A phase 1 study of cetuximab and lapatinib in patients with advanced solid tumor malignancies

Deeken, John F.; Wang, Hongkun; Subramaniam, Deepa; He, Aiwu Ruth; Hwang, Jimmy J.; Marshall, John L.; Urso, C.; Wang, Yiru; Ramos, Corinne; Steadman, Kenneth; Pishvaian, Michael J.

doi:10.1002/cncr.29224

Cited by 28 publications

(15 citation statements)

References 37 publications

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“…Furthermore, Siena et al reported that trastuzumab and lapatinib combination therapy induced a partial response in seven of 22 patients (32%) with HER2-positive CRC who were resistant to anti-EGFR antibody therapy [ 24 ]. Additionally, Deeken et al reported that the combination of cetuximab and lapatinib provided a partial response in some patients with CRC who were resistant to anti-EGFR antibody therapy [ 25 ]. Therefore, these data suggest that evaluation of HER2 in ctDNA may be helpful for determining the optimal therapy involving HER2-targeting combination therapy rather than anti-EGFR antibodies alone in patients with CRC.…”

Section: Discussionmentioning

confidence: 99%

HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer

et al. 2015

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BackgroundPatients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS benefit from epidermal growth factor receptor (EGFR)-targeted therapy. However, patients who are treated with anti-EGFR antibodies will eventually develop the resistance to those agents. HER2 amplification is one of the mechanisms conferring resistance to anti-EGFR antibody therapy and could therefore be a potential therapeutic target. The aim of this study was to detect HER2 amplification in circulating tumor DNA (ctDNA) from patients with CRC and acquired resistance to anti-EGFR antibody therapy.ResultsOur data showed that 22% (4/18) of patients in the cohort exhibited HER2 amplification. One of these patients was found to be positive for HER2 amplification in matched tumor specimens collected after cetuximab therapy, at which point the patient had acquired cetuximab resistance, despite being negative for HER2 amplification prior to therapy.MethodsWe analyzed plasma ctDNA using digital polymerase chain reaction (PCR) from 18 patients with CRC, who had been treated with anti-EGFR antibody-based therapy (cetuximab) and subsequently acquired resistant cetuximab. HER2 gene copy number was analyzed using fluorescence in situ hybridization in tumor samples before and after acquisition of resistance to cetuximab-based therapy.ConclusionAnalysis of plasma ctDNA by digital PCR could be useful for detecting HER2 amplification in patients with CRC who were resistant to anti-EGFR antibody therapy.

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Section: Discussionmentioning

confidence: 99%

HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer

et al. 2015

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“…Although patients with HER2 amplification were resistant to anti-EGFR antibody therapy, other treatment strategies, including lapatinib or trastuzumab, can overcome cetuximab resistance in CRCs [ 242 ]. Finally, in addition to the previously reported trial conducted by Siena et al [ 244 ], Deeken et al [ 248 ] concluded that the combination of cetuximab and lapatinib provided a partial response in some patients with CRC who were resistant to anti-EGFR antibody therapy.…”

Section: Bespoke Treatment: Role Of Biomarkers In Clinical Settingmentioning

confidence: 86%

Noninvasive Biomarkers of Colorectal Cancer: Role in Diagnosis and Personalised Treatment Perspectives

Pellino

Gallo

Pallante

et al. 2018

Gastroenterology Research and Practice

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Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. It has been estimated that more than one-third of patients are diagnosed when CRC has already spread to the lymph nodes. One out of five patients is diagnosed with metastatic CRC. The stage of diagnosis influences treatment outcome and survival. Notwithstanding the recent advances in multidisciplinary management and treatment of CRC, patients are still reluctant to undergo screening tests because of the associated invasiveness and discomfort (e.g., colonoscopy with biopsies). Moreover, the serological markers currently used for diagnosis are not reliable and, even if they were useful to detect disease recurrence after treatment, they are not always detected in patients with CRC (e.g., CEA). Recently, translational research in CRC has produced a wide spectrum of potential biomarkers that could be useful for diagnosis, treatment, and follow-up of these patients. The aim of this review is to provide an overview of the newer noninvasive or minimally invasive biomarkers of CRC. Here, we discuss imaging and biomolecular diagnostics ranging from their potential usefulness to obtain early and less-invasive diagnosis to their potential implementation in the development of a bespoke treatment of CRC.

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“…Yonesaka K et al[ 5 ] demonstrated that inhibiting HER2 signaling in HER2 - amplified colon cancer models could restore their sensitivity to EGFR monoclonal antibody in vitro and in vivo . Moreover, an HER2-positive mCRC patient who underwent anti-EGFR therapy responded well to lapatinib plus cetuximab[ 15 ]. Therefore, the inhibition of both HER2 and EGFR is another potential strategy to treat HER2-positive and RAS/BRAF wild-type mCRC.…”

Section: Discussionmentioning

confidence: 99%

Response of human epidermal growth factor receptor 2-positive colorectal cancer to lapatinib monotherapy: A case report

Guan

Liu

Wang³

et al. 2020

WJGO

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BACKGROUND Human epidermal growth factor receptor 2 (HER2) amplification is a molecular driver for a subset of colorectal cancers (CRCs) and one of the major causes of anti-epidermal growth factor receptor (EGFR) treatment failure. Compared to dual anti-HER2 treatments, which have been shown to be effective in HER2-positive metastatic CRC patients, single-agent anti-HER2 therapy is rarely used to treat CRC. CASE SUMMARY Herein, we report a case of RAS/BRAF-wild-type metastatic CRC that was identified as HER2-positive through circulating tumor DNA (ctDNA) testing by next-generation sequencing following the failure of two lines of therapy. Subsequently, the patient was given lapatinib monotherapy that led to a partial response with a progression-free survival of 7.9 mo. Moreover, serial ctDNA detection was used to monitor the efficacy of lapatinib. The aberration of HER2 copy number disappeared when radiographic assessment revealed a partial response. However, a high level of HER2 amplification was detected again at the time of disease progression. Finally, a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation was identified at the time of tumor progression, which may explain the acquired resistance to lapatinib. CONCLUSION This is the first case report of HER2-positive RAS/BRAF wild-type metastatic CRC patient responding to lapatinib monotherapy. It highlights that ctDNA testing is an effective and feasible approach to evaluate the efficacy of anti-HER2 therapy.

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A phase 1 study of cetuximab and lapatinib in patients with advanced solid tumor malignancies

Cited by 28 publications

References 37 publications

HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer

HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer

Noninvasive Biomarkers of Colorectal Cancer: Role in Diagnosis and Personalised Treatment Perspectives

Response of human epidermal growth factor receptor 2-positive colorectal cancer to lapatinib monotherapy: A case report

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