ESMO 2023 – butterflies for J&J

Among the multitude of late-breaking abstracts that ESMO decided yesterday to unveil prematurely after an apparent leak, those concerning Johnson & Johnson’s Rybrevant were among the most keenly awaited. And, at first sight anyway, the data are a mixed bag at best.

Most important are the results of Mariposa, a study testing Rybrevant, an anti-EGFR x cMet bispecific, plus the third-generation EGFR-targeting small molecule lazertinib, in first-line EGFR-positive NSCLC. A win on PFS versus Tagrisso had already been toplined, but the ESMO abstract reveals an unimpressive median result for J&J’s combo, and Tagrisso underperformance to boot.

Among the positives, Rybrevant plus lazertinib has clearly beaten Tagrisso, with a 30% reduction in risk of progression or death and a p value below 0.001. Also, the abstract reveals a “favourable trend” for overall survival at this interim look, with a non-statistically significant hazard ratio of 0.80.

Unconvincing?

However, the absolute numbers paint a less convincing picture. Tagrisso’s mPFS in Mariposa came in at 16.6 months – well short of the 18.9 months cited in the Astra drug’s label from its registrational Flaura trial, and notably down on the 19.9 months Tagrisso scored recently in the control arm of the Flaura2 study.

Rybrevant plus lazertinib’s mPFS of 23.7 months looks unimpressive if 19 months or more for Tagrisso is seen as the more realistic comparison. What’s more, Flaura2 showed the addition of chemo to Tagrisso yielding a massive 29.4 months of mPFS – with caveats – a result that could convince doctors to give the Astra chemo combo in preference to J&J’s doublet.

As an aside, the Mariposa abstract makes no mention of a third arm, lazertinib monotherapy, so the best that can be assumed is that this performed in line with Tagrisso.

mPFS cross-trial comparisons in 1st-line EGFRm NSCLC

Source: ESMO, IASLC & prescribing information.

The question of how much lazertinib brings to the party in EGFR-mutant NSCLC is also relevant in a separate late-breaker, covering the Mariposa-2 trial in post-Tagrisso NSCLC patients.

Here J&J had also toplined a PFS win, specifically for a Rybrevant/lazertinib/chemo triplet versus chemo alone, but said nothing about how the triplet performed against the third cohort, Rybrevant plus chemo. The ESMO late-breaker on Mariposa-2 lifts the lid on this comparison, and here there is some good news.

The triplet and doublet both beat chemo alone and, though the study wasn’t designed to compare the triplet against the doublet, there is a pleasing increase in mPFS with the addition of a third agent. The message on OS is less convincing, though the data here are probably too immature to draw meaningful conclusions.

Rybrevant is approved on an accelerated basis for a separate NSCLC setting, tumours bearing an exon 20 insertion in EGFR, and a third ESMO late-breaker details Papillon, a first-line trial that could confirm this US green light. 

The ESMO abstract shows a highly statistically significant 60% reduction in risk of progression or death for Rybrevant plus chemo versus chemo, as well as a “favourable trend” for an OS benefit (0.67 hazard ratio). This seems ample backing to give Rybrevant full US approval, though it would be a huge disappointment for J&J if the drug’s market ended at exon 20.

Key data from Mariposa-2

Source: ESMO.