This phase Ia dose-escalation study enrolled adult female patients with advanced/metastatic HR + HER2- breast cancer to evaluate safety and tolerability of FCN-437c, an oral CDK4/6 inhibitor. The preliminary safety data from these 17 patient have demonstrated acceptable safety profile. The majority AEs reported were myelosuppression, such as leukopenia, neutropenia and anemia, which were manageable and reversible with supportive care and were strongly correlated with dose level. Two patients in 450 mg dose group experienced DLTs in the third week after the initiation of the first cycle in the continuous dose treatment period, one G4 thrombocytopenia lasting for 11 days and one G4 leukopenia for 7 days. No DLT was reported in 300mg and lower dose level. Neutropenia and leukopenia were the most frequently reported Grade 3 and 4 AEs that occurred in patients in 200–450 mg dose groups, and were the main reason for dose reduction and dose interruption. In general, the hematological toxicity of FCN-437c is very similar to that established by palbociclib and ribociclib. The most common AEs induced by these two agents are also hematological toxicities and the primary Grade 3/4 AE is neutropenia, which is reported in 66.4% and 59.3% patients in registration trials when combined with AIs, respectively [10, 11].
Patients in different dose level groups also experienced mild to moderate non-hematological AEs, all of which were Grade 1 or 2. Prolonged electrocardiogram QT interval, hypoalbuminemia and rash were the most common observed non-hematological toxicities. It is nice to see that only G1 or G2 QTcF prolongation happening to 5 patients (29.4%) in this phase 1a study. Ribociclib has been reported with high prevalence of prolongation of QTc interval. Based on the results from MONALEESA-7, an increase of more than 60 ms from baseline in the QTcF interval occurred in 32 (10%) of 335 patients in the ribociclib group and led to dose interruptions or reductions in 13 (4%) of the patients .
By contrast, abemaciclib is reported with less frequent hematological toxicities such as Grade 3/4 neutropenia found only in 21.1% patients, but higher incidence of diarrhea, nausea, fatigue and creatinine increased [13, 14], which are not very common with FCN-437c treatment, only 3,2 and 4 patients reported diarrhea, nausea and fatigue respectively, all of which are G1 or G2, no creatinine increase was reported as study drug related in this study.
By using non-compartmental model, pharmacokinetics characteristics and parameters were analyzed based on FCN-437c plasma concentration. The exposure (Cmax and AUC0−∞) increased almost in proportion with dose following a single dose from 50 to 450 mg. The exposure (Cmax, AUC0−∞, AUC0 − 24, Cav-ss 24h) increased almost in proportion with dose following a multi-dose from 50 to 200mg. The concentration of FCN-437c reached steady state at Cycle 1 Day 15. As the dose increased, the average trough concentration increased in nearly equal proportion after multi-dose administration from 50 to 200mg. In multiple dose at 200–450 mg dose level, there appeared to be a trend of saturation. The elimination characteristics were similar between single dose and multiple dose in each cohort. After repeated administration, FCN-437c accumulated in the human body. Mean accumulation ratio for AUC0−∞ and Cmax ranged from 1.59 to 3.12 and 1.24 to 1.63, respectively. The variation between individuals is large based on the existing data, like the similar drug ribociclib. In addation, comparing the in vivo exposure levels at the same dose, FCN-437c is higher than ribociclib: Following a single dose, the Cmax (1477 ± 376ng/ml) of FCN-437c in the 200mg dose group has exceeded the average Cmax (933, 340–3200 ng∙h/ml) of ribociclib in the 600mg dose group; Following a multi-dose, the Cmax (1723 ± 983 ng/ml) and AUC0 − 24 (27253 ± 17592 ng∙h/ml) of FCN-437c in the 200mg dose group were also equivalent to the Cmax (1940, 859-5860ng/ml) and AUC0 − 24h (26600, 9960–89600 ng∙h/ml) of ribociclib in the 600 mg dose group.
MTD was established as 300 mg QD on the basis of safety profile. Considering that the occurrence of Grade 3/4 hematological AEs was much higher in 300mg dose group than that in 200 mg and resulted in more dose interruption and adjustment, there appears to be a trend of the exposure saturation from 200mg to 450mg, thus the recommended phase II dose was determined as 200 mg for further development.
As of the three marketed CDK4/6 inhibitors, combination therapies with endocrine agents (aromatase inhibitors or fulvestrant) significantly improved PFS and OS over the placebo plus endocrine agents in patients with HR + HER2- metastatic breast cancer in first- and second-line settings, regardless of endocrine therapy strategies, treatment lines, the number of metastatic sites or menopausal status [15, 16]. However, minor antitumor activities were demonstrated with palbociclib and ribociclib as single agent. Barely patients achieved partial response and approximately 30% of the patients had stable disease in phase I trials [17–19]. In phase II trial MONARCH-1, abemaciclib alone showed a confirmed objective response rate at 19.7% and clinical benefit rate at 42.4% among 132 heavily pre-treated patients, with a median PFS of 6.0 months and a median OS of 17.7 months . Therefore, abemaciclib has become the only CDK4/6 inhibitor approved as monotherapy for the treatment of patients with HR + HER2- advanced breast cancer with disease progression following prior endocrine therapy and chemotherapy.
Similar to palbociclib and ribociclib, FCN-437c as monotherapy showed modest tumor activity, however, there seems to be high potential anti-tumor capability of the combination with hormone therapy, given 60% of the patients exhibited stable disease with long disease control period by monotherapy, which is likely to be better than that from palbociclib and ribociclib phase 1 studies, warranting further exploration of the combination therapy in phase 2 study.
In conclusion, this study indicated a favorable safety profile of oral administration of single agent FCN-437c on a 3/1 schedule and the toxicities were generally tolerable and manageable. Major AEs were hematological toxicities and 200mg was determined to be recommended dose for further development based on the comprehensive assessment of safety and pharmacokinetics results. 60% of the patients exhibited stable disease with long disease control period by monotherapy warranted to explore the clinical antitumor activity of the combinations with other endocrine therapies. A phase II trial of FCN-437c is now ongoing in combination with letrozole or fulvestrant in female advanced/metastatic HR + HER2- breast cancer patients.