A Phase 1–2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC

Jyoti Malhotra; Petros Nikolinakos; Ticiana Leal; Jonathan Lehman; Daniel Morgensztern; Jyoti D. Patel; John M. Wrangle; Giuseppe Curigliano; Laurent Greillier; Melissa L. Johnson; Neal Ready; Gilles Robinet; Satwant Lally; David Maag; Ricardo Valenzuela; Vincent Blot; Benjamin Besse

doi:10.1016/j.jtho.2021.02.022

A Phase 1–2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC

Jyoti Malhotra^*, Petros Nikolinakos, Ticiana Leal, Jonathan Lehman, Daniel Morgensztern, Jyoti D. Patel, John M. Wrangle, Giuseppe Curigliano, Laurent Greillier, Melissa L. Johnson, Neal Ready, Gilles Robinet, Satwant Lally, David Maag, Ricardo Valenzuela, Vincent Blot, Benjamin Besse

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

46 Scopus citations

Abstract

Introduction: This open-label, phase 1–2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC). Methods: Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data. Results: A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses. Conclusions: Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.

Original language	English (US)
Pages (from-to)	1559-1569
Number of pages	11
Journal	Journal of Thoracic Oncology
Volume	16
Issue number	9
DOIs	https://doi.org/10.1016/j.jtho.2021.02.022
State	Published - Sep 2021

Funding

AbbVie provided financial support for the study ( NCT03026166 ). AbbVie participated in the design, study conduct, analysis and interpretation of data and writing, review, and approval of the manuscript. AbbVie and the authors thank patients and their families and caregivers; study investigators and staff; Emin Avsar and Giovanni Selvaggi (Bristol-Myers Squibb); and Philip Komarnitsky, Ahd Foullane, and Scott Gulbranson (AbbVie). Medical writing support was provided by Mary L. Smith, PhD, CMPP, Aptitude Health, Atlanta, Georgia, funded by AbbVie . Dr. Malhotra, Dr. Nikolinakos, Dr. Leal, Dr. Lehman, Dr. Morgensztern, Dr. Patel, Dr. Wrangle, Dr. Curigliano, Dr. Greillier, Dr. Johnson, Dr. Ready, Dr. Besse, and Dr. Robinet contributed to investigation and writing—reviewing and editing of the article. Mr. Lally, Dr. Maag, and Dr. Valenzuela contributed to formal analysis, data curation, and writing—reviewing and editing of the article. Dr. Blot contributed to supervision, writing—original draft preparation, and writing—reviewing and editing of the article. Disclosure: Dr. Besse reports receiving research funding (to institution) from AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Ignyta, Ipsen, Inivata, Janssen, Merck KGaA, Merck Sharp & Dohme, Nektar, Onxeo, OSE Immunotherapeutics, Roche, Pfizer, PharmaMar, Roche-Genentech, Sanofi, Servier, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma, and Tolero Pharmaceuticals. Dr. Curigliano reports a consulting/advisory role for Roche-Genentech, Eli Lilly, Novartis, Pfizer, Foundation Medicine, Bristol-Myers Squibb, and Samsung; honoraria from Ellipses Pharma and speakers? bureau for Roche-Genentech, Novartis, Eli Lilly, Pfizer, Foundation Medicine, and Samsung; and travel and expenses from Roche-Genentech and Pfizer. Dr. Greillier reports a consulting/advisory role for AbbVie, Roche, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, and Takeda. Dr. Johnson reports receiving research funding (to institution) from BerGenBio, Eli Lilly, EMD Serono, Janssen, Mirati Therapeutics, Genmab, Pfizer, AstraZeneca, Genentech-Roche, Stemcentrx, Novartis, Checkpoint Therapeutics, Array BioPharma, Regeneron, Apexigen, AbbVie, Tarveda, Adaptimmune, Syndax, Neovia, Boehringer Ingelheim, Sanofi, Hengrui Therapeutics, Merck, Daiichi Sankyo, Lycera, G1 Therapeutics, Dynavax, Loxo Oncology, CytomX, BeiGene, Birdie, Corvus, Incyte, Genocea, Gritstone, Amgen, Bristol-Myers Squibb, Kadmon, Clovis, Acerta, OncoMed, and Guardant Health; consulting/advisory role for Genentech-Roche, Celgene, Boehringer Ingelheim, Sanofi, Mirati, Loxo Oncology, Calithera, AstraZeneca, Merck, Araxes Pharma, Mersana Therapeutics, BeiGene, Incyte, Pfizer, Guardant Health, Bristol-Myers Squibb, and Ribon Therapeutics; and food/beverage/travel expenses from AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, EMD Serono, Bristol-Myers Squibb, Exelixis, Genentech, Incyte, Merck, Pfizer, Sysmex Inostics, and Vapotherm. Mr. Lally, Dr. Valenzuela, Dr. Maag, and Dr. Blot are employees and stockholders of AbbVie. Dr. Leal reports a consulting/advisory role for Takeda, AbbVie, AstraZeneca, Bristol-Myers Squibb, and Genentech. Dr. Lehman reports receiving research funding (to institution) from AbbVie and Ipsen and preclinical research material support (rovalpituzumab tesirine) from AbbVie. Dr. Malhotra reports a consulting/advisory role for AstraZeneca, Blueprint Medicines, research funding (to institution) from Bristol-Myers Squibb, BeyondSpring Pharmaceuticals, Celldex, and Biohaven Pharmaceuticals. Dr. Morgensztern reports a consulting/advisory role for AbbVie, Bristol-Myers Squibb, Takeda, and PharmaMar and research funding (to institution) from Incyte, Heat Biologics, Merck, Celgene, AbbVie, AstraZeneca, Bristol-Myers Squibb, and Pfizer. Dr. Patel reports roles for AbbVie (advisor), AstraZeneca (advisor), and Takeda (advisor). Dr. Ready reports a consulting/advisory role for AbbVie, Bristol-Myers Squibb, Merck, Celgene, AstraZeneca, Novartis, Pfizer, G1 Therapeutics, EMD Serono, Genentech; serving as paid advisor for AbbVie; and receiving research funding for Merck, Speaker unbranded, for Bristol-Myers Squibb. Dr. Robinet reports a consulting/advisory role for Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, and AstraZeneca and research funding (to institution) from AbbVie, AstraZeneca. Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche. Dr. Wrangle reports serving as site principal investigator for AbbVie but has no financial relationship. Dr. Nikolinakos declares no conflict of interest.AbbVie provided financial support for the study (NCT03026166). AbbVie participated in the design, study conduct, analysis and interpretation of data and writing, review, and approval of the manuscript. AbbVie and the authors thank patients and their families and caregivers; study investigators and staff; Emin Avsar and Giovanni Selvaggi (Bristol-Myers Squibb); and Philip Komarnitsky, Ahd Foullane, and Scott Gulbranson (AbbVie). Medical writing support was provided by Mary L. Smith, PhD, CMPP, Aptitude Health, Atlanta, Georgia, funded by AbbVie. Dr. Malhotra, Dr. Nikolinakos, Dr. Leal, Dr. Lehman, Dr. Morgensztern, Dr. Patel, Dr. Wrangle, Dr. Curigliano, Dr. Greillier, Dr. Johnson, Dr. Ready, Dr. Besse, and Dr. Robinet contributed to investigation and writing?reviewing and editing of the article. Mr. Lally, Dr. Maag, and Dr. Valenzuela contributed to formal analysis, data curation, and writing?reviewing and editing of the article. Dr. Blot contributed to supervision, writing?original draft preparation, and writing?reviewing and editing of the article.

Keywords

Antibody-drug conjugates
Clinical trials
Immunotherapy
Lung cancer
Small-molecule agents

ASJC Scopus subject areas

Oncology
Pulmonary and Respiratory Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jtho.2021.02.022

Cite this

Malhotra, J., Nikolinakos, P., Leal, T., Lehman, J., Morgensztern, D., Patel, J. D., Wrangle, J. M., Curigliano, G., Greillier, L., Johnson, M. L., Ready, N., Robinet, G., Lally, S., Maag, D., Valenzuela, R., Blot, V., & Besse, B. (2021). A Phase 1–2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC. Journal of Thoracic Oncology, 16(9), 1559-1569. https://doi.org/10.1016/j.jtho.2021.02.022

@article{5f9d4725015e4fbba0bdf247c462602e,

title = "A Phase 1–2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC",

abstract = "Introduction: This open-label, phase 1–2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC). Methods: Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data. Results: A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses. Conclusions: Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.",

keywords = "Antibody-drug conjugates, Clinical trials, Immunotherapy, Lung cancer, Small-molecule agents",

author = "Jyoti Malhotra and Petros Nikolinakos and Ticiana Leal and Jonathan Lehman and Daniel Morgensztern and Patel, {Jyoti D.} and Wrangle, {John M.} and Giuseppe Curigliano and Laurent Greillier and Johnson, {Melissa L.} and Neal Ready and Gilles Robinet and Satwant Lally and David Maag and Ricardo Valenzuela and Vincent Blot and Benjamin Besse",

note = "Publisher Copyright: {\textcopyright} 2021 International Association for the Study of Lung Cancer",

year = "2021",

month = sep,

doi = "10.1016/j.jtho.2021.02.022",

language = "English (US)",

volume = "16",

pages = "1559--1569",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

publisher = "International Association for the Study of Lung Cancer",

number = "9",

}

Malhotra, J, Nikolinakos, P, Leal, T, Lehman, J, Morgensztern, D, Patel, JD, Wrangle, JM, Curigliano, G, Greillier, L, Johnson, ML, Ready, N, Robinet, G, Lally, S, Maag, D, Valenzuela, R, Blot, V & Besse, B 2021, 'A Phase 1–2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC', Journal of Thoracic Oncology, vol. 16, no. 9, pp. 1559-1569. https://doi.org/10.1016/j.jtho.2021.02.022

TY - JOUR

T1 - A Phase 1–2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC

AU - Malhotra, Jyoti

AU - Nikolinakos, Petros

AU - Leal, Ticiana

AU - Lehman, Jonathan

AU - Morgensztern, Daniel

AU - Patel, Jyoti D.

AU - Wrangle, John M.

AU - Curigliano, Giuseppe

AU - Greillier, Laurent

AU - Johnson, Melissa L.

AU - Ready, Neal

AU - Robinet, Gilles

AU - Lally, Satwant

AU - Maag, David

AU - Valenzuela, Ricardo

AU - Blot, Vincent

AU - Besse, Benjamin

PY - 2021/9

Y1 - 2021/9

N2 - Introduction: This open-label, phase 1–2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC). Methods: Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data. Results: A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses. Conclusions: Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.

AB - Introduction: This open-label, phase 1–2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC). Methods: Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data. Results: A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses. Conclusions: Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.

KW - Antibody-drug conjugates

KW - Clinical trials

KW - Immunotherapy

KW - Lung cancer

KW - Small-molecule agents

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DO - 10.1016/j.jtho.2021.02.022

M3 - Article

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AN - SCOPUS:85103255413

SN - 1556-0864

VL - 16

SP - 1559

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JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

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ER -

A Phase 1–2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC

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UN SDGs

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