Geoffrey I. Shapiro, MD, PhD
Phase I trial results demonstrate that abemaciclib, a CDK 4/6 inhibitor, had significant clinical activity and an overall response rate of 31% in patients with hormone receptor (HR)-positive breast cancer. Additionally, the agent showed promise in patients with non–small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer (CRC).
In the HR-positive breast cancer subset, 61% of patients achieved a response or stable disease (SD) lasting ≥6 months. Based on data from this trial, the FDA previously granted a breakthrough therapy designation to abemaciclib for the treatment of patients with refractory HR-positive advanced or metastatic breast cancer.
“These data show that abemaciclib is an oral drug that can be taken on a continuous schedule and achieve durable clinical activity against multiple tumors including breast and lung cancers,” said one of the senior authors of the study, Geoffrey I. Shapiro, MD, PhD, director of the Early Drug Development Center at the Dana-Farber Cancer Institute.
The multicenter phase I study included 225 patients. In the dose escalation phase, 33 patients were enrolled, 13 on a once-daily schedule with doses of 50 mg, 100 mg, 150 mg, or 225 mg. In the twice-daily schedule (n = 20), varying doses included 75 mg, 100 mg, 150 mg, 200 mg, and 275 mg. The maximum tolerated dose (MTD) was set at 200 mg for the twice-daily schedule as dose-limiting toxicities of grade 3 fatigue and more were experienced starting at 200 mg.
In the expansion phase, 173 patients were being treated with abemaciclib as a single agent, including 47 patients for breast cancer, 68 for NSCLC, 17 for glioblastoma, 26 for melanoma, and 15 for CRC.
Among 36 patients with HR-positive breast cancer, 11 (31%) achieved partial response (PR) and 18 had SD, 11 of whom had SD for at least 24 weeks. The clinical benefit rate (complete response + PR + SD for ≥24 weeks) was 61%.
The median duration of response for HR-positive breast cancer patients was 13.4 months (95% CI, 3.7-13.4) and the median progression free-survival (PFS) was 8.8 months (95% CI, 4.2-16.0). The study authors noted that nonresponding breast tumors were likely to have a TP53 mutation and that HR-positive clinical activity was observed regardless of PIK3CA mutations.
Of the 68 patients with NSCLC, 29 patients had tumors with KRAS mutations. SD was achieved by 31 patients (46%), including 15 patients (22%) with SD for at least 24 weeks. Partial response was observed for 1 patient with KRAS-mutant NSCLC and 1 patient with KRAS wild-type squamous NSCLC.
KRAS mutations were associated with decreases in tumor size after abemaciclib single-agent treatment, whereas increases in tumor size were more frequent for KRAS wild-type disease. Nine patients with KRAS-mutant disease had stable disease for at least 24 weeks, while 4 KRAS wild-type disease patients achieved stable disease for at least 24 weeks. The median PFS was 2.8 months (95% CI, 1.8-5.6) for the KRAS-mutant population and 1.9 months (95% CI, 1.4-3.7) for the KRAS wild-type population.
Patients in the trial with glioblastoma, CRC, or melanoma were all tested for relevant pathway alterations. Three patients with glioblastoma achieved SD, 2 of whom have continued to receive treatment without progression for 19 and 23 cycles, respectively. Among the patients with CRC, 2 had SD, 1 of whom had a tumor with both KRAS and TP53 mutations. In the melanoma cohort, 6 patients had SD and 1 patient, who had a tumor with an NRAS mutation and copy-number loss at the INK4 locus, had a PR.
Among the 173 patients in the expansion phase, dose reductions were required for 43% (40/92) of patients receiving 200 mg twice daily and 21% (17/81) of patients treated with 150 mg twice daily. The most common adverse events (AEs) related to treatment were diarrhea, nausea, fatigue, vomiting, leukopenia, thrombocytopenia, and neutropenia. Two patients had grade 4 neutropenia, but there were no treatment-related deaths.
Shapiro discussed the abemaciclib outcomes in the context of another CDK 4/6 inhibitor that has had success, palbociclib.
“Abemaciclib, an oral CDK4/6 inhibitor, is a very different molecule from palbociclib, with distinct attributes that contribute to its discrete therapeutic effects, in particular, its single-agent activity. For example, abemaciclib has greater selectivity for CDK4 compared with palbociclib, which may explain why it does not affect white blood cell counts as severely, allowing it to be taken on a continuous schedule without treatment holidays. Abemaciclib also penetrates the central nervous system, whereas palbociclib does not, raising the possibility that it could be used to treat primary or metastatic brain tumors.”
In a statement, the other senior author on the study, Amita Patnaik, MD, associate director of Clinical Research at South Texas Accelerated Research Therapeutics, commented on the next steps with abemaciclib.