DISCUSSION
nausea, fatigue, diarrhea, toxicity, toxicities, gastrointestinal AEs, PDAC, anemia
ADVERSE EVENTS, ADVANCED CANCER, CANCER PROGRESSION, ANEMIA

Following a safety lead‐in of abemaciclib plus galunisertib, testing of this combination was stopped by the sponsor for reasons unrelated to safety, and it did not advance to Stage 1. In Stage 1, no abemaciclib‐containing arms demonstrated DCRs superior to SOC chemotherapy in the ITT population (15.2% and 12.1% vs. 36.4%). Thus, no treatment arms advanced to Stage 2 and the study was closed early due to futility. Our primary endpoint was the DCR in the ITT population rather than the response‐evaluable population, due to our intent not to exclude patients who discontinued study treatment early due to clinical deterioration for either toxicities or cancer progression. In this study, 12 patients withdrew consent after starting treatment, some possibly due to clinical deterioration, 14 discontinued due to disease‐related adverse events or treatment‐related toxicities, and 7 patients died while on study treatment. This reflects an advanced cancer population with grim prognosis.Median PFS was inferior with abemaciclib monotherapy (1.7 months) and abemaciclib in combination with LY3023414 (1.8 months) compared to standard chemotherapy (3.3 months). Of note, SOC performed better than anticipated (assumed median PFS of 1.5 months). OS rates were similarly lower in the abemaciclib‐containing arms compared with chemotherapy (abemaciclib: 2.7 months; abemaciclib plus LY3023414: 3.3 months; SOC: not reached). These results are comparable with those observed in a phase 1 study (To date, CDK4/6 inhibitors have been consistently ineffective for metastatic PDAC, possibly due to resistance mechanisms such as compensatory activation of the PI3K/mTOR and RAF/MAPK pathways.Hematologic side effects were common, but no significant differences were observed compared to SOC. More patients withdrew from treatment in Arm B compared to Arms A or D, possibly due to toxicity with increased rates of gastrointestinal AEs. Most common treatment‐related AEs with abemaciclib were fatigue, diarrhea, and nausea, whereas fatigue, anemia, and nausea were most common with SOC.The PK profile of abemaciclib was consistent with previous evaluations in patients with advanced cancer,