Exelixis claims a label-expanding Cabo success at last

Exelixis’s Cabometyx is a one-hit wonder in its blockbuster kidney cancer indication, but beyond this it has scored few successes. After numerous recent failures, however, the label-expanding Contact-02 study in castrate-resistant prostate cancer was this morning said to have succeeded at interim analysis.

Earlier this year Exelixis avoided a destructive battle with an activist investor, Farallon Capital, by agreeing to all three of the fund’s proposed board nominees, so all eyes are now on its R&D strategy. As such, any clinical study wins will be welcomed, although in the case of today’s success important questions could be raised about the control cohort in Contact-02, and consequently on the importance of a win on PFS.

Contact-02 had taken prostate cancer patients who had progressed on Zytiga or Xtandi, and gave them Cabometyx plus Roche’s Tecentriq as active treatment. Control cohort patients, meanwhile, merely received a second helping of a novel hormonal treatment, with the proviso that if they’d earlier failed on Zytiga they now had to get Xtandi, and vice versa.

Today Exelixis and its partner Ipsen toplined a positive result on progression-free survival at Contact-02’s first interim analysis; meanwhile OS, the other co-primary, was said to be immature and short of a significance threshold at this point.

Control problem?

So what’s not to like? Mainly the fact that in the control arm patients who had already failed a novel hormonal therapy were simply being given another one – a strategy that has little evidence of success.

Could such patients have got anything better? One option in prostate cancer is taxane chemotherapy, meaning Jevtana or Taxotere, but this was not an option, at least not within the scope of Contact-02. The trial had allowed some Taxotere pretreatment, with patients stratified for this, but arguably this should also have been considered in the post-Zytiga/Xtandi setting.

Exelixis’s statement claims that many patients who progress on Zytiga/Xtandi want an alternative to chemotherapy; this might well be true, but Contact-02 has not shown whether Cabometyx plus Tecentriq is in fact better than chemotherapy – just that it is better than something known already to have failed in a prior setting.

A further problem is OS. If the PFS benefit is illusory, and if a significant number of patients did go on to get taxane chemo on progression (outside the trial) this could confound Contact-02’s all-important co-primary endpoint, if subsequent taxane extends survival in the control and active cohorts alike. 

Pipeline in a drug

Last year global Cabometyx sales hit $1.9bn, but the vast majority of this came from the renal cancer indication.

The fact Cabometyx is a one-hit wonder became a hot topic when Farallon, a 7% Exelixis holder, called for the group to communicate a “coherent R&D strategy”, and said its 2023 R&D spending should be cut from the budgeted $1bn. The activist investor succeeded in getting three directors appointed in May, since when its next moves have been eagerly awaited.

Beyond renal cancer Exelixis has made a push into other tumours, aiming to turn Cabometyx into a pipeline in a product, but many of these efforts have fallen on stony ground. March brought the failure for PFS of the Contact-03 study, testing the ability of Cabometyx plus Tecentriq to resensitise to an anti-PD-(L)1 drug renal cancer patients who had already failed first-line checkpoint blockade.

Earlier came flops for Cosmic-312, a study aimed at moving Cabometyx into front-line liver cancer, and Contact-01 in lung cancer, while Cosmic-313, in first-line renal cancer, succeeded only on a technical basis. Tellingly, the phase 1/2 Cosmic-021 trial of Cabometyx plus Tecentriq in post-Zytiga/Xtandi prostate cancer patients yielded a response rate of 18%, dismissed by Stifel analysts as little better than what immunotherapy alone could do.

For now the clinical relevance of Contact-02 remains similarly unclear.

Selected label-expanding studies of Cabometyx

mCRPC=metastatic castration-resistant prostate cancer; NHT=novel hormonal therapy, eg Zytiga or Xtandi. Source: company statements & The Lancet.