Palbociclib in Breast Cancer
| Target | Development Name | Generic Name | Trade Name | Status |
|---|---|---|---|---|
| CDK4/6 | PD0332991 | palbociclib | Ibrance | FDA approved in combination with letrozole for ER-positive breast cancera |
a ER-positive, HER2-negative first-line metastatic breast cancer patients treated with palbociclib in combination with the aromatase inhibitor letrozole demonstrated an improvement in median progression-free survival compared with letrozole alone in a randomized phase 2 trial (Table 1; PALOMA-1; Finn et al. 2015). Based on the outcomes from this trial, the combination of palbociclib and letrozole received accelerated FDA approval for ER-positive, HER2-negative first-line metastatic breast cancer in 2015 (FDA 2015). The phase 3 trial of this combination is still ongoing.
A phase III trial evaluating palbociclib in combination with fulvestrant in metastatic ER-positive, HER2-negative breast cancer following disease progression during or after endocrine therapy showed improved progression-free survival relative to patients treated with placebo plus fulvestrant (Table 1; PALOMA-3; Turner et al. 2015). The trial was stopped early due to efficacy. In a subgroup analysis, premenopausal/perimenopausal patients with ovarian suppression demonstrated equivalent efficacy benefit with combination therapy as postmenopausal breast cancer patients (Turner et al. 2015).
In a preliminary report of a phase 1 study of palbociclib in combination with paclitaxel in RB+ third-line metastatic breast cancer (any ER status), patients experienced a 73% clinical benefit rate treated with combination therapy (Table 1; Clark et al. 2014).
RB1-positive metastatic breast cancer patients treated with single-agent palbociclib demonstrated a 19% clinical benefit rate and a median progression-free survival of 3.7 months. In a hormone receptor positive patient subset with greater than or equal to two prior lines of hormone therapy, the clinical benefit rate was 29% and the median progression-free survival was 5.0 months (Table 1; DeMichele et al. 2014).
Table 1. Reported Trials with Palbociclib in Breast Cancer.
| Reference | Study Type / Phase | Therapeutic setting | Treatment Agent | Mutation Status / Group | # Pts in Study | RR | PFS (months) | OS (months) |
|---|---|---|---|---|---|---|---|---|
| Turner et al. 2015 (PALOMA-3) | Phase 3 | ≥1st (no limit to prior therapies) metastatic or advanced breast cancer | palbociclib + fulvestrant | HR+ | 347 | 10.4% | 9.2 | |
| placebo + fulvestrant | 174 | 6.3% | 3.8 | |||||
| Finn et al. 2015 (PALOMA-1; TRIO-18) | Phase 2 | 1st line metastatic breast cancer |
letrozole | ER+ / HER2– (cohort 1+2) | 81 | 27% | 10.2 | 33.3 |
| ER+ / HER2– (cohort 1) | 32 | 5.7 | ||||||
| ER+ / HER2– / CCND1+ or p16+ (cohort 2) | 49 | 11.1 | ||||||
| letrozole + palbociclib | ER+ / HER2–(cohort 1+2) | 84 | 43% | 20.2 | 37.5 | |||
| ER+ / HER2– (cohort 1) | 34 | 26.1 | ||||||
| ER+ / HER2– / CCND1+ or p16+ (cohort 2) | 50 | 18.1 | ||||||
| DeMichele et al. 2014 | Phase 2 | ≥1st (no limit to prior therapies) metastatic breast cancer |
palbociclib | RB1+ | 37 | 3.7 | ||
| HR+ / RB1+ subset | 33 | 5.1 | ||||||
| ≥2 prior lines of hormone therapy | HR+ / RB1+ subset | 24 | 5.0 | |||||
| Clark et al. 2014 | Phase 1 | ≥3rd line metastatic breast cancer | palbociclib + paclitaxel | RB1+ | 15 | 40% |
NOTE: CR = complete response; ER = estrogen receptor; OS = overall survival; PFS = progression-free survival; PR = partial response; Pts = patients; RR = response rate (CR + PR); RB1 = retinoblastoma.
Table 2. Ongoing and Recruiting Clinical Investigation with Palbociclib in Breast Cancer.
| Study Type / Phase / ID | Therapeutic setting | Prior therapy requirement | Treatment Agent | Mutation Status / Group | # Pts in Study | Study Start Date |
|---|---|---|---|---|---|---|
| Phase 1b (NCT01976169) | 2nd line or greater, recurrent or metastatic breast cancer | Prior trastuzumab or HER2 targeted therapies required | palbociclib + Trastuzumab-DM1 | HER2+ RB1-proficient |
17 | January 2014 |
| Phase 3 (PEARL, NCT02028507) | Any line, locally advanced or metastatic breast cancer | Recurrence during or within 12 months of adjuvant letrozole or anastrozole or during or within 1 month of letrozole or anastrozole for metastatic disease | palbociclib + exemestane | ER+ and/or PR+ HER2– |
348 | March 2014 |
| capecitabine | ||||||
| Phase 3 (PALOMA-2, NCT01740427) | 1st line | No prior systemic anti-cancer therapy for advanced ER+ disease | palbociclib + letrozole | ER+ HER2– |
650 | February 2013 |
| placebo + letrozole | ||||||
| Phase 3 (PENELOPE-B, NCT01864746) | Early breast cancer at high risk of relapse after showing less than pathological complete response to neoadjuvant taxane-containing chemotherapy | Prior neoadjuvant chemotherapy including taxane of at least 16 weeks | palbociclib + standard anti-hormonal therapy | ER+ and/or PR+ HER2– |
800 | November 2013 |
| Placebo + standard anti-hormonal therapy | ||||||
| Phase 2 (NCT02040857) | Adjuvant setting, breast cancer | One month of adjuvant tamoxifen or aromatase inhibitor; at least two more years of adjuvant therapy planned | palbociclib + tamoxifen or letrozole or anastrozole or exemestane | ER+ and/or PR+ HER2– |
120 | January 2014 |
| Phase 2 (NCT01723774) | Neoadjuvant setting | palbociclib + anastrozole or anastrozole + goserelin | ER+ and/or PR+ HER2– PIK3CA mutation cohort |
29 | June 2013 |
NOTE: ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; PR = progesterone receptor; RB1 = retinoblastoma.
Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.
Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2015. Palbociclib in Breast Cancer. My Cancer Genome http://www.mycancergenome.org/content/molecular-medicine/palbociclib-breast-cancer/ (Updated June 17).
Last Updated: July 24, 2015