The investigational cyclin D–dependent kinase (CDK) 4/6 inhibitor abemaciclib was recently evaluated in several solid tumor types in a phase I multicenter trial.1 Given primarily as a single agent and with continuous dosing, abemaciclib showed encouraging early signals of clinical activity not only in advanced breast cancer, but in other malignancies, including non–small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. The findings support the concept that CDK4/6 inhibitors have a potential role in cancer therapeutics beyond hormone receptor–positive advanced or metastatic breast cancer, where they are currently indicated in combination with endocrine therapy.
Conducted in 225 patients, the study by Patnaik et al comprised a two-stage phase I trial design with dose escalation (n = 33) and expansion (n = 192) cohorts conducted in multiple a priori–determined tumor-specific groups.1 Most patients had at least two metastatic sites and had received multiple prior systemic therapies for advanced disease.
The investigators asked a number of important hypothesis-testing questions involving drug pharmacology, antitumor activity, and putative predictive biomarkers of response and resistance. They attempted to identify the tumor and molecular subtypes most likely to benefit from abemaciclib.
Response in Breast Cancer and NSCLC
The researchers established the recommended phase II dose of abemaciclib at 200 mg twice daily, the dose at which antitumor activity was observed in multiple solid tumor types.
In patients with heavily pretreated, advanced breast cancer (n = 47), benefit from the single agent varied according to hormone receptor and HER2 status. Median progression-free survival for the entire group was 5.8 months.
In a cohort of heavily pretreated, advanced hormone receptor–positive breast cancer (n = 36), abemaciclib was given in combination with fulvestrant. Responses were seen in 31%, and stable disease was noted in 50% (31% for ≥ 24 weeks); median progression-free survival was 8.8 months.
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In NSCLC (n = 68), the disease control rate was 49%, with 22% of patients achieving stable disease lasting for ≥ 24 weeks. At 6 months, 26% of patients were progression-free. Benefit was greater, however, in the KRAS-mutant subset (n = 29), consistent with preclinical findings. In a genetically engineered mouse model of KRAS-mutant disease, genetic ablation of CDK4 induce senescence and prevents tumor progression, the authors pointed out.
The disease control rate for the KRAS-mutant population was 55%, compared with 39% for the KRAS wild-type subset. Stable disease lasting for ≥ 24 weeks was achieved in 31%, vs 12%, respectively. Decrease in tumor size was more common in KRAS-mutant tumors, whereas KRAS wild-type tumors more frequently increased. Three of the four patients who exhibited no radiographic disease progression for ≥ 12 months harbored KRAS mutations. Interestingly, tumor size decreased in all four patients with KRAS mutations and concomitant STK11/LKB1 alterations, an aggressive phenotype.
Response in Other Tumor Types
The study also investigated the activity of abemaciclib in other tumors with relevant pathway alterations. In the glioblastoma cohort (n = 17), 3 patients achieved stable disease, 2 of whom were continuing on treatment without disease progression for 19 and 23 cycles. In the colorectal cancer cohort (n = 15), 2 patients achieved stable disease. In the melanoma cohort (n = 26), 1 patient had a partial response and 6 achieved stable disease, for a disease control rate of 27%. Of interest, the patient with metastatic melanoma who had a partial response exhibited a tumor with molecular alterations that induced aberrant kinase activity of CDK4 and CDK6.
Safety and Toxicity
In the single-agent tumor-specific cohorts (n = 173), the most common treatment-emergent adverse events (all grades) involved gastrointestinal tract disorders (63%, including diarrhea, nausea, vomiting, anorexia, weight loss), fatigue (41%), hematopoietic abnormalities (20%–25%, including leukopenia, neutropenia, thrombocytopenia, and anemia), and increased creatinine levels (11%).
Adverse events occurred within 2 weeks of treatment and were reversible. In the tumor-specific cohorts, grade 3 adverse events involving the gastrointestinal and hematopoietic systems were seen in ≤ 5% and ≤ 10%, respectively. Overall, neutropenia was rare (23%, all grades; 10%, grade 3/4), and febrile neutropenia occurred in only 1 of the 225 patients treated in the study. Grade 3/4 renal events were not observed.
The low risk for neutropenia with abemaciclib is a characteristic that enables this drug to be dosed continuously, in contrast to the intermittent dosing regimen required for both palbociclib and ribociclib, the authors noted. Prophylaxis (loperamide) for diarrhea, a side effect seen more often in this study than has been reported for the other selective CDK4/6 inhibitors, may reduce the risk for diarrhea, and this strategy is being investigated in ongoing studies. The study investigators noted that “diarrhea was manageable with antidiarrheal agents or dose reduction and did not result in patient [treatment] discontinuation.”
Absorption in Central Nervous System
The study also examined drug concentrations of abemaciclib in the cerebrospinal fluid, revealing levels that approached those of unbound plasma concentrations in selected study subjects where both plasma and cerebrospinal fluid samples were collected. According to the investigators, this suggests there is absorption across the blood–brain barrier that could allow for improved penetration into the central nervous system. In treated patients with glioblastoma multiforme, three patients achieved durable disease stabilization.
According to the investigators, the study establishes that “abemaciclib can be dosed safely on a continuous schedule.” They continued: “Sparing of the hematopoietic system” obviates the need for intermittent dosing (as required for palbociclib and ribociclib) and “provides important opportunities for combining abemaciclib with a broad range of targeted or cytotoxic agents.” ■
1. Patnaik A, Rosen LS, Tolaney SM, et al: Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 6:740-753, 2016.