BiQ Journal: Why the LITESPARK-012 Failure Could Be a Win for Kura Oncology

As most readers are probably aware, Merck hit a major roadblock today with the failure of Welireg in its P3 LITESPARK-012 trial for the treatment of 1L advanced ccRCC. In the trial, adding Welireg to Keytruda + Lenvima did not demonstrate a statistically significant improvement in OS or PFS compared with the Control Arm (Keytruda + Lenvima).

My take is that this is no way a knock against Welireg, which remains a potent HIF-2α inhibitor. I expect Welireg could become a cornerstone of 2L treatment in combination with Lenvima for patients refractory to 1L dual IO combination therapy (typically Nivo+Ipi). While I'm certainly not an oncologist, I think the simplest rationale for the failure of LITESPARK-012 is that adding Welireg to a potent TKI in the 1L setting for patients who are still TKI-naïve and therefore still sensitive to TKI therapy may add toxicity without significant benefit. Remember, Welireg works upstream of TKI blockade, so it makes sense that if patients are already responsive to TKI inhibition, adding a HIF-2α inhibitor to the mix may not produce a significant bump in efficacy. In a TKI-refractory population, however, Welireg continues to demonstrate a marked benefit.

The question that comes to my mind, however, is how this may impact the potential for Darlifarnib, and more generally, Kura Oncology (KURA). As an introduction, it might be helpful to review my earlier article on Darlifarnib, available here.

With the failure of Welireg in the 1L setting, first-line therapy for advanced ccRCC would typically involve either dual-IO therapy (Nivo+Ipi) or IO + TKI (pembro + Lenvima), depending on the situation. If dual-IO is used in the 1L, this leaves the option of IO + TKI available in the second line for refractory patients. Either way, however, most patients still end up on Cabo once they are refractory to earlier lines, and once refractory to Cabo, that's where Darlifarnib, if future trials are successful, could become SoC for TKI resensitization.

However, I think the failure of LITESPARK-012 opens up some interesting possibilities for Darlifarnib and, perhaps, more broadly for KURA. As discussed in my earlier article, Darlifarnib, a next-generation FTI, overcomes many of the limitations of first-generation FTIs. Let's review some of the key advantages of Darlifarnib versus 1st-generation FTIs: