Unhappy new year for Calithera

The company welcomes in 2021 with the failure of a pivotal study of its pipeline lead, telaglenastat.

Trial Results

One of the first big catalysts of 2021 for small-cap companies was the result of Calithera’s Cantata trial in renal cell carcinoma; unfortunately for investors, the study has turned out to be a complete failure.

The setback is particularly concerning since Cantata tested Calithera’s lead asset, the glutaminase inhibitor telaglenastat, and its immediate fallout is a 40% share price crash and the axing of 35% of the group’s workforce. Nevertheless, Calithera is not giving up on telaglenastat, a stance that could cause nervousness as the project’s next big study, Keapsake, nears readout later this year.

Calithera’s argument is that Keapsake, a combo of telaglenastat with Merck & Co’s Keytruda in first-line KEAP1/NRF2-mutated NSCLC, has an entirely different mechanistic rationale. This, management said on an analyst call today, is that the KEAP1/NRF2 mutation causes a dependence on glutaminase activity, a theory that fits telaglenastat’s mechanism in this genetically selected population.

Bust

Be that as it may, 100% of telaglenastat’s 2026 consensus sales forecast of $459m had, according to EvaluatePharma, been derived from the renal cell carcinoma indication that is now a bust.

Cantata had enrolled second and third-line subjects not selected for any mutations, and compared telaglenastat plus Exelixis’s approved Cabometyx versus Cabometyx alone. Despite being what management termed well designed and well run, the trial failed its primary progression-free survival endpoint, with the difference between the two cohorts yielding a highly non-significant p value of 0.65.

Telaglenastat appeared to have added absolutely nothing to Cabometyx’s activity: median PFS was 9.2 months with the combo, versus 9.3 months for the Exelixis drug alone. Cantata had been powered to detect a 31% improvement over the expected eight-month PFS for Cabometyx.

Immunotherapy has changed the renal cell cancer landscape over the past two years, but as this transformation concerns front-line treatment it seems not to be relevant in the setting of Cantata, which was said to have been well balanced for prior checkpoint blockade. Overall 65% of its participants had progressed on Opdivo plus Yervoy, one of several first-line standards of care.

Warning signs

There might have been warning signs over the Cantata readout, courtesy of a phase II renal cell cancer trial called Entrata, which gave telaglenastat third line on top of Novartis’s Afinitor.

This yielded unconvincing data: its primary endpoint of median PFS came in at 3.8 months for the combo versus 1.9 months for Afinitor alone (p=0.079). Analysts argued that a numerical benefit in the secondary overall survival endpoint indicated a “trend” in favour of telaglenastat, and stressed that enrolment into Entrata had been cut massively to focus on Cantata.

Whether Cantata has any bearing on Keapsake is the next question for investors to ponder.

Selected studies of Calithera's telaglenastat 
Trial Setting Result
Entrata 3L RCC, Afinitor combo, vs Afinitor mPFS 3.8 vs 1.9 mth (HR=0.64, p=0.079 met one-sided p≤0.2 threshold); mOS 14.4 vs 9.7 mth (HR=0.80, p=0.24)
Cantata 2/3L RCC, Cabometyx combo, vs Cabometyx Fail: mPFS 9.2 vs 9.3 mth (HR=0.94, p=0.65)
Keapsake 1L KEAP1/NRF2-mut NSCLC, Keytruda/chemo combo, vs Keytruda/chemo First data due later in 2021
Source: company reports.

This story has been amended to correct statistical analysis assumptions in the Entrata study.

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