CDK4/6 Inhibitors Changing Course of Care in HR+/HER2- Breast Cancer

Earlier diagnosis and more effective therapeutic options are enabling physicians to deliver better rates of disease control and improved quality of life to patients with hormone receptor–positive, HER2-negative metastatic breast cancer.

Neelima Denduluri, MD

Earlier diagnosis and more effective therapeutic options are enabling physicians to deliver better rates of disease control and improved quality of life (QoL) to patients with hormone receptor (HR)—positive, HER2-negative metastatic breast cancer, explained Neelima Denduluri, MD.

“Our goals of therapy are disease control while maintaining the QoL, [all the while delaying the need for] chemotherapy for as long as possible,” said Denduluri in a presentation during the 2018 OncLive® State of the Science Summit™ on Breast Cancer.

Such progress is, in large part, due to the advent of CDK4/6 inhibitors, 3 of which have received FDA approval for this patient population: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). During her presentation, Denduluri reviewed each CDK4/6 inhibitor as potential first-line and second-line therapies based on the data from the PALOMA-2, MONALEESA-2 and -7, and MONARCH 3 trials, which led to their approvals.

In the PALOMA-2 study, postmenopausal patients with advanced treatment-naïve estrogen receptor (ER)—positive, HER2-negative disease (n = 666) were randomized 2:1 to receive either 125 mg of palbociclib twice daily on a 3-weeks-on, 1-week-off schedule plus 2.5 mg of letrozole twice daily or placebo plus letrozole. Results demonstrated the superiority in median progression-free survival (PFS) and risk reduction with palbociclib/letrozole, at 24.8 months, compared with placebo at 14.5 months (HR, 0.58; 95% CI, 0.46-0.72; P <.001).1 In 2017, the FDA granted a full approval to the combination as frontline therapy for postmenopausal women with ER-positive, HER2-negative metastatic disease.1

In MONALEESA-2, postmenopausal patients with advanced, treatment-naïve, ER-positive, HER2-negative disease (n = 668) were randomized 1:1 to receive 600 mg of ribociclib twice daily on a 3-weeks-on, 1-week-off schedule plus 2.5 mg of letrozole twice daily or placebo plus letrozole.2 The same randomization and dosing schedule were used in the MONALEESA-7 trial, in which all patients had previously received a GnRH agonist, noted Denduluri. Although the study was restricted to pre-/perimenopausal patients (n = 672),3 women could have had prior exposure to tamoxifen or an aromatase inhibitor (AI), explained Denduluri.

However, due to a prolongation of the QTc prolongation with tamoxifen, physicians caution against its use in combination with ribociclib in practice, explained Denduluri, advising only an AI or fulvestrant.

In March 2017, the FDA approved the combination of ribociclib and an AI for frontline therapy, based on results from the MONALEESA-2 trial, which demonstrated a similar improvement in median PFS as was seen in the PALOMA-2 trial. In July 2018, the label for ribociclib was expanded to patients with pre-/perimenopausal HR-positive, HER2-negative advanced or metastatic breast cancer based on the results of MONALEESA-7, which indicated a 14-month improvement in median PFS with the combination versus AI monotherapy at 27.5 months and 13.8 months, respectively (HR, 0.569; 95% CI, 0.436-0.743).

Abemaciclib was examined in the MONARCH 3 trial, in which postmenopausal women with HR-positive, HER2-negative metastatic or locally advanced breast cancer who had not yet received systemic therapy (n = 493) were randomized 2:1 to receive either 150 mg of abemaciclib twice daily plus 1 mg of anastrozole or 2.5 mg of letrozole daily, or placebo plus anastrozole or letrozole. The median PFS rates were 28.2 months and 14.8 months with abemaciclib versus an AI, respectively (HR, 0.54; 95% CI, 0.418-0.698; P <.0001).4

“No matter which endocrine therapy backbone you use and which CDK4/6 inhibitor you use, the hazard ratios seem to be very similar,” said Denduluri. “They seem to improve PFS across the board.”

In terms of toxicity, all 3 agents are associated with neutropenia and fatigue, although ribociclib and abemaciclib are associated with hepatotoxicity. Distinct from the other 2 agents, however, abemaciclib is associated with a higher rate of early-onset diarrhea as well as venous thromboembolic events, reported Denduluri.

“We may have to dose reduce, but patients are likely going to derive the same degree of benefit from the drug if the dose reduction is necessary,” said Denduluri.

Apart from their use in combination, all 3 inhibitors show single-agent activity as well, although, abemaciclib seems to show the most single-agent activity, according to Denduluri. As the only FDA-approved CDK4/6 monotherapy, abemaciclib should be administered at a modified dose of 200 mg twice daily, when given as a single agent.

If patients progress on frontline therapy, data from the PALOMA-3 and MONARCH 2 trials suggest that these agents carry significant clinical value in the second-line setting as well, specifically in combination with fulvestrant after progression on prior endocrine therapy.

In PALOMA-3, the combination of palbociclib and fulvestrant induced a clinically meaningful improvement in overall survival (OS) in patients with HR-positive, HER2-negative advanced breast cancer. Initial data from the trial served as the basis for the February 2016 FDA approval of the combination following progression on prior endocrine therapy. At a median follow-up of 44.8 months, the median OS was 34.9 months with the palbociclib combination versus 28.0 months with fulvestrant/placebo.5 The OS benefit was greatest in patients with sensitivity to prior endocrine therapy, in whom the median OS was 39.7 months in the palbociclib arm versus 29.7 months in the placebo arm.

Investigators noted benefit regardless of whether or not patients had received prior chemotherapy, said Denduluri.

“The median time to chemotherapy was nearly more than doubled with 17.6 months versus 8.8 months,” she added. “When we’re talking with the women or men we treat, we want to prolong the time to chemotherapy.”

In the MONARCH 2 trial, patients were randomized to receive either abemaciclib plus fulvestrant (n = 446) or fulvestrant plus placebo (n = 223). Perimenopausal women were eligible to enroll, although the majority of patients were postmenopausal, explained Denduluri. The median PFS was 16.4 months with abemaciclib compared with 9.3 months with fulvestrant (HR, 0.553; 95% CI, 0.449-0.681; P <.001).6

Based on available data, there is no evidence to suggest that 1 CDK4/6 inhibitor is better than another, explained Denduluri. According to an FDA pooled analysis of the PALOMA-2 and -3, MONALESSA-2, and MONARCH 2 and MONARCH 3 trials, equal efficacy was observed for patients regardless of progesterone receptor status, evidence of lobular or ductal disease, bone only or visceral disease, de novo metastatic disease, or having had a disease-free interval >12 months from adjuvant therapy.7

As such, physicians should employ clinical discretion, often rooted in an agent’s toxicity profile or a patient’s comorbidities, when deciding between agents, said Denduluri. For example, a patient with irritable bowel syndrome may not do as well with abemaciclib due to the high rates of diarrhea observed in the trials. Further, patients with low baseline blood counts may do better with abemaciclib as opposed to palbociclib and ribociclib.

Either as first-line treatment or following progression on endocrine therapy, CDK4/6 inhibitors show consistent benefit in PFS in women with advanced HR-positive HER2-negative breast cancer, irrespective of endocrine backbone, menopausal status, or clinical and pathologic features, concluded Denduluri.

References

  1. Finn RS, Martin M, Rugo HS, et al. PALOMA-2: primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2— advanced breast cancer (ABC). J Clin Oncol. 2016;34(suppl 15):abstr 507. doi: 10.1200/JCO.2016.34.15_suppl.507.
  2. Finn RS, Gelmon KA, Ettl J, et al. Impact of prior treatment on palbociclib plus letrozole (P+L) efficacy and safety in patients (pts) with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) first-line advanced breast cancer (ABC): a PALOMA-2 subgroup analysis. In: Proceedings from the 35th Annual Miami Breast Cancer Conference; March 8-11, 2018; Miami Beach, FL. Abstract 591.
  3. Tripathy D, Im S-A, Colleoni M, et al. First-line ribociclib or placebo combined with goserelin and tamoxifen or a nonsteroidal aromatase inhibitor in premenopausal women with hormone receptor—positive, HER2-negative advanced breast cancer: results from the randomized phase 3 MONALEESA-7 trial. In: Proceedings from the 35th Annual Miami Breast Cancer Conference; March 8-11, 2018; Miami, FL. Abstract 626.
  4. Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638-3646. doi:10.1200/JCO.2017.75.6155.
  5. Cristofanilli M, Slamon DJ, Ro J, et al. Overall survival (OS) with palbociclib plus fulvestrant in women with hormone receptor—positive (HR+), human epidermal growth factor receptor 2– negative (HER2–) advanced breast cancer (ABC): analyses from PALOMA-3. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA2_PR. academic.oup.com/annonc/article/29/ suppl_8/mdy424.009/5141510.
  6. Sledge GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875-2884. doi: 10.1200/JCO.2017.73.7585.
  7. Gao J, Cheng J, Bloomquist E, et al. Benefit of CDk4/6 inhibition in less common breast cancer subsets: a U.S. Food and Drug Administration pooled analysis. J Clin Oncol. 2018;36(suppl 15):1024. doi: 10.1200/JCO.2018.36.15_suppl.1024.