ESMO 2024 – Bristol heads for phase 3 in small-cell

Bristol Myers Squibb’s first-in-class anti-fucosyl-GM1 MAb BMS-986012 is headed into phase 3, having shown glimmers of a survival benefit in a controlled phase 2 trial. The study will test the project in combination with Opdivo and chemo in first-line small-cell lung cancer, the ESMO conference heard on Friday.

This is the same setting in which phase 2 data were just presented at ESMO, showing the BMS-986012 triplet yielding no meaningful benefit on PFS versus Opdivo and chemo, but a more hopeful result on median OS. The data will be of interest especially because the molecule appears to be the industry’s only one acting on fucosyl-GM1, according to OncologyPipeline.

Fucosyl-GM1 is a glycolipid that contains fucose and sialic acid, and was said by Dr Ewa Kalinka, of Instytut Centrum Zdrowia Matki Polki in Poland, to be highly expressed in most SCLC tumours, with limited expression in normal tissues.

At a prespecified interim analysis in August 2023 its phase 2 trial showed no benefit on PFS, with 5.8 months at median for the BMS-986012 triplet versus 5.2 months for Opdivo plus chemo alone, Kalinka told ESMO.

Unexpected promise

However, a second analysis, at a February 2024 cutoff, was done to investigate OS, and this showed unexpected promise: median OS of 15.6 months, a 4.2-month benefit versus control. This seemed to be driven by patients with brain metastases at baseline, who appeared to do especially well, according to a subgroup analysis.

That said, any OS benefit remains purely exploratory, with the trial having enrolled just 133 patients across its two cohorts, and very wide confidence intervals for OS (0.44-1.16). Pruritus, albeit mostly low grade, was the main toxicity that was increased with BMS-986012 treatment, despite the claim that fucosyl-GM1 was largely tumour-restricted.

On the back of these somewhat sketchy data planning is already under way for a phase 3 trial, presumably in far more patients, to confirm the findings, Kalinka said.

A key difference is that this will test the BMS-986012 triplet against a first-line SCLC standard of care, meaning Imfinzi plus chemo or Tecentriq plus chemo. An important limitation of the phase 2 study was the use of Opdivo plus chemo as the comparator, since this isn’t a western standard of care.

As such it’s worth comparing the data against AstraZeneca and Roche’s respective registrational trials, Caspian and Impower-133, in this setting. This at least suggests – on a cross-trial basis – that in the Bristol trial Opdivo plus chemo performed as expected, offering no meaningful benefit over chemo alone.

On the other hand, 15.6 months’ median OS for the BMS-986012 triplet is numerically above the numbers Imfinzi and Tecentriq scored. Perhaps this is the most important factor behind Bristol’s decision to go into phase 3; all the group needs to do now is repeat the result prospectively in a much larger trial.

Cross-trial comparison in 1st-line SCLC

Source: ESMO & OncologyPipeline.