Differences Between CDK4&6 Inhibitors Predict Future Approaches

To date, palbociclib is the only CDK4&6 inhibitor that has been approved for treatment of breast cancer. Since abemaciclib and ribociclib have demonstrated encouraging results in clinical trials, their eventual approval is also expected. Understanding the evidence behind each agent and the implications of the differences between them will be critical for guiding clinical decision making and determining potential future applications.

Current Data for Palbociclib

Palbociclib is the first orally, bioavailable, CDK4&6-selective inhibitor developed as a treatment for cancer. In preclinical studies, palbociclib induced G1 phase arrest in solid tumor cell lines with cyclin D1:CDK4 dysregulation and leukemia cell lines driven by D2/D3:CDK6. Trials in xenograft models showed that palbociclib achieved tumor stasis and regression, and that the presence of functional retinoblastoma product (pRb) was critical for treatment efficacy. These preclinical results confirmed that upregulation of the cyclin D:CDK4 and CDK6 axis is an important underlying mechanism for pathogenesis in many types of cancer.¹

Preclinical trial success led to phase I studies in advanced cancers— solid tumors and lymphoma—that were pRb-positive. Doseranging trials found that the maximum tolerated dose (MTD) and dosing schedule was 200 mg daily for 2 weeks, followed by an off-period of 1 week. Myelosuppression, particularly neutropenia, was the primary dose-limiting toxicity (DLT). Another phase I study established that the ideal dosing regimen was 125 mg daily for 3 weeks, followed by off-treatment for 1 week. Investigators found that while the 75-mg dose induced neutropenia in some patients, the neutropenia remained uncomplicated and tolerable even up to the 125-mg dose. The myelosuppressive effects of palbociclib were reversible and resolved after treatment was withdrawn. Other common toxicities tended to be low grade and included nausea, fatigue, and diarrhea.²

In phase II studies, palbociclib did not produce encouraging results as a single-agent therapy. Of 28 patients with pRb-positive advanced breast cancer, 6% had partial response (PR) and 14% had stable disease (SD) for more than 6 months. No response occurred in any patients with estrogen receptor (ER)‒negative status. In addition, 1 patient who had undergone multiple prior cycles of chemotherapy experienced febrile neutropenia.³

Fortunately, palbociclib fared better as a combination therapy with other anticancer agents. PALOMA-1, a phase I/II study, evaluated palbociclib plus letrozole, a nonsteroidal aromatase inhibitor (AI), versus letrozole alone as a first-line therapy in postmenopausal women with ER-positive, human epidermal growth factor receptor 2 (HER2)‒negative advanced breast cancer. The phase II segment explored the utility of CCND1 and p16 as potential biomarkers, but found that they did not predict treatment response any better than ER status alone.²In the second interim analysis of PALOMA-1, progressionfree survival (PFS) in the palbociclib-plus-letrozole group was more than triple that in the letrozole-only group (26.1 vs 7.5 months; HR, 0.37;P<.001).²The clinical benefit in the palbociclib arm was sustained in the final analysis: Median PFS was 20.2 months with palbociclib versus 10.2 months with letrozole alone (HR, 0.488;P<.001).⁴

Although neutropenia and myelosuppression were the most common adverse events (AEs), no instances of febrile neutropenia were noted. However, grade 3/4 toxicities, such as pulmonary embolism and infection, were more frequent in the palbociclib arm than in the control arm (5% vs 0%, respectively). Nevertheless, combination therapy with palbociclib and letrozole was considered to be well tolerated, with similar AE rates in both treatment groups.²

The success of PALOMA-1 led the US Food and Drug Administration (FDA) to grant breakthrough therapy designation to palbociclib.²In addition, the marked efficacy of palbociclib in ER-positive breast cancer confirmed the utility of using ER status to determine which patients are most likely to respond to CDK4&6 inhibition.⁴

PALOMA-2 is a phase III trial that was designed to verify the results of PALOMA-1 by assessing the safety and efficacy of palbociclib plus letrozole as a first-line therapy in advanced ER-positive, HER2-negative breast cancer. In April 2016, Pfizer announced that the study met its primary endpoint, with the palbociclib group having a longer PFS than the letrozole-only group. Detailed results will be presented at the American Society of Clinical Oncology 2016 Annual Meeting.⁵

Another phase III trial, PALOMA-3, addressed the treatment of women with advanced ER-positive, HER2-negative breast cancer who had relapsed or progressed on prior endocrine therapy. PALOMA-3 examined the efficacy of palbociclib in combination with fulvestrant, an ER antagonist, in this population. Median PFS was longer in the palbociclib group than in the fulvestrantonly group (9.5 vs 4.6 months; HR, 0.46;P<.0001). Follow-up for overall survival (OS) is ongoing.⁶The rates of neutropenia and leukopenia in the palbociclib arm (62% and 25%, respectively) were similar to those in the PALOMA-1 trial.^6,7The significant findings from PALOMA-3 led the FDA to approve palbociclib for treatment of advanced HR-positive, HER2-negative breast cancer after progression on endocrine therapy.

&ldquo;Patients in [the PALOMA-3] population are generally thought to be endocrine-refractory, and are traditionally given singledrug cytotoxic chemotherapy&hellip;, which is often of limited benefit, rarely produces meaningful objective responses, and frequently resulted in increased toxicity and reduced quality of life,&rdquo; the PALOMA-3 authors concluded. &ldquo;Our findings confirm the important observation that endocrine monotherapy has limited efficacy in patients with disease progression after previous exposure to endocrine therapy, irrespective of clinical or molecularly defined endocrine sensitivity, suggesting a need for the routine use of more effective combination regimens.&rdquo;⁶

Current Data for Ribociclib

Preclinical trials have shown that ribociclib induces tumor regression and has activity as a single agent in melanoma and breast cancer.²In one study, paired tumor biopsies were obtained from patients before and after ribociclib treatment. Ki67 and phosphorylated pRb were reduced by approximately 50%, although corresponding clinical effect was not reported. Partial responses were seen in 1 patient with ER-positive breast cancer plus PI3K mutation and CCND1 amplification, as well as 1 patient with melanoma of CCND1-amplified, BRAF/NRAS wild type. Overall, 14% had SD for 6 or more cycles.¹

Early but limited results from ongoing phase I/II trials are available. One study evaluating ribociclib plus exemestane and everolimus in advanced ER-positive, HER2-negative breast cancer showed that the combination appears to be feasible.²In a phase Ib/II study, ribociclib plus PI3K inhibitor BYL719 and letrozole was well tolerated in 15 postmenopausal women with advanced ER-positive, HER2-negative breast cancer. Common AEs included neutropenia, nausea, and hyperglycemia, with 1 instance of dose-limiting neutropenia.⁸Preliminary clinical activity was seen with both combinations of ribociclib.^2,8Acceptable safety profiles and evidence of clinical activity were also seen with ribociclib as monotherapy for pRb-positive solid tumors and lymphomas, and as combination therapy with BRAF inhibitor LGX818 in advanced melanoma.^1,4

Based on the experience with palbociclib, ribociclib development was expedited to phase III trials.4 MONALEESA-2 is evaluating ribociclib plus letrozole in postmenopausal women with advanced ER-positive, HER2-negative breast cancer (NCT01958021). MONALEESA-3 is studying ribociclib plus fulvestrant in a similar population (NCT02422615). Ribociclib in combination with goserelin with or without tamoxifen is being investigated in premenopausal women with HR-positive, HER2- negative breast cancer (NCT02278120).

Current Data for Abemaciclib

Unlike palbociclib and ribociclib, abemaciclib had significant single-agent activity in phase I studies. In one trial of women with advanced breast cancer, abemaciclib had activity only in the ER-positive group. Response and disease control rates (DCRs) in ER-positive patients were 31% and 81%, respectively. PFS was also markedly higher in women with ER-positive disease (8.8 vs 1.1 months for ER-negative). In an expansion cohort of the same trial, PR and clinical benefit rates (CBRs) were 28% and 72%, respectively, among 25 patients with advanced, HRpositive, HER2-negative breast cancer who had failed multiple lines of prior treatment.⁹

Clinical benefit was seen with combination therapy, as well. Another cohort of the phase I study evaluated abemaciclib plus fulvestrant in patients with ER-positive disease refractory to previous therapies. The DCR was 72.2%. Diarrhea was the most common AE, occurring in 66% of patients, but nearly all cases were grade 2 or lower. The overall and grade 3/4 rates of neutropenia were 40% and 21%, respectively.⁴

Based on the phase I results, abemaciclib received breakthrough therapy designation from the FDA in 2015. As with ribociclib, abemaciclib has been expedited to phase III trials.³MONARCH 2 is evaluating abemaciclib plus fulvestrant in patients with advanced, HR-positive, HER2-negative breast cancer that has relapsed or is refractory to standard therapy (NCT02107703). MONARCH 3 combines abemaciclib with a nonsteroidal AI as a first-line therapy in advanced, previously untreated, HR-positive, HER2-negative breast cancer (NCT02246621).

Finally, the clinical single-agent activity seen with abemaciclib makes it unique among the CDK4&6 inhibitors. A phase II trial, MONARCH 1, is investigating abemaciclib as a monotherapy in women with refractory, HR-positive, HER2-negative breast cancer (NCT02102490).⁴

Future Approaches

The most notable difference between the CDK4&6 inhibitors is their toxicity profiles. Myelosuppression, particularly neutropenia, is the primary DLT for palbociclib and ribociclib.1 Rates of neutropenia are approximately 40% for both agents, and febrile neutropenia in palbociclib is rare (0.6% in PALOMA-3).^2,4,6

&ldquo;Neutropenia, although common, was not accompanied by serious clinical outcomes and is likely to be the result of an ontarget effect of CDK4&6 inhibition on marrow progenitor cells,&rdquo; the authors of PALOMA-1 noted. &ldquo;The absence of serious complications resulting from palbociclib-associated neutropenia probably reflects a cytostatic rather than cytotoxic effect of the drug on bone marrow progenitor cells, different from what is seen with typical cytotoxic drugs.&rdquo;¹⁰In addition, patients in the palbociclib studies did not have any mucositis or skin toxicity, which are common portals for infection that induces febrile neutropenia during chemotherapy.⁴

Patients who received abemaciclib had milder hematologic toxicity, specifically neutropenia. The all-grade rate of neutropenia was 49% and grade 3/4 events were seen in 21% of patients. With palbociclib plus letrozole, the overall rate of neutropenia was 75% and 54% of patients had a grade 3/4 event.4 One possible rationale for the difference in neutropenia rates is that abemaciclib is a more potent inhibitor of CDK4 than palbociclib or ribociclib (CDK4 IC50 0.6 to 2 nmol/L vs 11 nmol/L and 10 nmol/L, respectively). In addition, overall hematologic and nonhematologic toxicities may be fewer with abemaciclib because it is more specific for CDK4 than for CDK6.¹

Neutropenia is not a DLT for abemaciclib, which may be dosed continuously, unlike palbociclib and ribociclib, which each require an off-treatment week per cycle. The ability to continuously dose abemaciclib may explain its success as a single agent in clinical trials when monotherapy with other CDK4&6 inhibitors have shown disappointing results.¹

Gastrointestinal toxicity, however, is more common with abemaciclib than with the other CDK4&6 inhibitors. In a phase I trial, the incidence of diarrhea was 66%, although only 6% of patients had grade 3 diarrhea and none had grade 4.⁴Lowering the dosage of abemaciclib may help eliminate or reduce the severity of diarrhea. Supportive medications may also be used to treat this side effect; 2 trials investigating abemaciclib now administer the drug with prophylactic loperamide (NCT02677844, NCT02441946).¹

Finally, abemaciclib crosses the blood-brain barrier, which makes it an attractive agent for treating primary and secondary central nervous system malignancies.¹The relatively impermeable nature of the blood-brain barrier poses a significant challenge for clinicians treating brain tumors. Brain metastases are the most common type of brain tumor, occurring in up to 40% of patients, particularly in the melanoma, lung, and breast cancer populations. In addition, patients with glioblastoma multiforme (GBM) have a 5-year survival rate of less than 3%, indicating a strong unmet need. Rb pathway dysregulation is present in 78% of GBM cases and plays an important role in many peripheral cancers, so CDK4&6 inhibitors may offer an effective treatment in these patients.¹¹

Abemaciclib has a wide distribution, with cerebrospinal fluid concentrations similar to those found in plasma.¹In GBM xenograft models, abemaciclib had a 10-fold higher increase in brain-to-plasma concentration ratio than palbociclib. As a result, lower dosages of abemaciclib than palbociclib were needed to reach therapeutic unbound concentrations in the brain. In addition, abemaciclib had similar efficacy as temozolomide for increasing survival time, and using abemaciclib in conjunction with temozolomide had an additive and possibly synergistic treatment effect.¹¹

Phase I results of abemaciclib in GBM demonstrated decreased tumor size and PFS greater than 16 months in 2 of 17 patients.1 A phase II trial is currently evaluating abemaciclib as a monotherapy for patients with brain metastases from melanoma, non-small cell lung cancer, and HR-positive breast cancer (NCT02308020).

REFERENCES

1. Sherr CJ, Beach D, Shapiro GI. Targeting CDK4 and CDK6: from discovery to therapy.Cancer Discov. 2016;6(4):353-367.
2. Murphy CG, Dickler MN. The role of CDK4/6 inhibition in breast cancer.Oncologist. 2015;20(5):483-490.
3. DeMichele A, Clark AS, Tan KS, et al. Cancer Therapy: Clinical CDK 4/6 Inhibitor Palbociclib (PD0332991) in Rb+ Advanced Breast Cancer: Phase II Activity, Safety, and Predictive Biomarker Assessmen [published on December 11, 2014].Clin Cancer Res.DOI: 10.1158/1078-0432.CCR-14-2258
4. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers.Breast Cancer Res. 2016;18(1):17.
5. Pfizer Announces Positive Top-Line Results for Phase 3 PALOMA-2 Clinical Trial of IBRANCE&reg; (palbociclib) [news release]. New York, NY: Pfizer Inc. April 19, 2016. http://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_ positive_top_line_results_for_phase_3_paloma_2_clinical_trial_of_ibrance_palbociclib. Accessed May 10, 2016.
6. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2- negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial [published correction appears in Lancet Oncol. 2016;17:429].Lancet Oncol.2016;17(4):425-439.
7. Turner NC, Ro J, Andr&eacute; F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer.N Engl J Med. 2015;373(3):209-219.
8. Juric D, Hamilton E, Garcia Est&eacute;vez L, et al. Abstract P5-19-24: Phase Ib/II study of LEE011 and BYL719 and letrozole in ER+, HER2— breast cancer: safety, preliminary efficacy and molecular analysis.Cancer Res. 2014;75(9 suppl; abstr P5-19-24).
9. Patnaik A, Shapiro GI, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non—small cell lung cancer, and other solid tumors [published online May 23, 2016].Cancer Discov. doi: 10.1158/2159- 8290.CD-16-0095.
10. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/ TRIO-18): a randomised phase 2 study.Lancet Oncol. 2015;16(1):25-35.
11. Raub TJ, Wishart GN, Kulanthaivel P, et al. Brain Exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft.Drug Metab Dispos.2015;43(9):1360-1371.

CDK4&6 inhibitors have the potential to be effective treatments for advanced breast cancer. Differences in pharmacokinetics, potency, and efficacy have important clinical implications. These differences will affect patient selection as well as provide new directions for future investigation, including the development of therapies for other cancer types.