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Oncology drug developers have been able to leverage knowledge about a cause of proliferation— dysregulated activity of the cyclin-dependent kinases (CDKs)—to create a new class of therapy that has rapidly been integrated into the breast cancer treatment paradigm.
Charles J. Sherr, MD, PhD
Many therapies for patients with breast cancer focus on targeting cancer cell proliferation, with a goal of diverting cells to a more senescent phenotype. In recent years, oncology drug developers have been able to leverage knowledge about a cause of proliferation— dysregulated activity of the cyclin-dependent kinases (CDKs)—to create a new class of therapy that has rapidly been integrated into the breast cancer treatment paradigm.
CDKs are serine/threonine kinases that affect the G1-S phase transition of the cell cycle, which is mediated by action on the retinoblastoma (Rb) protein (FIGURE).1,2 Aberrant activity of the CDK—Rb axis contributes to unrestricted cell growth. In the past 2 years, the FDA has approved 3 agents that disrupt oncogenic activity in this axis by inhibiting CDK4/6: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).
Palbociclib, the first agent in this class to gain the FDA’s approval, is indicated for the treatment of women with hormone receptor (HR)— positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor (AI) as initial endocrine therapy in postmenopausal women as well as in combination with fulvestrant (Faslodex) following progression on endocrine therapy.
Ribociclib is approved for use in combination with an AI as initial endocrine-based therapy for postmenopausal women. Abemaciclib is indicated as monotherapy for patients who have previously received endocrine therapy and chemotherapy as well as in combination with fulvestrant in those with advanced disease following progression on endocrine therapy. Both agents also are designated for women with HR-positive, HER2-negative disease.
Although prospects for patients have improved with the use of these drugs, the effects of these inhibitors in many subsets of patients have not been investigated. The potential synergy of CDK4/6 inhibitors with other treatment strategies, including immunotherapeutic and targeted approaches, is currently being investigated in various clinical trials with the hope of identifying combinations of these agents that increase responses and improve duration of response.
Charles J. Sherr, MD, PhD, of St. Jude Children’s Research Hospital, Memphis, Tennessee, and colleagues noted in a review article published in Cancer Discovery, “In the next few years, we are likely to see combinations of targeted therapies—some obvious combinations being RAF/ MEK/ERK and PI3K inhibitors used in conjunction with those targeting CDK4/6—for which trials are now underway.”3Brain Metastasis
Brain metastases are a common incidence in patients with breast cancer, specifically those with HER2-positive disease. A phase II trial has been designed to evaluate potential antitumor activity of the CDK4/6 inhibitor palbociclib in patients with metastatic HER2- positive breast cancer with brain metastasis (NCT02774681). The primary endpoint is the radiographic response rate in the central nervous system (CNS) as measured by the modified Response Assessment in Neuro-Oncology Brain Metastasis criteria. Additional outcomes include the incidence of adverse events (AEs), overall survival (OS), progression-free survival (PFS), objective response rate (ORR), time to CNS progression, change in cognitive function, change in genomic landscape of CNS and non-CNS tumors, change in quality of life, and cyclin D1 aberrations. This study is currently recruiting, with an estimated enrollment of 33 patients and a primary completion date of November 2019.
Additionally, a phase II trial has been created to determine the safety and efficacy of abemaciclib in approximately 247 patients with HR-positive breast cancer, non—small cell lung cancer, or melanoma that has spread to the brain (NCT02308020). Investigators are focusing on the percentage of patients who achieve a complete or partial response as the primary endpoint. Moreover, secondary outcome measures will include best overall intracranial response, duration of intracranial response, intracranial disease control rate (DCR), intracranial clinical benefit rate (CBR), OS, ORR, overall DCR, PFS, and change from baseline in neurologic symptoms on the MD Anderson Symptom Inventory– Brain Tumor Scale. The ongoing trial is set to be completed in October 2018.
An ongoing phase I/II trial was designed to evaluate the combination of ribociclib and bicalutamide in advanced androgen receptor—positive triple-negative breast cancer (NCT03090165). Here, researchers will determine the maximum-tolerated dose (MTD) and the CBR of the combination. Additional outcome measures include duration of response (DOR), safety and tolerability, pharmacokinetics, PFS, OS, and ORR. Approximately 58 patients will be enrolled in the trial, which is estimated to be completed in September 2018.
Ongoing clinical trials are also investigating the efficacy of palbociclib in women of different ethnicities who have breast cancer. For example, the PALINA trial, a phase II openlabel study, is evaluating the hematological safety of palbociclib combined with letrozole and fulvestrant in African-American women with HR-positive, HER2-negative advanced breast cancer (NCT02692755). The primary outcome is the proportion of patients who complete therapy without developing a hematological event. Investigators will also be looking at the number of patients who require dose delays or reductions attributed to neutropenia, as well as the CBR. An estimated 35 patients will enroll in this study, which has an approximate primary completion date of December 2018.
Moreover, PALOMA-4 is a multicenter, double-blind, randomized phase III study that is evaluating the CBR and PFS following treatment with palbociclib and letrozole versus placebo and letrozole in approximately 330 Asian postmenopausal women with estrogen receptor (ER)—positive, HER2-negative advanced breast cancer who have not received prior systemic therapy (FIGURE 1; NCT02297438). Additional endpoints include OS, ORR, DOR, Euro Quality of Life Health State Profile Utility Score, change from baseline in Functional Assessment of Cancer Therapy–Breast, tumor tissue biomarkers, and probability of participant survival. The trial has an estimated primary completion date of March 29, 2019.
HR-Positive Breast Cancer: Combinations in Early Disease
To improve outcomes for patients with earlystage breast cancer, combinations with CDK4/6 inhibitors are being considered. The phase II neoMONARCH clinical trial is looking at a combination of neoadjuvant abemaciclib with anastrozole in patients with HR-positive, HER2-negative early-stage breast cancer (NCT02441946). Findings from the study were presented during the 2017 San Antonio Breast Cancer Symposium.4 The ORR at 16 weeks, by caliper measurement, was 53.6% overall (95% CI, 46.8%-60.2%), and 7.6% of patients experienced a complete response. The combination induced complete cell cycle arrest, as measured by Ki-67 level, for 67.8% of patients.
HR-Positive Breast Cancer: Combinations in Advanced or Metastatic Disease
Combination regimens with CDK4/6 inhibitors are also being explored in patients with advanced and metastatic disease, specifically those who express HR positivity. For example, the ongoing phase II nextMONARCH 1 study is evaluating the safety and efficacy of the combination of abemaciclib plus tamoxifen or abemaciclib alone in approximately 225 women with previously treated HR-positive, HER2-negative metastatic breast cancer (NCT02747004). Researchers are using PFS as a primary endpoint. Additional outcomes of the study, which is expected to be completed in February 2018, include ORR, DOR, OS, mean steady state exposure of abemaciclib and its metabolites, mean steady state exposure of tamoxifen and endoxifen, change from baseline in symptom burden, and change from baseline in pain and symptom burden assessment.
The phase I/II open-label TRINITI-1 trial is exploring the efficacy of a triplet regimen composed of ribociclib, everolimus (Afinitor), and exemestane as a potential treatment for patients with locally advanced or metastatic breast cancer following treatment with a CDK4/6 inhibitor (FIGURE 2; NCT02732119). Investigators will determine the MTD and/or the recommended phase II dose for the 3-drug combination as well as the CBR. Additional endpoints include PFS, OS, ORR, duration of overall response, and time to definitive deterioration of ECOG performance status in 1 category of the score. This study is currently recruiting, with an estimated enrollment of 51 patients and an estimated primary completion date of May 25, 2018.
The combination of palbociclib, fulvestrant, and erdafitinib, a fibroblast growth factor receptor inhibitor, is being investigated in an openlabel, multi-institution, phase Ib trial to evaluate the safety, tolerability, and preliminary antitumor activity in approximately 32 patients with ER-positive/HER2-negative/FGFR-amplified metastatic breast cancer (NCT03238196). The primary endpoint is the incidence of treatment-emergent AEs, but investigators are also determining PFS, ORR, and CBR, and assessing AEs, and pharmacokinetics. This trial has an estimated primary completion date of September 2020.
The combination of ribociclib plus letrozole and alpelisib, a PI3K inhibitor), is being explored in patients with ER-positive breast cancer (NCT01872260). Investigators are looking at primary endpoints of incidence of dose-limiting toxicities, safety, and pharmacokinetic profiles of ribociclib and letrozole. This study, estimated to enroll 253 patients, has an estimated primary completion date of April 30, 2019.
Moreover, the phase II LEADER trial is evaluating the combination of ribociclib with adjuvant endocrine therapy in patients with ER-positive breast cancer (NCT03285412). Researchers are using as a primary endpoint the number of patients who complete 12 months of treatment. Should more than 66% of participants complete 12 months of treatment with ribociclib—at least 75% of intended doses—the treatment will be considered safe and reasonably well tolerated.
Ribociclib is also being investigated in combination with standard endocrine therapy in the phase III MONALEESA-7 trial in patients with pre- and perimenopausal advanced HR-positive, HER2-negative breast cancer (NCT02278120). Findings from the ongoing study were presented at the 2017 San Antonio Breast Cancer Symposium, showing a median PFS of 23.8 months with the combination of ribociclib with tamoxifen or a non-steroidal aromatase inhibitor and goserelin, a luteinizing hormone-releasing hormone analog.5
The open-label, randomized phase II monarcHER study is investigating the efficacy of abemaciclib plus trastuzumab (Herceptin) with or without fulvestrant or chemotherapy in patients with HR-positive, HER2-positive locally advanced or metastatic breast cancer following prior treatment with at least 2 HER2-directed therapies (NCT02675231). The primary endpoint of the trial, with an estimated primary completion date of August 2018, is PFS with additional endpoints being OS, ORR, DOR, DCR, CBR, pharmacokinetics, and changes from baseline in pain and symptom burden assessment on the Modified Brief Pain Inventory—Short Form, in symptom burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–C30, and in health status on the EuroQol 5-Dimension, 5-Level Questionnaire. This study is enrolling approximately 225 patients.
HR-Positive Breast Cancer: Adjuvant Therapy Trials
CDK4/6 inhibitors are also being tested in the adjuvant space for patients with HR-positive breast cancer. For example, the randomized, open-label, phase III monarchE study is exploring the safety and efficacy of the most recently approved CDK4/6 inhibitor, abemaciclib, in patients with high-risk, node-positive, early-stage, HR-positive, HER2-negative breast cancer (FIGURE 3; NCT03155997). Investigators are evaluating invasive disease— free survival (iDFS) as the primary endpoint. Additional outcomes include iDFS in patients with Ki-67 index ≥20%, distant relapse-free survival, OS, pharmacokinetics, and changes from baseline on the Functional Assessment of Cancer Therapy–Breast, Functional Assessment of Cancer Therapy–Endocrine Symptoms, Functional Assessment of Chronic Illness Therapy– Fatigue, and the EuroQol 5-Dimension, 5-Level Questionnaire.
PALLAS, an ongoing international, multicenter, open-label, randomized phase III study, is testing whether adding palbociclib to adjuvant endocrine therapy will improve iDFS in patients with HR-positive, HER2-negative early breast cancer (NCT02513394). The secondary endpoint is safety at 2 years of palbociclib with adjuvant endocrine therapy versus adjuvant endocrine therapy alone. Expected to complete in September 2020, the trial is enrolling approximately 4600 patients.
Checkpoint inhibitors in combination with CDK4/6 inhibitors is a treatment strategy researchers have also been exploring to ramp up benefit for larger populations of patients with breast cancer.
For example, the ongoing phase Ib JPCE clinical trial is looking at the combination of abemaciclib with the PD-1 inhibitor pembrolizumab (Keytruda) (NCT02779751). Preliminary findings from the third cohort, which included 28 patients with HR-positive, HER2-negative metastatic breast cancer, were presented at the 2017 San Antonio Breast Cancer Symposium.6 The combination demonstrated a tolerable safety profile in this patient population with no grade 4/5 AEs observed. Serious AEs were reported in 21.4% of patients and AEs led to discontinuations in 14.3%. At 16 weeks, the combination demonstrated an ORR of 14.3%; 60.7% of patients demonstrated stable disease.
Additionally, a phase I, open-label study has been designed to evaluate the combination of ribociclib and PDR001, an anti—PD-1 monoclonal antibody, for the treatment of patients with metastatic HR-positive, HER2-negative breast cancer in combination with fulvestrant (NCT03294694). It is also being looked at for the treatment of patients with metastatic epithelial ovarian cancer. Investigators will determine the MTD and the recommended phase II dose of the combination of ribociclib plus PDR001 as well as the combination of ribociclib plus PDR001 with fulvestrant. Additional outcome measures are AEs and ORR. This study is currently recruiting, with an estimated enrollment of 60 patients and a primary completion date of June 1, 2018.
“It is obvious that this class of agents with their efficacy, low and easily manageable toxicity, and oral dosage is a very important treatment option for breast cancer,” noted Dorota Kwapisz, MD, MSc, of Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland, in a review article.7
In conclusion, Sherr and colleagues stated, “Despite the decades required for drug discovery and clinical applications, much remains to be learned. Future work will indicate whether the promise of CDK4/6 inhibitors, most advanced for breast cancer, can be validated and extended to other cancers.”1