CDK4/6 Inhibitors Reach New Benchmarks in Overall Survival in HR+ Breast Cancer

Article

The release of new evidence that CDK4/6 inhibition results in survival gains for patients with hormone receptor–positive, HER2-negative metastatic breast cancer marks a new milestone for the therapeutic approach and may help set the stage for expanding use of these agents into earlier clinical settings.

Debu Tripathy, MD, Professor and Chairman Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

Debu Tripathy, MD, Professor and Chairman Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

Debu Tripathy, MD

The release of new evidence that CDK4/6 inhibition results in survival gains for patients with hormone receptor (HR)—positive, HER2-negative metastatic breast cancer marks a new milestone for the therapeutic approach and may help set the stage for expanding use of these agents into earlier clinical settings.

The big news for this class of therapy unfolded last year with phase III clinical trial fi ndings showing that 2 of the FDA-approved agents, ribociclib (Kisqali) and abemaciclib (Verzenio), demonstrated overall survival (OS) improvements in combination with endocrine therapy (ET) compared with ET alone in randomized clinical trials involving this patient population, according to Debu Tripathy, MD.

“If you look at all the changes in how we treat hormone receptor—positive breast cancer with the introduction of new endocrine therapies and then more recently biological therapies, they have been approved because they improve time to progression. But they generally had not shown a survival advantage,” Tripathy said in an interview in advance of the 37th Annual Miami Breast Cancer Conference® (MBCC).

That changed in the CDK4/6 inhibitor landscape with the publication of updated results from pivotal trials for ribociclib in MONALEESA-3 and MONALEESA-7 and for abemaciclib in MONARCH-2, Tripathy noted. “Roughly, the survival advantage is about a 25% to 30% relative reduction in the risk of death, so a pretty important benefi t has now been identified,” he said.

Palbociclib (Ibrance), the first CDK4/6 inhibitor to gain approval, has not yet demonstrated a statistically significant OS advantage in a randomized trial, although the median OS is improved for patients who received the drug with ET in clinical trials. Those results might change with further analyses, Tripathy said.

A leading investigator in the pivotal ribociclib studies, Tripathy is professor and chairman in the Department of Breast Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston. He is serving as a cochair of MBCC.

In addition to updated survival data, Tripathy discussed other key facets of CDK4/6 therapies in advance of MBCC, including evolving insights into mechanisms of resistance to the agents and expanding use of the drugs into adjuvant treatment settings.

The Rise of CDK4/6 Inhibitors

The introduction of CDK4/6 inhibitors has changed the standard of care for patients with advanced HR-positive, HER2-negative breast cancer in the United States. The drug class was launched in 2015 with the FDA’s approval of palbociclib, followed by ribociclib and abemaciclib in 2017, based on clinical trial findings showing that each of the agents significantly delays progression when added to ET in patients with metastatic disease.1-3

By 2019, nearly half of newly diagnosed patients in this setting received a CDK4/6 inhibitor plus ET as fi rst-line treatment for metastatic breast cancer, shifting the paradigm away from ET alone and chemotherapy, according to findings from a real-world study presented at last year’s San Antonio Breast Cancer Symposium (2019 SABCS).

To analyze treatment patterns, investigators culled through deidentified patient records in the Flatiron Health Analytic database for women ≥18 years who received first-line treatment for HR-positive, HER2-negative metastatic breast cancer between August 1, 2015, approximately 6 months after the approval of palbociclib, and November 30, 2018. In all, they reviewed treatments given to 4112 patients.

The number of patients receiving a CDK4/6 inhibitor plus ET rose in each of the 4 prescribing years reviewed—from 22.0% in 2015 to 48.4% in 2018. By contrast, during the same time frame, the amount of patients receiving ET alone declined from 55.7% to 35.6%, and the rate of those receiving chemotherapy fell from 22.2% to 16.0% (Figure 1).4

Survival Findings

Although there are several variations in the specifi c indications for each of the approved CDK4/6 inhibitors, all of the drugs are approved for patients with HR-positive, HER2-negative advanced or metastatic breast cancer.

Ribociclib

The FDA has approved ribociclib in combination with an aromatase inhibitor (AI) for pre/ perimenopausal or postmenopausal women as initial endocrine-based therapy or with fulvestrant (Faslodex) following disease progression on ET for postmenopausal women.

In MONALEESA-3 (NCT02422615), 726 patients were randomized 2:1 to receive either ribociclib at 600 mg once daily (21 days, followed by 7 days off , for a 28-day cycle) or matching placebo in addition to fulvestrant at 500 mg (day 1 of each cycle plus day 15 of cycle 1) as first-line or second-line treatment. The eligible population included men and postmenopausal women who had ≤1 line of prior therapy for advanced disease or who had experienced progression during or within 12 months of adjuvant or neoadjuvant ET.

At 42 months, the OS rate was 57.8% (95% CI, 52.0%-63.2%) in the ribociclib arm and 45.9% (95% CI, 36.9-54.5) in the placebo group, which translated into a 28% reduction in the relative risk of death (P = .00455).5

In the overall population, patients who received the ribociclib regimen achieved a greater OS benefit than those in the placebo group regardless of the line of therapy. In the overall population, the median OS was not reached (95% CI, 42.5 months-not estimable [NE]) among patients in the ribociclib arm (n = 484) compared with 40.0 months (95% CI, 37.0-NE) in the placebo group (n = 242), which translated into a hazard ratio for death of 0.72 (95% CI, 0.57-0.92) favoring ribociclib. The hazard ratios were 0.70 (95% CI, 0.48-1.02) as fi rst-line therapy and 0.73 (95% CI, 0.53-1.00) after early relapse or as second-line treatment.

In the MONALEESA-7 trial (NCT02278120), the eligible population comprised pre- or perimenopausal women 18 to 59 years of age with locoregionally recurrent or metastatic disease not amenable to curative therapy. Prior ET as neoadjuvant or adjuvant therapy was allowed.

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At 42 months, the estimated OS rate for those in the ribociclib group (n = 335) was 70.2% (95% CI, 63.5%-76.0%) and 46.0% (95% CI, 32.0%-58.9%) in the placebo group (n = 337), which resulted in a hazard ratio for death favoring ribociclib of 0.71 (95% CI, 0.54- 0.95; log-rank P = .00973). The median OS was NE in the ribociclib arm compared with 40.9 months (95% CI, 37.8-NE) in the placebo group. The benefit favoring the addition of ribociclib was similar regardless of the type of ET that patients received, with hazard ratios of 0.70 (95% CI, 0.50-0.98) among those who took a nonsteroidal AI and 0.79 (95% CI, 0.45-1.38) for those who received tamoxifen.6

Abemaciclib

The FDA has approved abemaciclib in combination with an AI as initial endocrine-based therapy for postmenopausal women or with fulvestrant following disease progression after ET and as monotherapy for adults with disease progression following ET and prior chemotherapy in the metastatic setting.

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In all, 669 patients were randomized 2:1 to receive abemaciclib at 150 mg twice daily on a 28-day cycle or a matching placebo plus fulvestrant at 500 mg (days 1 and 15 of the fi rst cycle and day 1 of each subsequent cycle). Participants who had not reached menopause also received a gonadotrophin-releasing hormone agonist such as goserelin.

After a median follow-up of 47.7 months, a benefi t was observed with abemaciclib in the intention-to-treat (ITT) population as well as across stratifi cation factors. In the ITT group, the median OS among patients who received abemaciclib (n = 446) was 46.7 months compared with 37.3 months among those who received placebo (n = 223).7

This translated into a significant increase in survival for the abemaciclib group, with a hazard ratio of 0.757 (95% CI, 0.606-0.945; P = .01). Investigators noted that the benefit was greater among participants with visceral disease and primary resistance to prior ET, which had hazard ratios of 0.675 (95% CI, 0.511-0.891) and 0.686 (95% CI, 0.451-1.043), respectively.

Palbociclib

Palbociclib was first indicated in combination with letrozole for postmenopausal women as initial endocrine-based therapy for metastatic disease. The drug was subsequently approved in combination with an AI as initial endocrinebased therapy in postmenopausal women or in men or with fulvestrant in patients whose disease has progressed after ET based on fi ndings from the PALOMA-3 study (NCT01942135).

In PALOMA-3, 521 patients were randomized 2:1 to receive palbociclib at 125 mg daily (21 days, followed by 7 days off , for a 28-day cycle) plus fulvestrant at 500 mg (every 14 days for the first 3 injections, followed by every 28 days) or a matching placebo plus fulvestrant. The study recruited patients who had disease progression after previous ET regardless of menopausal status. Concurrent goserelin was added for premenopausal patients.

Although the addition of palbociclib improved OS, the difference in the ITT population was not statistically significant. After a median follow-up of 44.8 months, the median OS among participants in the palbociclib arm (n = 347) was 34.9 months (95% CI, 28.8-40.0) compared with 28.0 months (95% CI, 23.6 to 34.6) in the placebo group (n = 174). That finding resulted in a hazard ratio for death of 0.81 (95% CI, 0.64-1.03; P = .09).8

Of note, the OS advantage with palbociclib was greater for participants with sensitivity to previous endocrine therapy (n = 410). Investigators defi ned this measure as the combined incidence of complete response, partial response, or stable disease for ≥24 weeks occurring after ≥1 prior lines of ET for metastatic disease or after ≥24 months of adjuvant ET. In this group, the median OS was 39.7 months (95% CI, 34.8-45.7) in the palbociclib arm versus 29.7 months (95% CI, 23.8 to 37.9) in the placebo group. The hazard ratio favoring palbociclib was 0.72 (95% CI, 0.55-0.94).

Meanwhile, a real-world analysis of palbociclib’s efficacy showed that the addition of the CDK4/6 inhibitor to letrozole improved OS compared with letrozole alone as first-line therapy for patients with metastatic breast cancer, according to findings presented at 2019 SABCS.

A retrospective review of electronic health records in the Flatiron database calculated a 48% reduction in the risk of disease progression or death with the addition of palbociclib to letrozole versus letrozole alone. The median OS was not yet reached in the palbociclib arm compared with 38.1 months (95% CI, 32.3-NE) in the letrozolealone group for a hazard ratio of 0.52 (95% CI, 0.40-0.68; P <.0001).9

Resistance Mechanisms

In addition to survival data, another advance in the CDK4/6 inhibitor field has been a growing understanding about mechanisms of resistance to the agents, Tripathy said.

CDK4/6 inhibitors are small molecules that target cyclin-dependent kinases, which help modulate the cell cycle and frequently play a role in cancer progression. The cell cycle is a highly regulated series of events that take the cell from a quiescent state (G0) through an initial growth phase (G1), DNA replication (S), a second growth phase (G2), and mitosis. CDKs 4 and 6 promote unchecked cell growth by phosphorylating the retinoblastoma (Rb) protein, which in turn releases transcription factors, including members of the E2 family transcription factors (E2F), which facilitate continued progression (Figure 2).10

“We’ve known from the laboratory that there are probably certain changes that we think make tumors resistant to CDK inhibitors, such as the loss of Rb. But that doesn’t seem to be a very common mechanism of resistance in patients,” Tripathy said.

Next-generation sequencing of circulating tumor DNA obtained through tissue or blood in clinical trial participants is showing that many patients who develop resistance do not have a clear genomic alteration, Tripathy said. Nevertheless, he said, overexpression of cyclin E at baseline, which is present in about one-third of cases, has been implicated in resistance to therapy.

“Cyclin E can bypass CDK4/6 inhibition by directly activating cyclin CDK2,” he said. “CDK2 is downstream of the cell cycle, and so it represents an escape mechanism. So, cyclin E binds and activates CDK2.”

Additional genetic abnormalities have been observed in studies, including activation or amplification of fibroblast growth factor receptor and several others. “They don’t explain all the clinical cases of resistance,” Tripathy said. “There’s still a lot more that we need to understand. We’re not quite ready to use these data in selecting the patients who should or shouldn’t receive CDK inhibitors.”

Adjuvant Setting

Looking forward, investigators are anticipating the results of ongoing clinical trials into the use of CDK4/6 inhibitors in the adjuvant setting. The studies focus on patients with early-stage disease who are at high risk for recurrence.

“None of the results are available yet,” said Tripathy. “There are randomized trials with each of the approved CDK inhibitors that compare placebo or no treatment to CDK inhibitor therapy for either 2 or 3 years. So we’ll see if that can have an impact on outcome.”

Ongoing studies in this setting include the following:

  • PALLAS (NCT02513394)—standard ET for at least 5 years with or without palbociclib for 2 years in patients with stage II or III early invasive breast cancer
  • PENELOPE-B (NCT01864746)—standard ET with or without palbociclib in a 28-day cycle for 13 cycles in patients with residual disease and a high risk of relapse after neoadjuvant chemotherapy
  • NATALEE (NCT03701334)—standard ET for at least 5 years with or without ribociclib for 3 years in patients with stage II or III breast cancer
  • MonarchE (NCT03155997)—standard ET for at least 5 years with or without abemaciclib for 2 years in patients with high-risk, node-positive breast cancer

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References

  1. Ibrance [prescribing information]. New York, NY: Pfizer Labs; September 2019. www.accessdata.fda.gov/drugsatfda_docs/ label/2019/207103Orig1s012lbl.pdf. Accessed February 21, 2020.
  2. Kisqali [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; September 2019. www.accessdata.fda. gov/drugsatfda_docs/label/2020/209092s003lbl.pdf.Accessed February 21, 2020.
  3. Verzenio [prescribing information]. Indianapolis, IN: Eli Lilly and Co; September 2019. www.accessdata.fda. gov/drugsatfda_docs/label/2019/208716s003lbl.pdf.Accessed February 21, 2020.
  4. Brufsky A, Chen C, Mardekian J, Liu X, McRoy L, Torres MA. Characteristics of MBC patients receiving first-line treatments in the US real-word setting in the era of CDK4/6 inhibitors. Poster presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Poster P1-19-26.
  5. Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514-524. doi: 10.1056/NEJMoa1911149.
  6. Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi: 10.1056/NEJMoa1903765.
  7. Sledge Jr GW, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor— positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial [published online ahead of print September 29, 2019]. JAMA Oncol. doi:10.1001/jamaoncol.2019.4782.
  8. Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379(20):1926-1936. doi: 10.1056/NEJMoa1810527.
  9. DeMichele A, Cristofanilli M, Brufsky A, et al. Overall survival for first-line palbociclib plus letrozole vs letrozole alone for HR+/HER2— metastatic breast cancer patients in US real-world clinical practice. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Poster P1-19-02.
  10. Scott SC, Lee SS, Abraham J. Mechanisms of therapeutic CDK4/6 inhibition in breast cancer. Semin Oncol. 2017;44(6):385- 394. doi: 10.1053/j.seminoncol.2018.01.006.

In the MONARCH-2 trial (NCT02107703), investigators tested the addition of abemaciclib to fulvestrant in adult women with advanced breast cancer of any menopausal status whose disease had progressed within 12 months of adjuvant ET or during neoadjuvant, adjuvant, or first-line ET.

In all, 672 patients were randomized 1:1 to receive either ribociclib at 600 mg daily (21 days, followed by 7 days off , for a 28-day cycle) or matching placebo in combination with ET. The ET consisted of goserelin for all patients at 3.6 mg (day 1 of each 28-day cycle) plus either a daily nonsteroidal AI (letrozole at 2.5 mg or anastrozole at 1 mg) or 20-mg tamoxifen.

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