Phase II Trial of Cabozantinib in Recurrent/Metastatic Endometrial Cancer: A Study of the Princess Margaret, Chicago, and California Consortia (NCI9322/PHL86)

Abstract

Purpose: The relevance of the MET/hepatocyte growth factor pathway in endometrial cancer tumor biology supports the clinical evaluation of cabozantinib in this disease.

Patients and methods: PHL86/NCI#9322 (NCT01935934) is a single arm study that evaluated cabozantinib (60 mg once daily) in women with endometrial cancer with progression after chemotherapy. Coprimary endpoints were response rate and 12-week progression-free-survival (PFS). Patients with uncommon histology endometrial cancer (eg, carcinosarcoma and clear cell) were enrolled in a parallel exploratory cohort.

Results: A total of 102 patients were accrued. Among 36 endometrioid histology patients, response rate was 14%, 12-week PFS rate was 67%, and median PFS was 4.8 months. In serous cohort of 34 patients, response rate was 12%, 12-week PFS was 56%, and median PFS was 4.0 months. In a separate cohort of 32 patients with uncommon histology endometrial cancer (including carcinosarcoma), response rate was 6% and 12-week PFS was 47%. Six patients were on treatment for >12 months, including two for >30 months. Common cabozantinib-related toxicities (>30% patients) included hypertension, fatigue, diarrhea, nausea, and hand-foot syndrome. Gastrointestinal fistula/perforation occurred in four of 70 (6%) patients with serous/endometrioid cancer and five of 32 (16%) patients in exploratory cohort. We observed increased frequency of responses with somatic CTNNB1 mutation [four partial responses (PRs) in 10 patients, median PFS 7.6 months] and concurrent KRAS and PTEN/PIK3CA mutations (three PRs in 12 patients, median PFS 5.9 months).

Conclusions: Cabozantinib has activity in serous and endometrioid histology endometrial cancer. These results support further evaluation in genomically characterized patient cohorts.

Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

NCD has received financial support from Celgene and Astra Zeneca; HH from AstraZeneca and Roche; GF from NCI and support from Genentech, Tesaro, Iovance, Corcept, Merck, Abbvie, Syndax and 47 Inc. DM reports funding from Tesaro, Genentech, Astra Zeneca, Merck and Clovis. All other authors declare no potential conflicts of interest relevant to this work.

©2020 American Association for Cancer Research.

Figures

Fig 1.. CONSORT diagram.

Outlines patients enrolled in both experimental and exploratory cohorts. * Identifies patients who discontinued study treatment prior to formal response evaluation (i.e. Tumor Response Assessment or TRA): in exploratory cohort this included 6 pts, 5 of which discontinued treatment due to adverse event (AE) and 1 withdrew consent; in endometrioid cohort, this included 3 patients with AEs. “Off treatment” box outlines reasons why patients discontinued study with “PD”: progressive disease; “AE”: adverse event and “other” including withdrawal of consent, physician preference and inter-current illness.

Fig 2.. Summary of activity of cabozantinib.

Summary of activity of cabozantinib in both experimental (a, b, c) and exploratory (d, e, f) patient cohorts. (a, d) Objective tumor responses with dotted lines indicating boundaries for stable disease. (b, e) Time on treatment (b, e) with dotted line highlighting 12-week time-point. Patients who also achieved a partial response on study are indicated in blue. (c, f) Progression-free-survival in experimental and exploratory cohorts color-coded for tumor sub-groups.

Fig 3.. Somatic Profiling Summary.

Summary of somatic profiling of endometrioid, serous and carcinosarcoma histology endometrial cancer patient treated with cabozantinib. (a) Progression-free-survival (in months) is aligned against molecular variants classified by OncoKB; oncogenic variants are highlighted in green, variants that are unclassified or of uncertain significance are marked in orange and germline variants in yellow. Samples not analyzed are indicated in grey. (b) Heat map summarizing frequencies of common mutations by histologic cohort.

Fig 4.. Spiderplots of tumor responses in molecular subgroups of interest.

Tumour volume changes over time in patients with (a) CTNNB1 variant (green) vs all others (blue) and (b) concurrent KRAS and PTEN/PIK3CA mutations (red) vs all others (blue).