ESMO Asia 2023 – deaths raise doubts about Merus’s Rybrevant challenger

Merus had already admitted that its EGFR/cMet bispecific MCLA-129 had no future in head and neck cancer, and now updated findings from a phase 1/2 trial have cast doubt on its prospects in non-small cell lung cancer, too.

The latest data, presented at the ESMO Asia congress over the weekend, suggest that MCLA-129 could have a hard time catching up with Johnson & Johnson’s similarly acting Rybrevant. Perhaps more importantly, they also raised questions about MCLA-129’s toxicity: 13 of 60 patients experienced treatment-related interstitial lung disease, and three of these died.

Merus still has hopes for MCLA-129, and plans to add another arm to the same study early next year, looking at a chemo combo in second-line NSCLC; another cohort is also ongoing in cMet exon 14 skipping NSCLC. 

Merus's stock was off 6% this morning; perhaps the damage has been limited by the company having shifted its focus to petosemtamab, its EGFR and LGR5-targeting bispecific.

First-line NSCLC

The NSCLC data presented at ESMO Asia involved first as well as second-line disease. In both cases MCLA-129 was combined with AstraZeneca’s third-generation EGFR TKI Tagrisso in patients with EGFR mutations. 

In first-line NSCLC Merus touted a 75% overall response rate among 16 evaluable patients, but this dropped to 56% if only confirmed responses were counted.

As a benchmark, a combination of J&J’s Rybrevant and its third-generation EGFR TKI lazertinib, yielded an ORR of 86%, versus 85% in a Tagrisso control arm, in the first-line Mariposa trial

MCLA-129 looks to have fallen short here, but in any case Merus said during an investor call last month that further development in first-line NSCLC would only be possible with a partner.

Second-line NSCLC

In second-line NSCLC, MCLA-129 plus Tagrisso was given to patients who had progressed on Tagrisso; some had also received prior chemotherapy.

Among 34 evaluable subjects, Merus noted an ORR of 35%, or 32% if only confirmed responses were considered. 

It is harder to see how MCLA-129 stacks up against Rybrevant here as J&J’s second-line study, Mariposa-2, tested a combination of Rybrevant plus chemo, with or without lazertinib.

Still, this will give Merus a handy bar to aim for when it reports its own chemo combo data next year. Mariposa-2 found an ORR of 64% with Rybrevant plus chemo and 63% with the triplet. 

AstraZeneca is also ahead here, with its Tagrisso-chemo combo already outdoing Tagrisso monotherapy in the Flaura-2 trial, albeit with greater toxicity. 

Adverse events

And toxicity already looks like it could be an issue for MCLA-129, with the 22% rate of interstitial lung disease standing out. 23% of patients also discontinued owing to treatment-emergent adverse events, while 12% suffered grade three or greater infusion-related reactions.

Meanwhile, in head and neck cancer, Merus has already thrown in the towel after seeing just two partial responses – one confirmed after data cut-off – among 20 second-line patients receiving MCLA-129 monotherapy.

For now, lung cancer is still in play, but the signs don’t look good.