Abstract 52P
Background
Colorectal cancer (CRC) is the third most common cause of cancer-related deaths. Pharmacologic inhibition of HSP90 using agents such as XL888 has been shown to improve epha2+tumor cell recognition and T-lymphocyte recruitment through several mechanisms. Pembrolizumab (Pembro) is a highly selective checkpoint inhibitor. We developed a phase Ib trial to evaluate the safety, immunogenicity and preliminary antitumor activity of Pembro and XL888 in patients with advanced CRC.
Methods
Results of the dose escalation phase were previously reported (JCO 38, 830-830(2020); recommended phase II dose (RP2D) of XL888 at 90 mg taken orally, twice during the week in combination with Pembro 200 mg IV, every 3 weeks. Patients (pts) with advanced CRC who have progressed on at least one line of systemic chemotherapy were eligible for the expansion CRC cohort of the trial. Other selected inclusion criteria were ≥18 years of age, ECOG PS 0-1 and measurable disease per RECIST v1.1. The primary endpoint was overall response rate (ORR).
Results
We enrolled 16 patients who were treated at the RP2D; median age - 56.5 yrs (IQR: 50-63 yrs), mostly left sided tumors (68%), 100% mismatch repair proficient (MMRp/MSS) and had received at least 2 prior lines of systemic tx for mCRC. Mutational status - RAS (85.7%), BRAF (7.1%), and one pt had HER2 amplification (7.1%). All pts eligible and evaluable for safety, ORR, PFS, and OS. There was no objective response and 2 pts had stable disease (SD) as best response on tx. Median PFS - 1.9 mos (95% CI: 1.3 - 2.0 mos) and median OS - 5.5 mos (95% CI: 3.0 to 9.9 mos). Treatment related adverse events (TRAEs) of any grade - fatigue (62%), diarrhea (50%), cough, abdominal and back pain (31.3% each), anorexia, constipation, nausea, vomiting, decreased serum magnesium and increased liver enzymes (25% each). There was no grade 5 TRAE.
Conclusions
The combination Pembro and XL888 had an acceptable safety profile but did not elicit responses in heavily treated advanced CRC pts. Correlative studies using paired biopsies and blood are ongoing to determine how dual HSP90/PD-1 blockade impacts stromal and immune biomarkers in relationship to the clinical outcome measures. Funding and medications for the study were provided by Merck/Exelixis (NCT03095781) and NIH/NCI (R01CA228406).
Clinical trial identification
NCT03095781.
Legal entity responsible for the study
Emory University.
Funding
Merck/Exelixis.
Disclosure
O. Alese: Financial Interests, Personal and Institutional, Advisory Board: Taiho Oncology, Ipsen Pharmaceuticals, GSK, Bristol Myers Squibb, Pfizer, Exelixis; Financial Interests, Personal, Advisory Board: AstraZeneca, Aadi Bioscience, Seagen Inc., Takeda; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Xencor Inc., Cue Biopharma, Inc., Merck, Recordati. All other authors have declared no conflicts of interest.