Exploratory phase II evaluation of cabozantinib in recurrent/metastatic uterine carcinosarcoma (CS): A study of the Princess Margaret, Chicago, and California phase II consortia.

Abstract

5587 Background: Carcinosarcoma (CS) is a rare ( < 5%) aggressive subtype of endometrial cancer (EC). Patients (pts) with progression on platinum-based chemotherapy (CTX) have limited options, there is no standard 2ndline treatment and median progression-free survival (PFS) is < 2months (mt), 6-mt PFS less than 20%. Limited molecular data on CS aligns with epithelial EC, providing rationale for evaluating similar strategies such as targeting MET and angiogenesis. Cabozantinib (cabo) is multi-targeted tyrosine kinase inhibitor against MET, VEGFR, TIE2, RET, AXL and KIT. Methods: PHL-86 (NCI#9322/NCT01935934) is a multi-centre, non-randomized, phase II trial of cabo (60 mg oral daily dose on a 28-day cycle) in EC pts recurring within a year of adjuvant CTX or with progression after 1stline of CTX for metastatic disease. Pts with rare histology including CS, were enrolled in an exploratory cohort. Activity of interest for further evaluation was defined as 4 responses (either partial response [PR] or 12-wk PFS) out of 10 pts of a given histotype. CT scans were performed after cycle 3 and every 2 cycles thereafter. Results: From 2013 to 2016, 32 pts were treated in the exploratory cohort, 19 pts with CS. Median age was 66 years (range 25-75); prior treatment included CTX (17: 1 line, 6: 2 lines) and/or radiation (11). Fifteen pts were evaluable for response, with 1 PR (7%) and 8 pts with 12-wk PFS (53%). Median PFS was 3 mt (95% CI: 2.7 – 4.6) with estimated 6-mt PFS of 13% (2 to 33%). Toxicity evaluation is available for 19 pts. Common events were fatigue and GI upset. Most frequent > Grade3 toxicities were hypertension (5), anemia (4), diarrhea (2). Four pts had GI fistula (2) or perforation (2). Mutation profiling in archival tissue showed TP53 (73%), PIK3CA (40%), KRAS (27%), PTEN(13%) with > 1 mutation present in 14/15 pts analyzed. The 1 pt with no somatic mutations had a PR (31% decrease) on cabo (PFS 6.7mt). Conclusions: Cabo in CS cohort met the predefined endpoint for further evaluation and compares favourably with other agents in this poor prognosis disease. Larger studies are required to define depth and durability of response and identify relevant biomarkers. Clinical trial information: NCT01935934.

Cabozantinib for the treatment of solid tumors: a systematic review

“…80–83,85–95,103 The rate of dose reductions ranged from 34% 82 to 87% 87 in seven studies that reported these data. The most common grade 3–4 AEs included hypertension (⩽36% in 10 studies), 80–83,85,86,88,90,91,95 diarrhea (⩽26% in seven studies), 80,81,83,85,90,91,95 and increased lipase (⩽15% in five studies). 81,82,86,91,93…”

“…86 One study, which also measured response as the primary endpoint, evaluated patients with unresectable metastatic pheochromocytomas and paragangliomas; results showed that 6/15 patients (40%) had PR. 87 PFS was the primary endpoint in four studies that evaluated patients with recurrent/metastatic endometrial cancer ( n = 102), 88 cholangiocarcinoma ( n = 19), 89 uterine carcinosarcoma ( n = 15), 90 and gastrointestinal stromal tumor ( n = 50). 91 Prior to the studies, patients had progressed after one or two lines of therapy.…”

“…Evidence from nonrandomized phase I and II clinical studies : In all, 16 phase II studies evaluated the safety of cabozantinib 60 mg in various tumor types. 80–83,85–95,103 The rate of dose reductions ranged from 34% 82 to 87% 87 in seven studies that reported these data. The most common grade 3–4 AEs included hypertension (⩽36% in 10 studies), 80–83,85,86,88,90,91,95 diarrhea (⩽26% in seven studies), 80,81,83,85,90,91,95 and increased lipase (⩽15% in five studies).…”

“…[80][81][82][83][85][86][87][88][89][90][91][92][93][94][95]103 The rate of dose reductions ranged from 34% 82 to 87% 87 in seven studies that reported these data. The most common grade 3-4 AEs included hypertension (⩽36% in 10 studies), [80][81][82][83]85,86,88,90,91,95 diarrhea (⩽26% in seven studies), 80,81,83,85,90,91,95 and increased lipase (⩽15% in five studies). 81,82,86,91,93 In a phase I study of patients with advanced or metastatic solid tumors, including an expansion cohort of patients with NSCLC, the most common grade 3-4 AEs were gamma glutamyl transferase increase (17%), hypertension (13%), and lymphopenia (13%) in the dose-escalation cohort, and hypertension (30%), neutropenia (25%), and ALT increase, PPES, hypophosphatemia, and dyspnea (all 15%) in the NSCLC expansion cohort.…”

“…In all, 18 phase II studies and one phase I study evaluated patients with various types of tumor. [79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96] In all but one of these studies, 79 the cabozantinib dose was 60 mg. In one study in 50 patients with relapsed or refractory metastatic urothelial carcinoma (mUC), the primary endpoint, ORR (95% CI), was 19% (9-34%).…”