NATIONAL HARBOR, MD. – An immunochemotherapy regimen produced mixed results in a phase 2 trial of patients with previously untreated metastatic colorectal cancer.
The regimen – avelumab and cetuximab plus oxaliplatin, leucovorin, and 5-fluorouracil (mFOLFOX6) – failed to meet the primary endpoint for progression-free survival (PFS) but was associated with “promising” yet “preliminary” overall survival, according to, of University Medical Center Hamburg-Eppendorf (Germany).
Dr. Tintelnot presented these results from the AVETUX trial () at the annual meeting of the Society for Immunotherapy of Cancer.
The trial enrolled 43 patients with previously untreated, metastatic colorectal cancer, and 39 of them had wild-type RAS and BRAF mutations. Among those 39 patients, the median age was 62 years (range, 29-82 years), 13 patients were female, and 36 patients had left-sided tumors.
A total of 30 patients had liver metastasis, 12 had lung metastasis, and 18 had lymph node metastasis. Most patients (n = 36) had microsatellite stable tumors, 2 were microsatellite instability high, and 1 was microsatellite instability low.
Patients received IV cetuximab at 250 mg/m2 over 60-90 minutes (day 1 and 8), with a first dose of 400 mg/m2; mFOLFOX6 according to local standard – IV oxaliplatin at 85 mg/m2 IV (day 1), IV leucovorin at 400 mg/m2 IV (day 1), and IV bolus 5-fluorouracil at 400 mg/m2 (day 1) and IV at 2,400 mg/m2 (days 1-3); and IV avelumab at 10 mg/kg over 60-90 minutes (day 1 from cycle 2 onward).
The median number of treatment cycles was 8 (range, 1-34) for oxaliplatin, 13 (range, 1-35) for 5-fluorouracil, 12 (range, 1-35) for cetuximab, and 16 (range, 0-34) for avelumab. The median duration of cetuximab/avelumab treatment was 5.4 months (range, 0.7-18.4 months).
The study’s primary endpoint was 12-month PFS, and the researchers expected the PFS to rise from 40% to 57%. Unfortunately, the 12-month PFS was 40%, so the primary endpoint was not met.
However, the treatment produced a “very high” overall response rate at 81% (30/37), according to Dr. Tintelnot. A total of 4 patients achieved a complete response, 26 had a partial response, 4 had stable disease, and 3 progressed.
Dr. Tintelnot also noted a “promising” but “preliminary” overall survival rate – 84% at a median follow-up of 16.2 months. He said these results suggest PFS may not be the ideal endpoint for this combination.
Dr. Tintelnot said the combination was safe, with no unexpected toxicities. The most common grade 3-4 adverse events were infection of catheter, device, urinary tract, etc. (32%); abdominal pain, diarrhea, etc. (24%); skin reaction (21%); anemia, blood disorders, and hemolytic-uremic syndrome (18%); administration, infusion-related, and allergic reactions (16%); cognitive disturbance, meningism, syncope, and psychiatric disorders (16%); and peripheral sensory polyneuropathy and paresthesia (16%).
Dr. Tintelnot and colleagues also conducted translational research evaluating programmed death-ligand 1 (PD-L1) expression and serial circulating tumor DNA in patients on this trial.
The team found no clear correlation between PFS and T-cell diversification, tumor-infiltrating lymphocytes, or tumor proportion score. Dr. Tintelnot said this suggests classical predictive factors for PD-1/PD-L1 inhibitor treatment have a limited role with this combination.
The researchers did find that circulating tumor mutations might help predict early relapse with the regimen. The team identified 26 patients with mutations detectable in their blood. There was an immediate decline of circulating tumor mutations after treatment initiation, and reemergence of mutation clones was associated with progression.
Lastly, the researchers found that avelumab, cetuximab, and mFOLFOX6 suppressed the development of epidermal growth factor receptor–resistant subclones. There were no epidermal growth factor receptor mutations detected during follow-up.
This research was sponsored by AIO-Studien-gGmbH. Dr. Tintelnot disclosed no conflicts of interest.
SOURCE: Tintelnot J et al. SITC 2019,