J&J receives Tecvayli/Darzalex nod

Johnson & Johnson has secured another approval in early-stage multiple myeloma that could strengthen its grip on this landscape, with US regulators on Thursday clearing a combination of its BCMA-targeting T-cell engager Tecvayli with its anti-CD38 MAb Darzalex. 

The decision was driven by standout phase 3 data from the Majestec-3 trial, unveiled at ASH in December. In the study, the Tecvayli-Darzalex pairing cut the risk of progression or death by 83% versus a control regimen consisting of Darzalex plus dexamethasone and either Pomalyst or Velcade in patients naive or sensitive to anti-CD38 antibodies.

Despite the impressive efficacy signal, one potential concern emerged from the trial: the overall survival curves crossed during the study. Investigators attributed this to early infection-related deaths in the Tecvayli plus Darzalex arm; these occurred in 13 patients in that group, compared with four patients in the control arm. 

Researchers noted that 12 of the 13 infection-related deaths in the Tecvayli combination occurred before the study protocol was amended to reinforce immune globulin treatment and antimicrobial prophylaxis.

Even with that safety signal, the magnitude of the benefit was strong enough for the FDA to issue the regulatory filing a commissioner’s national priority voucher (CNPV) in mid-December, speeding the combo's path to approval. The decision marks the second oncology approval to come through the CNPV programme, following Hernexeos.

One prior line

Tecvayli's updated label states the combo can now be used in combination with Darzalex Faspro "in patients who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent". 

This wording makes no mention of prior treatment with anti-CD38 antibodies, increasingly used in newly diagnosed patients, leaving the decision on whether to use the combo in those patients to physicians. Majestec-3 itself included limited evidence for this population: only 31 patients, around 5% of the population, who received a previous anti-CD38 MAb were analysed for efficacy, with a hazard ratio for PFS of 0.19. 

Meanwhile, for patients not previously treated with an anti-CD38 antibody, Johnson & Johnson appears to be covering all the therapeutic gaps in second-line multiple myeloma, with both the Tecvayli-Darazalex combination and the BCMA-targeting Car-T Carvykti.

The approval also converted Tecvayli's 2022 accelerated approval, as monotherapy for patients who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, into full approval. 

Post-Darzalex

For patients previously treated with Darzalex, the phase 3 Majestec-9 trial, which focused on this population, could prove more relevant. In January J&J said Tecvayli monotherapy reduced the risk of disease progression or death by 71%, and cut the risk of death by 40%, versus standard of care regimens including Pomalyst, Velcade and dexamethasone or Kyprolis plus dexamethasone. 

J&J plans to file Tecvayli in the US and Europe in 2026 for relapsed or refractory multiple myeloma previously treated with CD38 antibodies. 

Additionally, this year could also see another big readout for J&J in the post-Darzalex population, from the Monumental-6 trial testing Tecvayli alongside the GPRC5D-targeting T-cell engager Talvey, as well as a Talvey-Pomalyst combo. If this succeeds, it could raise questions about whether Tecvayli or Talvey should be used here.

Tecvayli pivotal trials in 2L+ multiple myeloma

Notes: D=Darzalex; d=dexamethasone; E=Empliciti; K=Kyprolis; P=Pomalyst; R=Revlimid; V=Velcade. Source: OncologyPipeline.