Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer: Findings From the SUMMIT Basket Trial

Jonathan W. Goldman; Alejandro Martinez Bueno; Christophe Dooms; Komal Jhaveri; Maria de Miguel; Sarina A. Piha-Paul; Nisha Unni; Aviad Zick; Amit Mahipal; J. Marie Suga; Charles Naltet; Monica Antoñanzas; John Crown; Judith Bebchuk; Lisa D. Eli; Beth H. Lowenthal; Devalingam Mahalingam

doi:10.1016/j.cllc.2024.12.003

Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer: Findings From the SUMMIT Basket Trial

Jonathan W. Goldman^*, Alejandro Martinez Bueno, Christophe Dooms, Komal Jhaveri, Maria de Miguel, Sarina A. Piha-Paul, Nisha Unni, Aviad Zick, Amit Mahipal, J. Marie Suga, Charles Naltet, Monica Antoñanzas, John Crown, Judith Bebchuk, Lisa D. Eli, Beth H. Lowenthal, Devalingam Mahalingam

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

Abstract

Background: Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in 7% to 23% of patients with non-small-cell lung cancer (NSCLC). A small proportion of these (3–5%) are exon 18 mutations. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), had activity in the phase II SUMMIT basket study. We report efficacy and safety of neratinib in patients with EGFR exon 18-mutant NSCLC in SUMMIT, according to prior EGFR TKI treatment. Patients and Methods: Eligible patients had ECOG performance status 0–2. Prior EGFR TKIs, chemotherapy, and checkpoint inhibitors were allowed. Patients received neratinib (240 mg orally daily) and mandatory diarrhea prophylaxis with loperamide. The primary endpoint was objective response rate (ORR) at 8 weeks (ORR₈); other endpoints included ORR, progression-free survival (PFS), duration of response, and safety. Results: Thirty-one patients were included (24/7 with/without prior TKI). ORR₈ was 19.4% (95% CI 7.5–37.5); ORR was 32.3% (95% CI: 16.7–51.4); median PFS 5.75 months (95% CI: 2.27–9.23). Two of 7 patients with baseline central nervous system metastasis had partial responses (median PFS 3.6 months; 95% CI: 1.9–9.1). Six patients with G719A/X/C mutations had partial responses >10 months. Diarrhea was generally controlled (10% grade 3, no grade 4; one patient discontinued treatment because of diarrhea). Conclusion: Neratinib had meaningful activity in selected patients with EGFR exon 18-mutant NSCLC, including patients pretreated with ≥1 TKI. Diarrhea was generally low grade. Given the lack of effective treatments after EGFR TKI failure for NSCLC with uncommon mutations, further examination of neratinib is warranted.

Original language	English (US)
Journal	Clinical Lung Cancer
DOIs	https://doi.org/10.1016/j.cllc.2024.12.003
State	Accepted/In press - 2025

Funding

The authors would like to thank Bethann Hromatka (Puma Biotechnology) for publications support, Jane Liang and Daniel DiPrimeo (Puma Biotechnology) for programming support, and Deirdre Carman, Lee Miller, and Fiona Weston (Miller Medical Communications Ltd) for writing/editorial support, which was funded by Puma Biotechnology. SUMMIT was funded by Puma Biotechnology Inc. Puma Biotechnology Inc. also funded the provision of writing/editorial support provided by Deirdre Carman, Lee Miller, and Fiona Weston of Miller Medical Communications Ltd. Dr Piha-Paul received core grant P30CA016672 (CCSG Shared Resources) from the NIH/NCI to her institution.

Keywords

Basket study
NSCLC
Objective response rate
Rare mutations
Tyrosine kinase inhibitor

ASJC Scopus subject areas

Oncology
Pulmonary and Respiratory Medicine
Cancer Research

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10.1016/j.cllc.2024.12.003

Cite this

Goldman, J. W., Bueno, A. M., Dooms, C., Jhaveri, K., de Miguel, M., Piha-Paul, S. A., Unni, N., Zick, A., Mahipal, A., Suga, J. M., Naltet, C., Antoñanzas, M., Crown, J., Bebchuk, J., Eli, L. D., Lowenthal, B. H., & Mahalingam, D. (Accepted/In press). Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer: Findings From the SUMMIT Basket Trial. Clinical Lung Cancer. https://doi.org/10.1016/j.cllc.2024.12.003

@article{6e19b10243544b42a947a6b17cbe733c,

title = "Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer: Findings From the SUMMIT Basket Trial",

abstract = "Background: Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in 7% to 23% of patients with non-small-cell lung cancer (NSCLC). A small proportion of these (3–5%) are exon 18 mutations. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), had activity in the phase II SUMMIT basket study. We report efficacy and safety of neratinib in patients with EGFR exon 18-mutant NSCLC in SUMMIT, according to prior EGFR TKI treatment. Patients and Methods: Eligible patients had ECOG performance status 0–2. Prior EGFR TKIs, chemotherapy, and checkpoint inhibitors were allowed. Patients received neratinib (240 mg orally daily) and mandatory diarrhea prophylaxis with loperamide. The primary endpoint was objective response rate (ORR) at 8 weeks (ORR8); other endpoints included ORR, progression-free survival (PFS), duration of response, and safety. Results: Thirty-one patients were included (24/7 with/without prior TKI). ORR8 was 19.4% (95% CI 7.5–37.5); ORR was 32.3% (95% CI: 16.7–51.4); median PFS 5.75 months (95% CI: 2.27–9.23). Two of 7 patients with baseline central nervous system metastasis had partial responses (median PFS 3.6 months; 95% CI: 1.9–9.1). Six patients with G719A/X/C mutations had partial responses >10 months. Diarrhea was generally controlled (10% grade 3, no grade 4; one patient discontinued treatment because of diarrhea). Conclusion: Neratinib had meaningful activity in selected patients with EGFR exon 18-mutant NSCLC, including patients pretreated with ≥1 TKI. Diarrhea was generally low grade. Given the lack of effective treatments after EGFR TKI failure for NSCLC with uncommon mutations, further examination of neratinib is warranted.",

keywords = "Basket study, NSCLC, Objective response rate, Rare mutations, Tyrosine kinase inhibitor",

author = "Goldman, {Jonathan W.} and Bueno, {Alejandro Martinez} and Christophe Dooms and Komal Jhaveri and {de Miguel}, Maria and Piha-Paul, {Sarina A.} and Nisha Unni and Aviad Zick and Amit Mahipal and Suga, {J. Marie} and Charles Naltet and Monica Anto{\~n}anzas and John Crown and Judith Bebchuk and Eli, {Lisa D.} and Lowenthal, {Beth H.} and Devalingam Mahalingam",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2025",

doi = "10.1016/j.cllc.2024.12.003",

language = "English (US)",

journal = "Clinical Lung Cancer",

issn = "1525-7304",

publisher = "Elsevier Inc.",

}

Goldman, JW, Bueno, AM, Dooms, C, Jhaveri, K, de Miguel, M, Piha-Paul, SA, Unni, N, Zick, A, Mahipal, A, Suga, JM, Naltet, C, Antoñanzas, M, Crown, J, Bebchuk, J, Eli, LD, Lowenthal, BH & Mahalingam, D 2025, 'Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer: Findings From the SUMMIT Basket Trial', Clinical Lung Cancer. https://doi.org/10.1016/j.cllc.2024.12.003

TY - JOUR

T1 - Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer

T2 - Findings From the SUMMIT Basket Trial

AU - Goldman, Jonathan W.

AU - Bueno, Alejandro Martinez

AU - Dooms, Christophe

AU - Jhaveri, Komal

AU - de Miguel, Maria

AU - Piha-Paul, Sarina A.

AU - Unni, Nisha

AU - Zick, Aviad

AU - Mahipal, Amit

AU - Suga, J. Marie

AU - Naltet, Charles

AU - Antoñanzas, Monica

AU - Crown, John

AU - Bebchuk, Judith

AU - Eli, Lisa D.

AU - Lowenthal, Beth H.

AU - Mahalingam, Devalingam

PY - 2025

Y1 - 2025

N2 - Background: Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in 7% to 23% of patients with non-small-cell lung cancer (NSCLC). A small proportion of these (3–5%) are exon 18 mutations. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), had activity in the phase II SUMMIT basket study. We report efficacy and safety of neratinib in patients with EGFR exon 18-mutant NSCLC in SUMMIT, according to prior EGFR TKI treatment. Patients and Methods: Eligible patients had ECOG performance status 0–2. Prior EGFR TKIs, chemotherapy, and checkpoint inhibitors were allowed. Patients received neratinib (240 mg orally daily) and mandatory diarrhea prophylaxis with loperamide. The primary endpoint was objective response rate (ORR) at 8 weeks (ORR8); other endpoints included ORR, progression-free survival (PFS), duration of response, and safety. Results: Thirty-one patients were included (24/7 with/without prior TKI). ORR8 was 19.4% (95% CI 7.5–37.5); ORR was 32.3% (95% CI: 16.7–51.4); median PFS 5.75 months (95% CI: 2.27–9.23). Two of 7 patients with baseline central nervous system metastasis had partial responses (median PFS 3.6 months; 95% CI: 1.9–9.1). Six patients with G719A/X/C mutations had partial responses >10 months. Diarrhea was generally controlled (10% grade 3, no grade 4; one patient discontinued treatment because of diarrhea). Conclusion: Neratinib had meaningful activity in selected patients with EGFR exon 18-mutant NSCLC, including patients pretreated with ≥1 TKI. Diarrhea was generally low grade. Given the lack of effective treatments after EGFR TKI failure for NSCLC with uncommon mutations, further examination of neratinib is warranted.

AB - Background: Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in 7% to 23% of patients with non-small-cell lung cancer (NSCLC). A small proportion of these (3–5%) are exon 18 mutations. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), had activity in the phase II SUMMIT basket study. We report efficacy and safety of neratinib in patients with EGFR exon 18-mutant NSCLC in SUMMIT, according to prior EGFR TKI treatment. Patients and Methods: Eligible patients had ECOG performance status 0–2. Prior EGFR TKIs, chemotherapy, and checkpoint inhibitors were allowed. Patients received neratinib (240 mg orally daily) and mandatory diarrhea prophylaxis with loperamide. The primary endpoint was objective response rate (ORR) at 8 weeks (ORR8); other endpoints included ORR, progression-free survival (PFS), duration of response, and safety. Results: Thirty-one patients were included (24/7 with/without prior TKI). ORR8 was 19.4% (95% CI 7.5–37.5); ORR was 32.3% (95% CI: 16.7–51.4); median PFS 5.75 months (95% CI: 2.27–9.23). Two of 7 patients with baseline central nervous system metastasis had partial responses (median PFS 3.6 months; 95% CI: 1.9–9.1). Six patients with G719A/X/C mutations had partial responses >10 months. Diarrhea was generally controlled (10% grade 3, no grade 4; one patient discontinued treatment because of diarrhea). Conclusion: Neratinib had meaningful activity in selected patients with EGFR exon 18-mutant NSCLC, including patients pretreated with ≥1 TKI. Diarrhea was generally low grade. Given the lack of effective treatments after EGFR TKI failure for NSCLC with uncommon mutations, further examination of neratinib is warranted.

KW - Basket study

KW - NSCLC

KW - Objective response rate

KW - Rare mutations

KW - Tyrosine kinase inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85215595288&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85215595288&partnerID=8YFLogxK

U2 - 10.1016/j.cllc.2024.12.003

DO - 10.1016/j.cllc.2024.12.003

M3 - Article

C2 - 39828466

AN - SCOPUS:85215595288

SN - 1525-7304

JO - Clinical Lung Cancer

JF - Clinical Lung Cancer

ER -

Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer: Findings From the SUMMIT Basket Trial

Abstract

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