From ASCO 2013: response to Pazopanib+mTOR inhibitor in STS

[Johannes]

Reversal of acquired resistance to pazopanib in soft tissue sarcoma with addition of an mTOR inhibitor: A case report.

Background: Pazopanib (P) is a multikinase inhibitor targeting the VEGF and PDGF receptors capable of controlling soft tissue sarcoma for several months. Acquired resistance to P usually leads to chemotherapy resumption. We present a case of reversal of acquired resistance to P by addition of an mTOR inhibitor. Methods: A 46 year old female, completed five cycles of adjuvant treatment with epirubicin and ifosfamide followed by radiotherapy for a fully resected gluteal pleomorphic undifferentiated sarcoma. Ten months later, a single lung metastasis was resected, followed by trabectedin, then switched to gemcitabine and docetaxel after five cycles due to progression. Seven cycles were given with stable disease as best response. Upon progression, P 800mg/d was initiated as part of a compassionate program and continued for six months with a partial response. When disease progressed, treatment was switched to doxorubicin, dacarbazine and cyclophosphamide with rapid progression after two cycles, both complicated by febrile neutropenia. Uncontrolled disease after stopping P, limited response to chemotherapy in the past and worsening myelosupression led us to reintroduce P at 400mg/d in combination with sirolimus 2mg/d with the intention of overcoming acquired resistance to P by inhibiting downstream intracellular mediators. Results: One week after P and sirolimus initiation, pain in a paracostal protruding lesion subsided with softening and a decrease in mass size. After six weeks a CT scan demonstrated a partial response by Choi criteria with an 18% tumor shrinkage and decreased enhancement. Most of the lesions were previously of mixed density and became predominantly necrotic. Treatment was very well tolerated. Conclusions: We report a renewed response to P with addition of an mTOR inhibitor in advanced pleomorphic undifferentiated sarcoma. Crosstalk between pathways, upregulation of PI3K/mTOR signaling along with a rebound effect stirred by cessation of VEGFR blockade may have all contributed to more aggressive disease at the time of progression and may explain reversal of resistance by the addition of a downstream inhibitor such as sirolimus. A study designed to prove this concept is underway.