Interim Analysis of Phase 2 Data Show Olaparib-Pembrolizumab Combo Safe in Advanced Cholangiocarcinoma

The use of olaparib (Lynparza) and pembrolizumab (Keytruda) was associated with a safe and manageable toxicity profile in the treatment of patients with advanced cholangiocarcinoma, according to results of a phase 2 trial presented at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.¹

In an interim update of the phase 2 trial (NCT04306367) researchers found that most notable adverse events (AEs) were manageable in the 12 patients enrolled in the trial. At the time of data cutoff, January 6, 2021, all patients received at least one dose of olaparib plus pembrolizumab. One patient developed grade 4 AE thrombocytopenia, as well as a grade 3 anemia, after 4 treatment cycles and is no longer on the study. According to the researchers, only 3 patients remain on the trial, but all grade 1-3 AEs were manageable.

Other AEs experienced in the study group included 3 patients that experienced grade 3 anemia, one with immune hepatitis, and one with diarrhea. There were several incidents of grade 1/2 AEs. Two cases of thrombocytopenia, one of anemia, one of rash, one of diarrhea, and one of nausea were reported. Of the observed patients, 3 patients had multiple AEs, and one patient was observed with grade 2 hyperbilirubinemia. The most treatment cycles given was in a patient wo received 9 treatment cycles and only developed grade 1 fatigue.

“We hypothesize that olaparib will increase tumoral response to pembrolizumab by inducing DNA damage and increasing tumor antigen number to produce a durable immune response against CCA, thereby, increasing the overall response rate (ORR) of pts from 17.5% (historic chemotherapy control) to 35%,” the researchers wrote of their goals for the wider study.

Currently, 1 patient had a partial response to the treatment, stable disease was observed in 4 patients, and disease progression occurred in 7 patients. Of the 3 patients actively enrolled in the trial, 1 patient achieved a partial response to treatment and 2 have stable disease.

The trial initially analyzed 36 patients with advanced cholangiocarcinoma who either previously failed or progressed on first line therapy to receive 300 mg of oral olaparib twice daily plus 200 mg of intravenous pembrolizumab every 3 weeks for a year or until unacceptable toxicity or disease progression occurred. Researchers also looked at the patient’s tumor makeup and gene expression via tumor biopsies collected at baseline, at week 4 and time of progression. Several patients had notable tumor expressions with 3 having multiple gene mutations and 4 only having one. Exploratory endpoints were included to see if there is a correlation between tumor mutations and response rates.

Full molecular results from FoundationOne CDx testing showed tumor mutations such as ATM (n = 2), SKT11 (n = 1), ARID1A (n = 2), and IDH1 (n = 2). Other mutations included RAD51C, TSC2, BCL2L1, CCNE1, EP300, FGF3, FGF4, GATA6, NOTCH3, TP53, and ZNF217.

Patients enrolled in the trial were aged over 18-years-old, had a histological diagnosis of advanced or metastatic cholangiocarcinoma and measurable disease. The median age of patients observed for this study was 62-years-old (47-74), and most patients were White females (n = 18).

“We are further delving into the tumor genetics of the patient with impressive ongoing partial response to better understand the mechanisms of this response before enrolling more patients onto the trial,” the researchers concluded.

_Reference

_{Yin C, Armstrong S, Weinberg B, et al. Phase II study of combination pembrolizumab and olaparib in patients with advanced cholangiocarcinoma: Interim results. Presented at: 2022 ASCO Gastrointestinal Cancers Symposium; January 20-22, 2022; Virtual. Abstract #452}