The development of CDK4&6 inhibitors has provided promising data regarding this new therapeutic option for patients with cancer, particularly for patients with breast cancer. Currently, there are 3 FDA-approved CDK4&6 inhibitors for the treatment of patients with breast cancer.
1“This encouraging efficacy signal is combined with a lack of emerging worrying toxicities at this point in clinical development.”
Advanced Breast Cancer Setting
Palbociclib is a reversible, highly selective inhibitor of CDK4&6. In March 2017, palbociclib was approved by the FDA for the treatment of hormone receptor (HR)positive, human epidermal growth factor receptor 2 (HER2)–negative, advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women.2This approval was based on the PALOMA-2 trial that included 666 postmenopausal women who were randomized 2:1 to receive palbociclib plus letrozole or placebo plus letrozole until disease progression or unacceptable toxicity.3 Patients who received palbociclib plus letrozole had a significantly longer median progression-free survival (PFS; 24.8 months) compared with patients who received placebo plus letrozole (14.5 months; HR, 0.58; 95% CI, 0.46-0.72; P <.001). Evaluation of safety data in 444 patients receiving palbociclib plus letrozole revealed neutropenia in 80% of patients. Other commonly reported adverse events (AEs) occurring in ≥10% of patients include infections, leukopenia, fatigue, nausea, stomatitis, alopecia, diarrhea, rash, anemia, asthenia, thrombocytopenia, vomiting, decreased appetite, dry skin, dysgeusia, and pyrexia. Commonly reported grade ≥3 AEs include neutropenia, leukopenia, infections, and anemia.
Abemaciclib was approved by the FDA in September 2017 for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer that has progressed following endocrine therapy.4Abemaciclib is approved in combination with fulvestrant following progression on endocrine therapy or as monotherapy in patients previously treated with endocrine therapy and chemotherapy after metastasis. This approval was based on a trial of 669 patients with HR-positive, HER2-negative breast cancer, demonstrating an improved median PFS in patients receiving abemaciclib plus fulvestrant compared with patients receiving placebo plus fulvestrant (16.4 vs 9.3 months). A single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer was designed to evaluate abemaciclib as a monotherapy. Of the patients treated with abemaciclib alone, 19.7% experienced complete or partial tumor shrinkage for a median of 8.6 months.5Frequently reported AEs include diarrhea, nausea, abdominal pain, vomiting, headache, infections, fatigue, decreased appetite, neutropenia, leukopenia, and anemia. Serious AEs include diarrhea, neutropenia, elevated liver function tests, and deep venous thrombosis/pulmonary embolism.
In March 2017, ribociclib, a reversible, highly selective inhibitor of CDK4 and CDK6, was approved by the FDA in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.6This approval was based on results from the MONALEESA-2 trial that included 668 postmenopausal women who received no prior therapy for advanced disease. These women were randomized to receive ribociclib plus letrozole or placebo plus letrozole until disease progression or unacceptable toxicity. A pre-planned interim efficacy analysis revealed a significantly improved median PFS in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole (not reached vs 14.7 months). An improved objective response rate (ORR) was also reported in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole (52.7% vs 37.1%). Commonly reported AEs in ≥20% of patients receiving ribociclib include neutropenia, nausea, diarrhea, fatigue, leukopenia, vomiting, alopecia, headache, constipation, and back pain. Frequent grade 3/4 AEs include vomiting, lymphopenia, neutropenia, leukopenia, and abnormal liver function tests.
Preclinical and Clinical Advances
In the preclinical setting, estrogen receptor (ER)-positive and HER2-amplified breast cancer cell lines were reported to be the most sensitive to treatment with palbociclib, whereas ER-negative and HER2-negative cell lines were the most resistant to treatment with palbociclib. A synergistic inhibitory effect was also observed when tamoxifen was added to palbociclib.7
The PALOMA-1/TRIO-18 trial was designed to evaluate the safety and efficacy of the combination of palbociclib and letrozole as first-line treatment for patients with ER-positive, HER2-negative breast cancer.8The phase Ib study determined the recommended phase II dose of palbociclib of 125 mg once daily for 3 weeks followed by 1 week without treatment, combined with letrozole 2.5 mg once daily in a 28-day cycle. Patients were randomized to receive the combination or letrozole only. The median PFS was significantly longer in patients receiving the combination (20.2 vs 10.2 months). Both the ORR and clinical benefit rate (CBR; complete response, partial response [PR], and stable disease) were higher in the combination arm compared with the letrozole arm (43% vs 33% and 81% vs 58%, respectively). No difference in overall survival was reported.
In the double-blind PALOMA-3 trial, 521 pre- and post-menopausal women with HR-positive, HER2-negative breast cancer who relapsed or progressed during prior endocrine therapy were enrolled to assess the efficacy of palbociclib plus fulvestrant compared with placebo plus fulvestrant. The median PFS was significantly longer in patients receiving palbociclib plus fulvestrant compared with placebo plus fulvestrant (9.5 vs 4.6 months; hazard ratio, 0.46; 95% CI, 0.36-0.59;P<.0001).9
A dose-escalation study reported that a dosage break is not necessary with abemaciclib, which is administered at 200 mg every 12 hours.10 Results from a phase I trial that included 47 patients with advanced breast cancer with a median of 7 prior systemic therapies reported a 70% disease control rate for all patients with breast cancer, and 81% for the 36 patients with HR-positive breast cancer. The median PFS was 5.8 months and 8.8 months for all patients with breast cancer and for HR-positive patients, respectively.11This study was expanded to determine the efficacy of abemaciclib plus fulvestrant in patients with HR-positive metastatic breast cancer. A total of 13 patients with a median of 4 prior systemic therapies were enrolled, resulting in 62% confirmed PRs and 23% unconfirmed PRs. No patients discontinued treatment due to toxicity.10
The phase II MONARCH-1 trial included 132 patients with previously treated HR-positive, HER2-negative breast cancer, reporting an ORR of 19.7% and a CBR of 42.4% with a median PFS of 6 months from treatment with abemaciclib monotherapy. Due to toxicity, 7.6% of patients discontinued treatment (TABLE 1).12The phase II monarcHER trial (NCT02675231) was designed to evaluate the effectiveness of abemaciclib plus trastuzumab (Herceptin) with or without fulvestrant or chemotherapy. A total of 225 women with HR-positive, HER2-positive locally advanced or metastatic breast cancer who had received at least 2 HER2-directed therapies were enrolled to assess PFS, and the trial is still ongoing.
The phase III MONARCH-2 trial was designed to evaluate PFS in postmenopausal patients with HR-positive, HER2-negative breast cancer treated with abemaciclib plus fulvestrant or fulvestrant alone. The median PFS was significantly longer in patients receiving abemaciclib plus fulvestrant compared with fulvestrant alone (16.4 vs 9.3 months; hazard ratio, 0.553; 95% CI, 0.449-0.681; P <.001). The ORR was also higher in patients with measurable disease who received the combination compared with fulvestrant alone (48.1% vs 21.3%).13An interim analysis of the phase III MONARCH-3 trial, designed to evaluate the effectiveness of non-steroidal aromatase inhibitors (NSAIs) plus abemaciclib in 450 postmenopausal patients with HR-positive, HER2-negative advanced breast cancer patients without prior therapy, demonstrated significantly improved PFS in patients receiving abemaciclib plus anastrozole or letrozole compared with patients receiving placebo plus anastrozole or letrozole (not reached vs 14.7 months). The ORR was also significantly improved in patients receiving abemaciclib vs placebo (59% vs 44%;P= .004).14
The phase III MONARCH plus trial was designed to evaluate abemaciclib combined with NSAI or letrozole in 450 postmenopausal patients with HR-positive, HER2-negative locoregionally recurrent or advanced breast cancer who received no more than 1 line of endocrine therapy or any prior chemotherapy (NCT02763566).
In a dose-escalation study of 132 patients with retinoblastoma (Rb) proteinpositive solid tumors and 18 breast cancer patients, the maximum-tolerated dose (MTD) of ribociclib was reported to be 900 mg, with the recommended phase II dose of 600 mg/day.15The SIGNATURE trial was designed to evaluate the efficacy of ribociclib in patients with solid tumors with CDK4&6 pathway activation who have received at least 1 prior treatment and do not have any standard therapy options remaining (NCT02187783). An ongoing randomized double-blind trial includes 132 patients with HR-positive, HER2-negative breast cancer who progressed on an aromatase inhibitor and a CDK4&6 inhibitor. Primary results are expected in May 2018.
In the advanced setting, phase I/II studies are ongoing, exploring combinations with ribociclib. The TRINITI-1 trial was designed to determine the MTD and CBR of ribociclib with everolimus (Afinitor) and exemestane (NCT02732119). Another trial was designed to determine the MTD and CBR of ribociclib with trastuzumab or trastuzumab emtansine (T-DM1; NCT02657343). A trial was designed to compare dose-limiting toxicities and PFS of ribociclib plus fulvestrant, ribociclib plus BKM120 plus fulvestrant, and ribociclib plus BYL719 plus fulvestrant (NCT02088684).
In the MONALEESA-2 trial, 668 postmenopausal, treatment-naïve women with HR-positive, HER2-negative breast cancer were enrolled and randomized to receive ribociclib plus letrozole or placebo plus letrozole. An interim analysis demonstrated a 44% improvement in PFS in patients receiving the combination compared with placebo plus letrozole.16 The CBR and ORR were also significantly improved in patients receiving the combination compared with placebo plus letrozole (53% vs 37% and 80% vs 72%, respectively). The PFS rate at 18 months was 63% with the combination versus 42% with letrozole and placebo.
The MONALEESA-3 trial was designed to evaluate the PFS of ribociclib combined with fulvestrant in 725 men and postmenopausal women with HR-positive, HER2-negative breast cancer who received 1 or no previous lines of endocrine treatment (NCT02422615). COMPLEEMENT-1 was designed to collect additional safety and efficacy data for the combination of ribociclib plus letrozole (NCT02941926). A total of 3000 men and pre-/postmenopausal women with HR-positive, HER2-negative advanced breast cancer without prior hormonal therapy will be enrolled to assess the number of grade 3/4 AEs to determine safety and tolerability.
Mechanism of Action Differences
Palbociclib induces a G1-S cell cycle block by blocking Rb and related protein phosphorylation, followed by the downregulation of S-phase cyclins and mitotic regulatory genes and the suppression of DNA replication and nucleotide biosynthesis.17,18The inhibition of the phosphorylation of Rb protein and subsequent downregulation of E2F-targeted genes account for cell cycle arrest.19,20The antitumor effects of palbociclib are limited based on the dependence on active Rb protein presence.21,22Palbociclib has also been implicated to have a role in the inactivation of FOXM1, a transcription factor, and its transcription targets that induce cellular proliferation.20,23-25Palbociclib has also demonstrated sensitization effects on cancer cells to other treatments used in combination, including ionizing radiation and chemotherapy.7,26Abemaciclib, conversely, has been reported to have increased selectivity for CDK4 versus CDK6.27
Other Differences Among Approved Agents
The most frequently reported toxicity associated with palbociclib is neutropenia, with other reported AEs including leukopenia, anemia, fatigue, back pain, diarrhea, and pulmonary embolism.8,28-32Neutropenia has been shown to be the only dose-limiting effect, with common non-hematological AEs including nausea, diarrhea, and fatigue.30
The AE profile of ribocicilb is similar to that of palbociclib.33Of patients treated with ribociclib, 10% exhibited asymptomatic QTcF prolongation (>450 ms) at 600 mg/day and 27% exhibited this AE at doses >600 mg/day.
The observed AEs with abemaciclib treatment are different from those reported with palbociclib and ribociclib, which may potentially be a result of a greater selectivity of abemaciclib for CDK4 compared with CDK6.34The dose-limiting toxicity related to abemaciclib is fatigue, with less neutropenia reported compared with palbociclib and ribociclib.27,35The most commonly reported AEs include fatigue, diarrhea, nausea, vomiting, leukopenia, thrombocytopenia, neutropenia, anorexia, increased creatinine, anemia, and weight loss (TABLE 2).11 Abemaciclib monotherapy treatment has resulted in increased ORRs compared with palbociclib and ribociclib.12,31,36
Patients receiving palbociclib should avoid simultaneous use of strong CYP3A inhibitors such as ketoconazole, ritonavir (Norvir), clarithromycin, and grapefruit juice. A dose reduction of palbociclib is required if a strong CYP3A inhibitor must be used. Palbociclib use combined with a sensitive CYP3A substrate with a narrow therapeutic index, including fentanyl, everolimus, and midazolam, may require a dose reduction of the CYP3A substrate.37
Similar recommendations exist for patients receiving ribociclib. Agents known to prolong the QT interval, including amiodarone, sotalol, and haloperidol (Haldol Decanoate), should be avoided in patients receiving ribociclib.38 Patients receiving abemaciclib should also avoid simultaneous use of strong CYP3A inducers and inhibitors, or a dose reduction of abemaciclib may be warranted.39,40
Following oral administration, palbociclib is slowly absorbed and eliminated in patients.28-30The median time from dosing to maximum plasma concentration was 4.2 to 5.5 hours. Its half-life was reported to be 23 to 26 hours, with no drug-drug interactions with letrozole.29The MTD recommended for monotherapy and combination strategies was reported as 125 mg once daily over 3 weeks on followed by 1 week off schedule. In a subset of patients, low absorption and drug exposure were observed in the fasted state, which was increased when palbociclib was administered with food. Reduced drug levels and effectiveness may be experienced if palbociclib is taken on an empty stomach.16
Following oral administration, ribociclib was absorbed with a median time from dosing to maximum plasma concentration of 1 to 5 hours.36The MTD of ribociclib was reported as 900 mg daily of 3 weeks on and 1 week off over a 28-day schedule.36The median time from dosing to maximum plasma concentration was 1 to 5 hours and the average half-life was found to be approximately 36 hours. The recommended initial dose of ribociclib is 600 mg taken once daily, preferably in the morning, orally.16The absorption of ribociclib is not affected by food.
Abemaciclib has also been shown to be slowly absorbed, with a median time from dosing to maximum plasma concentration of 4 to 6 hours.11Abemaciclib is widely eliminated and distributed, with the average half-life ranging from 17.4 to 38.1 hours. The MTD was reported to be 200 mg every 12 hours, given continuously throughout the cycle.11Abemaciclib has been shown to cross the blood-brain barrier, which led to the design of a clinical trial evaluating the effects of abemaciclib in patients with brain metastases (NCT02308020).41
Palbociclib, ribociclib, and abemaciclib have been approved by the FDA for the treatment of patients with breast cancer based on promising clinical trial results. These therapies are similar but have differences related to drug interactions and AEs that should be considered when optimizing individual patient treatment decisions. These trial results have led to the initiation of further studies investigating CDK4&6 combination therapies in an effort to further improve patient outcomes in breast cancer.
Conleth G. Murphy, MD, of Bon Secours Hospital, Cork, Ireland, and Maura N. Dickler, MD, of Memorial Sloan Kettering Cancer Center, New York, New York, commented in The Oncologist, “The results of clinical trials with oral CDK4&6 inhibitors to date have offered promising glimpses of significant activity in hormone-sensitive breast cancer. This activity, combined with a favorable toxicity profile, makes this family of novel therapies very exciting. It is to be hoped that the currently accruing phase III studies will build on this promise and confirm the place of these therapies in the breast cancer armamentarium.”42