Lifesaver or “cause of death”?

After “unprecedented” results in a phase 1/2 trial, teclistamab (Tecvayli, Janssen Biotech) received accelerated FDA approval for adults with relapsed/refractory multiple myeloma who had received at least four lines of therapy. Typically, patients in this situation only have a few weeks to live. The nod from the FDA in Oct. 25 for teclistamab, the first bispecific B-cell maturation antigen-directed CD3 T-cell agent to be approved, was based on data from a phase 1/2 study called MagesTEC-1 (NCT03145181; NCT04557098). Patients in the study had an overall response rate of 61.8%, and 26.7% of people in the study had no detectable disease.

This is “unprecedented,” said Nikhil Munshi, MD, a professor of medicine at Harvard Medical School, Boston, who was not involved in the study. “Pomalidomide got a 30% response rate approved, carfilzomib got a 29% response rate, selinexor got a 31% response rate and so on and so forth. … So here’s teclistamab with [this] response rate in patients with five, six lines of therapy. …[It’s] will be so sought after because this is a great drug.”

The first cut of the data appears in the New England Journal of Medicine.

At the 6-month mark, 90.6% of nonresponders had disease progression, and at 9 months, 66.5% of patients remained stable.

The study’s principal investigator, Saad Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York, said, “What was most striking was the high response rate and the durability of the response.”

Usmani said ease of administration was the other aspect of teclistamab that appealed to him. The drug is administered by subcutaneous injection weekly after a short recovery period.

He compared this treatment to chimeric antigen (CAR) T-cell therapy, the only option with similar efficacy in such sick patients: “I can prescribe [teclistamab] today and my patient will receive it tomorrow,” said Usmani. “With CAR T, I prescribe myself today and it will take 4-6 weeks for us to collect the T cells and another 6-7 weeks for the product to come back. ” Usmani said many patients die before CAR T reaches them.

Community oncology will benefit greatly from teclistamab, particularly in patients for whom CAR T is not feasible, said Kashyap Patel, MD, president of the American Cancer Society. “Most of my patients are in the minority with multiple myeloma and they can’t travel many miles to go to a CAR T center.[cutaneous] injection, which the patient can receive [teclistamab] given at the doctor’s office and continue to live their normal lives.”

However, how should the broader oncology community make sense of drug approval based solely on response to a single-arm phase 1/2 trial, without survival data?

Patel said, “Phase 1 plus Phase 2 data is probably a bit early, but time will tell eventually.” He cited melflufen as a cautionary tale: a product that received emergency treatment for multiple myeloma, then withdrawn when new data showed it increased the risk of death.

When Munshi was asked about the trial design for expedited approval, he replied, “you’re touching on a subject that is very close to me, a subject that has a lot of significance right now.

He went on to say that overall survival (OS) is no longer a viable endpoint in trials in diseases such as multiple myeloma for a number of reasons. Most importantly, he noted, “Survival has gone up to 10 or 15 years [so] today, if you decide between one [drug] against another, there will be seven or eight more treatments before the patient dies.”

Similarly, progression-free survival (PFS) in multiple myeloma is now up to 5 years, Munshi said. “Do we want a patient to wait 5 years to get a really good new drug?”

For these reasons and others, Munshi said, myeloma researchers are increasingly relying on a surrogate called “negative minimal residual disease” (negative MRD)—in other words, a condition where myeloma cells can no longer be detected in the bone marrow. MRD is tracked using next-generation flow or next-generation sequencing of myeloma cell DNA from bone marrow aspirates down to 1 in 100,000 or 1,000,000 cells.

In 2020, Munshi and colleagues published a large meta-analysis showing that negative MRD in a patient with multiple myeloma was a significant predictor of both progression-free survival (hazard ratio, 0.33; P < 0.001) and overall survival (HR, 0.45; P <.001). The team concluded: "MRD may fulfill all criteria to be a clinically valid surrogate biomarker for PFS and OS in [multiple myeloma]."

In MajesTEC-1 overall, 26.7% of patients on teclistamab had no evidence of residual disease at the 1 in 100,000 threshold. Among patients who showed a “complete response” according to International Mergeoma Working Group criteria, 46% had no residual disease.

Munshi emphasized that such patients are not necessarily a ‘doctor’. It will take a few more years to prove that. He pointed out: “Simply, physiologically, [negative MRD] means that if a patient has one [myeloma] cell in a million, it’s going to take a lot longer for that cell to grow up and become myeloma.”

On Nov. 8 and 9, the FDA and the International Myeloma Society held a workshop to discuss the difficult issue of surrogate endpoints and single-arm trials for drug approval entitled “The Future of Drug Development in Myeloma.” Munshi was the helmsman.

Jury at the meeting, principal investigator of the MajesTEC-1 trial, Ajai Chari, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, summed up the problem: “No one disagrees that randomized controlled trials are the best way to do The question is, if you are a patient who has exhausted all available treatments, do you have the time to wait? … The role of expedited approval is to get the drug to the patient faster. But what does it not record? How do we make these express agreements more meaningful and not have to retreat to safety?”

Jonathan Vallejo, also on the panel, agreed that safety is key. The ideal scenario for accelerated approval would be a drug that would be better than an available treatment, and “in some sense, it’s much safer.” However, such situations are rare.

“Most of the time, we don’t have these products coming in that don’t have any toxicity labels,” he said. “So one thing we have to think about carefully in the single-arm experimental setting is, what are the toxicities? How do they stack up?”

Chari said that for his part, he would like to see more transparency around “cause of death” in all investigations leading to faster approvals. He said he was “tired” of seeing deaths labeled as “not attributable” to the drug by the investigator or the drug company.

“Let me decide. Show me the deaths and show me the stage of multiple myeloma at that point,” Chari said. “That’s a sign — if you’re a patient who’s responding and dying, the FDA should be a little more careful.”

The FDA has added a warning box to the teclistamab product information regarding apoptotic syndrome and neurotoxicity.

Cytokine release syndrome, the most common adverse event overall, occurred in 72% of patients, usually 2 days after the first additional dose.

Neurologic toxicities occurred in 57% of patients, including headache (25%), dyskinesia (16%), sensory neuropathy (15%), and encephalopathy (13%). About 6% of patients develop a serious, life-threatening neurological disease called immune effector-associated neurotoxicity syndrome.

Overall, serious side effects occurred in 54% of participants in MajesTEC-1, and 5% of people in the study died of side effects during the study, most commonly infection.

Because of its safety profile, teclistamab is only available through a limited program called the TECVAYLI Risk Evaluation and Mitigation Strategy.

Continued approval of teclistamab for this indication “may be subject to verification and description of clinical benefit in confirmatory studies,” according to the FDA.

To that end, eight additional studies of teclistamabi are underway, targeting approximately 1,300 multiple myeloma patients worldwide. Three of these studies are in newly diagnosed patients. Four additional trials are scheduled to come online in the next 3 months, bringing the final number of patients testing teclistamab to approximately 4,700. The trials will look at teclistamab sequentially or in combination with standards such as bortezomib and pomalidomide. All studies are open.

Patel believes that until these studies say otherwise, the benefits of teclistamab outweigh the risks. “I’m very pleased that we have one more option in this space, especially a fourth or fifth line for patients who want to continue to fight the disease,” Patel concluded.

Munshi has published advisory boards/consultants for Adaptive, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Oncopep and Pfizer and is the scientific founder of Oncopep and DCT. The 2020 meta-analysis by Munshi et al was funded by Janssen-Cilag. Patel disclosed funding from Janssen for diversity initiatives and membership of the South Carolina Medicaid P&T Committee. Usmani declared conflicts of interest with Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Abbvie, Genentech, Gilead, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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