Selected Articles from This Issue

Abstract

Abemaciclib is an oral, potent and selective CDK4 & 6 inhibitor, dosed on a continuous schedule and approved as monotherapy and in combination with either fulvestrant or an aromatase inhibitor for HR+, HER2− advanced breast cancer (ABC). ESR1 mutation and PI3K pathway dysregulation are associated with resistance to endocrine therapy, and treatment with CDK4 & 6 inhibitors has been hypothesized as a therapeutic strategy to overcome endocrine resistance. In this exploratory analysis, Tolaney and colleagues show in HR+, HER2− ABC, abemaciclib plus fulvestrant improved both PFS and OS, regardless of PIK3CA or ESR1 mutation status. Additionally, abemaciclib plus fulvestrant improved other endpoints, including TTC, CFS and PFS2, regardless of PIK3CA or ESR1 mutation status. These findings support further evaluation in suitably powered trials.Combined targeting of the lineage-specific master transcription factor, ETV1, and signaling factor, KIT, by the combination of KIT and MEK inhibitors, is synergistic in preclinical GIST models. Chi and colleagues report the results of a phase Ib clinical trial designed to both evaluate the safety of the combination of imatinib and binimetinib and to determine the recommended phase II dose (RP2D) and early efficacy signal of this drug combination in patients with refractory advanced KIT/PDGFRA-mutant and KIT/PDGFRA wild-type GIST including SDH-deficient GIST. The study demonstrated that the combination of imatinib/binimetinib was safe with manageable side effects and determined the RP2D. They observed durable pathological responses in a small cohort of SDH-deficient GIST patients in the phase Ib expansion at RP2D. The promising clinical activity of the combination treatment in SDH-deficient GIST observed is worthy of further clinical investigation.Cyclin-dependent kinase 4/6 inhibition may have synergistic anticancer activity when combined with taxane chemotherapy. To explore this combination in metastatic castration-resistant prostate cancer (mCRPC), de Kouchkovsky and colleagues conducted a phase Ib/IIa study of ribociclib plus docetaxel in mCRPC patients who had progressed on an androgen receptor signaling inhibitor (ARSI). With intermittent ribociclib dosing and prophylactic growth factor, the combination demonstrated an acceptable safety profile, achieved a 6-month radiographic progression-free survival (rPFS) rate of 65.8%, and a median rPFS of 8.1 months. These results compare favorably to outcomes seen with docetaxel monotherapy after ARSI therapy. Further prospective study is warranted.KRAS is the most commonly mutated driver oncogene in solid tumors, including non-small cell lung cancer (NSCLC), with mutations spanning codons 12, 13 and 61. To explore the role of different mutant KRAS isoforms in pre-clinical models and samples from patients, Ricciuti and colleagues developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability across the 6 most common KRAS mutant variants. In addition, by surveying a large institutional dataset totaling >3000 NSCLC they identified clinicopathologic and genomic characteristics which correlated with unique KRAS mutant isoforms. Together, these findings revealed that KRAS mutations are highly heterogenous in terms of biological outcome and genomic profiling, and that this heterogeneity can be exploited to unveil novel potentially actionable vulnerabilities for KRAS mutant NSCLC.