of the surrogate end point for the clinical outcome, and evidence from clinical trials that treatment effects on the surrogate end point correspond to effects on the long-term clinical outcome.

“MRD fulfills all these criteria in multiple myeloma,” Landgren said.

Sean Devlin, PhD, associate professor of biostatistics and associate attending biostatistician at Memorial Sloan Kettering Cancer Center, presented data, methodology, and results of the EVIDENCE meta-analysis. The analysis included data from 16 phase 2 or 3 randomized clinical trials in patients with newly diagnosed transplant-eligible or -ineligible multiple myeloma. The investigators of EVIDENCE also established a sensitivity cutoff for MRD assays of 10^-5 or better.

At an individual level, MRD and PFS and MRD and OS were strongly associated according to a Copula global odds ratio with a 95% confidence interval. Devlin and Landgren summarized that the results supported the consideration of MRD as an early clinical end point reasonably likely to predict clinical benefit in multiple myeloma that may be used to support accelerated approval.

The second industry presentation was from the International Independent Team for Endpoint Approval of Myeloma Minimal Residual Disease (I2TEAMM). Brian G. M. Durie, MD, Cedars-Sinai Comprehensive Cancer Center, presented the advantages of MRD as an early end point. These include earlier readouts of 9 to 12 months, timely approvals of life-saving therapies and combinations, and major positive impacts for patients.

“In myeloma, MRD negativity is the new complete remission,” said Bruno Paiva, PhD, director of flow cytometry in the Department of Hematology and Immunology at the University of Navarra, Spain, and a member of I2TEAMM.

Qian Shi, PhD, professor of biostatistics and oncology at Mayo Clinic, presented data and results from I2TEAMM’s meta-analysis. The findings similarly showed a high individual-level correlation between MRD and PFS/OS. The 9- and 12-month MRD negativity rate at 10^-5 sensitivity threshold reasonably likely predicted clinical benefit of PFS and OS among patients with newly diagnosed transplant-eligible and -ineligible and relapsed/refractory multiple myeloma.

FDA’s Perspective

Rachel Ershler, MD, MHS, clinical reviewer for the Division of Hematologic Malignancies II, and Jing Zhang, PhD, statistical reviewer for the Division of Biometrics IX, presented the FDA’s considerations on the discussion. Ershler and Zhang noted that the FDA agreed with the general approaches and interpretation of the results.

Zhang confirmed that in the I2TEAMM and University of Miami analyses, there was a strong individual-level association for PFS and OS, but trial-level associations were weak to moderate in disease subpopulations for PFS and were generally weaker for OS.

Ershler explained that a strong trial-level association could become a validated surrogate end point and support regular approval; however, very few oncology end points have met this standard, and most end points that support accelerated approval have not been assessed for trial-level surrogacy or have weak trial-level associations.

Zhang also presented strengths and weaknesses of the meta-analyses. Strengths included the broad experience across multiple settings and randomized trials, high sensitivity of assays used, and stringent analysis methods that had been discussed with the FDA. However, the heterogeneity in trial designs, variations in MRD assays used, and unknown impact of disease setting were identified as limitations.

ODAC's Decision

The first discussion question posed to the ODAC was to the adequacy of the available data to support the used of MRD as an accelerated approval end point in multiple myeloma.

“When you look at the data, especially the patient-level data, I think that's clear that it meets the criteria for accelerated approval. I think that this is 1 of the most prognostic tests that we've seen in the disease,” said Christopher Lieu, MD, ODAC member and associate professor of medicine at the University of Colorado Cancer Center.

“In terms of the biologic significance…there certainly is the biologic correlation that if you get that low with your MRD, you're probably going to have a longer [response]. Responders do better,” Thomas Martin, MD, ODAC member and associate chief of the Division of Hematology/Oncology at the University of California San Francisco.

The second discussion topic posed was whether the available data supports the use of MRD as an end point in different myeloma disease settings, and the third discussion topic was about the acceptability of time points for MRD assessment. The voting question asked if the evidence supported the use of MRD as an accelerated approval end point in multiple myeloma clinical trials.

“There is great harm in not acting,” said Christopher Hourigan, DM, DPhil, temporary ODAC member and director of the Virginia Tech Fralin Biomedical Research Institute Cancer Research Center.

REFERENCE:

Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. April 12, 2024. Accessed April 12, 2024. https://tinyurl.com/2rexatkp