Roche seeks alpha to defeat Novartis

Roche’s second attempt at targeting breast cancer with a PIK3CA mutation appears to have delivered an important win, after its first failed back in 2018. The group’s PI3K alpha inhibitor inavolisib has hit the PFS primary endpoint in its first-line phase 3 trial, Inavo-120, and the data will be filed with regulators.

Though this comes four years after the approval of the industry’s first PI3K alpha inhibitor, Novartis’s Piqray, Roche claims that inavolisib has best-in-class potential. And for good reason: Piqray carries only a second-line label, isn’t being studied in the front line, and has failed two other pivotal breast cancer studies.

And Roche will prove decisively which drug is best, though this will take several years; the phase 3 Inavo-121 study, testing inavolisib head to head versus Piqray in the Novartis’ drug’s approved second-line setting, won’t read out until after 2026, according to Roche’s most recent financial update.

PFS win

In the meantime, Roche is celebrating inavolisib's first-line HER2-negative PIK3CA-positive breast cancer win in the Inavo-120 trial, in which its PI3K alpha inhibitor plus Ibrance and Faslodex beat Ibrance and Faslodex alone on PFS. 

While no data have been revealed yet, Roche called the PFS benefit statistically significant and clinically meaningful. Overall survival data are immature but said to be heading in a positive direction, and it’s assumed that PFS is an approvable endpoint since it was on this basis that Piqray was greenlit in the second-line setting.

A space for PI3K inhibition has been carved out thanks to the finding that some breast cancers are driven by the PIK3CA mutation, which is said to be precisely actionable by the PI3K mechanism, and it is thanks to preselecting for these patients that Piqray scored in its pivotal Solar-1 trial. However, specificity for the PI3K alpha isoform is needed to avoid unacceptable toxicity.

It was in fact Roche that led this space at one point, with a molecule called taselisib, which showed promise in the phase 2 Lorelei study. But the subsequent phase 3 Sandpiper trial failed, largely for toxicity reasons, and Roche went back to the drawing board to find a more alpha-specific molecule; inavolisib is the result of this effort.

What’s next?

If inavolisib secures approval in the HER2-negative breast cancer settings of Inavo-120 and Inavo-121, this won’t be Roche's only focus.

The company highlights a third pivotal study, Inavo-122, looking at front-line maintenance in HER2-positive patients, and here inavolisib is being combined with Phesgo, the hyaluronidase-based fixed-dose combination of Perjeta and Herceptin. This is another a long-term readout, with clinicaltrials.gov citing a 2028 primary completion date.

However, Inavo-122 is notable for testing the same setting as Piqray’s Epik-B2 study, which was terminated earlier this year. Piqray has also failed in triple-negative breast cancer in Epik-B3, a tumour where Roche isn’t testing inavolisib, as well as in phase 3 ovarian and head and neck cancer trials.

As for other competitors, OncologyPipeline reveals a few in early clinical trials, most notably Lilly’s Takeda-derived serabelisib and its allosteric PI3K alpha H1047R inhibitor LOXO-782.

It’s often said that first in class doesn’t equal best in class, and Roche is hoping that the maxim holds true in PI3K alpha blockade.

Comparison of two PI3K alpha inhibitors

Note: *Inavo-121 mandates prior CDK4/6i. Source: prescribing info & OncologyPipeline.