Abemaciclib in combination with single-agent options in patients with stage IV non–small cell lung cancer: A phase Ib study

Edward S. Kim, Karen Kelly, Luis G. Paz-Ares, Pilar Garrido, Shadia Jalal, Daruka Mahadevan, Martin Gutierrez, Mariano Provencio, Eric Schaefer, Monte Shaheen, Erica L. Johnston, P. Kellie Turner, Siva Rama Prasad Kambhampati, Richard Beckmann, Anwar Hossain, William J. John, Jonathan W. Goldman

Research output: Contribution to journalArticle

Abstract

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non–small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules. Results: The three study parts enrolled 86 patients; all received 1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib–pemetrexed, 25% for abemaciclib–gemcitabine, and 54% for abemaciclib–ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively. Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies.

LanguageEnglish (US)
Pages5543-5551
Number of pages9
JournalClinical Cancer Research
Volume24
Issue number22
DOIs
StatePublished - Nov 15 2018

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Non-Small Cell Lung Carcinoma
gemcitabine
Pemetrexed
5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl)-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)pyrimidin-2-yl)amine
Appointments and Schedules
Cyclin-Dependent Kinase 6
Pharmacokinetics
Cyclin-Dependent Kinase 4
Safety
Appetite
Drug Combinations
Therapeutics
Neutropenia
Nausea
Disease-Free Survival
Fatigue
Diarrhea
ramucirumab

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Abemaciclib in combination with single-agent options in patients with stage IV non–small cell lung cancer : A phase Ib study. / Kim, Edward S.; Kelly, Karen; Paz-Ares, Luis G.; Garrido, Pilar; Jalal, Shadia; Mahadevan, Daruka; Gutierrez, Martin; Provencio, Mariano; Schaefer, Eric; Shaheen, Monte; Johnston, Erica L.; Kellie Turner, P.; Kambhampati, Siva Rama Prasad; Beckmann, Richard; Hossain, Anwar; John, William J.; Goldman, Jonathan W.

In: Clinical Cancer Research, Vol. 24, No. 22, 15.11.2018, p. 5543-5551.

Research output: Contribution to journalArticle

Kim, ES, Kelly, K, Paz-Ares, LG, Garrido, P, Jalal, S, Mahadevan, D, Gutierrez, M, Provencio, M, Schaefer, E, Shaheen, M, Johnston, EL, Kellie Turner, P, Kambhampati, SRP, Beckmann, R, Hossain, A, John, WJ & Goldman, JW 2018, 'Abemaciclib in combination with single-agent options in patients with stage IV non–small cell lung cancer: A phase Ib study' Clinical Cancer Research, vol. 24, no. 22, pp. 5543-5551. https://doi.org/10.1158/1078-0432.CCR-18-0651
Kim, Edward S. ; Kelly, Karen ; Paz-Ares, Luis G. ; Garrido, Pilar ; Jalal, Shadia ; Mahadevan, Daruka ; Gutierrez, Martin ; Provencio, Mariano ; Schaefer, Eric ; Shaheen, Monte ; Johnston, Erica L. ; Kellie Turner, P. ; Kambhampati, Siva Rama Prasad ; Beckmann, Richard ; Hossain, Anwar ; John, William J. ; Goldman, Jonathan W. / Abemaciclib in combination with single-agent options in patients with stage IV non–small cell lung cancer : A phase Ib study. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 22. pp. 5543-5551.
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abstract = "Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non–small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules. Results: The three study parts enrolled 86 patients; all received 1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57{\%} for patients treated with abemaciclib–pemetrexed, 25{\%} for abemaciclib–gemcitabine, and 54{\%} for abemaciclib–ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively. Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies.",
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T2 - Clinical Cancer Research

AU - Kim, Edward S.

AU - Kelly, Karen

AU - Paz-Ares, Luis G.

AU - Garrido, Pilar

AU - Jalal, Shadia

AU - Mahadevan, Daruka

AU - Gutierrez, Martin

AU - Provencio, Mariano

AU - Schaefer, Eric

AU - Shaheen, Monte

AU - Johnston, Erica L.

AU - Kellie Turner, P.

AU - Kambhampati, Siva Rama Prasad

AU - Beckmann, Richard

AU - Hossain, Anwar

AU - John, William J.

AU - Goldman, Jonathan W.

PY - 2018/11/15

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N2 - Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non–small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules. Results: The three study parts enrolled 86 patients; all received 1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib–pemetrexed, 25% for abemaciclib–gemcitabine, and 54% for abemaciclib–ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively. Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies.

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