CELECOXIB

A non-steroidal anti-inflammatory drug that targets the COX-2 enzyme and its supresses its role in immune responses. Research studies have mixed findings and in some trials researchers are starting to show which genes or bio-markers are associated to benefits and which signal likely risks of adding celecoxib. Unfortunately, celecoxib is a good example of repurposed drugs that fall short of pre-clinical expectations. A large analysis including across many trials that added celecoxib has reported less than 5% report meaningful impacts, and alarmingly about an equal number report accelerated progression. Its crucial to be aware that these drugs can only be considered when recommended by an oncologist.

A 2022 meta-analysis of thirty trials found a lack of clinical benefits to patients, but did see significantly improved risk reductions over 40% and extended progression free survival for lung cancer patients known to carry mutations to so called EFGR genes. This was based on a small phase II trial.

The well publicized (big pharma funded) REACT trial showed no benefit of adding celecoxib during breast cancer chemotherapy regimes. On the other hand, this ignored a significant relative risk reduction among the group that did not receive chemo, later found by other researchers (Highlight 1)

In colon cancer, celecoxib gave no significant changes in relative risk levels when used broadly. However, a very recent trial analyzed the effects on the 22% of patients with a specific PIK3CA tumor mutation and found significant reductions in their relative risks, about half. (Highlight 2). In similar efforts to target celecoxib in lung cancer patients, a study combining it with the TKI erlotinib showed no effects in the overall group. But, improved progression free survival was linked to those with EFGR positive status. For all patients with elevated PGEM, a marker of COX induced inflammation, there were tendencies to improved relative survival periods.

REMAGUS breast cancer trial reported no benefit of celecoxib in breast cancer during chemotherapy. A later analysis of the patient data showed much higher relative risks and shorter survival indications seen in patients with EFGR negative gene profiles taking celecoxib (see References).

In REACT, celecoxib treatment (400 mg daily for 2 years) in a subgroup of 655 breast cancer patients who did not receive chemotherapy reduced the hazard ratio for recurrence over 10 years by 35% (HR = 0.65, 95% confidence interval 0.41–1.04, P = 0.035 by a one-tailed test of significance). These results underscore the importance of further testing of celecoxib in patients with early-stage breast cancer who are not treated by chemotherapy.

..for patients with stage III resected colon cancer. Although the primary hypothesis for all patients did not show a statistically significant improvement in disease-free survival (DFS) with celecoxib, subgroup analysis by PIK3CA mutational status was a preplanned study. PIK3CA gain-of-function mutations were detected in 259 of 1,197 tumors with available whole-exome sequencing data. When stratified by PIK3CA status, patients with PIK3CA gain-of-function mutations treated with celecoxib exhibited improved DFS (adjusted hazard ratio [HR], 0.56 )</...

Furthermore, celecoxib plus neoadjuvant therapy improved the ORR in standard cancer therapy, especially neoadjuvant therapy (overall: RR = 1.13, 95%CI = 1.03–1.23; neoadjuvant therapy: RR = 1.25, 95%CI = 1.09–1.44), but not pCR. Our study indicated that adding celecoxib to palliative therapy prolongs the PFS of EGFR wild-type patients, with good safety profiles. Celecoxib combined with adjuvant therapy prolongs OS, and celecoxib plus neoadjuvant therapy improves the ORR. Thus, celecoxib-combined cancer therapy may be a promising therapy strat...

Combined erlotinib/celecoxib did not improve outcomes in an unselected [lung cancer] population, but selection by elevated baseline PGEM [urinary marker of inflammation] led to an increase in PFS with the celecoxib combination. Patients with EGFR wild type [i.e those with EFGR genes] status may benefit from the combination. Patients with EGFR wild type had an increased PFS in the celecoxib group (3.2 v 1.8 mos; p=0.03). PFS was numerically improved in the IIT group who received erlotinib/celecoxib compared to erlotinib/placebo

TABLE OF REFERENCES

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URL	Rating	Highlight	Highlight 2
https://pmc.ncbi.nlm.nih.gov/articles/PMC9578006/	3.5	In REACT, celecoxib treatment (400 mg daily for 2 years) in a subgroup of 655 breast cancer patients who did not receive chemotherapy reduced the hazard ratio for recurrence over 10 years by 35% (HR = 0.65, 95% confidence interval 0.41–1.04, P = 0.035 by a one-tailed test of significance). These results underscore the importance of further testing of celecoxib in patients with early-stage breast cancer who are not treated by chemotherapy.	Based on their findings, the REACT investigators concluded that “patients showed no evidence of a disease-free survival (DFS) benefit for 2 years’ treatment with celecoxib compared with placebo as adjuvant treatment of ERBB2-negative breast cancer.” This interpretation omits an important observed benefit of celecoxib in a subgroup of patients who did not receive chemotherapy.
https://ascopubs.org/doi/abs/10.1200/JCO.23.01680	3.5	Overall survival was similarly improved for patients with PIK3CA gain-of-function mutations (adjusted HR, 0.44 [95% CI, 0.22 to 0.85]) compared with PIK3CA wildtype patients (adjusted HR, 0.94 [95% CI, 0.68 to 1.30]; Pinteraction = .04). Although the test for heterogeneity in DFS did not reach statistical significance, the results suggest potential utility of PIK3CA to consider selective usage of COX-2 inhibitors in addition to standard treatment for stage III colon cancer.	..for patients with stage III resected colon cancer. Although the primary hypothesis for all patients did not show a statistically significant improvement in disease-free survival (DFS) with celecoxib, subgroup analysis by PIK3CA mutational status was a preplanned study. PIK3CA gain-of-function mutations were detected in 259 of 1,197 tumors with available whole-exome sequencing data. When stratified by PIK3CA status, patients with PIK3CA gain-of-function mutations treated with celecoxib exhibited improved DFS (adjusted hazard ratio [HR], 0.56 )
https://pmc.ncbi.nlm.nih.gov/articles/PMC9497539/	3.5	Furthermore, celecoxib plus neoadjuvant therapy improved the ORR in standard cancer therapy, especially neoadjuvant therapy (overall: RR = 1.13, 95%CI = 1.03–1.23; neoadjuvant therapy: RR = 1.25, 95%CI = 1.09–1.44), but not pCR. Our study indicated that adding celecoxib to palliative therapy prolongs the PFS of EGFR wild-type patients, with good safety profiles. Celecoxib combined with adjuvant therapy prolongs OS, and celecoxib plus neoadjuvant therapy improves the ORR. Thus, celecoxib-combined cancer therapy may be a promising therapy strategy	The current meta-analysis consisted of 30 RCTs and included data from 9655 cancer patients. Results showed that there were limited benefits in celecoxib-combined cancer therapy for OS, PFS, DFS, DCR, and pCR, but there was a better ORR (RR = 1.13, 95%CI = 1.03–1.23). Although celecoxib combined with palliative therapy showed no improvement in patient survival and the local control of the tumor, EGFR wild-type patients had a prolonged PFS with celecoxib-combined therapy (HR = 0.57)
https://pmc.ncbi.nlm.nih.gov/articles/PMC4864011/	3.5	107 patients were enrolled with comparable baseline characteristics. Patients with EGFR wild type had an increased PFS in the celecoxib group (3.2 v 1.8 mos; p=0.03). PFS was numerically improved in the IIT group who received erlotinib/celecoxib compared to erlotinib/placebo (5.4 v 3.5 mos; p=0.33) and increased in patients in the celecoxib arm with elevated baseline PGEM (5.4 v 2.2mos; p=0.15). Adverse events (AEs) were similar in both arms	Combined erlotinib/celecoxib did not improve outcomes in an unselected population, but selection by elevated baseline PGEM led to an increase in PFS with the celecoxib combination. Patients with EGFR wild type status may benefit from the combination.
https://www.mdpi.com/1718-7729/29/9/482	3	The current meta-analysis consisted of 30 RCTs and included data from 9655 cancer patients. Results showed that there were limited benefits in celecoxib-combined cancer therapy for OS, PFS, DFS, DCR, and pCR, but there was a better ORR (RR = 1.13, 95%CI = 1.03–1.23). Although celecoxib combined with palliative therapy showed no improvement in patient survival and the local control of the tumor, EGFR wild-type patients had a prolonged PFS with celecoxib-combined therapy (HR = 0.57, 95%CI = 0.35–0.94)	The addition of celecoxib to palliative therapy cannot improve survival and local control rates except for the PFS of EGFR wild-type patients, without obvious toxicities and AEs. In terms of adjuvant therapy, the addition of celecoxib can prolong the OS but not the DFS. Moreover, the combination of celecoxib with neoadjuvant therapy can improve the ORR for breast cancer. In general, further studies evaluating the celecoxib efficacy on cancer therapy should be conducted with caution in certain populations to reduce high clinical trial costs and use of medical recourses.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10943275/	N/A	. The majority of studies did not demonstrate an improvement in either progression‐free survival (86.1% of studies testing progression‐free survival) or in overall survival (94.3% of studies testing overall survival). Progression‐free survival was improved in five studies (7.4%), and overall survival was improved in three studies (4.4%). Overall survival was significantly worse in two studies (3.8% of studies testing overall survival), and progression‐free survival was worse in one study (2.8% of studies testing progression‐free survival).	Despite promising pre‐clinical and population‐based data, cardiovascular drugs and anti‐inflammatory medications have overall not demonstrated benefit in the treatment or preventing recurrence of cancer. These findings may help guide future potential clinical trials involving these medications when applied in oncology.
https://jamanetwork.com/journals/jamaoncology/fullarticle/2781890	N/A	A total of 2639 patients (median age, 55.2 years [range, 26.8-86.0 years]) were recruited; 1763 received celecoxib, and 876 received placebo. Most patients’ tumors (1930 [73%]) were estrogen receptor positive or progesterone receptor positive and ERBB2 negative. A total of 1265 patients (48%) had node-positive disease, and 1111 (42%) had grade 3 tumors. At a median follow-up of 74.3 months (interquartile range, 61.4-93.6 years), DFS events had been reported for 487 patients (19%): 18% for those who received celecoxib (n = 323; 5-year DFS rate = 84%) vs 19% for those who received placebo	Overall, this study observed no benefit from adding celecoxib to conventional adjuvant treatment for this cohort of patients with ERBB2-negative primary invasive breast cancer after total resection. Contrary to expectations, no significant increase in adverse effects was observed; in particular, there was no evidence of an increase in gastrointestinal or cardiac adverse effects with celecoxib. The MA.27 study also failed to show any benefit with celecoxib as adjuvant therapy for breast cancer
https://ascopubs.org/doi/full/10.1200/JCO.18.00636	N/A	Celecoxib use during chemotherapy adversely affected survival in patients with breast cancer, and the effect was more marked in PTGS2-low and/or estrogen receptor–negative tumors. COX-2 inhibitors should preferably be avoided during docetaxel use in patients with breast cancer who are undergoing NAC (chemotherapy)	After 94.5 months of follow-up, EFS was significantly lower in the celecoxib group (hazard ratio [HR], 1.7; 95% CI, 1 to 2.88; P = .046). A significant interaction between PTGS2 expression and celecoxib use was detected (Pinteraction = .01). In the PTGS2-low group (n = 100), EFS was lower in the celecoxib arm (HR, 3.01; 95% CI, 1.45 to 6.24; P = .002) than in the standard treatment arm. Celecoxib use was an independent predictor of poor EFS, distant relapse–free survival, and OS
https://ascopubs.org/doi/10.1200/JCO.2007.13.8081	N/A	This study failed to demonstrate the value of dual eicosanoid inhibition or benefit from either agent alone in addition to chemotherapy. However, a prospectively defined subset analysis suggests an advantage for celecoxib and chemotherapy for patients with moderate to high COX-2 expression	Patients with increased COX-2 expression (index ≥ 4), receiving celecoxib had better survival than did COX-2–expressing patients not receiving drug (HR = .342, P = .005 for OS; HR = .294, P = .002 for failure-free survival). Multivariate analysis confirmed the interaction of COX-2 and celecoxib on survival
https://www.sciencedirect.com/science/article/abs/pii/S095980491730062X	N/A	Median follow-up was nearly 8 years (94.4 months, 20–127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2–0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58)	We previously reported the pCR results of this multicenter randomised phase II study aiming to determine the impact of adding celecoxib or trastuzumab to NAC in stage II–III breast cancers [10]. We showed that celecoxib did not improve the pCR rates in HER2-negative population, whereas trastuzumab added to NAC was associated with an increased pCR rate in patients with HER2-positive tumours [10]. Here, we report the long-term outcome of the patients treated in this study and evaluate the prognostic factors associated with DFS and OS.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6669949/	N/A	Overall, our study does not support a role for COX2 inhibitors in the treatment of early HR+ breast cancer. Furthermore, our data suggest that the use of low-dose aspirin does not have an effect on breast cancer recurrence. The results of ongoing trials (38,39) clarifying the role of higher doses of aspirin and of celecoxib in preventing breast cancer recurrence are awaited with interest.	Adding the COX-2 inhibitor celecoxib to standard aromatase inhibitor therapy in the adjuvant treatment of early breast cancer did not have any effect on EFS, DFS, or OS. The fact that users of low-dose aspirin had higher all-cause mortality but no increased risk regarding breast cancer–associated end points (EFS, DDFS) in multivariable analyses means that these patients had a higher risk for non–breast cancer–associated—presumably cardiovascular—mortality (31). In this context, it seems important to point out that not “use of low-dose aspirin” (indicating a causative role) was associated with increased mortality, but that “users of low-dose aspirin” (where aspirin is a likely surrogate marker for higher cardiovascular risk)
https://pmc.ncbi.nlm.nih.gov/articles/PMC8025124/	N/A	In this randomized clinical trial that involved 2526 patients, the addition of celecoxib for 3 years, compared with placebo, to standard adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) did not significantly improve disease-free survival (76.3% vs 73.4% at 3 years; hazard ratio for disease recurrence or death, 0.89).	The reasons for discordance between the observational studies and the results of this trial are unclear. In this trial, a selective COX-2 inhibitor was used. Although COX-2–dependent pathways are associated with antineoplastic effects of NSAIDs, it is plausible that COX-2–independent pathways are critical and affected by aspirin more effectively than by celecoxib. There are multiple ongoing adjuvant colon cancer trials with aspirin that will define the role of aspirin in this setting
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2757632	N/A	In unresectable stage III NSCLC, adding celecoxib to concurrent chemoradiation did not improve survival. A smaller, not statistically significant proportion of patients in the CCRT with celecoxib group compared with the CCRT alone group developed symptomatic radiation pneumonitis. Among patients with the high-risk genotype, adding celecoxib to CCRT did not improve overall or progression-free survival.	There was no difference in median PFS (17.0 [95% CI, 9.9-24.1] months vs 16.0 [95% CI, 10.9-21.0] months; P = .38). The 2-, 3-, and 5-year PFS rates were 38.0%, 21.9%, and 16.1%, respectively, among patients in the CCRT with celecoxib group and 25.4%, 17.7%, and 6.8%, respectively, among patients in the CCRT group. The overall complete response rates were 82.2% among patients in the CCRT with celecoxib group and 80.4% among patients in the CCRT group, which showed no significant difference (P = .16).

CELECOXIB

TABLE OF REFERENCES

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