Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

Abstract

Objective: We describe a phase II clinical trial of the combination of ribociclib and letrozole for treatment of relapsed oestrogen receptor (ER)-positive ovarian cancer (OC) and endometrial cancer (EC). The primary endpoint was the proportion of patients alive, progression-free survival (PFS), and still on treatment at 12 weeks (PFS12), with 45% or greater considered positive.

Methods: Patients with measurable, relapsed ER-positive OC or EC (platinum-sensitive or resistant) were eligible and treated with 400 mg of oral ribociclib and 2.5 mg of oral letrozole daily. Patient-derived xenografts (PDXs) were created from imaging-guided tumour biopsies.

Results: Forty patients (20 OC and 20 EC) were enrolled. A PFS12 of 55% was observed in the EC cohort and 50% in the OC cohort. A PFS greater or equal to 24 weeks (PFS24) was seen in 20% (4/20) of the OC cohort and 35% (7/20) of the EC cohort. The greatest benefit was seen in low-grade serous OC (LGSOC) (3/3, 100% PFS24) and grades 1 and 2 EC (5/11, 45% PFS24). All three LGSOC patients obtained at least a partial response lasting for over 2 years, with two of the three patients still on treatment. PDX tumour engraftment was feasible in 45% of patients. Positive survival effects of the combination of ribociclib and letrozole were observed in two of three EC PDX models.

Conclusion: Ribociclib and letrozole have promising clinical activity in relapsed ER-positive OC and EC, particularly in LGSOC and relapsed ER-positive grade 1 and 2 EC. Generation of PDX models is feasible with positive survival effects observed in EC models.

Trial registration number: ClinicalTrials.gov registry (NCT02657928).

Keywords: endometrial cancer; letrozole; ovarian cancer; ribociclib.

Conflict of interest statement

Competing interests: GC-O and SJW report grants from Novartis during the conduct of the study. MSB reports grants from Immune Design, Pharmacyclics, Marker Therapeutics, Merck, Genentech and Bristol Myers Squibb, outside the submitted work. We certify that the other authors have no financial affiliation/interest (eg, employment, stock holdings, consultant arrangements, honoraria in the subject matter, materials or products) mentioned in this manuscript.

© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.

Figures

Figure 1

Progression-free survival. Cohort A is the ovarian cancer cohort and cohort B is the endometrial cancer cohort.

Figure 2

Overall survival. Cohort A is the ovarian cancer cohort and cohort B is the endometrial cancer cohort. NE, not estimated.

Figure 3

ER expression in primary patient samples and the corresponding PDX. ER expression was detected by immunohistochemistry techniques in primary patient samples (left side) and the corresponding PDX models (right side). Three examples of endometrial carcinomas (U1561.005, U1561.008 and U1561.010) are shown, demonstrating both the ER and histological pattern preservation across samples. Digital images are captured at 70 μm (30×) using ImageScope. PDX, patient-derived xenograft; ER, oestrogen receptor.

Figure 4

In vivo experiments testing the efficacy of ribociclib and letrozole in three PDX models of recurrent endometrial cancer. Three PDX models were tested in vivo for efficacy studies. (A) Tumour growth curves showed that tumour regression below baseline was not observed in any of the study arms, although a slower proliferation was observed in the combination arm when compared with standard treatment (letrozole) and untreated controls. (B) An overall survival benefit was observed in the combination arm when compared with standard therapy (letrozole) in two of three models. PDX, patient-derived xenograft.