Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer

J M van Berge Henegouwen; M Jebbink; L R Hoes; H van der Wijngaart; L J Zeverijn; D L van der Velden; P Roepman; W W J de Leng; A M L Jansen; E van Werkhoven; V van der Noort; A J van der Wekken; A J de Langen; E E Voest; H M W Verheul; E F Smit; H Gelderblom

doi:10.1016/j.ejca.2022.05.009

Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer

J M van Berge Henegouwen
, M Jebbink
, L R Hoes
, H van der Wijngaart
, L J Zeverijn
, D L van der Velden
, P Roepman
, W W J de Leng
, A M L Jansen
, E van Werkhoven
, V van der Noort
, A J van der Wekken
, A J de Langen
, E E Voest
, H M W Verheul
, E F Smit
, H Gelderblom

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

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Abstract

INTRODUCTION: In 1-3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC'.

METHODS: Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease ≥ 16 weeks). Patients were enrolled using a Simon-like 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained.

RESULTS: Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38%); including an objective response rate of 8.3% (2 patients had a partial response) and 7 patients with stable disease ≥ 16 weeks. The most frequently observed HER2 mutation was p.Y772_A775dup (71%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95% CI 3-6) and 10 months (95% CI 4 - not reached), respectively. Whole genome sequencing data (available for 67% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed.

CONCLUSION: Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC.

Original language	English
Pages (from-to)	114-123
Number of pages	10
Journal	European Journal of Cancer
Volume	171
Early online date	15 Jun 2022
DOIs	https://doi.org/10.1016/j.ejca.2022.05.009
Publication status	Published - Aug 2022

Keywords

HER2 mutation
Non-small lung cancer
Precision medicine
Targeted therapies
Whole genome sequencing

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1-s2.0-S0959804922002878-mainFinal published version, 1.33 MBLicence: CC BY

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van Berge Henegouwen, J. M., Jebbink, M., Hoes, L. R., van der Wijngaart, H., Zeverijn, L. J., van der Velden, D. L., Roepman, P., de Leng, W. W. J., Jansen, A. M. L., van Werkhoven, E., van der Noort, V., van der Wekken, A. J., de Langen, A. J., Voest, E. E., Verheul, H. M. W., Smit, E. F., & Gelderblom, H. (2022). Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer. European Journal of Cancer, 171, 114-123. https://doi.org/10.1016/j.ejca.2022.05.009

@article{18db07af2aef440382889e147f3e71ca,

title = "Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer",

abstract = "INTRODUCTION: In 1-3\% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC'.METHODS: Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease ≥ 16 weeks). Patients were enrolled using a Simon-like 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained.RESULTS: Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38\%); including an objective response rate of 8.3\% (2 patients had a partial response) and 7 patients with stable disease ≥ 16 weeks. The most frequently observed HER2 mutation was p.Y772\_A775dup (71\%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95\% CI 3-6) and 10 months (95\% CI 4 - not reached), respectively. Whole genome sequencing data (available for 67\% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed.CONCLUSION: Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC.",

keywords = "HER2 mutation, Non-small lung cancer, Precision medicine, Targeted therapies, Whole genome sequencing",

author = "\{van Berge Henegouwen\}, \{J M\} and M Jebbink and Hoes, \{L R\} and \{van der Wijngaart\}, H and Zeverijn, \{L J\} and \{van der Velden\}, \{D L\} and P Roepman and \{de Leng\}, \{W W J\} and Jansen, \{A M L\} and \{van Werkhoven\}, E and \{van der Noort\}, V and \{van der Wekken\}, \{A J\} and \{de Langen\}, \{A J\} and Voest, \{E E\} and Verheul, \{H M W\} and Smit, \{E F\} and H Gelderblom",

note = "Funding Information: The DRUP trial is supported by the Barcode for Life Foundation (BFL); the Dutch Cancer Society [grant number 10014]; the Hartwig Medical Foundation (HMF) and all participating pharmaceutical companies: Amgen ; AstraZeneca ; Bayer ; Boehringer Ingelheim ; Bristol-Myers Squibb ; Clovis Oncology ; Eisai ; Janssen; Lilly; MSD; Novartis; Pfizer ; Roche . Funding Information: The DRUP trial is supported by the Barcode for Life Foundation (BFL); the Dutch Cancer Society [grant number 10014]; the Hartwig Medical Foundation (HMF) and all participating pharmaceutical companies: Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Clovis Oncology; Eisai; Janssen; Lilly; MSD; Novartis; Pfizer; Roche.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AW received grants from Boehringer Ingelheim, Pfizer, AstraZeneca, Roche and Takeda and was involved in advisory boards for Lilly, Boehringer Ingelheim, Pfizer, AstraZeneca, Roche, Takeda and Janssen. All outside the submitted work and all money has been received by the UMCG. The other authors declare no competing interests.The authors thank the Hartwig Medical Foundation for their in-kind support by performing sequencing and biomarker analyses on baseline biopsies; the Independent Data Monitoring Committee for their advice on cohort decisions and monitoring of preliminary safety data; and the authors would like to thank the patients, the investigators and research staff from all participating hospitals. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = aug,

doi = "10.1016/j.ejca.2022.05.009",

language = "English",

volume = "171",

pages = "114--123",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Limited",

}

van Berge Henegouwen, JM, Jebbink, M, Hoes, LR, van der Wijngaart, H, Zeverijn, LJ, van der Velden, DL, Roepman, P, de Leng, WWJ , Jansen, AML, van Werkhoven, E, van der Noort, V, van der Wekken, AJ, de Langen, AJ, Voest, EE, Verheul, HMW, Smit, EF & Gelderblom, H 2022, 'Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer', European Journal of Cancer, vol. 171, pp. 114-123. https://doi.org/10.1016/j.ejca.2022.05.009

TY - JOUR

T1 - Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer

AU - van Berge Henegouwen, J M

AU - Jebbink, M

AU - Hoes, L R

AU - van der Wijngaart, H

AU - Zeverijn, L J

AU - van der Velden, D L

AU - Roepman, P

AU - de Leng, W W J

AU - Jansen, A M L

AU - van Werkhoven, E

AU - van der Noort, V

AU - van der Wekken, A J

AU - de Langen, A J

AU - Voest, E E

AU - Verheul, H M W

AU - Smit, E F

AU - Gelderblom, H

N1 - Funding Information: The DRUP trial is supported by the Barcode for Life Foundation (BFL); the Dutch Cancer Society [grant number 10014]; the Hartwig Medical Foundation (HMF) and all participating pharmaceutical companies: Amgen ; AstraZeneca ; Bayer ; Boehringer Ingelheim ; Bristol-Myers Squibb ; Clovis Oncology ; Eisai ; Janssen; Lilly; MSD; Novartis; Pfizer ; Roche . Funding Information: The DRUP trial is supported by the Barcode for Life Foundation (BFL); the Dutch Cancer Society [grant number 10014]; the Hartwig Medical Foundation (HMF) and all participating pharmaceutical companies: Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Clovis Oncology; Eisai; Janssen; Lilly; MSD; Novartis; Pfizer; Roche.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AW received grants from Boehringer Ingelheim, Pfizer, AstraZeneca, Roche and Takeda and was involved in advisory boards for Lilly, Boehringer Ingelheim, Pfizer, AstraZeneca, Roche, Takeda and Janssen. All outside the submitted work and all money has been received by the UMCG. The other authors declare no competing interests.The authors thank the Hartwig Medical Foundation for their in-kind support by performing sequencing and biomarker analyses on baseline biopsies; the Independent Data Monitoring Committee for their advice on cohort decisions and monitoring of preliminary safety data; and the authors would like to thank the patients, the investigators and research staff from all participating hospitals. Publisher Copyright: © 2022 The Authors

PY - 2022/8

Y1 - 2022/8

N2 - INTRODUCTION: In 1-3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC'.METHODS: Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease ≥ 16 weeks). Patients were enrolled using a Simon-like 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained.RESULTS: Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38%); including an objective response rate of 8.3% (2 patients had a partial response) and 7 patients with stable disease ≥ 16 weeks. The most frequently observed HER2 mutation was p.Y772_A775dup (71%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95% CI 3-6) and 10 months (95% CI 4 - not reached), respectively. Whole genome sequencing data (available for 67% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed.CONCLUSION: Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC.

AB - INTRODUCTION: In 1-3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC'.METHODS: Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease ≥ 16 weeks). Patients were enrolled using a Simon-like 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained.RESULTS: Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38%); including an objective response rate of 8.3% (2 patients had a partial response) and 7 patients with stable disease ≥ 16 weeks. The most frequently observed HER2 mutation was p.Y772_A775dup (71%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95% CI 3-6) and 10 months (95% CI 4 - not reached), respectively. Whole genome sequencing data (available for 67% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed.CONCLUSION: Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC.

KW - HER2 mutation

KW - Non-small lung cancer

KW - Precision medicine

KW - Targeted therapies

KW - Whole genome sequencing

UR - https://www.scopus.com/pages/publications/85132341434

U2 - 10.1016/j.ejca.2022.05.009

DO - 10.1016/j.ejca.2022.05.009

M3 - Article

C2 - 35716537

SN - 0959-8049

VL - 171

SP - 114

EP - 123

JO - European Journal of Cancer

JF - European Journal of Cancer

ER -

Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer

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