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The Expert Committee, after evaluation, declines to list the medicine proposed in the application.
The Model List of Essential Medicines reports reasons that Committee Members have identified for denying listing.
Rejected
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Rejected
ATC codes: L01EF01
Indication
Other specified malignant neoplasms of breast ICD11 code: 2D1Y
INN
Palbociclib
Medicine type
Chemical agent
List type
Complementary
Formulations
Oral > Solid: 75 mg ; 100 mg ; 125 mg
EML status history
Application rejected in 2021 (TRS 1035)
Sex
All
Age
Adolescents and adults
Therapeutic alternatives
abemaciclib (ATC codes: L01EF03)
ribociclib (ATC codes: L01EF02)
Patent information
Main patent is active in several jurisdictions. For more information on specific patents and license status for developing countries visit www.MedsPal.org
Tags
Wikipedia
DrugBank
Expert Committee recommendation
The Expert Committee noted that breast cancer continues to be the leading cause of cancer death in women, and that more than half of women diagnosed with breast cancer have HR+/HER2– disease. The Committee noted the results of clinical trials on CDK 4/6 inhibitors in the first- and second-line treatment settings suggest a potentially meaningful survival benefit with this class of medicines when added to endocrine therapy compared with endocrine therapy alone. However, the Committee considered that, while promising, these survival data are currently immature. In particular, in the first-line setting, it is not yet known if the progression-free survival gains seen in trials will translate to overall survival benefit in the long term. Other areas of uncertainty identified by the Committee included questions on the optimal dose and duration of treatment, use in early-stage disease, and whether meaningful clinical differences exist between individual medicines within the pharmacological class. The Committee also noted that CDK4/6 inhibitors are unlikely to be cost-effective in most settings at their current high prices and would pose serious affordability challenges, especially in low- and middle-income countries. The Expert Committee therefore did not recommend the listing of CDK 4/6 inhibitors on the EML at this time. The Committee recognized that more mature survival data are likely to be available in the near future, and requested that an application with updated survival data be submitted for consideration by the Expert Committee in 2023. The Committee also considered that CDK 4/6 inhibitors could be flagged to the Medicines Patent Pool as candidates for consideration for negotiating public health-oriented licences, noting that the timelines for negotiating such licences are lengthy. The outcome of negotiations might provide important insight for future EML consideration on potential accessibility of this class of medicines in low- and middle-income countries.
Background
CDK 4/6 inhibitors have not previously been considered for inclusion on the EML. In 2015, as part of a comprehensive review of cancer medicines on the EML, the following medicines were endorsed for inclusion on the EML for use in protocols for the treatment of metastatic breast cancer: capecitabine, cyclophosphamide, docetaxel, doxorubicin, paclitaxel, vinorelbine, anastrozole and tamoxifen. Trastuzumab was also recommended for treatment of HER2+ early stage and metastatic breast cancer (1). CDK4/6 inhibitors act on the CDK4/6 pathway which is overreactive in many breast cancers. Inhibition of the CDK4/6 pathway activates the tumour suppressor retinoblastoma-associated protein leading to cell cycle arrest. CDK4/6 inhibitors are generally not used as monotherapy but are combined either with aromatase inhibitors or fulvestrant. Aromatase inhibitors, represented by anastrozole, are currently included in the EML. Fulvestrant is not currently included, but a separate application for listing was submitted for consideration in 2021.
Public health relevance
Breast cancer is the leading cause of cancer death in women globally, responsible for 6.6% of all cancer deaths in 2018 (2). In high-income countries, the incidence of breast cancer is high and mortality rates are low, while in low- and middle-income countries, the incidence is lower but mortality rates are higher. The overall 5-year survival rates for high-income countries are estimated to be higher than 85%. In comparison, in low- and middle-income countries, 5-year survival rates are reported to range between 38% and 60% (3). While improved early detection and advances in systemic therapy for early-stage disease have resulted in some decline in breast cancer mortality since 1989, metastatic breast cancer remains largely incurable with a median survival of about 24 months (4). Factors associated with poor survival include age ≥ 50 years, visceral disease, shorter disease-free interval, tumours associated with aneuploidy, tumours with a high S-phase fraction, p53 accumulation, low bcl-2 expression, negative HR status and positive HER2 status (5). Five-year survival for patients with metastatic disease is about 18% in Europe (6). The HR+/HER2– breast cancer subtype is the most common, reported in more than two thirds of all cases (7).
Benefits
First-line therapy for HR+/HER2– advanced or metastatic breast cancer in pre- and postmenopausal women Abemaciclib MONARCH 3 was a randomized, double-blind, placebo-controlled phase III trial of abemaciclib in combination with aromatase inhibitors as initial therapy for advanced breast cancer (8,9). The trial included 493 postmenopausal women who were randomized 2:1 to abemaciclib plus a nonsteroidal aromatase inhibitor (anastrozole or letrozole according to the physician’s choice) or placebo plus a nonsteroidal aromatase inhibitor. After median follow-up of 26.7 months, median investigator-assessed progression-free survival was 28.2 months in the abemaciclib arm versus 14.8 months in the placebo arm, an absolute progression-free survival gain of 13.4 months (hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.42 to 0.70). Mature data for the secondary endpoint of overall survival are not yet available. Based on results from MONARCH 3, abemaciclib received a score of 3 on the European Society for Medical Oncology magnitude of clinical benefit scale (ESMO-MCBS) v1.1 for first-line treatment in combination with an aromatase inhibitor for locally advanced or metastatic HR+/HER2– breast cancer in postmenopausal women (10). Palbociclib PALOMA 2 was a randomized, double-blind, placebo-controlled phase III trial of palbociclib in combination with letrozole as first-line therapy for advanced breast cancer (11). The trial included 666 postmenopausal women who were randomized 2:1 to either palbociclib plus letrozole or placebo plus letrozole. Median progression-free survival was 24.8 months in the palbociclib arm versus 14.5 months in the placebo arm, an absolute progression-free survival gain of 10.3 months (HR 0.58, 95% CI 0.46 to 0.72. Mature data for the secondary endpoint of overall survival are not yet available. Based on results from PALOMA 2, palbociclib received a score of 3 on the ESMO-MCBS v1.1 as first-line treatment in combination with letrozole for metastatic HR+/HER2– breast cancer (10). Ribociclib MONALEESA 2 was a randomized, double-blind, placebo-controlled phase III trial of ribociclib in combination with letrozole as first-line therapy for advanced breast cancer (12). The trial included 668 postmenopausal women who were randomized 1:1 to either ribociclib plus letrozole or placebo plus letrozole. After median follow-up of 26.4 months, median progression-free survival was 25.3 months in the ribociclib arm versus 16.0 months in the placebo arm, an absolute progression-free survival gain of 9.3 months (HR 0.57, 95% CI 0.46 to 0.70). Mature data for the secondary endpoint of overall survival are not yet available. Based on results from MONALEESA 2, ribociclib received a score of 3 on the ESMO-MCBS v1.1 as first-line treatment in combination with letrozole for metastatic HR+/HER2– breast cancer in postmenopausal women (10). MONALEESA 7 was a randomized, double-blind, placebo-controlled phase III trial of ribociclib plus endocrine therapy (anastrozole, letrozole or tamoxifen, each combined with goserelin) as first-line therapy for advanced breast cancer (13,14). The trial included 672 premenopausal women who were randomized 1:1 to either endocrine therapy with ribociclib or endocrine therapy with placebo. Median progression-free survival was 23.8 months in the ribociclib arm versus 13.0 months in the placebo arm, an absolute progression-free survival gain of 10.8 months (HR 0.55, 95% CI 0.44 to 0·69) (13). The estimated overall survival at 42 months was 70.2% in the ribociclib arm versus 46.0% in the placebo arm (HR 0.71, 95% CI 0.54 to 0.95) (14). An absolute gain in overall survival of 16 months for ribociclib was calculated based on the point estimate for the HR. Based on results from MONALEESA 7, ribociclib received a score of 5 on the ESMO-MCBS v1.1 as first-line treatment in combination with endocrine therapy for metastatic HR+/HER2– breast cancer in premenopausal women (10). Second-line therapy Abemaciclib MONARCH 2 was a randomized, double-blind, placebo-controlled phase III trial of abemaciclib in combination with fulvestrant as second-line therapy for advanced breast cancer (15,16). The trail included 669 women of any menopausal status who were randomized 2:1 to receive abemaciclib or placebo each combined with fulvestrant. After median follow-up of 19.5 months, median progression-free survival was 16.4 months in the abemaciclib arm versus 9.3 months in the placebo arm, an absolute progression-free survival gain of 7.1 months (HR 0.55, 95% CI 0.45 to 0.68) (15). After median follow-up of 47.7 months, median overall survival was 46.7 months in the abemaciclib arm versus 37.3 months in the placebo arm, an absolute overall survival gain of 9.4 months (HR 0.76, 95% CI 0.61 to 0.95) (16). Based on results from MONARCH 2, abemaciclib received a score of 4 on the ESMO-MCBS v1.1 as second-line treatment in combination with fulvestrant for advanced HR+/HER2– breast cancer in postmenopausal women (10). Palbociclib PALOMA 3 was a randomized, double-blind, placebo-controlled phase III trial of palbociclib in combination with fulvestrant as second-line therapy for advanced breast cancer (17,18). The trail included 521 women of any menopausal status who were randomized 2:1 to either palbociclib or placebo, each combined with fulvestrant. After median follow-up of 8.9 months, median progression-free survival was 9.5 months in the palbociclib arm versus 4.6 months in the placebo arm, an absolute progression-free survival gain of 4.9 months (HR 0.46, 95% CI 0.36 to 0.59) (17). After a median follow-up of 44.8 months, median overall survival was 34.9 months in the palbociclib arm versus 28.0 months in the placebo arm, an absolute gain in overall survival of 6.9 months (HR 0.81, 95% CI 0.64 to 1.03) (18). Based on results from PALOMA 3, palbociclib received a score of 4 on the ESMO-MCBS v1.1 as second-line treatment in combination with fulvestrant for metastatic HR+/HER2– breast cancer (10). Ribociclib MONALEESA 3 was a randomized, double-blind, placebo-controlled phase III trial of ribociclib plus fulvestrant as first- and second-line therapy for advanced breast cancer (19,20). The trial included 726 postmenopausal women who were randomized 2:1 to either ribociclib or placebo, each combined with fulvestrant. Median progression-free survival was 20.5 months in the ribociclib arm versus 12.8 months in the placebo arm, an absolute progression-free survival gain of 7.7 months (HR 0.59, 95% CI 0.48 to 0.73) (19). The estimated overall survival at 42 months was 57.8% in the ribociclib arm versus 45.9% in the placebo arm (HR 0.72, 95% CI 0.57 to 0.92) (20). An absolute gain in overall survival of 16 months for ribociclib was calculated based on the point estimate for the HR. Based on results from MONALEESA 3, ribociclib received a score of 4 on the ESMO-MCBS v1.1 as first- or second-line treatment in combination with fulvestrant for metastatic HR+/HER2– breast cancer in postmenopausal women (10). Meta-analysis of randomized controlled trials A systematic review and meta-analysis of eight randomized controlled trials (4580 patients, of whom 2802 received palbociclib, ribociclib or abemaciclib in combination with endocrine therapy (aromatase inhibitors, tamoxifen or fulvestrant)) evaluated the efficacy of CDK4/6 inhibitors for the treatment of metastatic breast cancer and tested the heterogeneity between different compounds with regard to their effect to improve progression-free survival and overall survival (21). For progression-free survival, the pooled analysis showed a statistically significant improvement in patients treated with the CDK4/6 inhibitor in combination with endocrine therapy versus patients treated with endocrine therapy alone (HR 0.55, 95% CI 0.50 to 0.59). For overall survival, the pooled analysis showed a statistically significant reduction in the risk of dying in patients receiving CDK4/6 inhibitors (HR 0.76, 95% CI 0.68 to 0.85). The effect was independent of sensitivity or not to aromatase inhibitors. Pooled analysis of data for each CDK4/6 inhibitor showed a statistically significant reduction in the risk of dying only for ribociclib and abemaciclib; for palbociclib the HR for overall survival was 0.83, 95% CI 0.68 to 1.02. Real-world studies The RENATA study was a prospective study of real-world use of palbociclib in combination with endocrine therapy in 128 participants (127 women, one man) of any menopausal status treated in two centres in Argentina between 2015 and 2019 (22). Median progression-free survival was 36.7 months with first-line treatment and 24.2 months with second-line treatment. The overall response rate was 45.3% and 25.0% in the first- and second-line setting, respectively. Median overall survival in the entire population was not reached.
Harms
The main adverse effect of the pharmacological class of CDK4/6 inhibitors is haematological toxicity. Their use is associated with a predictable, reversible and generally non-infection-prone neutropenia – related to the cell cycle effects on the haematopoiesis of the cell cycle blockade (23). A systematic review and meta-analysis of the efficacy and safety of CDK4/6 inhibitors from the phase III clinical trials reported an onset of grade 3 and 4 neutropenia in 65%, 58% and 26% of patients using palbociclib, ribociclib and abemaciclib, respectively (24). However, the occurrence of febrile neutropenia indicating possible infection was reported in less than 1% of the trial population with any of these compounds. In general, the onset of moderate to severe neutropenia prompts a delay, temporary interruption or dose reduction of the CDK4/6 inhibitor and rarely requires other interventions due to the reversible nature of this side-effect. Granulocyte stimulating factors and/or antibiotic prophylaxis are not commonly used, as febrile neutropenia occurs quite rarely (25). The only precaution recommended with the use of this class of agents therefore is a complete count blood at the beginning of each cycle and, as a precaution, 2 weeks after the start of the first two cycles to check the bone marrow reserve. Moreover, CDK4/6 inhibitors are associated with molecule-specific safety profiles that informs the clinicians’ decision to use one compound over another one, along with patient preference. The different safety profiles are currently the most important factor taken into account in the treatment decision for patients with HR+/HER2– advanced breast cancer in the first- or second-line of therapy, in the absence of direct comparisons. The principal differences in the safety profiles of abemaciclib, palbociclib and ribociclib from the phase III trials are summarized in Table 6. Table 6. Adverse events in patients treated with CDK4/6 inhibitors, percentage of patients Adverse event Abemaciclib Palbociclib Ribociclib Any grade 3 and 4 adverse event 58% 74% 79% Grade 3 and 4 neutropenia 26% 65% 58% Febrile neutropenia < 1% < 1% < 1% Anaemia 30% (7% grade 3) 24% (5.5% grade 3/4) 19% Increased aspartate aminotransferase or alanine aminotransferase All grade < 10% All grade < 10% 25% (9% grade 3) Diarrhoea 87% diarrhoea (13% grade 3) 25% 52% Nausea 45% nausea (3% grade 3) 35% 35% Treatment discontinuation was highest with abemaciclib, in part related to the higher rates of treatment-related diarrhoea (25). The use of ribociclib has been associated with a prolongation of the QT-interval. An electrocardiogram finding of a QT-interval corrected for heart rate according to the Friderica formula (QTcF) > 450 ms was observed in 7% of the patients treated with ribociclib and 1% in the placebo arm (13,14,26). Moreover, 10% of patients receiving ribociclib experienced a QTcF prolongation of +60 ms or more in at least one postbaseline electrocardiogram assessment compared with 2% in the placebo arm. QT prolongation was more commonly observed when tamoxifen was the endocrine agent in association (16%) than when an aromatase inhibitor was used (7%). While no clinical symptoms or arrhythmias (e.g. ventricular tachycardia or torsades de pointes) were reported with the QTcF prolongation, the treatment was interrupted or reduced in 4% of the patients in the ribociclib arm, in line with the trial protocol. The United States Food and Drug Administration recommend initial electrocardiogram monitoring for patients receiving ribociclib. No potentially clinically relevant effect on the QTc interval has been reported with abemaciclib or palbociclib (27). Other studies have addressed the possible differences in safety of CDK4/6 inhibitors in different ethnic populations. An analysis of real-world use of palbociclib with endocrine therapy in patients with HR+/HER2– advanced breast cancer in Argentina found a higher rate of febrile neutropenia than observed in the phase III trials (22). A real-world study on the use of palbociclib in 169 patients with metastatic breast cancer in South Korea reported neutropenia (mostly grade 3 or 4) in 88.3% of patients which is higher than reported in phase III studies (28). Similarly, a higher incidence of haematological toxicity was reported in a phase II single-arm trial of palbociclib plus letrozole as first-line treatment in 42 postmenopausal participants with advanced breast cancer in Japan; neutropenia was reported in 100% of participants, of whom 93% had grade 3 or 4 neutropenia (29). Sufficient data are lacking on the haematological effects of CDK4/6 inhibitors in women of African ethnicity, in whom a high incidence of benign ethnic neutropenia has been reported (30,31).The phase II PALINA trial is evaluating the safety of palbociclib in combination with letrozole or fulvestrant in African American women; the results had not been reported at the time the application was submitted (32).
Additional evidence
Results from the PALINA trial were published in June 2021. This trial included 35 African American women with HR+/HER2– advanced breast cancer. Duffy null polymorphism, which is associated with reduced neutrophil counts in individuals of African ancestry, was present in 19 participants. Grades 3 and 4 neutropenia were observed in significantly more participants with Duffy null status compared to Duffy wild-type (72% versus 23.2%). Duffy null status was also associated with significantly lower overall mean (standard deviation) dose intensity (81.9% (15.9%) versus 95.7% (5.9%)), and a significantly lower clinical benefit rate (66.7% versus 84.6%). No cases of febrile neutropenia or permanent treatment discontinuation due to neutropenia were reported.
Cost / cost effectiveness
Many cost–effectiveness analyses have found CDK4/6 inhibitors unlikely to be cost-effective at current prices and usual willingness-to-pay thresholds. A study in Singapore evaluated the cost–effectiveness of adding ribociclib to goserelin and an aromatase inhibitor or tamoxifen as initial therapy for premenopausal women with breast cancer, using a partitioned survival model based on the MONALEESA 7 trial (33). The base-case analysis resulted in an incremental cost–effectiveness ratio of Singapore $ 197 667 (about US$ 148 700 using the average 2020 exchange rate) per quality-adjusted life-year (QALY). The authors concluded that ribociclib was unlikely to be cost-effective in this setting for the approved indication. A cost–effectiveness analysis of palbociclib or ribociclib (both plus letrozole) in the United States estimated an incremental cost–effectiveness ratio per QALY gained of US$ 634 000 for palbociclib and US$ 440 000 for ribociclib (34). A Canadian cost–effectiveness analysis of ribociclib plus endocrine therapy versus endocrine therapy alone reported an incremental cost–effectiveness ratio of CA$ 197 832 per QALY gained as a best estimate (35). The authors had some concerns about the certainty of the cost–effectiveness estimations for the use of CDK4/6 inhibitors in first-line treatment of premenopausal women, as they were based mostly on the predicted clinical benefit beyond the actual trial follow-up. An Italian study reported that when abemaciclib was used as first-line treatment, the estimated cost was € 2246 a month of progression-free survival gained, less expensive at full dose than ribociclib and palbociclib. In the second-line setting, in combination with fulvestrant, ribociclib was the least expensive, with an estimated cost of € 2070 a month of progression-free survival gained (36). A Chinese cost–effectiveness analysis of palbociclib as second-line therapy reported an incremental cost–effectiveness ratio of US$ 182 779 per QALY. When the price of palbociclib was reduced to 30%, 20% and 10% of the current price, the resultant incremental cost–effectiveness ratios were US$ 79 558, US$ 64 812, and US$ 50 066 per QALY, respectively. To meet 50% probability of cost–effectiveness, the estimated price required was US$ 32.52/100 mg at a willingness-to-pay threshold of US$ 58 480 per QALY. The authors concluded that adding palbociclib to a fulvestrant regimen is unlikely to be cost-effective as second-line endocrine therapy for patients with HR+/HER2– metastatic breast cancer, at the current price in China (37).
WHO guidelines
WHO guidelines for the treatment of breast cancer are not available.
Availability
Abemaciclib (trade name Verzenio, Eli Lilly) has regulatory approval in multiple countries globally. It has primary patent protection until 2029. Palbociclib (trade name Ibrance, Pfizer) has regulatory approval in multiple countries globally. It has primary patent protection until 2023. Ribociclib (trade name Kisqali, Novartis) has regulatory approval in multiple countries globally. It has primary patent protection until 2027–2029. Generic products are not currently available.
Other considerations
The EML Cancer Medicines Working Group advised that it did not support the inclusion of CDK4/6 inhibitors as a therapeutic class or as individual medicines on the EML at this time. For all the medicines proposed, the Working Group noted that long-term trial follow-up is limited, and that the survival benefit observed is currently uncertain. A review of the data after longer follow-up could be considered for a future EML update. Based on clinical benefit, only ribociclib meets the EML criteria for first-line survival benefit and ESMO-MCBS score. However, there are concerns about bias in the MONALEESA 7 trial, including high censoring rates, which reduce confidence in the estimates of benefit. In addition, the eligible patient population for these medicines is likely to be very large, current costs are very high with cost–effectiveness analyses finding these treatments not to be cost-effective in most settings at current prices. Treatment duration is long and therefore the effect on the budget of health systems would be substantial and unaffordable in many settings
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