Merck vs Merck in late-line kidney cancer

It’s taken well over a year for Merck & Co to unveil the full extent of its clinical development collaboration with Exelixis on the Cabometyx follow-on zanzalintinib, and the latest revelation, courtesy of clinicaltrials.gov, is something of a surprise.

The newly revealed phase 3 Litespark-034 study, sponsored by Merck, will see the big pharma group seeking to beat its own approved kidney cancer drug Welireg, a new listing on the registry shows. This follows the collaboration’s first phase 3, Litespark-033, which had a more obvious goal, namely to show whether zanzalintinib and Welireg could beat Cabometyx.

That latter trial began last November, and concerned the early setting of renal cell carcinoma patients who had progressed on adjuvant anti-PD-(L)1 therapy, but who had otherwise received no systemic treatment. That study's aim was fairly logical, given that Exelixis’s basic purpose with zanzalintinib is to replace Cabometyx, a blockbuster franchise soon to face patent expiry.

Any better?

But now comes Litespark-034, in the later-line renal cancer setting of Welireg’s approved use of patients who have progressed on first-line PD-(L)1 blockade as well as VEGF inhibition, together or sequentially. 

In Litespark-034 zanzalintinib will be added on top of Welireg, and compared against Welireg alone. The co-primary endpoints are overall and progression-free survival, and this phase 3 study is to begin in the middle of April, according to the new clinicaltrials.gov listing.

Of course, should this succeed it won’t eliminate Welireg from the treatment spectrum, but merely suggest that the drug should be given in combination with zanzalintinib rather than alone. But it shows that the Exelixis deal is a complex clinical trial collaboration, with specific goals for each partner rather than the more typical supply of an approved drug into another company’s study.

The collaboration was signed in October 2024, and called for Merck to sponsor two phase 3 trials in renal cancer, whose designs weren’t disclosed until the Litespark-033 and 034 listings went live. Merck additionally agreed to supply Exelixis with Keytruda into the Stellar-305 trial in squamous head and neck cancer.

Benchmark

In renal cancer Welireg was approved in December 2023 on the basis of the Litespark-005 study, in patients after PD-(L)1 and VEGF therapy, and the results of this trial represent a baseline that the Welireg/zanzalintinib combo will be trying to beat in Litespark-034.

Litespark-005 showed median OS of 21.4 months, and median PFS of 5.6 months, but only the latter measure yielded a statistically significant result versus everolimus, the comparator in that study. Any developments in this space are being closely watched by Arcus, whose rival HIF2α inhibitor casdatifan is starting to look competitive against Welireg in late-line renal cancer – albeit so far only on a cross-trial basis.

Welireg’s US label warns of the risk of anaemia and hypoxia, while Cabometyx has fairly typical toxicities for a kinase inhibitor. As another multi-kinase inhibitor zanzalintinib likely carries similar risks to Cabometyx, so in any study that, like Litespark-034, combines the two mechanisms the spotlight will remain on safety. 

Selected phase 3 trials of Welireg in renal cell carcinoma

Source: OncologyPipieline.