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A marketing authorization application has been submitted to the European Medicines Agency seeking the approval of teclistamab for the treatment of patients with relapsed or refractory multiple myeloma.
A marketing authorization application has been submitted to the European Medicines Agency seeking the approval of teclistamab (JNJ-64007957) for the treatment of patients with relapsed or refractory multiple myeloma.1
The application is supported by findings from the phase 1/2 MajesTEC-1 trial (NCT03145181; NCT04557098). At a median follow-up of 7.8 months (range, 0.5-18.0), when the agent was administered at the recommended phase 2 dose (RP2D) of 1500 µg/kg weekly, it elicited an objective response rate (ORR) of 62.0% (95% CI, 53.7%-69.8%), a very good partial response (VGPR) or better rate of 58.0%, a complete response (CR) of 7.3%, a CR or better rate of 28.7%, and a stringent complete response (sCR) rate of 21.3% in this patient population.2
“We are pleased to announce the submission of teclistamab to the European Medicines Agency,” Peter Lebowitz, MD, PhD, global therapeutic area head of oncology at Jassen Research & Development, LLC, stated in a press release. “Once again, this shows our commitment to continue to provide innovative, transformative therapies for patients with relapsed or refractory multiple myeloma.”
The investigational, off-the-shelf, T-cell–redirecting bispecific antibody was designed to target both BCMA and CD3. It is known that multiple myeloma cells have high BCMA expression and that the agent redirects CD3-positive T cells to BCMA-expressing myeloma cells to prompt the elimination of those cells.
The first-in-human, open-label, multicohort, multicenter, dose-escalation MajesTEC-1 trial enrolled patients with relapsed or refractory multiple myeloma who received 3 or more prior lines of therapy and who were triple-class exposed.
To be eligible for enrollment, patients had to be at least 18 years of age, have measurable disease, and have received a prior proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 therapy. Patients could not have received prior BCMA-targeted therapy. In the phase 1 portion of the trial, patients were relapsed, refractory, or intolerant to established therapies; in the phase 2 portion, they previously received 3 or more lines of therapy.
In the first week of treatment, patients were given step-up doses of subcutaneous teclistamab at 60 µg/kg and 300 µg/kg. In cycles 1 and later, they were given weekly doses of the bispecific antibody at 1500 µg/kg. Treatment was given until progressive disease.
The primary end point of the trial was ORR, and secondary end points included duration of response (DOR), VGPR or better rate, CR or better rate, sCR rate, time to response, minimal residual disease (MRD) status, progression-free survival (PFS), overall survival (OS), safety, pharmacokinetics, immunogenicity, and patient-reported outcomes.
Results from the phase 1 portion of the research indicated that the agent had favorable tolerability when delivered at the RP2D. At a median follow-up of 6.1 months, the agent also was found to have promising efficacy, having produced an ORR of 65%, and a VGPR or better rate of 58% in a total of 40 patients.
At the 2021 ASH Annual Meeting, interim data from the phase 2 portion of the trial were shared, as well as updated data on patients who received the RP2D in the phase 1 portion of the research.
As of September 7, 2021, a total of 125 patients received teclistamab at the RP2D in the phase 2 portion of the research. Of these patients 50 discontinued because of progressive disease (n = 29), death (n = 9), physician decision (n = 7), patient withdrawal (n = 4), or toxicity (n = 1), leaving 75 patients who were still receiving treatment with the agent.
The median age among the 165 patients included in the safety analysis was 64.0 years (range, 33-84), with 14.5% of patients aged 75 years and older; 58.2% of patients were male, 81.2% were White, and 25.9% of patients had high-risk cytogenetics.
Participants had received a median of 5 prior lines of therapy (range, 2-14), and all were triple-class exposed. Notably, 70.3% of patients were penta-drug exposed, 77.6% were triple-class refractory, 30.3% were penta-drug refractory, and 89.7% were refractory to their last line of therapy.
At the time of the clinical cutoff, efficacy data from the phase 2 portion of the research were noted to have still been immature. However, the response rates achieved by the 40 patients treated in the phase 1 portion of the research proved to be consistent with what has previously been reported.3
The median time to first response was 1.2 months (range, 0.2-5.5). The MRD negativity rate was 24.7% (95% CI, 18.0%-32.4%) at a threshold of 10-5; this rate was 16.7% (95% CI, 11.1%-23.6%) at a threshold of 10-6. In those who achieved a CR or better with teclistamab, the MRD negativity rate was noted to be 41.9%.
The median follow-up for the 93 responders was 8.0 months (range, 2.4+ to 18.0) and 91.4% of these patients had at least 6 months of follow-up. The median DOR had not yet been reached, and responses proved to deepen over time. At the time of data cutoff, 88.2% of responders were alive without the need for subsequent treatment or without having experienced progressive disease. Only 11 of the 93 responders had disease progression or died.
The event-free rate among responders at 6 months was 92.5% (95% CI, 80.6%-97.2%); at 9 months, this rate was 85.9% (95% CI, 70.0%-93.7%). The PFS rate at 6 months was 64.4% (95% CI, 56.0%-71.7%); at 9 months, this rate was 58.5% (95% CI, 48.8%-67.0%).
The median OS had not yet been reached at the time of presentation.
No new safety signals were observed in the phase 2 portion of the research. Data showed that 53.3% of patients reported serious toxicities, with 33 patients experiencing serious adverse effects that were related to teclistamab. Moreover, 35.2% of patients had injection-site reactions, although all these effects were grade 1 or 2. Sixty-three percent of patients experienced infections, 35.2% of which were grade 3 or 4. Opportunistic infections were reported in 5.5% of patients.
Cytokine release syndrome (CRS) was experienced by 71.5% of patients, and 32.7% had 2 or more CRS events. The median time to onset was 2 days (range, 1-6), and the median duration was also 2 days (range, 1-9). Supportive care measures were required in 66.1% of patients, and this included tocilizumab (Actemra; 36.4%), low-flow oxygen via nasal cannula (12.7%), steroids (7.9%), and single vasopressor (0.6%).
All CRS events were grade 1 or 2, with the exception of 1 transient grade 3 event that fully resolved. All effects resolved, and no discontinuations were needed because of this toxicity.
Nine deaths from toxicities were reported but none of them were deemed to be associated with teclistamab; 7 patients died from COVID-19, 1 from pneumonia, and 1 from hemoperitoneum.
In December 2021, a biologics license application seeking the approval of teclistamab in patients with relapsed or refractory multiple myeloma was submitted to the FDA.4 This application was also supported by findings from MajesTEC-1.