Menu
Cyclin-dependent kinase (CDK)4/6 inhibitors have become an important treatment option for patients with hormone receptor (HR)-positive advanced breast cancer (ABC). Here we outline the key efficacy and safety results reported thus far from the PALOMA, MONALEESA, and MONARCH series of clinical trials of palbociclib, ribociclib, and abemaciclib, respectively.
The trials are sponsored by Pfizer, Novartis Pharmaceuticals, and Eli Lilly and Company, respectively.
| Phase 2 | |
|---|---|
|
Patient population: Treatment-naïve, postmenopausal women with HR-positive, HER2-negative ABC |
Treatment: Palbociclib 125 mg/day for 3 weeks of each 4‑week cycle plus letrozole 2.5 mg/day versus letrozole alone |
As reported in The Lancet Oncology in 2014, adding palbociclib to letrozole significantly prolonged the primary endpoint of progression-free survival (PFS), with a hazard ratio (HR) for progression or death of 0.488 relative to letrozole alone. The results were similar for patients with HR-positive, HER2-negative disease (HR=0.299) and those who additionally had tumors with cyclin D1 amplification and/or loss of p16 (HR=0.508).
The most frequent grade 3–4 adverse events (AEs) in the combination versus letrozole alone groups were neutropenia (54 vs 1%) and leukopenia (19 vs 0%).
The PFS boost offered by palbociclib addition was maintained across almost all the subgroups (reported in Breast Cancer Research in 2016), and the addition of the CDK4/6 inhibitor did not negatively affect pain severity or pain interference with daily activities (published in Current Medical Research and Opinion in 2016).
Overall survival (OS) results from the trial – which appeared in Breast Cancer Research and Treatment in 2020 – showed a numerical, but not statistically significant, improvement in median OS with palbociclib plus letrozole relative to letrozole alone (37.5 vs 34.5 months).
| Phase 3 | |
|---|---|
|
Patient population: Previously untreated postmenopausal women with HR-positive, HER2-negative ABC |
Treatment: Palbociclib 125 mg/day for 3 weeks of each 4-week cycle or placebo plus letrozole 2.5 mg/day |
This trial confirmed the results of the PALOMA-1/TRIO-18 study, showing a significant improvement in PFS with palbociclib versus placebo, at a median of 24.8 versus 14.5 months, giving an HR for progression or death of 0.58. The safety profile was also similar with higher rates of grade 3 or 4 neutropenia (66.4 vs 1.4%) and leukopenia (24.8% vs 0.0%) in the palbociclib than the placebo group. These data appeared in The New England Journal of Medicine in 2016.
Further reports from PALOMA-2 showed that the significant PFS gain afforded by palbociclib was maintained with longer follow-up (published in Breast Cancer Research and Treatment in 2019) as well as in participants of Asian ethnicity (published in the Journal of Global Oncology in 2019). Another report in Japanese patients (published in the International Journal of Clinical Oncology in 2018) showed a numerical but nonsignificant PFS benefit with palbociclib versus placebo.
According to a 2018 publication in the Annals of Oncology, palbociclib addition did not impair health-related quality of life (HRQoL) relative to placebo, and significantly improved pain scores.
A deeper dive into the hematologic safety profile of the CDK4/6 inhibitor, published in The Oncologist in 2019, highlighted that neutropenia was “mostly transient,” manageable with dose adjustments, and did not negatively impact the drug’s efficacy.
| Phase 3 | |
|---|---|
|
Patient population: Women who have received prior endocrine therapy for HR-positive, HER2-negative ABC |
Treatment: Palbociclib 125 mg/day for 3 weeks of each 4-week cycle or placebo plus fulvestrant 500 mg every 4 weeks (plus an extra dose on day 15 of cycle 1) |
The study met its primary endpoint at a preplanned interim analysis, reported in The New England Journal of Medicine in 2015, demonstrating a significant 58% reduction in the risk for disease progression or death in the palbociclib arm compared with the placebo group.
Once again, palbociclib-treated patients had a higher incidence of grade 3–4 neutropenia (62.0 vs 0.6%) and leukopenia (25.2 vs 0.6%) than their counterparts given placebo.
And palbociclib addition continued to offer a significant PFS advantage in the final analysis (The Lancet Oncology, 2016) and in the subgroups of premenopausal women (The Oncologist, 2017) and those of Asian ethnicity (Journal of Global Oncology, 2017), while the benefit in Japanese patients did not reach statistical significance (International Journal of Clinical Oncology, 2018).
HRQoL data – published in the Annals of Oncology in 2016 – showed that global QoL scores significantly favored the addition of palbociclib rather than placebo to fulvestrant; the combination was also associated with a significant improvement in pain scores from baseline.
Similar to PALOMA-2, a detailed safety analysis of this trial also showed “no apparent loss of efficacy” with the dose modifications necessary to manage the primary AE of neutropenia. These findings appeared in The Oncologist in 2016.
As reported in The New England Journal of Medicine in 2018, the median OS duration was longer with palbociclib than placebo (34.9 vs 28.0 months) in the overall cohort, but the between-group difference was not statistically significant. The subgroup of participants with sensitivity to prior endocrine therapy, however, had a significant 28% reduced mortality risk with palbociclib versus placebo.
| Phase 3 | |
|---|---|
|
Patient population: Treatment-naïve, Asian postmenopausal women with HR-positive, HER2-negative ABC |
Treatment: Palbociclib 125 mg/day for 3 weeks of each 4-week cycle or placebo plus letrozole 2.5 mg/day |
This trial is evaluating the addition of palbociclib to letrozole in Asian postmenopausal patients who have not received prior treatment for advanced disease. The primary endpoint of the study is PFS.
| Phase 3 | |
|---|---|
|
Patient population: Previously untreated postmenopausal women with HR-positive, HER2-negative ABC |
Treatment: Ribociclib 600 mg/day for 3 weeks of each 4-week cycle or placebo plus letrozole 2.5 mg/day |
The first interim analysis of this trial was published in The New England Journal of Medicine in 2016 and showed a significant improvement in PFS with ribociclib versus placebo, with the median unreached and 14.7 months, respectively (HR=0.56). The objective response rate was also significantly higher with ribociclib than placebo (52.7 vs 37.1%).
Neutropenia was the most common grade 3–4 adverse event (AE) in the ribociclib group, observed at a rate of 59.3% compared with 0.9% in the placebo group, followed by leukopenia (21.0 vs 0.6%).
The PFS benefit associated with ribociclib was maintained in a second interim analysis (published in the Annals of Oncology in 2018), and also in the subgroups of women aged 65 years or older (reported in Breast Cancer Research and Treatment in 2017), those with de novo advanced disease (reported in Breast Cancer Research and Treatment in 2017), and the subset of US patients (reported in Clinical Breast Cancer in 2019).
Moreover, as described in Breast Cancer Research and Treatment in 2018, the CDK4/6 inhibitor was also associated with an earlier and more durable response, greater degree of tumor shrinkage, and pain reduction, while another report in the same journal focusing on HRQoL showed no significant deterioration in the ribociclib group.
| Phase 3 | |
|---|---|
|
Patient population: Men or postmenopausal women who have received no more than one prior endocrine therapy for HR-positive, HER2-negative ABC |
Treatment: Ribociclib 600 mg/day for 3 weeks of each 4-week cycle or placebo plus fulvestrant 500 mg every 4 weeks (plus an extra dose on day 15 of cycle 1) |
As reported in the Journal of Clinical Oncology in 2018, the study’s primary endpoint of PFS was significantly improved with the addition of ribociclib versus placebo to fulvestrant, at an HR for progression or death of 0.59. The results were consistent regardless of whether patients received treatment in the first (HR=0.58) or second line (HR=0.57).
The most common AEs of grade 3 in the ribociclib group were neutropenia and leukopenia, reported by a respective 46.6% and 13.5% of patients compared with 0.0% of those given placebo, and neutropenia was also the most frequent grade 4 AE (6.8 vs 0.0%).
Adding ribociclib to fulvestrant was also associated with a significant OS advantage, such that the risk for death was 28% lower with ribociclib than placebo, according to a 2020 publication in The New England Journal of Medicine.
And once again, patients’ HRQoL was maintained with the addition of ribociclib, the researchers reported in Breast in 2020.
| Phase 3 | |
|---|---|
|
Patient population: Premenopausal women who have received up to one previous line of chemotherapy for HR-positive, HER2-negative ABC |
Treatment: Ribociclib 600 mg/day for 3 weeks of each 4-week cycle or placebo plus either tamoxifen 20 mg/day, letrozole 2.5 mg/day, or anastrozole 1 mg/day, all with goserelin 3.6 mg on day 1 of each cycle |
Supplementing endocrine therapy with ribociclib significantly boosted the primary endpoint of PFS, such that the risk for progression or death was 45% lower in the ribociclib group. Neutropenia and leukopenia continued to be the most frequent AEs of grade 3 or 4 in the ribociclib versus placebo group, at rates of 61% versus 4% and 14% versus 1%, respectively. These findings were published in The Lancet Oncology in 2018.
OS data reported in The New England Journal of Medicine in 2019 favored the combination of ribociclib plus endocrine therapy, with a reduction in the risk for death of 29% relative to placebo plus endocrine therapy.
Ribociclib addition was also associated with improved HRQoL, with a longer time to deterioration of at least 10% in global HRQoL scores with in the ribociclib than placebo treatment arm (published in Therapeutic Advances in Medical Oncology in 2020).
| Phase 2 | |
|---|---|
|
Patient population: Women with HR-positive, HER2-negative ABC who have progressed on endocrine therapy and received 1–2 chemotherapy regimens in the advanced setting |
Treatment: Abemaciclib 200 mg twice a day |
MONARCH 1 demonstrated the antitumor activity and tolerability of abemaciclib in heavily pretreated patients. As reported in Clinical Cancer Research in 2017, the objective response rate (ORR) was 19.7% and the clinical benefit rate was 42.4%.
Leukopenia (27.7%) and neutropenia (26.9%) were the most common treatment-emergent AEs of grade 3 or 4, followed by diarrhea (19.7%) and fatigue (12.9%).
| Phase 2 | |
|---|---|
|
Patient population: Women who have received 1–2 chemotherapy regimens for HR-positive, HER2-negative metastatic breast cancer and have progressed on endocrine therapy |
Treatment: Abemaciclib 150 mg twice daily plus tamoxifen 20 mg/day; abemaciclib 150 mg twice a day; or abemaciclib 200 mg twice daily plus prophylactic loperamide 2 mg/day |
Treatment with the combination of tamoxifen and abemaciclib did not significantly improve either PFS or ORR relative to single-agent abemaciclib, but the study “confirmed the single-agent activity” of the CDK4/6 inhibitor in this “heavily pretreated” patient population, said the researchers in Clinical Breast Cancer in 2020.
The incidence of any-grade and grade 3 diarrhea was comparable among patients who received abemaciclib monotherapy at the 150 mg dose and those given the higher dose with prophylactic loperamide, at 67.1% versus 62.3%, and 3.8% versus 7.8%, respectively.
| Phase 3 | |
|---|---|
|
Patient population: Women with HR-positive, HER2-negative ABC who have progressed on endocrine therapy |
Treatment: Abemaciclib 150 mg twice daily or placebo plus fulvestrant 500 mg every 4 weeks (plus an extra dose on day 15 of cycle 1) |
In this study, women treated with abemaciclib plus fulvestrant had significantly better PFS (median, 16.4 vs 9.3 months; HR=0.553) and ORR (48.1 vs 21.3%) than their counterparts given placebo plus fulvestrant. Neutropenia was the most frequent grade 3–4 treatment-emergent AE in the abemaciclib group, observed at a rate of 26.5% compared with 1.7% in the placebo group, followed by diarrhea (13.4 vs 0.4%) and leukopenia (8.8 vs 0.0%). These data were published in the Journal of Clinical Oncology in 2017.
A prespecified interim OS analysis was reported in JAMA Oncology in 2019, and showed a significant improvement with abemaciclib relative to placebo, at a median of 46.7 and 37.3 months, respectively, and an HR for death of 0.757.
As seen for palbociclib and ribociclib, abemaciclib also appeared to be associated with favorable HRQoL. Specifically, treatment with the CDK4/6 inhibitor led to significant delays in deterioration of social and cognitive functioning, as well as pain and most other symptoms, with the exception of diarrhea, which favored the control arm (reported in The Oncologist in 2019).
| Phase 3 | |
|---|---|
|
Patient population: Treatment-naïve postmenopausal women with HR-positive, HER2-negative ABC |
Treatment: Abemaciclib 150 mg twice daily or placebo plus either daily anastrozole 1 mg or letrozole 2.5 mg |
Abemaciclib plus endocrine therapy achieved significantly better PFS relative to endocrine therapy alone, both in the interim analysis published in the Journal of Clinical Oncology in 2017 (median, unreached vs 14.7 months; HR=0.54) and in the final PFS analysis described in npj Breast Cancer in 2019 (median, 28.2 vs 14.8 months; HR=0.54).
The safety profile in both analyses remained consistent with prior studies, such that the most frequent grade 3 or 4 AE in the abemaciclib versus placebo group were neutropenia (21.1 vs 1.2% and 23.9 vs 1.2% in the interim and final analysis, respectively), diarrhea (9.5 vs 1.2% in both), and leukopenia (7.6 vs 0.6% and 8.6 vs 0.6%).
The HRQoL data from this study – which appeared in The Oncologist in 2020 – showed that the between-group differences for certain scores statistically favored the placebo arm but, with the exception of diarrhea, the differences were not clinically meaningful.
| Phase 3 | |
|---|---|
|
Patient population: Postmenopausal women with HR-positive, HER2-negative ABC who have either received no prior systemic therapy (cohort A) or have progressed on endocrine therapy (cohort B) |
Treatment: Abemaciclib 150 mg twice daily or placebo plus: anastrozole 1 mg/day or letrozole 2.5 mg/day in cohort A; or fulvestrant 500 mg every 4 weeks (plus an extra dose on day 15 of cycle 1) in cohort B |
As reported in Therapeutic Advances in Medical Oncology in 2020, adding abemaciclib to endocrine therapy significantly improved PFS in treatment-naïve patients, with the median unreached compared with 14.7 months for placebo plus endocrine therapy (HR=0.499). This was also the case for the previously treated cohort, with respective median durations of 11.5 and 5.6 months (HR=0.376).
The most common grade 3 or worse AEs among abemaciclib- versus placebo treated patients remained neutropenia (26.4 vs 6.1% in cohort A; 29.8 vs 3.8% in cohort B) and leukopenia (13.2 vs 2.0% in cohort A; 22.1 vs 3.8% in cohort B). But the rates of diarrhea with abemaciclib were lower (3.9% and 1.9% in cohorts A and B, respectively) than in the other MONARCH trials.
| Phase 2 | |
|---|---|
|
Patient population: Women with HR-positive, HER2-positive ABC who have received at least two HER2-directed therapies |
Treatment: Abemaciclib 150 mg twice daily, plus trastuzumab and fulvestrant; abemaciclib 150 mg twice daily plus trastuzumab; or single-agent chemotherapy plus trastuzumab |
A report from the trial, published in The Lancet Oncology in 2020, revealed a significant PFS benefit of the triple regimen over the combination of chemotherapy and trastuzumab, with respective median times of 8.3 and 5.7 months, and an HR for progression or death of 0.67. By contrast, abemaciclib plus trastuzumab did not offer a significant advantage relative to the control.
Neutropenia was the most common grade 3–4 treatment-emergent AE in each of the treatment arms, occurring at rates of 22–27%.
| Phase 4 | |
|---|---|
|
Patient population: Endocrine therapy-naïve patients with HR-positive, HER2-negative ABC and poor prognostic factors |
Treatment: Abemaciclib or a nonsteroidal aromatase inhibitor (anastrozole or letrozole) (doses not specified) |
This trial aimed to investigate the combination of abemaciclib and a nonsteroidal aromatase inhibitor in participants with one or more poor prognostic factor (high grade tumor, negative progesterone receptor status, liver metastases, or treatment-free interval <36 months). It was withdrawn due to a strategic decision in light of emerging data for patients with HR-positive, HER2-negative metastatic breast cancer.
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2020 Springer Healthcare Ltd, part of the Springer Nature Group
The production and publication of this independent article is supported by an educational grant from Lilly.
medwireNews Senior Writer
