Upcoming events – Roche braves liver cancer and Incyte looks for a new Jak

In liver cancer Roche hopes to succeed where Bristol failed, while Incyte tests its Jakafi follow-on in first-line graft-versus-host disease.

Welcome to your weekly roundup of approaching clinical readouts. Roche’s Imbrave-150, a phase III study in first-line liver cancer testing Tecentriq plus Avastin against the standard of care, Bayer’s Nexavar, is due to read out in weeks, and what makes it especially interesting is that investors can handicap the result.

This is courtesy of GO30140, a randomised multi-cohort phase I study updated at Esmo, that showed liver cancer subjects given Tecentriq plus Avastin having a 45% reduced chance of progression compared with those given Tecentriq alone (p=0.0108).

That said, Imbrave-150 tests a truly front-line setting; in GO30140 patients had to be naive to systemic therapy and to have unresectable hepatocellular carcinoma, effectively indicating a slightly later line of therapy as subjects might have received radiotherapy, for instance.

Notably, no GO30140 subjects got Nexavar, so comparison necessitates looking across studies. Nexavar’s US label cites 5.5 months of median PFS, which is only slightly shorter than the 5.6 months of the combo in GO30140. Considering the earlier-line population, Tecentriq plus Avastin might be expected to confer longer PFS in Imbrave-150 versus GO30140.

Imbrave-150 did not enrol high PD-L1 expressers, which given the result of Bristol-Myers Squibb’s failed Checkmate-459 trial looks dubious. However, the Swiss company will be relying on the Avastin part of the combo to boost efficacy in PD-L1 non-expressers.

Perhaps the most intriguing signal from GO30140, which also enrolled subjects unselected for PD-L1 status, was that Roche was able to demonstrate the additive effect of Avastin over Tecentriq alone. But at Esmo the discussant of GO30140 cautioned that it was not clear whether Avastin could turn “cold” tumours “hot”, or which patients should get the combo.

Nevertheless, Evercore ISI’s Umer Raffat reckons the GO30140 data were strong enough to suggest that liver cancer is the indication in which Roche could at last differentiate its immuno-oncology offering.

Selected Roche trials in hepatocellular carcinoma
Study Design Setting Data Trial ID
GO30140 Includes Tecentriq + Avastin and Tecentriq-only cohorts Inoperable subjects naive to systemic therapy mPFS 5.6mth for combo, vs 3.4mth for monotherapy NCT02715531
Imbrave-150 Tecentriq + Avastin vs Nexavar First line OS & PFS co-primaries; reads out in Q4 2019 NCT03434379
Source: Roche & clinicaltrials.gov.

Incytes Gravitas

The first pivotal data are due before the end of the year for Incyte’s itacitinib in acute graft-versus-host disease (GVHD). Gravitas-301 is testing itacitinib, a Jak 1 inhibitor, plus corticosteroids, versus placebo and steroids in 439 steroid-naive patients.

The primary endpoint is overall response rate at day 28, and the study is powered to show a 16-percentage point improvement in the active arm over control, and a 40% reduction in non-relapse mortality at 6 months, a key secondary endpoint.

Incyte already has a Jak inhibitor approved for GVHD in the shape of Jakafi; the Jak 1 and 2 inhibitor got the go-ahead here in May but only in second-line, steroid-refractory patients, on the back of a single-arm phase II trial that showed a 55% ORR.

Jakafi has got off to a strong start in GVHD and Incyte has guided to sales of $80m for the year.

Analysts reckon that Incyte will want to diversify away from Jakafi, given approaching competition from Celgene's Inrebic, and generic erosion in 2028. Importantly, itacitinib also offers more attractive economics: Incyte owns all rights to itacitinib, while Jakafi is licensed to Novartis outside the US.

Second-line GVHD affects around 3,000 new patients per year in the US, versus some 15,000 first-line patients, according to Incyte. 

The group plans to file a US NDA for itacitinib early next year. A first-line trial in chronic GVHD patients is ongoing.

Incyte’s GVHD trials
  Acute GVHD Chronic GVHD
First line: itacitinib Gravitas-301 (NCT03139604): itacitinib vs placebo, results by YE 2019 Gravitas-309 (NCT03584516): itacitinib vs placebo, primary completion 2023
Second line: Jakafi Reach1 (NCT02953678): single-arm study, accelerated approval May 2019  Reach3 (NCT03112603): Jakafi vs best available therapy, results 2020
Reach2 (NCT02913261): Jakafi vs best available therapy, results by YE 2019
Source: Company presentation, clinicaltrials.gov

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