Dr. Thomas Abrams, MD
The TRIPLETE study from Italy is a simply designed phase 3 clinical trial in which 435 patients with newly diagnosed RAS and BRAF wild-type metastatic colorectal cancer were randomized in a 1:1 fashionto receive either modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) plus panitumumab or fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) plus panitumumab. In both arms, over 90% of patients were aged ≤70 years old, and 12% had right-sided disease. These factors are critical because older patients are less likely to benefit from multidrug chemotherapy, and patients with right-sided disease would not be expected to respond to epidermal growth factor receptor inhibitors, irrespective of RAS status. The study's primary endpoint was objective response rate (ORR) according to the revised Response Evaluation Criteria in Solid Tumours guidelines ( RECIST 1.1 ). Secondary endpoints included safety and progression-free survival (PFS). ORR was 73% in the experimental arm and 76% in the control arm (odds ratio [OR] 0.87; P = .526). There were no differences in PFS, early tumor shrinkage rate, R0 resection rate, or depth of response either.
Though I would have liked to have seen a leucovorin calcium (folinic acid), fluorouracil,and irinotecan hydrochloride (FOLFIRI) arm as well, I believe that these results are enough to cast significant doubt on the burgeoning belief that in metastatic colorectal cancer, more chemotherapy is better for those who can tolerate it.
AtezoTRIBE, also out of Italy, is a randomized, phase 2 study that randomly selected patients with newly diagnosed metastatic colorectal cancer to receive FOLFOXIRI and bevacizumab with or without atezolizumab. I am less sanguine about this study design, vis-à-vis the TRIPLETE study, as patients in AtezoTRIBE were randomized in a 2:1 fashion, with two thirds therefore receiving treatment on the experimental arm. The 2:1 randomization was rationalized on the basis of the supposition that patients are more likely to enroll on a study if they know they have a greater chance of receiving a novel treatment. However, I have never seen a study supporting that hypothesis with data, and a 2:1 randomization significantly reduces statistical power. Patients were stratified on the basis of tumor mutational burden (TMB) and Immunoscore IC (high or low as determined by CD8 cell density, programmed death ligand 1 cell density, as well as proximity and clustering of the two cell groups). There were similar rates of high TMB (7% control and 8% experimental) and high Immunoscore IC (25% control and 22% experimental) in both arms. The primary endpoint was PFS. At a median follow-up of 19.9 months, the experimental arm had astatistically improved median PFS (13.1 vs 11.5 months; adjusted hazard ratio 0.70; P = .018). Serious adverse events were reported in 27% vs 26% of patients, respectively. Of note, the subgroup analysis shows that PFS improvement was accrued in the experimental arm by patients with either high TMB, high Immunoscore IC, or both. Further studies will be needed in patients prospectively selected for high Immunoscore IC to see whether these observations hold. If so, Immunoscore IC could eventually replace TMB as a marker of potential immune therapy responsiveness in microsatellite-stable metastatic colorectal cancer.