Effect of cyclo-oxygenase inhibitor use during checkpoint blockade immunotherapy in patients with metastatic melanoma and non-small cell lung cancer

Abstract

BackgroundImmune checkpoint inhibitors (ICIs) improve survival outcomes in metastatic melanoma and non-small cell lung cancer (NSCLC). Preclinical evidence suggests that overexpression of cyclo-oxygenase-2 (COX2) in tumors facilitates immune evasion through prostaglandin E2 production and that COX inhibition synergizes with ICIs to promote antitumor T-cell activation. This study investigates whether concurrent COX inhibitor (COXi) use during ICI treatment compared with ICI alone is associated with improved time-to-progression (TTP), objective response rate (ORR) and overall survival (OS) in patients with metastatic melanoma and NSCLC.MethodsWe retrospectively reviewed 90 metastatic melanoma and 37 metastatic NSCLC patients, treated with ICI between 2011 and 2019. Differences in TTP and OS by ICI+COXi versus ICI alone were compared using Kaplan-Meier and Cox regression. Interaction between ICI+COXi versus ICI alone and pretreatment neutrophil–lymphocyte ratio (NLR) was examined. Independent radiology review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was performed.ResultsFor patients with melanoma, median TTP was significantly prolonged in ICI+COXi versus ICI alone (245 vs 100.5 days, p=0.002). On multivariate analysis, ICI+COXi associated with increased TTP (HR 0.36, 95% CI 0.2 to 0.66, p=0.001), adjusted for age, pretreatment NLR, and gender. For NSCLC patients, ICI+COXi also associated with increased TTP compared with ICI alone on multivariate analysis (HR 0.45; 95% CI 0.21 to 0.97; p=0.042) adjusted for age. ORR at 6 months was significantly higher in patients who received ICI+COXi compared with ICI alone in both melanoma (58.6% vs 19.2%, p=0.0005) and NSCLC (73.7% vs 33.3%, p=0.036) cohorts. In the melanoma cohort, high pretreatment NLR (>5) associated with decreased TTP (HR 3.21, 95% CI 1.64 to 6.3; p=0.0007); however, ICI+COXi significantly associated with increased TTP in high NLR (>5) patients (HR 0.08, 95% CI 0.03 to 0.25), but not in low NLR (≤5) patients (HR 0.65, 95% CI 0.32 to 1.32). Similar outcomes were found in an adjusted melanoma cohort after RECIST review.ConclusionsOur study suggests that COXi use concurrently with ICI significantly associated with longer TTP and improved ORR at 6 months in patients with metastatic melanoma and NSCLC compared with ICI alone. Furthermore, COXi use appears to reverse the negative prognostic effect of a high NLR by prolonging TTP in patients with melanoma.

Mitochondrial function is controlled by melatonin and its metabolites in vitro in human melanoma cells

“…43,44 It represents the most rapidly rising malignancy in the Caucasian population. [45][46][47] It is derived from genetically altered melanocytes following complex interactions between genetic, constitutive and environmental factors. 45,48,49 In cutaneous melanoma, BRAF mutations are more common on intermittently sunexposed skin.…”

“…Nowadays, melanoma is one of the deadliest cancers in the world with an increasing incidence 43,44 . It represents the most rapidly rising malignancy in the Caucasian population 45‐47 . It is derived from genetically altered melanocytes following complex interactions between genetic, constitutive and environmental factors 45,48,49 .…”

Thinking Small: Small Molecules as Potential Synergistic Adjuncts to Checkpoint Inhibition in Melanoma

“…Lastly, a variety of host factors including: immune genetics, such as HLA genotypes [ 44 ]; metabolic factors; other drugs or therapies, including antibiotics [ 45 , 46 , 47 ]; in addition to the patient’s gut microbiome [ 48 , 49 , 50 ], have a marked impact on the responsiveness to checkpoint therapy. While the myriad of techniques to manipulate these factors is beyond the scope of this review, it is vital to note that a wide array of potential avenues exist to augment baseline immune function and subsequent responsiveness to immune checkpoint inhibition.…”

“…With broad effects including platelet aggregation, prostaglandin mediator production, and mitochondrial uncoupling, aspirin and other NSAIDs, and particularly cyclooxygenase (COX) inhibitors, are garnering much attention due to their mechanistic sensibility and apparent clinical benefit in improving ICI efficacy. The use of COX inhibitors concurrently with ICI treatment has been associated with longer time to disease progression and improved the ORR at 6 months in a cohort of melanoma and non-small cell lung cancer patients [ 45 ]. In melanoma models, the COX2 pathway contributes to tumor immune evasion through the effects of prostaglandin E2, and inhibition of this pathway has led to synergy with αPD-1 in a preclinical setting [ 34 , 103 , 104 ].…”

NRF2‐dependent stress defense in tumor antioxidant control and immune evasion

“…Similar observations were made with the COX2 inhibitor celecoxib, which sensitized pancreatic cancer to immune checkpoint blockade in mouse models (Markosyan et al., 2019). In humans, a retrospective study revealed an increased time to progression in checkpoint inhibitor‐treated melanoma patients if they also co‐administered COX inhibitors (Wang et al., 2020). Clinical phase II trials are underway to test the effect of aspirin in combination with PD‐1 and CTLA4‐targeting checkpoint inhibitors in melanoma (http://www.clinicaltrials.gov).…”