Assessment, Analysis, and Discussion
GnP, melanoma, PDAC, head and neck, and small-bowel cancer, gall bladder, NRAS
GLIOBLASTOMA MULTIFORME, MELANOMA, SOLID TUMORS, METASTATIC CANCER, MUTANT
Despite the high frequency of KRAS mutations in PDAC, and the well-validated role for KRAS in supporting PDAC growth, until recently, direct therapeutic targeting of KRAS has not been a clinical option. Given the ability of activated RAF to phenocopy mutant KRAS and drive full development of invasive and metastatic cancer,In a phase I study, ulixertinib monotherapy at 600 mg BID or above achieved a PR of 17% in patients with refractory NRAS or BRAF-mutant solid tumors including melanoma, gall bladder, glioblastoma multiforme, head and neck, and small-bowel cancer.Assessment of preliminary efficacy in our study was limited by overall poor treatment tolerance and high dropout rates before planned radiographic assessment. Despite this shortcoming, biochemical response (>50% decline) was observed in 44% of patients, which to some degree reflected the efficacy and strongly suggests the need to address the adaptive resistance mechanisms. For instance, ulixertinib treatment resulted in compensatory upregulation of protective autophagy and activation of the upstream HER family of receptor tyrosine kinases.In conclusion, ERK kinases remain as important therapeutic target in PDAC but our study showed that ulixertinib in combination with GnP did not improve measures of efficacy, largely due to poor tolerability of this triplet. Ulixertinib at 600 mg achieved intratumoral on-target effect by lowering KRAS signatures. Future success in targeting ERK will require rational therapeutic combinations with robust preclinical efficacy and manageable side effects.