The majority of metastatic breast cancer patients (more than 70%) have hormone receptor-positive (HR+) disease and are thus readily treated with endocrine therapy (ET). However, many of these patients undergo progression while on ET, and for them, the mechanisms underlying their resistance must be overcome for successful treatment.
Preclinical studies have shown that the cyclin D overexpression, which is present in more than 50 percent of breast cancer patients, is required for estrogen receptor-positive proliferation. Cyclin D1 both forms a complex with and functions as a regulator of cyclin-dependent kinases 4 and 6 (CDK4/6). Inhibition of CDK4 and CDK6 has been shown to inhibit cell growth for breast cancer. However, this inhibition is short-term, as temporary G1 arrest is halted upon dosing cessation. Thus, continuous CDK4/6 inhibition has been shown to be necessary for sustained growth arrest and apoptosis.
To evaluate the efficacy of CDK4/6 inhibition in a HR+ and HER2- advanced breast cancer patient population, the phase III MONARCH 2 trial, headed by George W. Sledge, Jr., MD, Professor of Medicine and Chief, Division of Oncology, Stanford University, evaluated combination abemaciclib plus fulvestrant (a selective estrogen receptor degrader) therapy against fulvestrant monotherapy (NCT02107703) (Abstract 1000).
Abemaciclib is an orally-bioavailable, potent, selective, small molecule inhibitor of CDK4 and CDK6. In enzymatic assays, it was shown to disrupt cyclin D1/CDK4 and cyclin D6/CDK3 in an efficient manner. Mechanistically, abemaciclib prevents the CDK4- and CDK6-mediated phosphorylation of retinoblastoma tumor suppressor protein, thus inducing G1 arrest and thereby halting cell growth. In a different preclinical investigation, abemaciclib showed good antitumor activity in a HR+, HER2- mouse xenograft model.
In October 2015, the FDA granted breakthrough therapeutic designation to abemaciclib for the treatment of advanced or metastatic breast cancer patients with refractory HR+ disease largely on the basis of results obtained in the phase I JPBA trial (NCT01394016). In addition to this trial (MONARCH 2), abemaciclib is also undergoing evaluation in other clinical trials, e.g. JUNIPER and MONARCH 3.
In the phase III JUNIPER trial (NCT02152631), abemaciclib plus best supportive care is being compared against erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), plus best supportive care for the treatment of KRAS-mutant non-small cell lung cancer patients who have had disease progression while on platinum-based chemotherapy. MONARCH 3 (NCT02246621) is an ongoing phase III study comparing the combination of abemaciclib plus a non-steroidal aromatase inhibitor (e.g., letrozole or anastrozole) versus placebo for the treatment of post-menopausal HR+, HER2- metastatic or locoregionally recurring breast cancer patients with no prior systemic therapy.
The phase III MONARCH 2 study was a placebo-controlled, randomized, and double blind study that compared the use of fulvestrant with or without abemaciclib in HR+, HER2- advanced breast cancer patients who had undergone disease progression while on prior ET. The trial was limited to females 18 years or older, Eastern Cooperative Oncology Group (ECOG) status of 0 or 1, measurable tumors using RECIST v. 1.1, or nonmeasurable tumors from bone-only disease (i.e., lytic, blastic, or mixed).
Additionally, patients were required to have disease progression in one of the following scenarios: while receiving adjuvant or neoadjuvant ET; 12 months or less after adjuvant ET; or while receiving ET for advanced breast cancer. While there was no exclusion with regards to menopausal status, those women who were pre- or perimenopausal received a gonadotropin-releasing hormone agonist.
Key exclusion criteria included the receipt of more than one ET or prior chemotherapy for advanced breast cancer; prior therapy with fulvestrant, CDK4/6 inhibitors, or everolimus; the presence of visceral crises; and either the presence or a history of CNS metastasis. When asked why HER2+ patients were not included in these studies, Sledge replied, “Patients with that disease status are candidates for therapy with trastuzumab, a monoclonal antibody that targets the HER2 receptor.”
In this study, 855 patients were assessed for inclusion at 142 centers in 19 countries, and of these, 669 were randomized in a 2:1 ratio to either abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223).
Patients received 500 mg fulvestrant intramuscularly on days 1 & 15 of the first cycle and day 1 of each subsequent 28-day cycle. Patients were given abemaciclib or placebo twice daily. Initially, patients in the abemaciclib arm were dosed at 200 mg, twice daily; however, after initial safety and dose-reduction data were obtained, the protocol was amended to use 150 mg abemaciclib b.i.d. dosing. “This dose lowering was largely a result of the grade 3 diarrhea that we were observing in these patients. This condition was more manageable with the lowered dosage level,” Sledge explained.
The primary endpoint of this study was investigator-assessed progression-free survival (PFS), measured from randomization assignment until objective progressive disease (PD) or death for any reason. Secondary endpoints included the objective response rate (ORR), defined as the number of patients showing complete or partial response (CR or PR); the clinical benefit rate (CBR), defined as the numbers for those showing CR plus PR plus stable disease (SD) for 6 or more months; duration of response (DOR), defined as time from CR or PR until PD or death; and safety and tolerability.
The median age in the abemaciclib arm was 59 years (range: 32 to 91), while in the placebo arm, the median age was 62 (range: 32 to 87). In the abemaciclib arm, 111 patients displayed primary ET resistance while 326 showed secondary ET resistance; in the placebo arm, 58 showed primary and 163 showed secondary ET resistance. For the abemaciclib arm, 72 were pre- or perimenopausal and 371 were postmenopausal. For the placebo arm, the menopausal statuses were as follows: pre- or perimenopausal–42; postmenopausal–180. The majority of the participants in this study were Caucasian (abemaciclib–237; placebo–136) or Asian (abemaciclib–149; placebo–65).
Between August 2014 and December 2015, 669 patients were randomized to either the abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223) arms. For this report, the data cutoff was Feb. 14, 2017. As of that date, 170 in the abemaciclib arm and 45 in the placebo arm were still receiving the investigational drug. Patients in the abemaciclib arm received a median 15 cycles of treatment, while those in the placebo arm had a median 9 cycles. Those patients receiving 200 mg abemaciclib prior to the mandatory dose-reduction amendment to the protocol (n = 121) received the compound for a median 34 days prior to dose reduction or discontinuation.
In the intent-to-treat (ITT) population, the abemaciclib arm attained a median PFS of 16.4 months, as compared to 9.3 months for the placebo arm (hazard ratio (HR) 0.553; 95% CI 0.449 – 0.681; P = 0.001). The ORR (CR + PR) for the ITT population was 35.2 percent (95% CI 30.8 - 39.6%) in the abemaciclib patients and 16.1 percent (95% CI 11.3 – 21.0%) in the placebo arm. Additionally, the CBR (CR + PR + SD ≥ 6 months) was 72.2 percent (95% CI 68.0 – 76.4%) for the abemaciclib arm and 56.1 percent (95% CI 49.5 – 62.6% for the placebo group. “Responses to therapy tended to be durable, with 67.8 percent of the abemaciclib patients achieving a 12-month DOR,” Sledge noted. The median duration of response had not been reached for the abemaciclib patient group. Interestingly, after a year in the study (i.e., 12 treatment cycles), the mean tumor size change was -62.5 percent in the abemaciclib arm and -32.85 percent for the placebo arm. As of the cutoff date, the overall survival data were not mature.
The most serious adverse events noted in the abemaciclib arm were grade 3 or 4 diarrhea. “This was the reason that the protocol for the study was amended from 200 mg to 150 mg b.i.d. dosing for abemaciclib; typically, this condition was managed via dose delays or reductions,” Sledge said. “There was slightly less drug-associated neutropenia for abemaciclib relative to other CDK4/6 inhibitors.”
Commenting on these results, Sledge stated, “The PFS data for the abemaciclib arm is significantly longer than in previous studies; this is especially encouraging when one considers these data in light of the ET resistance of these patients. Additionally, the response rates are the highest to date for this patient population, however, the survival data are not yet mature.”
When asked if this therapy might be beneficial for triple negative breast cancer patients, Sledge answered, “This drug may not be relevant for those patients, as there is some evidence that the pathway inhibited may be circumvented in that disease setting. Preclinical work suggests that continuous inhibition of the pathway is optimal to prevent re-growth of the breast cancer.”
With regard to the future directions for this promising therapy, “Given the extremely positive results observed in this and in other studies, the use of abemaciclib may be warranted in the adjuvant setting,” Sledge concluded.
Richard Simoneaux is a contributing writer.