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Pink Sheet – Minimal Residual Disease 'Coming Soon' As An Approval Endpoint, Celgene Says

Pink Sheet – Minimal Residual Disease 'Coming Soon' As An Approval Endpoint, Celgene Says

Executive Summary

Celgene’s ASH briefing notes ‘unprecedented’ MRD-negative data in Phase I study in multiple myeloma development program for CAR-T therapy bb2121; firm sees potential opportunity for the marker to pave way for approval in earlier-line settings of the disease.

Celgene Corp. believes minimal residual disease (MRD) may someday be the ticket to approval of its investigational chimeric antigen receptor T-cell (CAR-T) therapy in early lines of multiple myeloma, even though the regulatory path is currently uncertain.


The company’s management spoke about the prospects for MRD to serve as a surrogate endpoint supporting approval during a Dec. 10 investor presentation at the American Society of Hematology (ASH) annual meeting.


The issue came up in the context of the company’s discussion of impressive Phase I data for bb2121, a CAR-T therapy that targets B cell maturation antigen. The agent is being developed in collaboration with bluebird bio Inc.


In the study of heavily pre-treated multiple myeloma patients, 17 out of 18 subjects (94%) treated with bb2121 dosed at 150m, 450m or 800m cells achieved an objective response, with a complete response (CR) rate of 56% (10 out of 18) at data cut-off. (See sidebar for coverage from our sister publication Scrip.)


Patients in the study had a median of seven prior lines of therapy and had received at least one autologous stem-cell transplant.


“The data that really surprised all of us when it first came out, we started looking very early for evidence of minimal residual disease using a next-gen sequencing assay that picks up one in 100,000 residual myeloma cells,” said Kristen Hege, vice president of translational development for Celgene’s hematology/oncology programs. “As early as four weeks, you can see most of these patients were MRD-negative.”


In total, nine of 10 patients for whom there were evaluable MRD data were negative, and most patients retained this status with longer-term follow-up. The only one of the 10 patients who did not achieve MRD-negative status did not respond to treatment, Hege said.


Median duration of follow-up in the trial is 40 weeks, and median progression-free survival (PFS) has not been reached. However, PFS rates at six and nine months were 81% and 71%, respectively.

In a Phase I study of heavily pre-treated myeloma patients, MRD-negative status was reported for 90% of patients with evaluable samples.

“The MRD data, I think, is really unprecedented,” Hege said. “Moving forward we plan to collect a lot of MRD data because we think it’s going to be very valuable.”

Can MRD Speed The Route To Earlier-Line Settings?

Celgene and bluebird recently initiated a global pivotal trial, KarMMa, a single-arm study that will enroll at least 80 patients who have failed at least three prior regimens, including an immunomodulatory drug, a proteasome inhibitor and an anti-CD-38 agent.


The primary endpoint will be overall response rate, with the aim of supporting accelerated approval in this refractory setting. Key secondary endpoints will be complete response rate and MRD. “We plan to test that using genomic assays, ultrasensitive flow assays and gather that data very frequently over the course of the trial to document the durability of these deep MRD negative responses,” Hege said.


The fourth-line myeloma trial will be followed by a Phase III, randomized trial in the third-line setting, where bb2121 will be tested against the combination of Celgene’s Pomalyst (pomalidomide), Janssen Biotech Inc.’s Darzalex (daratumumab) and dexamethasone.


PFS will be the primary endpoint, with secondary endpoints including complete response rate, MRD negative rate and survival.


“We of course are also going to explore label expansion opportunities in the second-line setting,” Hege said. “And we’re looking at our opportunities in first-line myeloma in high-risk patient populations.”


Hege’s presentation prompted a question as to how long it might take to secure approval for first- or second-line indications and whether using MRD negativity as a surrogate endpoint could speed up the process.


Nadim Ahmed, president of hematology and oncology, said that for bb2121, if a trial took a “broad all-comers approach to the front-line setting, you’d be waiting a long time for those results.”


“I think that’s where we have to be smart,” Ahmed said. “If you think about high-risk disease, that’s still an area where we see very, very poor outcomes. You combine that with a potential MRD approach, then I think you can start to develop a very creative approach to kind of get there quicker than you perhaps traditionally would. And we’re looking at all of those opportunities.”

Where Do The Regulators Stand?

When asked where regulators currently stand on their willingness to engage in discussions about MRD negativity as an endpoint, Chief Medical Officer and Head of Global Regulatory Affairs Jay Backstrom responded, “Stay tuned.”


“I think I’m on record of saying it’s coming soon, maybe about a year or two ago,” Backstrom said. “I can tell you that the academics want it, the data are coming. We know how to get there. And there’s a collaborative effort underway now, so coming soon.”

Complete response “translates into long-term outcomes in myeloma. MRD negativity, we could argue, is a super CR.” – Celgene’s Backstrom

“FDA has been on record of giving guidance for how to get there,” Backstrom said. “CR translates into long-term outcomes in myeloma. MRD negativity, we could argue, is a super CR really driving it down. And today, you could embed that into a study.”


“The real question is whether or not you can get an early approval on the MRD negativity endpoint while you wait for the longer-term outcomes,” Backstrom continued. “That’s where they haven’t established guidance to give us as a surrogate, but I really do think the data are beginning to show the way. And it’s just a matter of getting through the regulatory hurdles, but we could run a study today with that embedded. And companies are doing that.”


When it comes to the ability of MRD to support approval in multiple myeloma, Ahmed said, ” I think somebody just probably has to bite the bullet and do the study, the definitive prospective study, because I think the feel … we’re getting from regulators is there’s a lot of academic work done in this setting which will help to build the case, but I think probably what they want to see is some sort of prospective-built study to really test that question.”


“I think we’ll be able to definitely get there, but we’re just going to have to show that MRD does pertain to longer-term outcome,” Ahmed said.

FDA Not Yet Convinced

FDA has signaled that while it is enthusiastic and supportive of efforts to establish MRD as a surrogate for clinical benefit in hematologic malignancies, it is not yet convinced.


In an editorial published in the January 2017 issue of JAMA Oncology, senior officials in the Office of Hematology and Oncology Products (OHOP) highlighted “lingering questions” about use of MRD as a potential surrogate endpoint. These include the threshold for defining an MRD level that best correlates with clinical benefit, the ability of MRD to predict responses in different lines of treatment and different patient populations, the timing of assessment, and the most appropriate testing methods.


The agency raised similar concerns at a September 2016 stakeholder workshop. However, one agency official also suggested that rigorous MRD data collection in clinical trials would help advance use of the marker for regulatory purposes. (Also see “Cancer Trial Endpoints: Minimal Residual Disease Eyed As Surrogate” – Pink Sheet, 20 Sep, 2016.)


More recently, Amy McKee, OHOP’s supervisory associate director, told the Friends of Cancer Research annual meeting that the agency does not currently view the data sufficient to support the use of MRD as the basis for an approval. (Also see “Supplemental Oncology Approvals: ‘Reverse Accelerated Approval,’ Not Lowering The Bar” – Pink Sheet, 27 Nov, 2017.)

‘Era Of Willingness’ To Doing Things Differently

Despite FDA’s publicly expressed concerns, Celgene President and Chief Operating Officer Scott Smith suggested the atmosphere is ripe for the agency’s acceptance of MRD as a surrogate.


“I think there’s a willingness within the regulatory authorities, particularly the FDA under Scott Gottlieb’s leadership right now … to look at different approaches, to think about ways that we can get transformational therapies into patients’ hands earlier,” Smith said.


FDA is open to reconsidering the need for long trials and whether biomarkers can help get products to market more quickly, he said.


“I think there’s a real era of willingness to try and do some different things to be able to answer some of these questions right now,” Smith said. “It’s let’s wait and see. … But I think it feels to me like the discussions are productive and the environment is at least susceptible to that.”


BMO Capital Markets analyst Ian Somaiya also found reason to be hopeful that regulatory approval based on MRD negativity isn’t such a far-fetched idea.


In a Dec. 11 note, Somaiya said that following several supportive clinical trial presentations at ASH correlating MRD to PFS and overall survival, “plus evidence that new assay technologies are improving sensitivity to levels not previously achieved with near 100% predictive potential, we are inclined to agree with Celgene management, who indicated at their analyst event that approvability on MRD negativity should be ‘coming soon.'”…