The sun sets on Exelixis’s pipeline in a product

After Cabometyx’s latest clinical setback Exelixis might have to turn to follow-on projects for future growth.

Cabometyx has been a big success for Exelixis, its use as part of an Opdivo combo in first-line kidney cancer propelling the company to a $5bn-plus valuation. But plans to expand into other settings have fired numerous blanks, and yesterday the Contact-03 trial failed.

Contact-03 aimed to broaden Cabometyx’s second-line renal cancer use, and its failure leaves just one notable label-expanding study that has yet to read out. To its credit Exelixis has quietly been building an early-stage R&D pipeline behind the Cabometyx warhorse, and it seems likely that the spotlight will now increasingly fall on these projects.

Most important among these is zanzalintinib (XL092), a next-generation Exelixis-originated small molecule that, like Cabometyx, targets VEGF among other kinases. Zanzalintinib is in two phase 3 studies, Stellar-303, in combination with Tecentriq in colorectal cancer, and Stellar-304, testing an Opdivo combo in renal cell carcinoma.

Stellar-304 aims to replicate Cabometyx’s success in front-line renal cancer, a setting that represents the bulk of the Exelixis/Ipsen drug’s $1.4bn US sales last year. Cabometyx is also approved for second-line liver cancer and thyroid cancer (including under the Cometriq brand), but these uses are relatively minor.

Post-checkpoint flop

Single-agent Cabometyx is approved for second-line kidney cancer, and here Exelixis had sought to strengthen its position by combining it with Roche’s Tecentriq in Contact-03, a study specifically in patients who had failed checkpoint inhibition, the front-line standard of care.

Yesterday Exelixis said that Contact-03 had failed for progression-free survival versus Cabometyx alone; the co-primary overall survival endpoint therefore looks unlikely to be hit. There was logic in trying to resensitise to an anti-PD-(L)1 drug patients who had already failed checkpoint blockade, but this has clearly not played out.

The setback follows the failures of Cosmic-312, a study aimed at moving Cabometyx into front-line liver cancer, and of Contact-01, which like Contact-03 had tried to resensitise checkpoint blockade failures back to PD-(L)1 therapy, but in lung cancer. Cosmic-313, aiming to strengthen Cabometyx’s first-line renal cancer position, succeeded only on a technical basis.

Meanwhile, cohort 6 of the phase 1/2 Cosmic-021 trial tested Cabometyx plus Tecentriq in prostate cancer patients who had progressed on Xtandi or Zytiga, but yielded a response rate of just 18%. Exelixis had initially aimed to use this as a path to approval, but then abandoned this plan to wait instead for results from the controlled Contact-02 study.

This plan now comes into focus as Contact-02 is the last remaining significant study that could yet expand Cabometyx’s label. It should yield PFS data for the combo versus Xtandi/Zytiga in the second half, but given the disappointing signal from Cosmic-021, success looks like a long shot.

Recent Cabometyx label-expanding studies
Trial Setting Results 
Cosmic-021 cohort 6 2nd-line (post NHT) mCRPC (Tecentriq combo) 18% ORR, uncompetitive vs rivals
Contact-02 2nd-line (post NHT) mCRPC (Tecentriq combo, vs NHT) Ends Jun 2023
Cosmic-311  2nd-line thyroid (Cabometyx vs placebo post VEGFr) US approved
Cosmic-313 1st-line renal (Keytruda + Yervoy +/- Cabometyx) Technically hit PFS, but uncompetitive vs rivals
Contact-03 2nd-line (post checkpoint inhibitor) renal cancer (Tecentriq combo, vs Cabometyx) Failed for PFS
Contact-01  2nd-line (post checkpoint inhibitor + chemo) NSCLC (Tecentriq combo, vs docetaxel)  Failed for OS
Cosmic-312 1st-line liver (Cabometyx + Tecentriq vs Sutent) Hit PFS (HR=0.63, p=0.0012), but failed OS (HR=0.90, p=0.44)
mCRPC=metastatic castration-resistant prostate cancer; NHT=novel hormonal therapy, eg Zytiga or Xtandi. Source: Evaluate Pharma, company statements & The Lancet.

If attention does now turn to zanzalintinib the immediate focus should be on this project’s phase 1 Stellar-002 trial, evaluating numerous combos in several cancer settings.

It should also be noted that, however disappointing Cabometyx’s expansion plans have been, this drug will continue to be of huge significance for Exelixis for some time to come; revenues will not peak for another three years, according to Evaluate Pharma sellside consensus, at which point they will be well above $3bn globally, including Ipsen’s ex-US contribution.

However, kidney cancer will be responsible for over 80% of this total.

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