Phase I Study and Biomarker Analysis of Lapatinib and Concurrent Radiation for Locally Advanced Breast Cancer

Abstract

Purpose. This phase I study assessed the toxicity and safety of combining daily lapatinib with radiation therapy. Sequential tumor biopsies were obtained to evaluate changes in biomarkers, such as epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) signaling pathways.Methods. Eligibility for this dose-escalation study included unresectable and locally recurrent or chemotherapyrefractory and locally advanced breast cancer, and adequate organ function. Patients underwent three serial biopsies: at baseline, after 1 week of lapatinib alone, and after 1 week of lapatinib and radiation. Endpoints included determination of toxicity, maximum tolerated dose, and analysis of the effect of lapatinib with or without radiation on EGFR and HER2 signaling pathways by immunohistochemistry.Results. Doses of lapatinib up to 1,500 mg/day were well tolerated. Toxicity of grade 3 or more was limited to radiation dermatitis and pain. Out of 19 patients treated, in field responses per Response Evaluation Criteria in Solid Tumors criteria were complete in four patients and partial in six patients. Serial biopsies were obtained in 16 patients with no complications. Total Her2 was relatively unchanged while phospho-Her2, phospho-Akt, and phospho-ERK showed variable responses to both lapatinib alone and dual therapy with lapatinib and radiation.Conclusions. The combination of lapatinib and radiation was well tolerated in this patient cohort. Overall local response rates were comparable to those reported in other studies in this patient population. Biopsies were safely performed at all time points. Inhibition of HER2 and downstream signaling pathways was identified, although no strong correlation with response was seen. The Oncologist

Xenograft assessment of predictive biomarkers for standard head and neck cancer therapies

“…Most retrospective studies assessing putative biomarkers only utilize pretreatment samples as, historically, tissue is not routinely obtained while patients are under treatment. Our analysis of posttreatment samples was significantly more successful than a prior clinical study in which we assessed posttreatment biopsies and demonstrated that multiple samples contained only necrotic tumor and were not analyzable . Due to the improved tissue quality, we obtained in this study, we were able to identify posttreatment changes in pAkt and pERK expression as potentially related to radiation response.…”

Safety and Tolerability of Metastasis-Directed Radiation Therapy in the Era of Evolving Systemic, Immune, and Targeted Therapies

“…A number of phase I and II studies using conventionally fractionated RT have most commonly reported dermatologic side effects only. 126 , 127 , 128 , 129 …”

“…There is little data reporting toxicity outcomes when combining Lapatinib with hypofractionated RT. A number of phase I and II studies using conventionally fractionated RT have most commonly reported dermatological side-effect onlys [125][126][127][128] .…”

Diagnosis and Treatment of Bone Metastases in Breast Cancer: Radiotherapy, Local Approach and Systemic Therapy in a Guide for Clinicians

“…Moreover, for lapatinib and T-DM1, there are preclinical study with xenograft of HER2−positive breast cancer cells where the radiosensitizing effect of these drugs is confirmed [ 84 , 85 , 86 ]. Even in small clinical trials lapatinib and T-DM1 given at standard dose (respectively 1500 mg/day per os and 3.6 mg/kg intravenously every three weeks) in combination with RT were well tolerated [ 87 , 88 ]. However, it is important to note that a significant number of cases of radionecrosis was reported with concomitant T-DM1 and SRS for brain metastases in HER2−positive MBC.…”