Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial

J. Rodon Ahnert; D. S.W. Tan; I. Garrido-Laguna; W. Harb; A. Bessudo; J. T. Beck; S. Rottey; N. Bahary; N. Kotecki; Z. Zhu; S. Deng; K. Kowalski; C. Wei; N. Pathan; R. J. Laliberte; W. A. Messersmith

doi:10.1016/j.esmoop.2023.101584

Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial

J. Rodon Ahnert, D. S.W. Tan, I. Garrido-Laguna, W. Harb, A. Bessudo, J. T. Beck, S. Rottey, N. Bahary, N. Kotecki, Z. Zhu, S. Deng, K. Kowalski, C. Wei, N. Pathan, R. J. Laliberte, W. A. Messersmith

Investigational Cancer Therapeutics

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Background: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC). Patients and Methods: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT). Results: A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed. Conclusions: Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents. Clinical trial registration: ClinicalTrials.gov NCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491

Original language	English (US)
Article number	101584
Journal	ESMO Open
Volume	8
Issue number	4
DOIs	https://doi.org/10.1016/j.esmoop.2023.101584
State	Published - Aug 2023

Keywords

MEK inhibitor
PARP inhibitor
PD-L1
immune checkpoint inhibitor
metastatic pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.esmoop.2023.101584

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Rodon Ahnert, J., Tan, D. S. W., Garrido-Laguna, I., Harb, W., Bessudo, A., Beck, J. T., Rottey, S., Bahary, N., Kotecki, N., Zhu, Z., Deng, S., Kowalski, K., Wei, C., Pathan, N., Laliberte, R. J., & Messersmith, W. A. (2023). Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial. ESMO Open, 8(4), Article 101584. https://doi.org/10.1016/j.esmoop.2023.101584

Rodon Ahnert, J, Tan, DSW, Garrido-Laguna, I, Harb, W, Bessudo, A, Beck, JT, Rottey, S, Bahary, N, Kotecki, N, Zhu, Z, Deng, S, Kowalski, K, Wei, C, Pathan, N, Laliberte, RJ & Messersmith, WA 2023, 'Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial', ESMO Open, vol. 8, no. 4, 101584. https://doi.org/10.1016/j.esmoop.2023.101584

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title = "Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial",

abstract = "Background: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC). Patients and Methods: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT). Results: A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed. Conclusions: Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents. Clinical trial registration: ClinicalTrials.gov NCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491",

keywords = "MEK inhibitor, PARP inhibitor, PD-L1, immune checkpoint inhibitor, metastatic pancreatic ductal adenocarcinoma",

author = "{Rodon Ahnert}, J. and Tan, {D. S.W.} and I. Garrido-Laguna and W. Harb and A. Bessudo and Beck, {J. T.} and S. Rottey and N. Bahary and N. Kotecki and Z. Zhu and S. Deng and K. Kowalski and C. Wei and N. Pathan and Laliberte, {R. J.} and Messersmith, {W. A.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = aug,

doi = "10.1016/j.esmoop.2023.101584",

language = "English (US)",

volume = "8",

journal = "ESMO Open",

issn = "2059-7029",

publisher = "BMJ Publishing Group",

number = "4",

}

TY - JOUR

T1 - Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma

T2 - dose-finding results from phase Ib of the JAVELIN PARP MEKi trial

AU - Rodon Ahnert, J.

AU - Tan, D. S.W.

AU - Garrido-Laguna, I.

AU - Harb, W.

AU - Bessudo, A.

AU - Beck, J. T.

AU - Rottey, S.

AU - Bahary, N.

AU - Kotecki, N.

AU - Zhu, Z.

AU - Deng, S.

AU - Kowalski, K.

AU - Wei, C.

AU - Pathan, N.

AU - Laliberte, R. J.

AU - Messersmith, W. A.

PY - 2023/8

Y1 - 2023/8

N2 - Background: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC). Patients and Methods: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT). Results: A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed. Conclusions: Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents. Clinical trial registration: ClinicalTrials.gov NCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491

AB - Background: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC). Patients and Methods: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT). Results: A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed. Conclusions: Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents. Clinical trial registration: ClinicalTrials.gov NCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491

KW - MEK inhibitor

KW - PARP inhibitor

KW - PD-L1

KW - immune checkpoint inhibitor

KW - metastatic pancreatic ductal adenocarcinoma

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U2 - 10.1016/j.esmoop.2023.101584

DO - 10.1016/j.esmoop.2023.101584

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C2 - 37379764

AN - SCOPUS:85162901749

SN - 2059-7029

VL - 8

JO - ESMO Open

JF - ESMO Open

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Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial

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