An experimental drug known as a CDK inhibitor yielded encouraging and durable results against several different types of cancers, including breast cancer, lung cancer, glioblastoma, and melanoma, according to a new report in Cancer Discovery.
The results of the trial supported the U.S. Food and Drug Administration (FDA) decision in October, 2015 to grant breakthrough therapy designation to abemaciclib (previously known as LY2835219) for patients with refractory hormone receptor–positive advanced or metastatic breast cancer.
CDK inhibitors target switch-like proteins that normally allow cells to divide only when appropriate. The CDK proteins in cancer cells are often overactive, leading to uncontrolled proliferation and growth. Abemaciclib blocks two switches, CDK4 and CDK6, and is known as a CDK4/6 inhibitor.
In February 2015, the FDA approved a different CDK4/6 inhibitor, palbociclib (Ibrance) for use in combination with the aromatase inhibitor letrozole for treating postmenopausal women with estrogen receptor–positive, HER2-negative advanced breast cancer.
“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,” said a senior author of the study, Geoffrey Shapiro, MD, PhD, Director of the Early Drug Development Center at Dana-Farber Cancer Institute in Boston.
“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,” Shapiro said.
The co-senior author was Amita Patnaik, MD, of South Texas Accelerated Research Therapeutics in San Antonio, Texas. Patnaik, Shapiro, and colleagues enrolled 225 patients with a variety of types of advanced cancer in the phase I clinical trial designed to evaluate the safety and preliminary efficacy of abemaciclib. In the dose escalation phase, the researchers determined that the maximum tolerated dose was 200 milligrams (mg) every 12 hours; the dose-limiting toxicity was fatigue.
In the expansion phase, single-agent abemaciclib was administered to 47 patients with breast cancer, 68 with NSCLC, 17 with glioblastoma, 26 with melanoma, and 15 with colorectal cancer. Among these patients, the most common treatment-related adverse events were fatigue, diarrhea, nausea, vomiting, anorexia, weight loss, kidney dysfunction, and decreased red and white blood cell counts. Overall, side effects were manageable and abemaciclib was well tolerated.
Imaging showed partial responses in patients with breast cancer, NSCLC, and melanoma. Among the 36 patients with hormone receptor–positive breast cancer, 11 had a partial response, with only four of the 11 responders having continued prior endocrine therapy. An additional 18 patients had stable disease. The median duration of response was 13.4 months and the median progression-free survival for this population was 8.8 months.
Among the 68 patients with NSCLC, 29 had tumor harboring KRAS mutation, a lung cancer subset not amenable to other targeted therapies. Among these 29 patients, 1 had partial response, while stable disease for 24 weeks or longer was achieved for 9 additional patients. Among the 26 patients with melanoma, one had a partial response and six had stable disease. Three of the 17 patients with glioblastoma had stable disease, with two of them continuing to receive treatment without disease progression for 19 and 23 cycles, respectively. The results among glioblastoma patients were consistent with the ability of abemaciclib to cross the blood brain barrier, demonstrated in preclinical models and by levels in cerebrospinal fluid of patients that approximated those in plasma.
“This 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 Shapiro.
Patnaik added, “Because this study included 225 patients with different types of cancer, confirmatory clinical trials in specific patient populations are necessary to precisely define the role of abemaciclib in cancer care. Multiple clinical trials have already been initiated to evaluate abemaciclib as a treatment for certain groups of patients with breast cancer and NSCLC, as well as children with primary brain tumors and adults with brain metastases.”
The study was funded by Eli Lilly and Company.