Singapore/Lugano - Data collected in Japanese and Korean patients included in the global PALOMA3 trial provides evidence that combining palbociclib with fulvestrant is an effective strategy to overcome endocrine resistance in women with hormone receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer. The analysis of efficacy and safety of the combined therapy in an Asian population was presented (1) at the first ESMO Asia 2015 Congress in Singapore, and results are in line with those reported in all patients (both Asian and non-Asian) earlier this year.
Endocrine resistance is a major clinical issue that makes advanced breast cancer more difficult to treat. Hormone therapy is generally well tolerated and an easy-to-administer option for breast cancer, with demonstrated benefits in patients whose tumours express hormone receptors (HR), particularly the HR+/HER2- subgroup. The ideal option for patients is to be on one endocrine therapy after another, as long as the disease responds or remains unchanged. "However, unavoidably, resistance develops in almost all advanced patients a median ten months after the first-line hormonal agent is administered, and a much shorter median time after the second- or third-line hormonal agents, eventually driving patients to switch to the more toxic chemotherapy," one of the study authors, Dr. Jungsil Ro, Center for Breast Cancer at the National Cancer Center, Goyang, Korea, said.
Palbociclib is an orally active selective inhibitor of the CDK 4/6 growth signal that blocks cell proliferation and cellular division. It has high activity in HR+ breast cancer cell lines and is synergistic in combination with different endocrine therapies.
The PALOMA3 trial assessed the safety and efficacy of the combination of palbociclib and fulvestrant in premenopausal and postmenopausal women with HR+/HER2- advanced breast cancer that progressed during prior endocrine therapy. By March 2015, 105 Asian patients in Korea and Japan were randomised, 74 to receive palbociclib plus fulvestrant and 31 to placebo plus fulvestrant. "For postmenopausal women, the study definitely showed positive results ---progression-free survival more than doubled. Patients suffered from more adverse events in the palbociclib arm, specifically haematologic toxicity, which was easily manageable. "For premenopausal women, the outcome looks as promising as in postmenopausal women, although the numbers are quite small for definitive conclusions," Ro said.
The analysis containing Asian patients nicely confirms that combining palbociclib with fulvestrant is a promising therapeutic approach. "Although median progression-free survival in Asian patients was not reached for the drug combination, it is a reasonable therapeutic option in this population," ESMO spokesperson, Dr. Fabrice André, Institut de Cancérologie Gustave Roussy, Villejuif, France, said. "Palbociclib shows clinical activity with modest toxicity. Although the difference in toxicity profile between Asian and non-Asian populations is really interesting, no clear explanation could be made from this study because of the existing differences reported in non-Asian and Asian patients."
To support the superiority of this drug combination over the hormonal agent alone, a longer follow-up for the overall survival result is needed, Ro said. "So far, we do not have predictive biomarkers to select patients for palbociclib in addition to fulvestrant other than the subtype itself, HR+/HER2- breast cancer. We also need to see that other results from the first-line hormone therapy with palbociclib clinical trial verify the efficacy of the drug, but a longer time is needed to have these results."
Commenting on the results, ESMO spokesperson Dr. Evandro de Azambuja, medical director of the Br.E.A.S.T. Data Centre, Jules Bordet Institute in Brussels, Belgium, not involved in the study, said: "Targeting CDK4/6 represents a further promising option to address endocrine resistance. Other mechanisms of resistance to endocrine therapy include the activation of tyrosine kinase signalling, the up-regulation of the PI3 kinase mammalian target of rapamycin (mTOR) signalling and, lastly, the mutation of ESR1."
On the basis of the impressive results from the phase II PALOMA-1 trial, the combination of palbociclib plus letrozole has been approved by U.S. Food and Drug Administration (FDA) for the treatment of postmenopausal women with ER+, HER2- advanced breast cancer as initial endocrine-based therapy for their metastatic disease.
Notes to Editors
Information contained in this press release was provided by the abstracts authors and reflects the content of the studies. It does not necessarily express ESMO's point of view.
(1) Abstract 53O_PR, Efficacy and safety of palbociclib plus fulvestrant in Asian women with hormone receptor-positive (HR+)/human epidermal growth factor-2 negative (HER2-) metastatic breast cancer (MBC) that progressed on prior endocrine therapy (ET) J. Ro, S.-A. Im, N. Masuda, Y.-H. Im, K. Inoue, Y. Rai, R. Nakamura, J.H. Kim, K. Zhang, C. Giorgetti, P. Schnell, C. Huang Bartlett, H. Iwata, will be presented during Breast Cancer session on Saturday 19th December, h. 16:30
Abstract will be available online on 18th December 2015, 23:55 hours (SGT)
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Efficacy and safety of palbociclib plus fulvestrant in Asian women with hormone receptor-positive (HR+)/human epidermal growth factor-2 negative (HER2-) metastatic breast cancer (MBC) that progressed on prior endocrine therapy (ET)
J. Ro1, S.-A. Im2, N. Masuda3, Y.-H. Im4, K. Inoue5, Y. Rai6, R. Nakamura7, J.H. Kim8, K. Zhang9, C. Giorgetti10, P. Schnell11, C. Huang Bartlett12, H. Iwata13
1Center for Breast Cancer, National Cancer Center, Goyang, Korea, 2Medical Oncology, Seoul National University, Seoul, Korea, 3Department of Surgery, Breast Oncology, NHO Osaka National Hospital, Osaka, Japan, 4Professor, Division of Hematology/Medical Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea, 5Division of Breast Oncology, Saitama Cancer Center, Saitama, Japan, 6Principal of Sagara Hospital, Breast Surgery, Sagara Hospital, Hakuaikai Medical Corporation Sagara Hospital, Kagoshima, Japan, 7Division of Breast Surgery, Chiba Cancer Center Hospital, Chiba, Japan, 8Professor Division of Hematology/Medical Oncology, Seoul National University Bundang Hospital, Gyeonggi-do, Korea, 9Oncology Clinical Statistics, Pfizer Inc., San Diego, CA, USA, 10Clinical Oncology, Pfizer, Italy, Milan, Italy, 11Pfizer Inc., New York, NY, USA, 12Clinical Oncology, Pfizer Inc., New York, NY, USA, 13Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
Aim/Background: Endocrine resistance is a major clinical issue for patients (pts) with HR+/HER2- breast cancer. The standard of care (SOC) is to re-challenge with ET before switch to chemotherapy (CT). PALOMA3 assessed whether Palbociclib (P) + fulvestrant (F) prolonged progression-free survival (PFS) vs F + placebo (PLB) in pts with HR+/HER2- MBC whose disease had progressed on prior ET. Primary analysis showed median PFS of 9.2 vs 3.8 m (HR 0.42, P<0.001) in full population (Turner et al NEJM 2015). We present the efficacy and safety in Asian pts with longer follow-up.
Methods: In the Ph 3 PALOMA3 study, 521 pts were randomized 2:1 to P (125 mg/d oral [3 wks drug, 1 wk off]) + F (500 mg, SOC) or PLB + F. Pre-/perimenopausal pts also received goserelin. One previous line of CT for MBC was allowed. Safety assessments occurred at baseline and on D1 per cycle; blood counts every 2 wks for first 2 cycles and on D1 of subsequent cycles. Primary endpoint was investigator-assessed PFS. Secondary endpoints: overall survival, response assessment, patient-reported outcomes, safety. PALOMA3 enrolled pts in Korea and Japan.
Results: By March 2015, 105 Asian pts were randomized (P+F, 74; PLB+F, 31). Baseline characteristics were well balanced. Compared to non-Asians, median age was lower in Asians (52 vs 58 y) and more were pre/perimenopausal (42% vs 15%). 59% of Asian pts had visceral disease, 80% had documented endocrine responsiveness, 34% had 1 line of CT for MBC. Median PFS in Asian pts was not reached for P+F (95% CI 9.2-NR) and 5.8 m for PLB+F (3.5-9.5m) (HR 0.485 [95% CI 0.270-0.869], P=0.0065). Most common Grade 3/4 adverse events (AEs) in Asian pts were neutropenia (92%) and leucopenia (29%); febrile neutropenia occurred in 4.1% (P+F). No pt stopped P+F due to AEs. 51% of Asian pts had dose reduction due to AEs. 48% were on 100mg dose.
Conclusions: P+F improved PFS in Asians with HR+/HER2- MBC that progressed on prior ET. The safety profile was consistent with that seen in Non-Asians; neutropenia was the most common AE, and can be managed by dose reduction. P+F may be a reasonable therapeutic option in Asian pts. Clinical trial identification: Clinical Trial ID: NCT01942135
Disclosure: J. Ro: Dr. Ro has served as a consultant/advisor to Nippon Kayaku (NK) and has received travel support from Eisai
S.-A. Im: 2c. Receipt of Intellectual Property Rights / Patent Holder: NA 2d. Consulting Fees (e.g. advisory boards): Roche, Novartis, AstraZeneca 2f. Contracted Research (NOTE: Pls must provide disclosure in this category): AstraZeneca in 2014
N. Masuda: Fees for Non-CME Services Received Directry from Commercial Interest or their agents (speaker\'s Bureaus) Chugai, AstraZenaca Contracted Research Chugai, Novaltis, Pfizer, AstraZeneca, Lilly
K. Inoue: research funding Pfizer, Lily, Chugai, Taiho, Daiichi-Sankyo, Palexel
K. Zhang: Dr. Zhang is an employee of and owns stock in Pfizer Inc and receives stock options from Pfizer Inc.
C. Giorgetti: Dr. Giorgetti is an employee of, and owns stock in Pfizer Inc and receives stock options from Pfizer Inc.
P. Schnell: Dr. Schnell is an employee of, and owns stock in Pfizer Inc and receives stock options from Pfizer Inc.
C. Huang Bartlett: Dr. Huang Bartlett is an employee of and owns stock in Pfizer Inc and receives stock options from Pfizer Inc.
H. Iwata: Dr. Iwata has received honoraria from AstraZeneca, Eisai, Daiichi-Sankyo, Chugai, and Pfizer Inc.
All other authors have declared no conflicts of interest.
Keywords: palbociclib, metastatic breast cancer, Asian, endocrine resistance