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Clinical Trial
. 2024 Oct 1;4(10):2823-2834.
doi: 10.1158/2767-9764.CRC-24-0255.

Targeting the Epidermal Growth Factor Receptor Pathway in Chemotherapy-Resistant Triple-Negative Breast Cancer: A Phase II Study

Clinton Yam #  1 , Miral Patel  2 , Holly A Hill  3 , Ryan Sun  4 , Roland L Bassett Jr  4 , Elisabeth Kong  3 , Senthil Damodaran  1 , Kimberly B Koenig  1 , Sausan Abouharb  1 , Sadia Saleem  1 , Ajit K Bisen  1 , Rashmi K Murthy  1 , David L Ramirez  1 , Gaiane M Rauch  2 , Beatriz E Adrada  2 , Rosalind P Candelaria  2 , Xiaoping Wang  5 , Elizabeth A Mittendorf  6   7   8 , Alastair M Thompson  9 , Jason B White  1 , Elizabeth E Ravenberg  1 , Alyson R Clayborn  1 , Qing-Qing Ding  10 , Daniel J Booser  1 , Oluchi Oke  1 , Abenaa M Brewster  1 , Gabriel N Hortobagyi  1 , Nuhad K Ibrahim  1 , Jennifer K Litton  1 , Vicente Valero  1 , Banu K Arun  1 , Debu Tripathy  1 , Jeffrey T Chang  11 , Ken Chen  3 , Anil Korkut  3 , Stacy L Moulder  1 , Lei Huo  10 , Bora Lim #  1 , Naoto T Ueno #  1
Affiliations
Clinical Trial

Targeting the Epidermal Growth Factor Receptor Pathway in Chemotherapy-Resistant Triple-Negative Breast Cancer: A Phase II Study

Clinton Yam et al. Cancer Res Commun. .

Abstract

Purpose: Epidermal growth factor receptor (EGFR) pathway activation causes chemotherapy resistance, and inhibition of the EGFR pathway sensitizes triple-negative breast cancer (TNBC) cells to chemotherapy in preclinical models. Given the high prevalence of EGFR overexpression in TNBC, we conducted a single-arm phase II study of panitumumab (anti-EGFR monoclonal antibody), carboplatin, and paclitaxel as the second phase of neoadjuvant therapy (NAT) in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02593175).

Patients and methods: Patients with early-stage, AC-resistant TNBC, defined as disease progression or ≤80% reduction in tumor volume after four cycles of AC, were eligible for this study and received panitumumab (2.5 mg/kg i.v., every week × 13), paclitaxel (80 mg/m2 i.v. every week × 12), and carboplatin (AUC = 4 i.v., every 3 weeks × 4) as the second phase of NAT. A two-stage Gehan-type design was used to detect an improvement in the pathological complete response (pCR)/residual cancer burden class I (RCB-I) rate from 5% to 20%. Whole-exome sequencing was performed on diagnostic tumor biospecimens, where available.

Results: From November 3, 2016, through August 23, 2021, 43 patients with AC-resistant TNBC were enrolled. The combined pCR/RCB-I rate was 30.2%. The most common treatment-related adverse events were neutropenia (72%) and anemia (61%), with 7 (16%), 16 (37%), and 8 (19%) patients experiencing grade 4 neutropenia, grade 3 neutropenia, and grade 3 anemia, respectively. No new safety signals were observed.

Conclusions: This study met its primary endpoint (pCR/RCB-I = 30.2% vs. 5% in historical controls), suggesting that panitumumab should be evaluated as a component of NAT in patients with chemotherapy-resistant TNBC in a larger, randomized clinical trial.

Significance: The epidermal growth factor receptor (EGFR) pathway has been implicated as a driver of chemotherapy resistance in triple-negative breast cancer (TNBC). Here, we evaluate the combination of panitumumab, carboplatin, and paclitaxel as the second phase of neoadjuvant therapy (NAT) in patients with AC-resistant TNBC. This study met its primary efficacy endpoint, and molecular alterations in EGFR pathway genes did not seem to influence response to the study regimen.

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Conflict of interest statement

C. Yam reports grants from Amgen during the conduct of the study, as well as grants from Genentech, BostonGene, Sanofi, Pfizer, Astellas, and Novartis, grants and other support from Gilead, and personal fees from MDHealth Brazil and Binaytara Foundation outside the submitted work. E. Kong reports grants from National Library of Medicine during the conduct of the study. S. Damodaran reports grants from Sermonix, EMD Serono, AstraZeneca, Taiho Oncology, Daiichi Sankyo, Medilink Therapeutics, Duality Biologics, and Novartis outside the submitted work. R.P. Candelaria reports that funding sources to the institution for the submitted work have been declared on the title page of the article by the corresponding author. He did not personally receive additional payments or services from a third party. E.A. Mittendorf reports other support from AstraZeneca, BioNTech, Merck, Moderna, Bristol Myers Squibb, Roche/Genentech, and Merck Sharp & Dohme, nonfinancial support from Gilead, and grants from Roche/Genentech outside the submitted work. A.M. Thompson reports other support from Eli Lilly and Company outside the submitted work. E.E. Ravenberg reports other from Eli Lilly and Company outside the submitted work, as well as employment with Eli Lilly and Company and receiving compensation and stock options. J.K. Litton reports grants from Pfizer, Merck, Genentech, AstraZeneca, and Zenith outside the submitted work. V. Valero reports grants and other support from MD Anderson Cancer Center during the conduct of the study. D. Tripathy reports grants and personal fees from Novartis and Ambryx and personal fees from Pfizer, AstraZeneca, Stemline-Menarini, Personalis, Sermonix, Roche, Gilead, Puma Biotechnology, BeiGene, Jazz Pharmaceuticals, and Zetagen outside the submitted work. A. Korkut reports grants from BostonGene outside the submitted work. S.L. Moulder reports other support from Eli Lilly and Company during the conduct of the study, as well as other support from Eli Lilly and Company outside the submitted work. L. Huo reports other support from MD Anderson Cancer Center during the conduct of the study. B. Lim reports serving in a consultancy/advisory role for Celcuity, Natera, Daiichi Sankyo, Novartis, Pfizer, and AstraZeneca; honoraria from Puma Biotechnology, Novartis, and Pfizer; and grant/research funding from Genentech, Takeda, Merck, Celcuity, Eli Lilly and Company, Puma Biotechnology, and Calithera Biosciences. N.T. Ueno reports other support from Pear Bio and Phoenix Molecular Designs, personal fees from Kyowa Hakko Kirin, Pfizer, Bayer, MEDSIR, Genomic Health, Bristol Myers Squibb, AstraZeneca, Carna Biosciences, Eisai, Bayer, Gilead, Eli Lilly and Company, and Oncocyte, grants from Amgen and Preferred Medicine, and grants and personal fees from Daiichi Sankyo outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1
Figure 1
Response to AC. Waterfall plot showing percent sonographic volumetric change to initial AC chemotherapy received prior to enrollment in study. One of the 43 patients enrolled in this study is not represented on this plot as an ultrasound was not done at the end of AC. Colors represent the total number of cycles of AC received prior to enrollment in study (red = 1; gray = 2; blue = 4). Horizontal dashed line indicates an 80% decrease in calculated tumor volume when compared with baseline measurements.
Figure 2
Figure 2
Genomic alterations and pathological response to therapy. Oncoplot showing somatic mutations in the EGFR pathway assessed by WES for each patient sample obtained at the time of diagnosis (n = 23). TMB was defined as the number of somatic mutations per megabase (Mb) of the sequenced genome.
Figure 3
Figure 3
Survival outcomes. A, Kaplan–Meier plot of EFS for all patients. B, Kaplan–Meier plot of EFS separated by pathological response. C, Kaplan–Meier plot of MFS for all patients. D, Kaplan–Meier plot of MFS separated by pathological response. E, Kaplan–Meier plot of OS for all patients. F, Kaplan–Meier plot of OS separated by pathological response.
See this image and copyright information in PMC

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