Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease.

Mark A. Socinski; Frederic J. Kaye; David R. Spigel; Fred J. Kudrik; Santiago Ponce; Peter M. Ellis; Margarita Majem; Paul Lorigan; Leena Gandhi; Martin E. Gutierrez; Dale Nepert; Jesus Corral; Luis Paz-Ares

doi:10.1016/j.cllc.2016.09.002

Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease.

Mark A. Socinski
, Frederic J. Kaye
, David R. Spigel
, Fred J. Kudrik
, Santiago Ponce
, Peter M. Ellis
, Margarita Majem
, Paul Lorigan
, Leena Gandhi
, Martin E. Gutierrez
, Dale Nepert
, Jesus Corral
, Luis Paz-Ares

Division of Cancer Sciences (L5)

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

Abstract

Introduction

This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC).

Patients and Methods

A run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED-SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m2 days 1 to 3 plus LM (arm 1) or alone (arm 2).

Results

In the phase 1 study (n = 33), a dose of LM at 112 mg/m2 with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m2. In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug.

Conclusion

The combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes.

Keywords
Clinical trial; Combination therapy; SCLC; Targeted drug delivery; Tolerability

Original language	English
Article number	PMID: 2834110
Pages (from-to)	68-76
Number of pages	8
Journal	Clinical Lung Cancer
Volume	18
Issue number	1
Early online date	3 Oct 2016
DOIs	https://doi.org/10.1016/j.cllc.2016.09.002
Publication status	Published - 1 Jan 2017

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

SDG 3 Good Health and Well-being

Research Highlights, Institutes and Platforms

Manchester Cancer Research Centre

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10.1016/j.cllc.2016.09.002

Cite this

Socinski, M. A., Kaye, F. J., Spigel, D. R., Kudrik, F. J., Ponce, S., Ellis, P. M., Majem, M., Lorigan, P., Gandhi, L., Gutierrez, M. E., Nepert, D., Corral, J., & Paz-Ares, L. (2017). Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease. Clinical Lung Cancer, 18(1), 68-76. Article PMID: 2834110. https://doi.org/10.1016/j.cllc.2016.09.002

@article{cef0f846992043489b8cd75b44cae359,

title = "Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease.",

abstract = "Introduction This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). Patients and Methods A run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED-SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m2 days 1 to 3 plus LM (arm 1) or alone (arm 2). Results In the phase 1 study (n = 33), a dose of LM at 112 mg/m2 with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m2. In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29\%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug. Conclusion The combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes. Keywords Clinical trial; Combination therapy; SCLC; Targeted drug delivery; Tolerability",

author = "Socinski, \{Mark A.\} and Kaye, \{Frederic J.\} and Spigel, \{David R.\} and Kudrik, \{Fred J.\} and Santiago Ponce and Ellis, \{Peter M.\} and Margarita Majem and Paul Lorigan and Leena Gandhi and Gutierrez, \{Martin E.\} and Dale Nepert and Jesus Corral and Luis Paz-Ares",

year = "2017",

month = jan,

day = "1",

doi = "10.1016/j.cllc.2016.09.002",

language = "English",

volume = "18",

pages = "68--76",

journal = "Clinical Lung Cancer",

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Socinski, MA, Kaye, FJ, Spigel, DR, Kudrik, FJ, Ponce, S, Ellis, PM, Majem, M, Lorigan, P, Gandhi, L, Gutierrez, ME, Nepert, D, Corral, J & Paz-Ares, L 2017, 'Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease.', Clinical Lung Cancer, vol. 18, no. 1, PMID: 2834110, pp. 68-76. https://doi.org/10.1016/j.cllc.2016.09.002

Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease. / Socinski, Mark A.; Kaye, Frederic J.; Spigel, David R. et al.
In: Clinical Lung Cancer, Vol. 18, No. 1, PMID: 2834110, 01.01.2017, p. 68-76.

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

TY - JOUR

T1 - Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease.

AU - Socinski, Mark A.

AU - Kaye, Frederic J.

AU - Spigel, David R.

AU - Kudrik, Fred J.

AU - Ponce, Santiago

AU - Ellis, Peter M.

AU - Majem, Margarita

AU - Lorigan, Paul

AU - Gandhi, Leena

AU - Gutierrez, Martin E.

AU - Nepert, Dale

AU - Corral, Jesus

AU - Paz-Ares, Luis

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Introduction This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). Patients and Methods A run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED-SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m2 days 1 to 3 plus LM (arm 1) or alone (arm 2). Results In the phase 1 study (n = 33), a dose of LM at 112 mg/m2 with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m2. In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug. Conclusion The combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes. Keywords Clinical trial; Combination therapy; SCLC; Targeted drug delivery; Tolerability

AB - Introduction This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). Patients and Methods A run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED-SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m2 days 1 to 3 plus LM (arm 1) or alone (arm 2). Results In the phase 1 study (n = 33), a dose of LM at 112 mg/m2 with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m2. In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug. Conclusion The combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes. Keywords Clinical trial; Combination therapy; SCLC; Targeted drug delivery; Tolerability

UR - https://www.scopus.com/pages/publications/84994032179

U2 - 10.1016/j.cllc.2016.09.002

DO - 10.1016/j.cllc.2016.09.002

M3 - Article

SN - 1525-7304

VL - 18

SP - 68

EP - 76

JO - Clinical Lung Cancer

JF - Clinical Lung Cancer

IS - 1

M1 - PMID: 2834110

ER -

Socinski MA, Kaye FJ, Spigel DR, Kudrik FJ, Ponce S, Ellis PM et al. Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease. Clinical Lung Cancer. 2017 Jan 1;18(1):68-76. PMID: 2834110. Epub 2016 Oct 3. doi: 10.1016/j.cllc.2016.09.002

Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease.

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