Abstract P2-13-34: A phase II trial of lapatinib and everolimus for HER2 positive metastatic breast cancer
Authors: Rooney Anthony , Sharma Priyanka , O'Dea Anne P , Nye Lauren , Elia Manana , He Jianghua , Fabian Carol , Khan Qamar 
Published: March 2022

Abstract
Background: Targeted agents against HER2 have been a cornerstone of the treatment armamentarium for HER2 positive breast cancer since the approval of trastuzumab by the FDA in 1998 for metastatic HER2 positive breast cancer. However, many patients will develop resistance to HER2 targeted therapies and succumb to their disease. Novel therapeutic combinations are needed to overcome resistance to currently available therapies and improve patient outcomes. Activation of the mTOR pathway via pTEN loss or PI3K mutation has been identified in vitro as a mechanism of trastuzumab resistance, and preclinical studies have shown that mTOR inhibition enhances the efficacy of trastuzumab by reversing trastuzumab resistance mediated by PTEN loss. Moreover, two phase I trials evaluating the addition of the mTOR inhibitor everolimus to trastuzumab and chemotherapy reversed trastuzumab resistance in patients with heavily pretreated metastatic HER2 positive breast cancer, providing rationale for continued exploration of this combination in phase II trials.Methods: We report the results of a single arm, open-label phase II pilot study for patients with histologically or cytologically confirmed HER2 positive locally advanced or metastatic breast adenocarcinoma that had progressed on at least one prior HER2 targeted therapy. Enrolled patients received everolimus 5 mg PO daily and lapatinib 1000 mg PO daily until disease progression or unacceptable toxicity. Radiographic tumor assessment was performed at trial entry and every 8 weeks thereafter. Primary endpoint was 6-month overall response rate (ORR). Secondary endpoints included 6-month progression free survival (PFS), 6-month clinical benefit rate (CBR), and safety and tolerability of the combination. NCI CTCAE version 4.0 was used for toxicity and serious event reporting. The primary endpoint of 6-month ORR was computed using the point estimate and the 1-sided 97.5% confidence interval by the exact binomial method and compared to the previously reported 7% response rate of lapatinib monotherapy in this setting.Results: A total of 23 patients were enrolled. The median age at enrollment was 48, and the median number of prior lines of therapy was 4 (range 1-9). 13 patients had previously been treated with lapatinib, and CNS disease on trial entry was present in 7 (30.4%) patients. 6-month ORR was 0% (0-14.8%, 97.5% 1-sided CI) and 6-month CBR was 13% (2.8 - 33.6%, 95% CI). Median progression free survival was 112 days (109-115 days, 95% CI). 6-month PFS rate was 13% (2.8-33.6%, 95% CI). No CNS responses were observed. 17 serious adverse events (SAE) of grade 3 or greater were reported. The most common grade 3 or greater SAEs were dyspnea (4 patients - 17%), pleural effusion (3 patients - 13%), abdominal pain and ileal obstruction (2 patients each - 8.7%).Conclusion: The combination of lapatinib and everolimus was not found to be an active regimen in patients who had previously progressed on at least one line of prior HER2 targeted therapy. We would not recommend further exploration of this combination in phase II or phase III trials in this patient population.
Citation Format: Anthony Rooney, Priyanka Sharma, Anne P O'Dea, Lauren Nye, Manana Elia, Jianghua He, Carol Fabian, Qamar Khan. A phase II trial of lapatinib and everolimus for HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-34.