One of the biggest challenges in any cancer combination trial is optimising the therapeutic window.  This is especially the case when there are known overlapping toxicities.  We’ve seen this happen many times in the past with targeted therapies where promising approaches from preclinical studies are subsequently abandoned in phase 1 trials because the toxicities can limit the dose that can be achieved, thereby impacting the response rates or outcomes in a negative fashion.

Immunotherapy trials also present additional challenges to be addressed in the form of immune-related adverse events, which might be potentiated or reactivated by subsequent targeted therapies, not all of which can be predicted from preclinical experiments.

Several KRAS inhibitors have already been abandoned in phase 1 development due to unexpected systemic events surfacing, as have various IO-IO or IO-targeted therapy combinations.

What happens when the KRAS and IO worlds collide?  Are there toxicities which might scupper future promising combinations and send us all back to the drawing board again?  Does the lion roar or whimper?

In our latest post, we explore the ins and outs of one such emerging controversy, including some thought leader persectives…

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