About the Breast Cancer Therapy Expert Group (BCTEG)
Meeting objectives and role of funding sources
Introduction
CDK 4/6 inhibitors: brief summary of clinical evidence in mBC
Agent | Trial | Study Type and Treatments | Population Studied | Key Efficacy Findings | Key Safety Findings |
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Palbociclib | PALOMA 1 | Phase 2; Open-label Palbociclib or Placebo + Letrozole | Postmenopausal; HR+, HER2−, ABC ~43% of pts had prior CT | Median PFS 10.2 mo for placebo + letrozole vs. 20.2 mo for palbociclib + letrozole (HR 0.488, 95% CI 0.319–0.748; P = 0.0004). ORR (43% vs. 33%; P = 0.047) and CBR (81% vs. 58%; P = 0.0009) favored palbociclib + letrozole | Gr 3/4 Events (palbociclib vs. placebo) Neutropenia 54% versus 1% Leucopenia 19% versus 0% Fatigue 4% versus 1% No febrile neutropenia or neutropenia-related infections |
PALOMA 2 | Double-blind, Phase 3 Palbociclib or Placebo + Letrozole | Postmenopausal; HR+, HER2− ABC No prior therapy for advanced disease | Primary efficacy endpoint, PFS, met; favors palbociclib (24.8 mo vs. 14.5 mo; HR 0.58; 95% CI 0.46; 0.72; P < 0.001) Consistent benefit in PFS across subgroups OS data immature at time of analysis ORR 42.1% versus 34.7%; P = 0.06 CBR 84.9% versus 70.3%; P < 0.001 | Most common toxicities (30% or more patients) included neutropenia, leucopenia, fatigue, nausea, arthralgia, alopecia Febrile neutropenia occurred in 1.8% of palbociclib treated patients versus 0% in placebo group | |
PALOMA 3 | Randomized; Double-blind, Phase 3 Palbociclib or Placebo + Fulvestrant ~ 1/3 with prior CT for metastatic disease | HR+, HER2− ABC Progression on prior endocrine therapy | Primary efficacy endpoint, PFS, met at interim analysis; favors palbociclib (9.2 mo vs. 3.8 mo; HR 0.42; 95% CI 0.32; 0.56; P < 0.001) Benefit observed across major subgroups examined based on HRs. OS data immature at time of analysis ORR 10.4% versus 6.3%; P = 0.16 CBR 34.0% versus 19.0%; P < 0.001 | Toxicities occurring in 30% or more patients (Palbociclib vs. Placebo); Gr 3/4, Palbociclib versus Placebo Neutropenia (78.8% vs. 3.5%); 62.0% versus 0.6% Leukopenia (45.5% vs. 4.1%); 25.2% versus 0.6% Fatigue (38.0% vs. 26.7%); 2.0% versus 1.2% Low rate of febrile neutropenia (0.6%, both groups) | |
Ribociclib | MONALEESA-2 | Randomized; Double-blind, Phase 3 | Postmenopausal; HR+, HER2− recurrent or metastatic BC No prior therapy for advanced disease | Primary efficacy endpoint, PFS, met at interim analysis; favors ribocilclib (Not reached vs. 14.7mo; HR 0.56; 95% CI 0.43; 0.72; P < 3.29 × 10−6) OS data immature at time of analysis ORR 40.7% versus 27.5%; P < 0.001 CBR 79.6% versus 72.8% P = 0.02 Ribociclib also favored in subgroup of patients with HR+, HER2− ABC at diagnosis (Median PFS not reached w/ribociclib vs. 16.4 mo w/placebo HR 0.45, 95% CI 0.27–0.75) | Toxicities occurring in 30% or more patients (Ribociclib vs. Placebo); Gr 3/4, Ribociclib versus Placebo Neutropenia (74.3% vs. 5.2%); 59.3% versus 0.9% Nausea (51.5% vs. 28.5%); 2.4% versus 0.6% Infections (50.3% vs. 42.4%); 4.2% versus 2.4% Fatigue (36.5% vs. 30.0%); 2.4% versus 0.9% Diarrhea (35.0% vs. 22.1%); 1.2% versus 0.9% Alopecia (33.2% vs. 15.5%); Gr 3/4 not applicable Leukopenia (32.9% vs. 3.9%); 21.0% versus 0.6% Febrile neutropenia occurred within 4 weeks in 1.5% of patients in ribociclib group vs. 0% placebo group QTc prolomgation occured in 11(3.3%) and 1 sudden death in the setting of hypokalemia and G2 QTc prolongation in the ribociclib group |
MONALEESA-7 | Double-blind, randomized, Phase III Ribociclib or placebo + tamoxifen/NSAI and goserelin | Pre- or peri-menopausal women with HR+, HER2− ABC who had received ≤ 1 line of CT and no prior ET for ABC | PFS significantly improved with ribociclib (median PFS, 23.8 vs. 13.0 months; HR 0.553; P = 9.83 × 10−8) ORR 51% versus 36% (ribociclib vs placebo) arm; P = 3.17 × 10−4) CBR 80% versus 67%; P = 3.40 × 10−4. | Most frequent all-grade AEs; ≥ 25% of patients; ribociclib vs placebo arm) Neutropenia (76% vs 8%) Hot flush (34% vs 34%) Nausea (32% vs 20%) Leukopenia (31% vs 6%) Arthralgia (30% vs 27%) Gr 3/4 Events in ≥ 5% of patients: Neutropenia (61% vs 4%) Leukopenia (14% vs 1%) Febrile neutropenia: 2% versus < 1% AEs leading to permanent discontinuation: 4% versus 3% | |
Abemaciclib | MONARCH-1 | Phase 2 single arm Abemaciclib until PD | HR+/HER2− mBC, PD after ET and CT 1–2 lines CT for metastatic disease | Confirmed ORR 19.7% CBR 42.4% Median PFS 6.0 mo Median OS 17.7 mo | Diarrhea, fatigue, and nausea most common AEs 7.6% discontinued due to AEs |
MONARCH-2 | Phase 3; randomized, double-blind placebo-controlled Abemaciclib or Placebo + Fulvestrant | HR+, HER2− ABC PD after ET No prior CT for ABC | PFS 16.4 mo versus. 9.3 mo (HR 0.553; 95% CI 0.449; 0.681; P < 0.001) Benefit consistent across subgroups ORR 35.2% versus 16.1% P < 0.001 CBR 72.2% versus 56.1% P < 0.001 | Toxicities occurring in 30% or more patients (Abemaciclib vs. Placebo); Gr 3/4, Abemaciclib vs. Placebo Diarrhea (86.4% vs. 24.7%); 13.4% versus 0.4% Neutropenia (46.0% vs. 4.0%); 26.5% versus 1.7% Nausea (45.1% vs. 22.9%); 2.7% versus 0.9% Fatigue (39.9% vs. 26.9%); 2.7% versus 0.4% Abdominal Pain (35.4% vs. 15.7%); 2.5% versus 0.9% | |
MONARCH-3 | Abemaciclib or Placebo, + NSAI | HR+, HER2− ABC No prior systemic therapy for metastatic disease | Primary efficacy endpoint, PFS, favors abemaciclib (HR 0.543; 95% CI 0.409; 0.723; P = 0.000021); benefit observed across subgroups OS data immature at time of analysis
Response Rate
All patients ORR favors abemaciclib (48.2% vs. 34.5%; P = 0.002) CBR trended better w/abemaciclib (78.0% vs. 71.5%; P = NS) Patients with measurable disease at baseline ORR favors abemaciclib (59.2% vs. 43.8%; P = 0.004) CBR favors abemaciclib (79.4% vs. 69.2%; P = 0.024) | Toxicities (30% or more patients, Abemaciclib vs. Placebo); Gr 3/4, Abemaciclib vs. Placebo Diarrhea (81.3% vs. 29.8%); 9.5% versus 1.2% Neutropenia (41.3% vs. 1.9%); 21.1% versus 1.2% Fatigue (40.1% vs. 31.7%); 1.8% versus 0% Nausea (38.5% vs. 19.9%); 0.9% versus 1.2% 1 pt with nonserious febrile neutropenia in abemaciclib arm Gr 3/4 neutropenia in 21.1%; not associated with neutropenic fever Diarrhea (Gr 3) occurred early, managed with dose reduction and antidiarrheal medications |
CDK 4/6 treatment: what are the differentiators?
What are the differentiators, current or future, that drive your decision to treat using the various endocrine options available for the treatment of metastatic breast cancer?
Barriers to use of CDK 4/6 inhibitors
What significant clinical toxicities, financial barriers, and/or common community practice misunderstandings exist regarding the use of CDK 4/6 inhibitors?
Agent (trade name) | Year approved | Indication | Most common adverse events and required monitoring |
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Palbociclib (Ibrance®) | 2015 | HR+, HER2− Advanced or metastatic breast cancer, in combination with: A. An AI as initial endocrine based therapy in postmenopausal women; or B. Fulvestrant, in women with disease progression following endocrine therapy. | (Incidence ≥ 10%) Neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, diarrhea, thrombocytopenia, rash, vomiting, decreased appetite, asthenia, pyrexia Required Monitoring: CBC |
Ribociclib (Kisqali®) | 2017 | Postmenopausal women with HR+, HER2− Advanced or metastatic breast cancer in combination with an AI as initial endocrine-based therapy. | (Incidence > 20%) Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, back pain Required Monitoring: QT interval prolongation, Electrocardiograms (ECGs), Electrolytes, Liver Function Tests (LFTs), CBC |
Abemaciclib (Verzenio™) | 2017 | In combination with fulvestrant for HR+, HER2−, Advanced or metastatic breast cancer with disease progression following endocrine therapy; or As monotherapy for HR+, HER2−, Advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting | (Incidence ≥ 20%) Diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, thrombocytopenia Required Monitoring: Liver Function Tests (LFTs), CBC, Monitor for venous thrombosis and pulmonary embolism |
Sequencing Therapies for ER+/HER2– MBC
How would you approach patients that have progressed on a CDK 4/6 inhibitor?
Biomarkers for CDK 4/6 inhibitors
What biomarkers, if any, have been shown to predict benefit, or lack thereof, when using CDK4/6 inhibitors (e.g., ESR1, CND1 amplification, p16 loss, or RB1 expression)?
Summary and key points
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Level 1 evidence now supports use of a CDK 4/6 inhibitor in combination with endocrine therapy for patients with HR+, HER2−, mBC as first-line treatment.
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Currently, there are no biomarkers that reliably define patients who will or will not benefit from the addition of a CDK 4/6 inhibitor to endocrine therapy; ESR1 mutational status should not restrict use of a CDK 4/6 inhibitor.
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Financial considerations may limit the use of these agents, and treatment-related toxicities such as diarrhea and fatigue may be dose limiting; although neutropenia is a frequent occurrence with these agents, the rate of febrile neutropenia is low.
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Additional research is needed to identify the optimal sequencing of CDK 4/6 inhibitors in relation to other therapies as well as optimal duration of therapy; at present, use in the upfront setting is better than waiting for a later line of therapy or adding after endocrine therapy has started.