The combination of ziv-aflibercept and capecitabine demonstrated an acceptable safety profile and encouraging clinical efficacy for patients with metastatic colorectal cancer, according to findings from the ongoing phase II X-TRAP trial.
In the phase II study, 61% of patients had received >2 prior therapies. In those evaluable for efficacy (n = 43), the partial response rate with the combination was 2%, with an overall disease control rate of 63%. The progression-free survival (PFS) rate at >6 months was 23%. Median PFS was 4.2 months and median overall survival was 7.1 months.
Overall, there were no treatment-related grade 4/5 adverse events (AEs) seen with the combination. At the phase II doses of capecitabine (100 mg/m2BID, days 1-14) and ziv-aflibercept (6 mg/kg every 3 weeks), the most common grade 3 AEs were hypertension (22%), proteinuria (6%), thrombocytopenia (4%), oral mucositis (4%), and hand-foot syndrome (4%).
In an interview withTargeted Oncology, lead investigator of the X-TRAP study, John H. Strickler, MD, assistant professor, Duke University Medical Center, discussed the tolerability of the combination, as well as the future of the combination in patients with mCRC.
TARGETED ONCOLOGY:Can you tell us a little bit about the X-TRAP trial?
The X-TRAP trial is a two-part study. In the first part, we were establishing the safety, tolerability, recommended phase II dose, and maximum tolerate dose of capecitabine and ziv-aflibercept in all patients with solid tumors. Once we established that recommended phase II dose, we then pursed a 50 patient, non-randomized, single-arm, phase II expansion cohort of patients with treatment-refractory metastatic colorectal cancer. The primary endpoint of that study was PFS.
TARGETED ONCOLOGY:Can you describe the findings of the study?
The findings of the study in the phase I portion, in the dose-finding portion, we found that the combination of capecitabine and ziv-aflibercept had acceptable safety tolerability at the recommended phase II dose of 850 mg/m2. The dosing of ziv-aflibercept was given at 6 mg/kg. We then expanded into the phase II portion, where we continued to track safety and tolerability as well as the PFS.
In general, patients receiving the regimen faired well. There were no grade 4, grade 5, serious, or life-threating adverse events during the trial. In general, most patients tolerated the regimen well and dose modifications were made when toxicities did occur. The most common toxicities that occurred were the ones that we expected for these two therapies. These would be fatigue, mucositis on occasion, hand and foot syndrome, and hypertension were the most common.
We found that patients who are heavily treatment-refractory and may not have tolerated other options did manage to tolerate this combination fairly well. It was a pleasure to work with this regimen on a clinical trial basis because it was so well-tolerated. We felt that it was helping patients.
TARGETED ONCOLOGY:How would you recommend going about managing these toxicities?
In general, most patients found the recommended phase II dose to be tolerable. When patients did encounter difficulties with hand and foot syndrome, or really any of the toxicities we just talked about, using the protocol-designed modifications or holding certain therapies back made the regimen more tolerable.
TARGETED ONCOLOGY:Can you tell us a little bit about the efficacy of the combination?
The efficacy was in line with what we would expect from an active therapy in the treatment-refractory setting. Patients enrolled in the phase II portion of the study had a PFS of just over 4 months, which compares favorably with what's currently FDA approved.
With respect to overall survival, that data is currently maturing. Currently the median overall survival is slightly more than 7 months. Which, once again, compares favorably with FDA-approved therapies for patients with metastatic colorectal cancer.
These findings need additional validation within the context of a phase III clinical trial. Essentially, if these findings are borne out in a phase III trial, then this is a strategy that could be tolerable to patients in general. This means it could be for heavily treatment-refractory patients, patients who have received prior systemic chemotherapy like FOLFOXIRI, and patients who have exhausted their anti-EGFR therapy and other anti-VEGF therapies.
There are other groups that are looking at whether or not there are any possibilities of this treatment combination becoming a frontline treatment for mCRC. Those studies are ongoing in Europe.
TARGETED ONCOLOGY:Is there a specific patient profile that seems appropriate for this combination?
In general, we found this regimen was fairly well-tolerated by what we call the "real world" patient population. These are patients who are older, more heavily pre-treated, may not have the appetite for the toxicities of other therapies. This was a very manageable regimen for many patients.