Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: Expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18

Richard S. Finn, John P. Crown, Johannes Ettl, Marcus Schmidt, Igor M. Bondarenko, I. Láng, T. Pintér, Katalin Boer, Ravindranath Patel, Sophia Randolph, Sindy T. Kim, Xin Huang, Patrick Schnell, Sashi Nadanaciva, Cynthia Huang Bartlett, Dennis J. Slamon

Research output: Contribution to journalArticle

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Abstract

Background: Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6. In the randomized, open-label, phase II PALOMA-1/TRIO-18 trial, palbociclib in combination with letrozole improved progression-free survival (PFS) compared with letrozole alone as first-line treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer (20.2 months versus 10.2 months; hazard ratio (HR) = 0.488, 95 % confidence interval (CI) 0.319-0.748; one-sided p = 0.0004). Grade 3-4 neutropenia was the most common adverse event (AE) in the palbociclib + letrozole arm. We now present efficacy and safety analyses based on several specific patient and tumor characteristics, and present in detail the clinical patterns of neutropenia observed in the palbociclib + letrozole arm of the overall safety population. Methods: Postmenopausal women (n = 165) with ER+, HER2-negative, advanced breast cancer who had not received any systemic treatment for their advanced disease were randomized 1:1 to receive either palbociclib in combination with letrozole or letrozole alone. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary endpoint was PFS. We now analyze the difference in PFS for the treatment populations by subgroups, including age, histological type, history of prior neoadjuvant/adjuvant systemic treatment, and sites of distant metastasis, using the Kaplan-Meier method. HR and 95 % CI are derived from a Cox proportional hazards regression model. Results: A clinically meaningful improvement in median PFS and clinical benefit response (CBR) rate was seen with palbociclib + letrozole in every subgroup evaluated. Grade 3-4 neutropenia was the most common AE with palbociclib + letrozole in all subgroups. Analysis of the frequency of neutropenia by grade during the first six cycles of treatment showed that there was a downward trend in Grade 3-4 neutropenia over time. Among those who experienced Grade 3-4 neutropenia, 71.7 % had no overlapping infections of any grade and none had overlapping Grade 3-4 infections. Conclusion: The magnitude of clinical benefit seen with the addition of palbociclib to letrozole in improving both median PFS and CBR rate is consistent in nearly all subgroups analyzed, and consistent with that seen in the overall study population. The safety profile of the combination treatment in all subgroups was also comparable to that in the overall safety population of the study.

Original languageEnglish
Article number67
JournalBreast Cancer Research
Volume18
Issue number1
DOIs
Publication statusPublished - Jun 28 2016

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letrozole
Estrogen Receptors
Breast Neoplasms
Neutropenia
Safety
Disease-Free Survival
Therapeutics
Population
Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinase 4
Confidence Intervals
palbociclib
human ERBB2 protein

Keywords

  • Breast cancer
  • Cyclin-dependent kinase
  • Estrogen receptor-positive
  • HER2-negative
  • Neutropenia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer : Expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. / Finn, Richard S.; Crown, John P.; Ettl, Johannes; Schmidt, Marcus; Bondarenko, Igor M.; Láng, I.; Pintér, T.; Boer, Katalin; Patel, Ravindranath; Randolph, Sophia; Kim, Sindy T.; Huang, Xin; Schnell, Patrick; Nadanaciva, Sashi; Bartlett, Cynthia Huang; Slamon, Dennis J.

In: Breast Cancer Research, Vol. 18, No. 1, 67, 28.06.2016.

Research output: Contribution to journalArticle

Finn, Richard S. ; Crown, John P. ; Ettl, Johannes ; Schmidt, Marcus ; Bondarenko, Igor M. ; Láng, I. ; Pintér, T. ; Boer, Katalin ; Patel, Ravindranath ; Randolph, Sophia ; Kim, Sindy T. ; Huang, Xin ; Schnell, Patrick ; Nadanaciva, Sashi ; Bartlett, Cynthia Huang ; Slamon, Dennis J. / Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer : Expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. In: Breast Cancer Research. 2016 ; Vol. 18, No. 1.
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abstract = "Background: Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6. In the randomized, open-label, phase II PALOMA-1/TRIO-18 trial, palbociclib in combination with letrozole improved progression-free survival (PFS) compared with letrozole alone as first-line treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer (20.2 months versus 10.2 months; hazard ratio (HR) = 0.488, 95 {\%} confidence interval (CI) 0.319-0.748; one-sided p = 0.0004). Grade 3-4 neutropenia was the most common adverse event (AE) in the palbociclib + letrozole arm. We now present efficacy and safety analyses based on several specific patient and tumor characteristics, and present in detail the clinical patterns of neutropenia observed in the palbociclib + letrozole arm of the overall safety population. Methods: Postmenopausal women (n = 165) with ER+, HER2-negative, advanced breast cancer who had not received any systemic treatment for their advanced disease were randomized 1:1 to receive either palbociclib in combination with letrozole or letrozole alone. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary endpoint was PFS. We now analyze the difference in PFS for the treatment populations by subgroups, including age, histological type, history of prior neoadjuvant/adjuvant systemic treatment, and sites of distant metastasis, using the Kaplan-Meier method. HR and 95 {\%} CI are derived from a Cox proportional hazards regression model. Results: A clinically meaningful improvement in median PFS and clinical benefit response (CBR) rate was seen with palbociclib + letrozole in every subgroup evaluated. Grade 3-4 neutropenia was the most common AE with palbociclib + letrozole in all subgroups. Analysis of the frequency of neutropenia by grade during the first six cycles of treatment showed that there was a downward trend in Grade 3-4 neutropenia over time. Among those who experienced Grade 3-4 neutropenia, 71.7 {\%} had no overlapping infections of any grade and none had overlapping Grade 3-4 infections. Conclusion: The magnitude of clinical benefit seen with the addition of palbociclib to letrozole in improving both median PFS and CBR rate is consistent in nearly all subgroups analyzed, and consistent with that seen in the overall study population. The safety profile of the combination treatment in all subgroups was also comparable to that in the overall safety population of the study.",
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TY - JOUR

T1 - Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer

T2 - Expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18

AU - Finn, Richard S.

AU - Crown, John P.

AU - Ettl, Johannes

AU - Schmidt, Marcus

AU - Bondarenko, Igor M.

AU - Láng, I.

AU - Pintér, T.

AU - Boer, Katalin

AU - Patel, Ravindranath

AU - Randolph, Sophia

AU - Kim, Sindy T.

AU - Huang, Xin

AU - Schnell, Patrick

AU - Nadanaciva, Sashi

AU - Bartlett, Cynthia Huang

AU - Slamon, Dennis J.

PY - 2016/6/28

Y1 - 2016/6/28

N2 - Background: Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6. In the randomized, open-label, phase II PALOMA-1/TRIO-18 trial, palbociclib in combination with letrozole improved progression-free survival (PFS) compared with letrozole alone as first-line treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer (20.2 months versus 10.2 months; hazard ratio (HR) = 0.488, 95 % confidence interval (CI) 0.319-0.748; one-sided p = 0.0004). Grade 3-4 neutropenia was the most common adverse event (AE) in the palbociclib + letrozole arm. We now present efficacy and safety analyses based on several specific patient and tumor characteristics, and present in detail the clinical patterns of neutropenia observed in the palbociclib + letrozole arm of the overall safety population. Methods: Postmenopausal women (n = 165) with ER+, HER2-negative, advanced breast cancer who had not received any systemic treatment for their advanced disease were randomized 1:1 to receive either palbociclib in combination with letrozole or letrozole alone. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary endpoint was PFS. We now analyze the difference in PFS for the treatment populations by subgroups, including age, histological type, history of prior neoadjuvant/adjuvant systemic treatment, and sites of distant metastasis, using the Kaplan-Meier method. HR and 95 % CI are derived from a Cox proportional hazards regression model. Results: A clinically meaningful improvement in median PFS and clinical benefit response (CBR) rate was seen with palbociclib + letrozole in every subgroup evaluated. Grade 3-4 neutropenia was the most common AE with palbociclib + letrozole in all subgroups. Analysis of the frequency of neutropenia by grade during the first six cycles of treatment showed that there was a downward trend in Grade 3-4 neutropenia over time. Among those who experienced Grade 3-4 neutropenia, 71.7 % had no overlapping infections of any grade and none had overlapping Grade 3-4 infections. Conclusion: The magnitude of clinical benefit seen with the addition of palbociclib to letrozole in improving both median PFS and CBR rate is consistent in nearly all subgroups analyzed, and consistent with that seen in the overall study population. The safety profile of the combination treatment in all subgroups was also comparable to that in the overall safety population of the study.

AB - Background: Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6. In the randomized, open-label, phase II PALOMA-1/TRIO-18 trial, palbociclib in combination with letrozole improved progression-free survival (PFS) compared with letrozole alone as first-line treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer (20.2 months versus 10.2 months; hazard ratio (HR) = 0.488, 95 % confidence interval (CI) 0.319-0.748; one-sided p = 0.0004). Grade 3-4 neutropenia was the most common adverse event (AE) in the palbociclib + letrozole arm. We now present efficacy and safety analyses based on several specific patient and tumor characteristics, and present in detail the clinical patterns of neutropenia observed in the palbociclib + letrozole arm of the overall safety population. Methods: Postmenopausal women (n = 165) with ER+, HER2-negative, advanced breast cancer who had not received any systemic treatment for their advanced disease were randomized 1:1 to receive either palbociclib in combination with letrozole or letrozole alone. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary endpoint was PFS. We now analyze the difference in PFS for the treatment populations by subgroups, including age, histological type, history of prior neoadjuvant/adjuvant systemic treatment, and sites of distant metastasis, using the Kaplan-Meier method. HR and 95 % CI are derived from a Cox proportional hazards regression model. Results: A clinically meaningful improvement in median PFS and clinical benefit response (CBR) rate was seen with palbociclib + letrozole in every subgroup evaluated. Grade 3-4 neutropenia was the most common AE with palbociclib + letrozole in all subgroups. Analysis of the frequency of neutropenia by grade during the first six cycles of treatment showed that there was a downward trend in Grade 3-4 neutropenia over time. Among those who experienced Grade 3-4 neutropenia, 71.7 % had no overlapping infections of any grade and none had overlapping Grade 3-4 infections. Conclusion: The magnitude of clinical benefit seen with the addition of palbociclib to letrozole in improving both median PFS and CBR rate is consistent in nearly all subgroups analyzed, and consistent with that seen in the overall study population. The safety profile of the combination treatment in all subgroups was also comparable to that in the overall safety population of the study.

KW - Breast cancer

KW - Cyclin-dependent kinase

KW - Estrogen receptor-positive

KW - HER2-negative

KW - Neutropenia

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