Aspirin reduces the incidence of colorectal adenoma and colorectal cancer among high-risk persons. Observational studies suggest that aspirin may also improve disease-free survival after diagnosis, particularly among patients with tumors harboring somatic PIK3CA mutations. However, data from randomized trials are lacking.
We conducted a double-blind, randomized, placebo-controlled trial involving patients with stage I, II, or III rectal cancer or stage II or III colon cancer with somatic alterations in PI3K pathway genes. The patients were assigned in a 1:1 ratio to receive 160 mg of aspirin or matched placebo once daily for 3 years. Patients with prespecified PIK3CA hotspot mutations in exon 9 or 20 (group A alterations) and those with other moderate- or high-impact somatic variants in PIK3CA, PIK3R1, or PTEN (group B alterations) were eligible for randomization. The primary end point was colorectal cancer recurrence, assessed in a time-to-event analysis, in patients with group A alterations. Secondary end points included colorectal cancer recurrence in patients with group B alterations, disease-free survival, and safety. Research Summary Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer
Alterations in PI3K pathway genes were detected in 1103 of 2980 patients (37.0%) with complete genomic data. Of 515 patients with group A alterations and 588 patients with group B alterations, 314 and 312, respectively, were assigned to receive aspirin or placebo. The estimated 3-year cumulative incidence of recurrence was 7.7% with aspirin and 14.1% with placebo (hazard ratio, 0.49; 95% confidence interval [CI], 0.24 to 0.98; P=0.04) among patients with group A alterations and 7.7% and 16.8%, respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.83), among those with group B alterations. The estimated 3-year disease-free survival was 88.5% with aspirin and 81.4% with placebo (hazard ratio, 0.61; 95% CI, 0.34 to 1.08) among patients with group A alterations and 89.1% and 78.7%, respectively (hazard ratio, 0.51; 95% CI, 0.29 to 0.88), among those with group B alterations. Severe adverse events occurred in 16.8% of aspirin recipients and 11.6% of placebo recipients.
Aspirin led to a significantly lower incidence of colorectal cancer recurrence than placebo among patients with PIK3CA hotspot mutations in exon 9 or 20 and appeared to have a similar benefit among those with other somatic alterations in PI3K pathway genes. (Funded by the Swedish Research Council and others; ALASCCA ClinicalTrials.gov number, NCT02647099; EudraCT number, 2015-004240-19.)
New first line standard of care for BRAF mutant colon cancer considering the possibility if chemotherapy is really needed. There may be future trials. This trial led to accelerated FDA approval of this regimen.
The BREAKWATER trial evaluated encorafenib, cetuximab, and mFOLFOX6 as a first-line therapy for BRAF V600E–mutated metastatic colorectal cancer, showing very significant improvements in progression-free survival (PFS) (12.8 vs 7.1mos) and overall survival (OS) (30.3 vs 15.1mos). The combo also achieved a higher overall response rate (ORR). (60 vs 40%), positioning it as a new standard for this challenging patient population. Of note, side effects like nausea, diarrhea, and neuropathy, which were more frequent with this regimen. I would use this in the appropriate patient.
People prefer stool card over colonoscopy, and it is not inferior.
Interesting study where intermittent FOLFIRI + pan was seemingly just as effective as continuous therapy. The ongoing Phase III IMPROVE-2 is the confirmatory trial and if positive could change standard practice. Of note, intermittent meant eight (8) cycles followed by a holiday until progression when it was reinitiated.
This PLK1-inhibitor seems extremely promising. This phase II trial studied pre-treated KRAS-mut patients with FOLFIRI + bev + study drug and the response rates and PFS were quite remarkable. Given the compelling results, they went from this study to a phase III 1L study.