Adding Celecoxib to Adjuvant Chemotherapy Offers DFS, OS Benefit in PIK3CA-Mutated Stage III Colon Cancer

Jeffrey Meyerhardt, MD, MPH, FASCO

Patients with PIK3CA-activated stage III colon cancer experienced a survival benefit with the addition of the COX-2 inhibitor celecoxib to standard adjuvant chemotherapy, according to findings from the phase 3 CALGB/SWOG 80702 trial (NCT01150045) published in the Journal of Clinical Oncology.^1,2

Following stratification by PIK3CA status, patients with PIK3CA gain-of-function mutations who received celecoxib experienced a significant improvement in disease-free survival (DFS; adjusted HR, 0.56; 95%CI, 0.33-0.96) compared with PIK3CA wild-type patients (adjusted HR, 0.89; 95% CI, 0.70-1.14); however, the interaction test was nonsignificant (P interaction = .13). Similarly, an overall survival (OS) benefit was observed among patients with PIK3CA gain-of-function mutations who received celecoxib (adjusted HR, 0.44; 95% CI, 0.22-0.85) compared with PIK3CA wild-type patients(adjusted HR, 0.94; 95% CI, 0.68-1.30), with the interaction test being significant (P interaction = .04).²

“These findings strengthen a growing body of evidence suggesting that prostaglandin inhibitors could benefit a subgroup of patients with colon cancer,” Jeffrey Meyerhardt, MD, MPH, FASCO, chief clinical research officer, Douglas Gray Woodruff Chair in Colorectal Cancer Research, and co-director of the Colon and Rectal Cancer Center at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, in Boston, Massachusetts, said in a news release.¹ “They suggest a potential personalized approach to additional therapy for patients with early-stage colon cancer.”

“We needed to do a subgroup analysis of the Alliance 80702 trial data to determine if PIK3CA mutations are a predictor of response to celecoxib,” Jonathan Nowak, MD, PhD, the first author of the paper and a molecular and gastrointestinal pathologist at Brigham and Women’s Hospital and Dana-Farber Cancer Institute, investigator in the Hale Family Center for Pancreatic Cancer Research at Dana-Farber, and an assistant professor of pathology at Harvard Medical School, added.¹

Alliance 80702 enrolled patients at centers across the National Cancer Trials Network in the United States and Canada with margin-negative resected, histologically documented colon adenocarcinoma, entirely lying above the peritoneal reflection. To be eligible for the study patients needed to have tumors with either at least one pathologically confirmed positive lymph node or N1c designation. Patients also needed to be at least 18 years old with an ECOG performance status of 2 or less and adequate hepatic, renal, and hematologic values.³

Patients were randomly assigned 1:1 to receive 400 mg celecoxib daily or placebo and independently randomly assigned 1:1 to 6 treatments (3 months) or 12 treatments (6 months) of FOLFOX. FOLFOX treatment consisted of 2-hour infusions of 85 mg/m2 oxaliplatin and 400 mg/m2 leucovorin, followed by a 400-mg/m2 bolus infusion of fluorouracil, then a 46- to 48-hour continuous infusion of 2400 mg/m2 fluorouracil every 2 weeks. Investigators recommended that therapy commence between 21 to 56 days following surgical resection of the primary tumor.

The primary end point for the preplanned secondary molecular marker analysis was DFS. OS represented the secondary end point.²

At baseline in the overall population (N = 1197), the mean age was 61.3 years (SD, 10.8). Most patients were male (54.7%), White (82.6%), had an ECOG performance status of 0 (70.8%), had T3 stage disease (70.3%), had N1 stage disease (71%), had a right/transverse tumor location (53.5%), received 6 cycles of FOLFOX (51.3%), and had non-microsatellite instability-high tumors (89.6%).

Additional findings from the analysis showed that when patients with baseline aspirin use (n = 280) were excluded, the association between PIK3CA mutation status and response to celecoxib in terms of DFS was similar to that of the full cohort, whereas the association with OS was more pronounced in patients with PIK3CA gain-of-function mutations (adjusted HR, 0.35; 95% CI, 0.16-0.77) compared with wild-type patients (adjusted HR, 0.93; 95% CI, 0.63-1.38).

Additionally, patients with mismatch repair (MMR)–proficient, PIK3CA gain-of-function mutated tumors (HR, 0.54; 95% CI, 0.30-0.96) experienced a DFS benefit with the addition of celecoxib vs patients with MMR–proficient, PIK3CA wild-type tumors (HR, 0.94; 95% CI, 0.72-1.21). Similar improvement was seen with regard to OS in patients with MMR-proficient, PIK3CA gain-of-function mutated tumors (HR, 0.35; 95% CI, 0.17-0.72) vs those with MMR-proficient PIK3CA wild-type tumors (HR, 1.01; 95% CI, 0.71-1.42).

The median follow-up for survivors was 6 years. Overall, 187 patients died during the study and 310 experienced disease recurrence or death.

“If these results are confirmed in other ongoing studies, it will be important for physicians to understand the genetics within the tumors of patients with early-stage colon cancer to determine which patients may benefit from celecoxib in addition to other standard treatments,” Meyerhardt said in the news release.¹

References

1. Anti-inflammatory drug celecoxib could reduce risk of colon cancer recurrence for a subset of patients. News release. Dana-Farber Cancer institute. June 18, 2024. Accessed June 25, 2024. https://www.eurekalert.org/news-releases/1048557
2. Nowak JA, Twombly T, Ma C, et al. Improved survival with adjuvant cyclooxygenase 2 inhibition in PIK3CA-activated stage III colon cancer: CALGB/SWOG 80702 (Alliance). J Clin Oncol. Published online June 18, 2024. doi:10.1200/JCO.23.01680
3. Meyerhardt JA, Shi Q, Fuchs CS, et al. Effect of celecoxib vs placebo added to standard adjuvant therapy on disease-free survival among patients with stage III colon cancer: the CALGB/SWOG 80702 (Alliance) randomized clinical trial. JAMA. 2021;325(13):1277-1286. doi:10.1001/jama.2021.2454