ASH: In next BCMA myeloma race, Gracell dazzles with 100% response rate as Pfizer, BMS place their bets

Five years after Legend Biotech made a splash with an initial 100% tumor response rate for what would later become Johnson & Johnson-partnered Carvykti, another Chinese company has repeated the same remarkable data for its BCMA-targeted CAR-T therapy, this time in an earlier multiple myeloma setting.

Gracell Biotechnologies' BCMA/CD19 dual-targeting CAR-T therapy, GC012F, shrank tumors in all 16 patients with newly diagnosed multiple myeloma in a single-arm phase 1 trial in China, the company shared at the American Society of Hematology (ASH) 2022 annual meeting. The data cutoff was Oct. 14., and the median follow-up was eight months.

Based on the promising results, Gracell is talking to the FDA to start a clinical trial in both the U.S. and China among patients with previously treated multiple myeloma, Wendy Li, M.D., Gracell’s chief medical officer, told Fierce Biotech. The Nasdaq-listed company is still ironing out the exact trial design with the FDA, and it’s evaluating the dosing to move forward—the China trial tested a single infusion of GC012F at three different dose levels. But the new study will include patients who’ve previously received a BCMA-targeted agent, Li said.

The China trial is the first for a BCMA-targeted agent in newly diagnosed multiple myeloma. But Gracell is going after previously treated patients first for the U.S.-China study because it represents a high unmet medical need, especially in those who’ve relapsed after a CAR-T, Li said.

Li said she expects GC012F might perform even better in the new trial partly because the current China trial was conducted during strict COVID-19-related lockdowns.

A 100% overall response rate isn’t all that impressed people at ASH 2022. The trial enrolled patients who’re considered high-risk and eligible for stem cell transplant. Fourteen of the 16 patients (88%) achieved stringent complete response.

All but one of the patients tested negative for minimal residual disease (MRD) at the most recent follow-up with data available. Gracell uses a test with a high sensitivity of 10-6 to detect residue blood cancer cells. That one patient in question turned MRD-positive and had progressive disease at Month 4 of the study and wasn’t followed after that. It’s hard to pinpoint the exact reason for that individual’s disease progression, Gracie Xuefei Tong, Gracell’s senior director of finance and investor relations, said. But she highlighted the patient had five high-risk factors.

The safety profile of GC012F also looks like a win for Gracell. The trial recorded four (25%) cases of cytokine release syndrome (CRS)—a common and potentially dangerous immune side effect for CAR-T therapies. All CRS cases were grades 1 or 2 and were resolved within four days, according to Gracell. No neurotoxicity was observed.

By comparison, in a larger trial in a late-line myeloma setting, Bristol Myers Squibb’s FDA-approved BCMA-targeted CAR-T therapy Abecma posted an 85% CRS rate, including 9% that were grade 3 or above. Neurotoxicity happened in 28% of patients in Abecma’s KarMMa trial, including 4% that were grade 3 events. Legend and J&J’s Carvykti is linked to even more CRS and neurotoxicity.

Another potential key differentiator for GC012F is that Gracell’s technology doesn’t require ex vivo T-cell expansion and could significantly cut the time of T-cell activation and CAR transduction to between 22 and 36 hours, according to the company. This could potentially reduce patient’s wait time from about five weeks to one or two weeks, Li said.

That concurrent activation-transduction process and short turnaround time not only saves time and cost but could also explain the drug’s high efficacy because it keeps T cells in a younger and fitter state that allows them to proliferate once inside a patient’s body, Tong explained.

New BCMA therapies loom from large pharma companies

Gracell is currently looking for a partner to help move GC012F along, Li said. The dual-target CAR-T might go up against several Big Pharma candidates, including BCMA CAR-Ts and bispecifics by Pfizer, BMS, Regeneron and Gilead Sciences’ newly partnered Arcellx.

At ASH 2022, Pfizer reported 10.4-month follow-up data for its subcutaneous BCMAxCD3 bispecific antibody elranatamab from the pivotal phase 2 MagnetisMM-3 trial in a group of heavily pretreated myeloma patients.

Among patients who had tried a median five prior therapies, elranatamab triggered a response in 64% of patients, including 38% who achieved a complete response or better. Among 13 patients who had tried a BCMA-directed therapy, seven (54%) responded to elranatamab.

Pfizer designed elranatamab to have optimized affinity to BCMA and CD3, Chris Boshoff, M.D., Ph.D., Pfizer’s chief development officer for oncology and rare disease, said in a separate interview with Fierce Biotech.

Boshoff also argued that elranatamab has the best CRS profile in this late-line treatment setting. The drug showed a 58% CRS rate, all grade 1 or 2, and a 3% rate of neurotoxicity, all grade 1 or 2.

Elranatamab was given weekly and then once every two weeks in the current trial. Pfizer is exploring potentially extending the dosing interval even longer to once every month, Boschoff said.

The company launched MagnetisMM-3 with the intention to win approvals. Boshoff said that Pfizer expects to update on the regulatory timeline in early 2023.

But even without an approval, Pfizer is advancing elranatamab aggressively in clinical development. The company has started a phase 3 study, MagnetisMM-5, to test either elranatamab monotherapy or its combination with Johnson & Johnson’s Darzalex against a cocktail of Darzalex, BMS' Pomalyst and dexamethasone in patients who have tried BMS’ Revlimid and a proteasome inhibitor.

Two phase 3 trials will evaluate elranatamab in newly diagnosed patients. MagnetisMM-7 is using the bispecific as maintenance therapy versus Revlimid in patients after stem cell transplant. Based on existing data from single-agent elranatamab, Boshoff said Pfizer is “very confident in the probability of success of that trial.” The other trial, MagnetisMM-6, is being conducted in transplant-ineligible patients.

Pfizer is plotting combinations with newer therapies as well, including a CD47 candidate Pfizer got last year in its $2.3 billion acquisition of Trillium Therapeutics, Boshoff said.

“We will announce in 2023 some of the combinations we’re starting with other biotech partners…which I think is going to be very interesting,” Boshoff added.

Pfizer would likely go toe-to-toe with two other BCMAxCD3 bispecifics, namely Regeneron’s linvoseltamab, also known as REGN5458, and BMS' alnuctamab.

An abstract at ASH 2022 showed that overall response rate for linvoseltamab at 200 mg or above dose levels reached 75%—versus 40.8% for lower doses—in a group of phase 1/2 patients who had received median six prior lines of therapy. In an update, Regeneron reported a 64% ORR in those who got the now investigator-recommended 200mg dose. CRS occurred in 37% of patients in this subgroup, including one transient grade 3 event. But the overall rate of grade 3 or above side effects was 66%.

As for alnuctamab, a longer-term follow-up trial of an intravenous version in patients who had tried at least three prior therapies showed that the BMS drug produced a 39% response rate after a median follow-up of eight months. The CRS rate hit 76%, including one death, according to data presented at ASH 2022.

BMS recently shifted the drug from the intravenous formulation to subcutaneous for improved dosing convenience and a better CRS profile. As of Sept. 28, among 68 patients who had tried a median four prior lines of therapy, subcutaneous alnuctamab induced CRS in 53% of patients, with no grade 3 or above cases.

In terms of efficacy, under-the-skin alnuctamab shrank tumors in 53% of patients, although these data weren’t from the 60 mg target dose cohort because the follow-up there was really short.

BMS sees a potential to combine alnuctamab with its own CELMoD agents, Chief Medical Officer Samit Hirawat, M.D., told Fierce Biotech in an interview.

Besides alnuctamab and Abecma targeting BCMA, the Big Pharma also shared first results for its GPRC5D CAR-T therapy in relapsed or refractory multiple myeloma.

“The reason we have two or three different modalities that we are developing…is because we will need to continue to understand which therapy serves which patient population the best, as well as what is the most convenient for the patient,” Hirawat said.  

Meanwhile, it’s also worth noting that Gilead’s Kite Pharma just shelled out $225 million upfront to partner with Arcellx on the latter’s phase 2 BCMA-targeted CAR-modified T-cell therapy, CART-ddBCMA.

Editor's Note: The story has been updated to include new results from Regeneron's linvoseltamab.