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Abstract Details
Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without Mammalian Target of Rapamycin Inhibitors in Patients with Fibrolamellar Carcinoma.
Abou-Alfa, Ghassan K (GK);Meyer, Tim (T);Do, Richard Kinh Gian (RKG);Piha-Paul, Sarina A (SA);Light, Joseph S (JS);Sherrin, Scott (S);Yaqubie, Amin (A);O'Neill, Alison Clemens (AC);Harding, James J (JJ);Al-Rajabi, Raed (R);Denlinger, Crystal S (CS);Cano, Pablo (P);Cornelius, Albert S (AS);O'Reilly, Eileen M (EM);DiPrimeo, Daniel (D);Eli, Lisa D (LD);Gordan, John D (JD);Solit, David B (DB);
INTRODUCTION: Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including , and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC.
METHODS: Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint.
RESULTS: Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0-21.8) and the disease control rate was 13.3% (95% CI: 1.7-40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia ( = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis ( = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy.
CONCLUSION: In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.
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