The ranks of Rybrevant challengers swell

Companies are lining up to take on Johnson & Johnson’s anti-EGFR x cMet bispecific Rybrevant with similarly acting molecules, but it might come as a surprise that J&J itself features among them. That’s courtesy of a project coded JNJ-95437446, whose mechanism J&J has tried to keep secret, but which has now emerged to be an anti-EGFR x cMet ADC.

Similar secrecy surrounds another ADC, Kelun’s SKB571, whose development Merck & Co opted into in 2024; this too now appears to be a molecule that targets EGFR x cMet. Together, the disclosures take the list of clinical-stage ADCs that hit these two targets to 13, according to OncologyPipeline, with a further six in preclinical development.

At the time of going to press neither J&J nor Merck had responded to ApexOnco to confirm the mechanisms of JNJ-95437446 and SKB571 (the latter also carries the Merck code MK-2750). However, information posted on clinical study registries and elsewhere leaves little room for doubt.

A website listing clinical studies ongoing at Florida cancer centres lists the phase 1 trial of JNJ-95437446 on account of one of its locations being the Sarasota Drug Development Unit.

The entry is titled: “a phase 1 study of JNJ-95437446, a bispecific antibody-drug conjugate to EGFR and MET, for advanced solid tumours.” The trial started last July, but at the time nothing had been disclosed about JNJ-95437446’s mechanism either by the company or by its main listing on clinicaltrials.gov.

Secrecy

J&J’s secrecy surrounding JNJ-95437446 is understandable, given that should this molecule succeed it would naturally be expected to take market share from the approved Rybrevant. That said, J&J is no stranger to developing multiple therapies with the same target: in multiple myeloma it sells the anti-BCMA Car-T Carvykti and the anti-BCMA T-cell engager Tecvayli.

As for Merck, that company first disclosed its involvement in SKB571/MK-2750 in August 2024, when it opted into this Kelun ADC. Neither Merck nor Kelun have ever disclosed publicly the mechanism of SKB571/MK-2750, either in pipeline listings or when asked.

However, Kelun recently listed a new phase 2 trial of SKB571/MK-2750 due to start in February, and this will specifically recruit lung cancer patients whose tumours harbour cMet abnormalities. Moreover, a patent database lists the molecule as an anti-EGFR x cMet ADC, and Kelun is on record as having patented ADC molecules whose targets include EGFR and cMet.

Anti-EGFR x cMet ADCs

Notes: *mechanism evident from trial registries or other sources, but not confirmed by companies; **dual-payload ADC. Source: OncologyPipeline.

These developments come just as two more Rybrevant challengers, Jiangsu Simcere and Qilu, are set to enter clinical trials with similarly acting ADCs, as reported separately by ApexOnco.

The issue of challenging Rybrevant first became live when Genmab took GEN1286, an anti-EGFR x cMet ADC it got through ProfoundBio, into human trials in November 2024. Genmab has a residual interest in Rybrevant via a long-standing deal with J&J.

But the issue was rendered moot when Genmab appeared to discontinue GEN1286 recently, terminating its sole trial after recruiting just a few patients. Genmab does have a separate anti-EGFR x cMet asset, MCLA-129, derived from the subsequent acquisition of Merus, though this molecule too seems to lack promise.

Like Rybrevant MCLA-129 is a naked MAb rather than an ADC. OncologyPipeline lists several competing developers here too, though developing ADC versions seems to be the more popular strategy.

Anti-EGFR x cMet MAbs

Source: OncologyPipeline.