CDK4/6 Inhibitors Make Impact in HR-Positive Metastatic Breast Cancer

Adam M. Brufsky, MD, PhD

The introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors has resulted in a significant paradigm shift in the treatment of hormone receptor—positive breast cancer, helping to make the new agents part of rapidly developing improvements in personalized care for patients, according to an OncLive^® Peer Exchange panel of experts.

Anti-CDK4/6 Agents

CDK4/6 inhibitors, a category that currently consists of 3 FDA-approved agents, has taken the “estrogen receptor (ER)-positive part of the metastatic breast cancer world by storm,” noted Adam M. Brufsky, MD, PhD, who served as moderator of the program.Cyclin family proteins activate CDKs to help regulate cell cycle progression.¹ More than 50% of women with breast cancer have alterations in the cyclin D/CDK/retinoblastoma (Rb) pathway that cause overexpression of cyclin D, a protein family implicated in disease pathogenesis and progression.¹ Studies have also documented overexpression of other cyclins and of CDK4.¹ “Cyclin D is an important transcriptional product of the ER,” said panel member Joyce A. O’Shaughnessy, MD. In women with ER-positive breast cancer, amplification of cyclin D is associated with poor response to standard endocrine therapies,¹ especially in women with luminal B tumors, O’Shaughnessy said. “Our endocrine agents, even really good aromatase inhibitor inhibition or really good degradation of ER, are still not perfect in terms of totally clamping down on that pathway,” she said.

The need for better targeting of the cyclin D/ CDK/Rb pathway led to the development of first-generation CDK inhibitors.² These pan-CDK inhibitors had low selectivity, and clinical trials in ER-positive breast cancer proved disappointing.² As accumulating data emphasized the important role of CDK4 and CDK6 activity in ER-positive breast cancer, new agents were introduced that were highly selective for these 2 kinases. The FDA has now approved 3 CDK4/6 inhibitors for women with advanced or metastatic hormone receptor—positive, HER2-negative breast cancer: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). All 3 are oral medications; ribociclib and palbociclib are given in 28-day cycles, with 21 days on and 7 days off, while abemaciclib is given twice daily without interruption.

New First-Line Therapies

The European Medicines Agency has approved palbociclib and ribociclib, while abemaciclib remains under consideration. “We were waiting… for this kind of drug for more than 10 years because in the era of endocrine treatment of breast cancer patients, the last innovation has been aromatase inhibition ...I’m very happy to have these drugs on the market,” said Michael Untch, MD.Palbociclib

The FDA granted accelerated approval to palbociclib in February 2015 based on progression-free survival (PFS) findings from the phase II PALOMA-1 trial in which 165 patients were randomized to receive letrozole with or without palbociclib.3 Brufsky described the decision as highly unusual, but panelist Hope S. Rugo, MD, said the agency was on solid footing. “I think that in this situation it was quite reasonable—it gave people access to the drug,” said Rugo. She pointed out that the phase III study she was involved with, PALOMA-2, had already completed accrual, so the FDA could be confident it would receive more extensive data. “They didn’t have safety concerns that hadn’t been well described… and there was evidence of a significant prolongation of progression-free survival,” Rugo added. Final data from PALOMA-1, presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, showed a median PFS of 20.2 months in the palbociclib arm compared with 10.2 months in the letrozole-only arm (HR, 0.488). No significant difference in overall survival (OS) was observed between treatment groups.⁴

Although palbociclib is approved in the European Union, Untch said Germany’s Federal Joint Committee, which acts as a cost-effectiveness watchdog, ruled that the drug offered no benefit over existing therapies partly because the agency was dissatisfied with use of PFS as the primary endpoint. Untch said he believes PFS is an adequate endpoint and noted that a growing number of German oncologists are prescribing palbociclib.

Michael Gnant, MD, criticized regulatory agencies for insisting on OS data when evaluating the drugs. “Maybe it’s super provocative, but I would suggest that we should make a clear statement: OS in luminal breast cancer is not a rational endpoint any longer,” he said.

In March 2017, the FDA granted regular approval to palbociclib plus an aromatase inhibitor based on the results of PALOMA-2, which enrolled treatment-naïve postmenopausal women with ER-positive, HER2-negative recurrent or metastatic breast cancer (N = 666).⁵ Patients in PALOMA-2 were randomly assigned to palbociclib plus letrozole or letrozole alone until progression or unacceptable toxicity.5 Palbociclib plus letrozole prolonged PFS by approximately 10 months compared with letrozole monotherapy (24.8 vs 14.5 months, respectively; HR, 0.58; 95% CI, 0.46-0.72; P <.001).⁵

“When you look into the subgroups, you see that for bone-only disease...the HR is 0.36,” Gnant said. He added that time to subsequent treatment was also superior in the palbociclib group. The most common grade 3 or 4 adverse events (AEs) associated with palbociclib in PALOMA-2 were neutropenia, leukopenia, anemia, and fatigue.⁵ Approximately two-thirds of patients taking palbociclib developed neutropenia compared with 1.4% of patients taking only letrozole.⁵ In the phase III PALOMA-3 trial (N = 521), investigators randomly assigned patients to fulvestrant (Faslodex) alone or with palbociclib.⁶ Median PFS reached 9.5 months in the palbociclib arm versus 4.6 months in the fulvestrant-only arm (HR, 0.46; 95% CI, 0.36-0.59; P <.0001).6 Data revealed no relationship between treatment response and PIK3CA mutation status or hormone receptor expression level.⁶

Ribociclib

The FDA approved ribociclib in March 2017 after positive preliminary findings from the phase III MONALEESA-2 trial (N = 668).⁷ Gnant said MONALEESA-2’s design was nearly identical to that of PALOMA-2, with the aromatase inhibitor letrozole given alone or with the CDK4/6 inhibitor. However, participants were hormone receptor— positive, HER2-negative.⁷ Updated data presented at the 2017 ASCO Annual Meeting showed significantly longer PFS with ribociclib plus letrozole versus letrozole alone (25.3 vs 16.0 months; HR, 0.568; 95% CI, 0.457-0.704; P <.001).⁸ Gnant called the results “extremely reassuring.” No significant difference in OS was observed between cohorts.⁷

High rates of neutropenia also occurred in the ribociclib arm of MONALEESA-2, with 59% of patients developing grade 3/4 neutropenia compared with less than 1% of patients in the letrozole-only arm.7 Other common grade 3/4 events more frequently observed with ribociclib included leukopenia, increased liver enzymes, and lymphopenia.7

Gnant said the similar molecular structure of palbociclib and ribociclib probably explains the similar safety and efficacy results for both drugs. “There’s 1 difference, which I believe is unfortunate; in the MONALEESA trial, the issue of QTc prolongation popped up,” Gnant said. Preliminary data from MONALEESA-2 showed 2.7% of patients given ribociclib developed QTc prolongation, whereas no patient given letrozole monotherapy experienced QTc prolongation.⁷

New Second-Line Therapy

Thus, an electrocardiogram is typically required before starting ribociclib. As for the high rates of neutropenia with both CDK4/6 inhibitors, Gnant described the adverse effect as “mechanistically different from the neutropenia we see after chemotherapy.” He said patients rarely progress to neutropenic fever and counts recover promptly when the drug is stopped. O’Shaughnessy, an investigator for MONALEESA-2, said she recommends palbociclib or ribociclib with letrozole as first-line therapy for most patients with ER-positive metastatic breast cancer. “Initially, I wasn’t really sure that some patients with de novo metastatic disease or small-volume asymptomatic bone-only required it,” she said. However, she said she now believes data do not support keeping the new agents from such patients.Abemaciclib In September 2017, the FDA approved the combination of abemaciclib and fulvestrant for women with HR-positive, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy.⁹ Abemaciclib also received an indication for single-agent use in patients with metastatic disease that progressed after endocrine therapy and chemotherapy. “Abemaciclib inhibits CDKs in a slightly different way,” Rugo said. In addition to inhibiting CDK4/6 kinases, abemaciclib blocks Rb phosphorylation and progression from the G1 into the S phase of the cell cycle.¹⁰

The combination of abemaciclib and fulvestrant was compared with fulvestrant alone in the phase III MONARCH 2 trial (N = 669).¹¹ Participants had hormone receptor—positive, HER2-negative advanced breast cancer that had progressed during or after endocrine therapy. Abemaciclib was associated with significantly longer PFS than fulvestrant alone (16.4 vs 9.3 months; HR, 0.553; 95% CI, 0.449- 0.681; P <.001).¹¹

The safety profile of abemaciclib differed from that observed with palbociclib and ribociclib. “It doesn’t cause as much bone marrow toxicity by far—one-third of the number of patients have grade 3/4 neutropenia,” Rugo said. “The second big issue, which we think is probably related to this differential inhibition of CDK, is that patients have diarrhea,” she said. In MONARCH 2, 86.4% of patients in the abemaciclib arm experienced diarrhea (any grade) compared with 24.7% of patients in the fulvestrant-only arm. Rugo said “a clinically significant percentage of patients” developed grade 3 diarrhea. Other common treatment-related events included nausea and fatigue.¹¹

The phase II Monarch 1 trial evaluated singleagent abemaciclib in women whose metastatic breast cancer had progressed after endocrine therapy and 1 or 2 chemotherapy regimens (N = 132).¹² The latest data, which were presented at the 2017 European Society for Medical Oncology Congress, reported an objective response rate of 19.7%, a clinical benefit rate of 67%, median PFS of 5.95 months, and median OS of 22.3 months.¹³ “Some of the patients had quite durable responses. In fact, it’s certainly as good as, if not better than, capecitabine as a single agent in that setting,” Rugo said.

Conclusions

Diarrhea, fatigue, and nausea were again the most common AEs.¹² Rugo said the diarrhea associated with abemaciclib is intermittent and does not go away with longer use but that it is easily managed with loperamide.The CDK4/6 inhibitors have already started to change treatment paradigms for patients with hormone receptor—positive, HER2-negative advanced or metastatic breast cancer. While palbociclib and ribociclib are approved as first-line agents in combination with an aromatase inhibitor, abemaciclib is approved as a second- or third-line regimen; it is still being evaluated in the first-line setting. When using these new drugs, it is important for clinicians to educate patients about their potential AEs.

More research is needed to identify a biomarker able to predict treatment response and to determine the optimal sequence of therapy in patients with hormone receptor—positive, HER2-negative metastatic breast cancer. “We’re not going to get any of these works done unless we can collaborate across countries, between academics and the pharmaceutical industry, to make the best possible trials that serve our patients in the best way,” said Rugo.

References

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