Not so B-Fast for Roche

On first glance it might seem that Roche is losing faith in its KRAS G12C inhibitor – the company disclosed on Wednesday that it had discontinued the divarasib cohort of its phase 2/3 B-Fast study in second-line NSCLC.

However, a closer look shows that Roche is merely trimming a trial with an outdated comparator; B-Fast was testing divarasib versus docetaxel, while the focus is now on the recently initiated Krascendo-1 study, pitting Roche’s asset against the approved KRAS G12C blockers, Amgen’s Lumakras and Bristol Myers Squibb’s Krazati.

Here Roche is taking a different tack versus its fellow KRAS G12C latecomers; Merck & Co and Lilly have bypassed second-line NSCLC and gone straight for the first line, while Novartis has dropped out of the race entirely.

Roche’s move makes sense given the evolving landscape, but the company will need divarasib to live up to its claims of best-in-class potential to succeed in the second line. The Swiss group said during its pharma day in September that divarasib could bring in CHF1-2bn at peak.

Meanwhile, Roche hasn’t yet dislosed details of its planned phase 3 study of divarasib in first-line NSCLC, slated to start next year. During the pharma day, the company said the trial would test divarasib with or without immunotherapy (likely PD-(L)1 blockers) plus or minus chemo, with the exact regimen to be disclosed later.

So far Lilly is the only company to report data with a KRAS G12C/PD-1 inhibitor/chemo combo, but Roche is also evaluating a triplet as part of its phase 1/2 Krascendo-170 study, due to yield data this year or next.

Roche’s trials of divarasib in KRAS G12C-mutant NSCLC

Source: OncologyPipeline & clinicaltrials.gov.

While divarasib is still going strong, some other projects have fallen by the wayside as Roche continues to cut assets that don’t meet its internal bar for further development. As disclosed at the pharma day, Roche has abandoned forimtamig, its GPRC5D-targeting T-cell engager in multiple myeloma, and tobemstomig, its anti-PD-1 x Lag3 bispecific.

In GPRC5D perhaps Roche has decided that it can’t compete against the likes of Talvey, Johnson & Johnson’s approved T-cell engager; J&J plans to split out Talvey sales from next year, which will give an indication of how this launch is going.

Other groups are developing GPRC5D-targeting Car-T projects, while AstraZeneca notably has an ADC in development, the LaNova-originated AZD0305.

Meanwhile, other Lag3 projects have faltered outside melanoma, so perhaps Roche is wise to cut its losses here. Tobemstomig had been in development for various solid tumours, including melanoma and breast, lung, bladder and oesophageal cancers.

However, there is still room for new additions, and here Roche has disclosed a new oncology project, an LTBR agonist known as RG6221. Details are sparse for now, although a phase 1 study in combination with Tecentriq in solid tumours has begun.