KEY TAKEAWAYS
- This phase 1 trial evaluated the safety, immunogenicity, and initial antitumor efficacy of pembro combined with XL888.
- The primary endpoint was the ORR.
- The study concluded that pembro and XL888 had an acceptable safety profile but did not elicit responses.
Colorectal cancer (CRC) ranks as the 3rd leading cause of cancer-related mortality. Pharmacologic inhibition of HSP90 with agents like XL888 enhances epha2+ tumor cell recognition and T-lymphocyte recruitment via multiple pathways.
Olatunji Alese and colleagues developed this trial to assess the safety, immunogenicity, and initial antitumor efficacy of Pembrolizumab (Pembro), a highly selective checkpoint inhibitor, combined with XL888 in patients (pts) with advanced CRC.
Researchers studied the dose escalation phase results and set the recommended phase II dose (RP2D) of XL888 at 90 mg, taken orally twice a week with pembro 200 mg IV every 3 weeks.
Inclusion criteria included pts with advanced CRC and at least 1 line of systemic chemotherapy. Other criteria included being 18 or older, having an ECOG PS of 0-1, and having measurable disease per RECIST v1.1. The primary endpoint was the overall response rate (ORR).
The results showed that 16 pts were enrolled and treated at the RP2D, with a median age of 56.5 years (IQR: 50-63). Most had left-sided tumors (68%) and were mismatch repair proficient (MMRp/MSS; 100%), with at least 2 prior lines of systemic treatment. Mutational status included RAS (85.7%), BRAF (7.1%), and HER2 amplification (7.1%).
In the revealed data, no objective responses were observed, and 2 pts had stable disease (SD). The median PFS was 1.9 (95% CI: 1.3-2.0) months, and median OS was 5.5 (95% CI: 3.0-9.9)months. Standard treatment-related adverse events (TRAEs) included fatigue (62%), diarrhea (50%), and others (including cough, abdominal and back pain [31.3% each], anorexia, constipation, nausea, vomiting, decreased serum magnesium and increased liver enzymes [25% each]). No grade 5 TRAEs occurred.
The study concluded that the combination of pembro and XL888 had an acceptable safety profile but did not induce responses in pts with heavily treated advanced CRC. Ongoing correlative studies aim to to determine how dual HSP90/PD-1 blockade impacts on stromal and immune biomarkers.
The trial was sponsored by Emory University.
Source: https://cslide.ctimpembroeetingtech.com/esmogi24hybrid/attendee/confcal/show/session/3
Clinical Trial: https://www.clinicaltrials.gov/study/NCT03095781
Alese O, Gbolahan OB, McCook-Veal A, et al. (2024). “Phase Ib study of pembrolizumab and XL888 in patients with advanced colorectal cancer.” Presented at ESMO GI 2024. (Abstract 52P)
