ASCO: J&J's subcutaneous bispecifics tackle multiple myeloma in phase 1

Johnson & Johnson finished the FDA filing for its anti-BCMA CAR-T in multiple myeloma last month, but that doesn’t mean it’s letting off the gas. The drugmaker revealed phase 1 data for two bispecific antibodies showing they shrank the tumors of about 70% of patients whose cancer got worse despite trying several other treatments, including the three main types of myeloma-fighting drugs.

The data, to be presented next month at the annual meeting of the American Society for Clinical Oncology (ASCO) come from two phase 1 studies in multiple myeloma patients who have run out of options. 

One study, dubbed MajesTEC-1, tested teclistamab, a bispecific antibody targeting BCMA and CD3, in 40 patients with multiple myeloma whose cancer had returned after a median of five other treatments or had not responded to treatment in the first place. The treatment shrank the tumors of 65% of those patients and eliminated them in 40%. 

RELATED: ASCO: Johnson & Johnson's anti-BCMA CAR-T, improving with time, sweeps multiple myeloma aside 

The second study, known as MonumenTAL-1, found that talquetamab, a bispecific antibody targeting CD3 and a new target, GPRC5D, shrank the tumors of 70% of 30 myeloma patients who had tried a median of six prior treatments. 

Those patients received the recommended phase 2 dose of each respective drug, namely the dose level that J&J will carry forward into midstage development and beyond. Both drugs are given subcutaneously, that is, through an injection just under the skin, rather than through intravenous infusion more commonly seen with antibody medicines. 

After about seven months of follow-up, the median duration of response for teclistamab had not been reached, meaning that more than half of the patients were still responding to treatment at that point. Of the 26 patients whose tumors shrank enough for them to be considered responders, 22 (85%) of them were still alive and continuing treatment. For talquetamab, 17 of the 21 responders (81%) were alive and continuing treatment after a median of about six months. 

These figures suggest that the patients’ responses are deepening over time, said Craig Tendler, M.D., vice president of oncology clinical development and global medical affairs at J&J’s Janssen unit, going from seeing some tumor shrinkage to remission. 

RELATED: ASH: J&J links subcut BCMA bispecific to 73% response rate, plots aggressive investment 

“About 85% of [teclistamab] responders are still in remission at seven months, so the median is going to be far north of that, which, for a single agent in this population, is very, very encouraging,” said Tendler.

The phase 1 trials focused on gauging the safety and tolerability of the bispecifics, but the efficacy results look “extremely promising” to a very sick patient group, the majority of whom had no luck with their last line of therapy, Tendler said. 

More than 80% of the patients who received teclistamab and more than three-quarters of the talqeutamab patients had been failed by the three major types of multiple myeloma medicines. These include proteasome inhibitors such as Amgen’s Kyprolis and Takeda and J&J’s Velcade, immunomodulatory drugs including BMS’ Revlimid and Pomalyst and anti-CD38 antibodies like J&J’s own Darzalex. The teclistamab patients had received as many as 11 lines of therapy, while the talquetamab patients had tried as many as 14 prior lines of therapy. 

RELATED: GlaxoSmithKline jumps into myeloma with 'homemade' anti-BCMA drug Blenrep 

The most common side effects for teclistamab were cytokine release syndrome (70%), a well-known side effect of cell therapy where the engineered T cells work too well and activate the immune system too strongly, and neutropenia, an abnormally low white blood cell count. About 70% of the patients suffered CRS, but all cases were mild to moderate, didn’t require prolonged hospitalization and were “quite manageable,” Tendler said. About 65% of the patients developed neutropenia or low white blood cell count, which can risk infection, though is a common side effect in cancer treatments. 

Both side effects are expected for a drug that dials up the immune system to battle multiple myeloma in patients who have been through many other treatments, Tendler said. 

J&J is just one of many players tapping into BCMA to give advanced multiple myeloma patients new options. Amgen, Bristol Myers Squibb, Pfizer and Regeneron all have anti-BCMA bispecifics in the works. And the FDA approved GlaxoSmithKline’s anti-BCMA antibody-drug conjugate last year and BMS and bluebird bio’s BCMA-targeting CAR-T in March this year.  

RELATED: Bristol Myers, bluebird bio have their BCMA CAR-T nod, but latecomer J&J could have an advantage: analysts 

As for talquetamab, it had a different side effect profile, which isn’t surprising given it is a first-in-class antibody that targets CD3 and GPRC5D—short for G protein-coupled receptor (GPCR) family C group 5 member D. CRS hit about three-quarters of patients, and neutropenia afflicted about two-thirds of them. Just over three-quarters of patients developed a rash, which was managed with topical treatments, and 60% of them had dysgeusia, a distortion of their sense of taste. 

Neither drug caused any dose-limiting toxicities, namely side effects serious enough to stop a patient from stepping up to a higher dose. 

J&J is going after GPRC5D because multiple myeloma is still considered incurable. Though front-line treatments succeed in the majority of patients, they eventually relapse and need new options. 

“It is especially important to bring on new targets in the relapsed and refractory setting. It is unlikely that one targeted agent, whether a bispecific or a CAR-T, will cure a patient,” Tendler said. “We want to be able to have additional targets that could be used to rescue a patient who may have progressed after one of those other targeted therapies.” 

However, Tendler sees the potential to combine drugs that have different targets in the future, to combat the development of resistance in multiple myeloma. 

J&J is developing teclistamab and talquetamab for the sickest patients—as is usual in oncology drug development—but it plans to move into earlier lines of therapy. As it expands into other patient populations, it will test the drugs both alone and in combination with standard-of-care treatments to get “these highly active antibodies” into patients with earlier-stage disease and better immune function to fight their cancer.