Combined HER2 and mTOR Blockade Shows Activity in Various Solid Tumors

Somatic mutations or amplification of the gene encoding the HER2 receptor tyrosine kinase are common in non–small cell lung cancer (NSCLC) and breast cancer, respectively, and result in activation of the phosphoinositide 3-kinase (PI3K)–AKT–mTOR pathway, which contributes to resistance to the anti-HER2 monoclonal antibody trastuzumab. Preclinical studies of HER2-driven breast and lung cancer suggest that small-molecule HER2 kinase inhibitors such as neratinib synergize with mTOR inhibitors to suppress downstream mTOR signaling and inhibit tumor growth. Based on these findings, Gandhi and colleagues performed a phase I clinical trial to determine the maximum tolerated dose and evaluate the safety and efficacy of neratinib in combination with the mTOR inhibitor temsirolimus in 60 patients with metastatic solid tumors. The majority of patients were heavily pretreated and included patients with HER2-amplified breast cancer or HER2-mutant NSCLC who experienced tumor progression after trastuzumab treatment. This drug combination was tolerable, as the most frequent drug-related adverse events were diarrhea, which occurred in 93% of patients and resulted in dose-limiting toxicity in several patients, and low-grade nausea, vomiting, and stomatitis. Although dose interruption and dose reduction were frequently required, treatment with neratinib and temsirolimus induced antitumor responses across multiple tumor types, which were prolonged for more than a year in some patients and included 2 complete responses, 6 partial responses, and stable disease in 27 patients. This activity was observed in patients without known mutations in the HER2–PI3K pathway as well as the majority of patients with HER2-driven breast cancer and NSCLC, suggesting that the addition of an mTOR inhibitor may overcome trastuzumab resistance. These results identify a recommended dose of this therapeutic combination for phase II trials and suggest that dual HER2 and mTOR blockade may be effective in various HER2/PI3K-driven tumors.

Gandhi L, Bahleda R, Tolaney SM, Kwak EL, Cleary JM, Pandya SS, et al. Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2–dependent and other solid tumors. J Clin Oncol 2014;32:68–75.

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