Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): An open-label, multicenter, phase 1/2, basket study

Matthew G. Krebs; Jean Pierre Delord; Thomas R. Jeffry Evans; Maja De Jonge; Sang We Kim; Marie Meurer; Sophie Postel-Vinay; Jong Seok Lee; Helen K. Angell; Vidalba Rocher-Ros; Kassondra Meyer; Mei Lin Ah-See; Pia Herbolsheimer; Zhongwu Lai; Ana Nunes; Susan M. Domchek

doi:10.1016/j.lungcan.2023.107216

Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): An open-label, multicenter, phase 1/2, basket study

Matthew G. Krebs^*, Jean Pierre Delord, Thomas R. Jeffry Evans, Maja De Jonge, Sang We Kim, Marie Meurer, Sophie Postel-Vinay, Jong Seok Lee, Helen K. Angell, Vidalba Rocher-Ros, Kassondra Meyer, Mei Lin Ah-See, Pia Herbolsheimer, Zhongwu Lai, Ana Nunes, Susan M. Domchek

^*Corresponding author for this work

Medical Oncology

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Abstract

Introduction: Preclinical studies have demonstrated increased efficacy with combined DNA damage response inhibition and immune checkpoint blockade compared with either alone. We assessed olaparib in combination with durvalumab in patients with relapsed small cell lung cancer (SCLC). Methods: Patients with previously treated limited or extensive-stage SCLC received oral olaparib 300 mg twice daily, as run-in for 4 weeks, then with durvalumab (1500 mg intravenously every 4 weeks) until disease progression. Primary endpoints were safety, tolerability, and 12-week disease control rate (DCR). Secondary endpoints included 28-week DCR, objective response rate (ORR), duration of response, progression-free survival, overall survival, change in tumor size, and programmed death-ligand 1 (PD-L1) expression subgroup analyses. Results: Forty patients were enrolled and analyzed for safety; 38 were analyzed for efficacy. Eleven patients (28.9% [90% confidence interval (CI), 17.2–43.3]) had disease control at 12 weeks. ORR was 10.5% (95% CI, 2.9–24.8). Median progression-free and overall survival were 2.4 (95% CI, 0.9–3.0) months and 7.6 (95% CI, 5.6–8.8) months, respectively. The most common adverse events (≥40.0%) were anemia, nausea, and fatigue. Grade ≥ 3 adverse events occurred in 32 patients (80.0%). PD-L1 levels, tumor mutational burden, and other genetic mutations were evaluated, but no significant correlations with clinical outcomes were observed. Conclusions: Tolerability of olaparib with durvalumab was consistent with the safety profile of each agent alone. Although the 12-week DCR did not meet the prespecified target (60%), four patients responded, and median overall survival was promising for a pretreated SCLC population. Further analyses are required to identify patients most likely to benefit from this treatment approach.

Original language	English
Article number	107216
Journal	Lung Cancer
Volume	180
DOIs	https://doi.org/10.1016/j.lungcan.2023.107216
Publication status	Published - Jun 2023

Bibliographical note

Funding Information:
Matthew Krebs acknowledges support from National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, NIHR Manchester Clinical Research Facility at The Christie and Manchester Experimental Cancer Medicine Centre (Manchester, UK). Thomas R. Jeffry Evans acknowledges support from the Glasgow Experimental Cancer Medicine Centre (Cancer Research UK & Chief Scientist's Office, Scotland). Medical writing support, under the direction of the authors, was provided by Elizabeth Gandhi PhD, Oxford PharmaGenesis Ltd, Cambridge, UK and Joshua Dow PhD, Oxford PharmaGenesis Ltd, London, UK in accordance with Good Publication Practice 3 guidelines.

Funding Information:
This study was sponsored by AstraZeneca. The study was designed by the sponsor and study investigators. Data were collected by investigators and analyzed by the sponsor. All authors, including those employed by the sponsor of the study, contributed to the interpretation of the data and the development, writing, and approval of the manuscript. Medical writing support was funded by the sponsor. All authors had full access to the raw data in the study, and the corresponding author had final responsibility for the decision to submit for publication.

Publisher Copyright:
© 2023

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Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA)Final published version, 649 KBLicence: CC BY

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Krebs, M. G., Delord, J. P., Jeffry Evans, T. R., De Jonge, M., Kim, S. W., Meurer, M., Postel-Vinay, S., Lee, J. S., Angell, H. K., Rocher-Ros, V., Meyer, K., Ah-See, M. L., Herbolsheimer, P., Lai, Z., Nunes, A., & Domchek, S. M. (2023). Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): An open-label, multicenter, phase 1/2, basket study. Lung Cancer, 180, Article 107216. https://doi.org/10.1016/j.lungcan.2023.107216

@article{cc435098d64e45cb941444e0c09db8c4,

title = "Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): An open-label, multicenter, phase 1/2, basket study",

abstract = "Introduction: Preclinical studies have demonstrated increased efficacy with combined DNA damage response inhibition and immune checkpoint blockade compared with either alone. We assessed olaparib in combination with durvalumab in patients with relapsed small cell lung cancer (SCLC). Methods: Patients with previously treated limited or extensive-stage SCLC received oral olaparib 300 mg twice daily, as run-in for 4 weeks, then with durvalumab (1500 mg intravenously every 4 weeks) until disease progression. Primary endpoints were safety, tolerability, and 12-week disease control rate (DCR). Secondary endpoints included 28-week DCR, objective response rate (ORR), duration of response, progression-free survival, overall survival, change in tumor size, and programmed death-ligand 1 (PD-L1) expression subgroup analyses. Results: Forty patients were enrolled and analyzed for safety; 38 were analyzed for efficacy. Eleven patients (28.9\% [90\% confidence interval (CI), 17.2–43.3]) had disease control at 12 weeks. ORR was 10.5\% (95\% CI, 2.9–24.8). Median progression-free and overall survival were 2.4 (95\% CI, 0.9–3.0) months and 7.6 (95\% CI, 5.6–8.8) months, respectively. The most common adverse events (≥40.0\%) were anemia, nausea, and fatigue. Grade ≥ 3 adverse events occurred in 32 patients (80.0\%). PD-L1 levels, tumor mutational burden, and other genetic mutations were evaluated, but no significant correlations with clinical outcomes were observed. Conclusions: Tolerability of olaparib with durvalumab was consistent with the safety profile of each agent alone. Although the 12-week DCR did not meet the prespecified target (60\%), four patients responded, and median overall survival was promising for a pretreated SCLC population. Further analyses are required to identify patients most likely to benefit from this treatment approach.",

author = "Krebs, \{Matthew G.\} and Delord, \{Jean Pierre\} and \{Jeffry Evans\}, \{Thomas R.\} and \{De Jonge\}, Maja and Kim, \{Sang We\} and Marie Meurer and Sophie Postel-Vinay and Lee, \{Jong Seok\} and Angell, \{Helen K.\} and Vidalba Rocher-Ros and Kassondra Meyer and Ah-See, \{Mei Lin\} and Pia Herbolsheimer and Zhongwu Lai and Ana Nunes and Domchek, \{Susan M.\}",

note = "Funding Information: Matthew Krebs acknowledges support from National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, NIHR Manchester Clinical Research Facility at The Christie and Manchester Experimental Cancer Medicine Centre (Manchester, UK). Thomas R. Jeffry Evans acknowledges support from the Glasgow Experimental Cancer Medicine Centre (Cancer Research UK \& Chief Scientist's Office, Scotland). Medical writing support, under the direction of the authors, was provided by Elizabeth Gandhi PhD, Oxford PharmaGenesis Ltd, Cambridge, UK and Joshua Dow PhD, Oxford PharmaGenesis Ltd, London, UK in accordance with Good Publication Practice 3 guidelines. Funding Information: This study was sponsored by AstraZeneca. The study was designed by the sponsor and study investigators. Data were collected by investigators and analyzed by the sponsor. All authors, including those employed by the sponsor of the study, contributed to the interpretation of the data and the development, writing, and approval of the manuscript. Medical writing support was funded by the sponsor. All authors had full access to the raw data in the study, and the corresponding author had final responsibility for the decision to submit for publication. Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = jun,

doi = "10.1016/j.lungcan.2023.107216",

language = "English",

volume = "180",

journal = "Lung Cancer",

issn = "0169-5002",

publisher = "Elsevier Ireland Ltd",

}

Krebs, MG, Delord, JP, Jeffry Evans, TR, De Jonge, M, Kim, SW, Meurer, M, Postel-Vinay, S, Lee, JS, Angell, HK, Rocher-Ros, V, Meyer, K, Ah-See, ML, Herbolsheimer, P, Lai, Z, Nunes, A & Domchek, SM 2023, 'Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): An open-label, multicenter, phase 1/2, basket study', Lung Cancer, vol. 180, 107216. https://doi.org/10.1016/j.lungcan.2023.107216

TY - JOUR

T1 - Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA)

T2 - An open-label, multicenter, phase 1/2, basket study

AU - Krebs, Matthew G.

AU - Delord, Jean Pierre

AU - Jeffry Evans, Thomas R.

AU - De Jonge, Maja

AU - Kim, Sang We

AU - Meurer, Marie

AU - Postel-Vinay, Sophie

AU - Lee, Jong Seok

AU - Angell, Helen K.

AU - Rocher-Ros, Vidalba

AU - Meyer, Kassondra

AU - Ah-See, Mei Lin

AU - Herbolsheimer, Pia

AU - Lai, Zhongwu

AU - Nunes, Ana

AU - Domchek, Susan M.

N1 - Funding Information: Matthew Krebs acknowledges support from National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, NIHR Manchester Clinical Research Facility at The Christie and Manchester Experimental Cancer Medicine Centre (Manchester, UK). Thomas R. Jeffry Evans acknowledges support from the Glasgow Experimental Cancer Medicine Centre (Cancer Research UK & Chief Scientist's Office, Scotland). Medical writing support, under the direction of the authors, was provided by Elizabeth Gandhi PhD, Oxford PharmaGenesis Ltd, Cambridge, UK and Joshua Dow PhD, Oxford PharmaGenesis Ltd, London, UK in accordance with Good Publication Practice 3 guidelines. Funding Information: This study was sponsored by AstraZeneca. The study was designed by the sponsor and study investigators. Data were collected by investigators and analyzed by the sponsor. All authors, including those employed by the sponsor of the study, contributed to the interpretation of the data and the development, writing, and approval of the manuscript. Medical writing support was funded by the sponsor. All authors had full access to the raw data in the study, and the corresponding author had final responsibility for the decision to submit for publication. Publisher Copyright: © 2023

PY - 2023/6

Y1 - 2023/6

N2 - Introduction: Preclinical studies have demonstrated increased efficacy with combined DNA damage response inhibition and immune checkpoint blockade compared with either alone. We assessed olaparib in combination with durvalumab in patients with relapsed small cell lung cancer (SCLC). Methods: Patients with previously treated limited or extensive-stage SCLC received oral olaparib 300 mg twice daily, as run-in for 4 weeks, then with durvalumab (1500 mg intravenously every 4 weeks) until disease progression. Primary endpoints were safety, tolerability, and 12-week disease control rate (DCR). Secondary endpoints included 28-week DCR, objective response rate (ORR), duration of response, progression-free survival, overall survival, change in tumor size, and programmed death-ligand 1 (PD-L1) expression subgroup analyses. Results: Forty patients were enrolled and analyzed for safety; 38 were analyzed for efficacy. Eleven patients (28.9% [90% confidence interval (CI), 17.2–43.3]) had disease control at 12 weeks. ORR was 10.5% (95% CI, 2.9–24.8). Median progression-free and overall survival were 2.4 (95% CI, 0.9–3.0) months and 7.6 (95% CI, 5.6–8.8) months, respectively. The most common adverse events (≥40.0%) were anemia, nausea, and fatigue. Grade ≥ 3 adverse events occurred in 32 patients (80.0%). PD-L1 levels, tumor mutational burden, and other genetic mutations were evaluated, but no significant correlations with clinical outcomes were observed. Conclusions: Tolerability of olaparib with durvalumab was consistent with the safety profile of each agent alone. Although the 12-week DCR did not meet the prespecified target (60%), four patients responded, and median overall survival was promising for a pretreated SCLC population. Further analyses are required to identify patients most likely to benefit from this treatment approach.

AB - Introduction: Preclinical studies have demonstrated increased efficacy with combined DNA damage response inhibition and immune checkpoint blockade compared with either alone. We assessed olaparib in combination with durvalumab in patients with relapsed small cell lung cancer (SCLC). Methods: Patients with previously treated limited or extensive-stage SCLC received oral olaparib 300 mg twice daily, as run-in for 4 weeks, then with durvalumab (1500 mg intravenously every 4 weeks) until disease progression. Primary endpoints were safety, tolerability, and 12-week disease control rate (DCR). Secondary endpoints included 28-week DCR, objective response rate (ORR), duration of response, progression-free survival, overall survival, change in tumor size, and programmed death-ligand 1 (PD-L1) expression subgroup analyses. Results: Forty patients were enrolled and analyzed for safety; 38 were analyzed for efficacy. Eleven patients (28.9% [90% confidence interval (CI), 17.2–43.3]) had disease control at 12 weeks. ORR was 10.5% (95% CI, 2.9–24.8). Median progression-free and overall survival were 2.4 (95% CI, 0.9–3.0) months and 7.6 (95% CI, 5.6–8.8) months, respectively. The most common adverse events (≥40.0%) were anemia, nausea, and fatigue. Grade ≥ 3 adverse events occurred in 32 patients (80.0%). PD-L1 levels, tumor mutational burden, and other genetic mutations were evaluated, but no significant correlations with clinical outcomes were observed. Conclusions: Tolerability of olaparib with durvalumab was consistent with the safety profile of each agent alone. Although the 12-week DCR did not meet the prespecified target (60%), four patients responded, and median overall survival was promising for a pretreated SCLC population. Further analyses are required to identify patients most likely to benefit from this treatment approach.

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U2 - 10.1016/j.lungcan.2023.107216

DO - 10.1016/j.lungcan.2023.107216

M3 - Article

C2 - 37146473

AN - SCOPUS:85154620626

SN - 0169-5002

VL - 180

JO - Lung Cancer

JF - Lung Cancer

M1 - 107216

ER -

Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): An open-label, multicenter, phase 1/2, basket study

Abstract

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