Merus's next shot is colorectal cancer

Merus and Bicara remain locked in a battle in head and neck cancer, but now a separate opportunity, colorectal cancer, is presenting itself. By the end of this year Merus will find out whether petosemtamab has a future in this new use, in which Bicara's competing ficerafusp alfa has only recently made a start.

The two projects use different approaches, but each targets EGFR, a fact that underpins this as a potential setting for them. However, the only clinical data Merus has so far generated for petosemtamab in colorectal cancer, from a phase 1 multi-tumour trial in very late-line patients, yielded no responses.

That clearly makes this a high-risk catalyst backed only by preclinical work. However, with investor focus firmly on head and neck cancer, sellside analysts reckon no value is currently being ascribed to the colorectal opportunity, which in investment terms makes the phase 2 outcome look like a free bet.

Better anti-EGFR?

From a mechanistic point of view it makes sense for Merus to test petosemtamab in colorectal cancer.

The space features two approved anti-EGFR MAbs, Erbitux and Vectibix, as first-line chemo combos and later-line monotherapies, in RAS wild-type/EGFR-expressing disease. If petosemtamab, which hits EGFR as well as LGR5, is indeed a "better" EGFR-targeting agent then this should translate into promising efficacy in colorectal cancer.

The upcoming data come from three phase 2 expansion cohorts of a phase 1/2 basket trial. These test chemo combos in first and second-line settings, with the latter specifying KRAS wild-type status and no prior EGFR therapy; and a third-line or later monotherapy in RAS wild-type, post-EGFR subjects. There appears to be no requirement for high EGFR expression.

The first patients in these phase 2 cohorts were dosed in July 2024. For its part Bicara is only just expanding into third-line RAS wild-type colorectal cancer with ficerafusp alfa monotherapy or as part of a Keytruda combo. Ficerafusp isn't a MAb but a fusion protein, and hits TGF-β in addition to EGFR.

Cross-trial comparisons of approved anti-EGFR MAbs in colorectal cancer

Source: prescribing information.

In a recent initiation Wells Fargo analysts wrote that ORRs above 15% in the second-line, and 10% in the third-line settings, were necessary to be confident of petosemtamab's potential in colorectal cancer. 

However, Erbitux plus chemo's 23% ORR in the second line suggests that a higher response rate is needed to show differentiation. There are no precise comparators for monotherapy in EGFR therapy-relapsed disease. Meanwhile, a first-line petosemtamab/chemo combo must shoot for ORR well above 60%, and chemo alone gives 40-50%.

Early phase 1 petosemtamab data included a 33-strong cohort of colorectal cancer patients; 18 of these had KRAS wild-type disease, and all 18 had all been exposed to EGFR inhibitors. There were no responses.

Reasons for this lack of activity, apart from patients' generally advanced disease, included a large number with RAS mutations, where EGFR therapy tends not to work, and which isn't included in the relapsed phase 2 cohorts. While patients were technically EGFR positive, their levels of this biomarker tended to be somewhat low.

Tolerability could offer an edge, as rash, seen in 18% of patients, yielded no cases above grade 2; this is a major toxicity of Vectibix, for instance. Whether this matters, and whether the phase 2 petosemtamab cohorts comprise more amenable populations, will soon be revealed.