nintedanib and Colonic-Neoplasms

Fluoropyrimidines are currently the backbone of treatment for gastrointestinal (GI) cancers but development of resistance to these agents remains a major problem. Trifluridine/tipiracil is an oral chemotherapeutic agent recently approved for third-line treatment of chemorefractory metastatic colorectal cancer. This article reviews the clinical value of trifluridine/tipiracil as a monotherapy, including recent trials in GI cancers, and the potential benefit of combining it with other agents in patients with GI cancers, including the preclinical rationale for combination therapy and recently completed and ongoing clinical trials. Data gathered so far suggest that trifluridine/tipiracil has the potential to form the chemotherapeutic backbone in the continuum of care for GI cancers in the future.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Clinical Trials as Topic; Colonic Neoplasms; Docetaxel; Drug Combinations; Fluorouracil; Gastrointestinal Neoplasms; Humans; Immunotherapy; Indoles; Irinotecan; Organoplatinum Compounds; Oxaliplatin; Pyrrolidines; Quality of Life; Taxoids; Thymine; Trifluridine; Uracil

We used European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) data from the LUME-Colon 1 study to illustrate different methods of statistical analysis for health-related quality of life (HRQoL), and compared the results.. Patients were randomized 1:1 to receive nintedanib 200 mg twice daily plus best supportive care (n = 386) or matched placebo plus best supportive care (n = 382). Five methods (mean treatment difference averaged over time, using a mixed-effects growth curve model; mixed-effects models for repeated measurements (MMRM); time-to-deterioration (TTD); status change; and responder analysis) were used to analyze EORTC QLQ-C30 global health status (GHS)/QoL and scores from functional scales.. Overall, GHS/QoL and physical functioning deteriorated over time. Mean treatment difference slightly favored nintedanib over placebo for physical functioning (adjusted mean, 2.66; 95% confidence interval [CI], 0.97-4.34) and social functioning (adjusted mean, 2.62; 95% CI, 0.66-4.47). GHS/QoL was numerically better with nintedanib versus placebo (adjusted mean, 1.61; 95% CI, -0.004 to 3.27). MMRM analysis had similar results, with better physical functioning in the nintedanib group at all timepoints. There was no significant delay in GHS/QoL deterioration (10%) and physical functioning (16%) with nintedanib versus placebo (TTD analysis). Status change analysis showed a higher proportion of patients with markedly improved GHS/QoL and physical functioning in the nintedanib versus placebo groups. Responder analysis showed a similar, less pronounced pattern.. Analyses of EORTC QLQ-C30 data showed that HRQoL was not impaired by treatment with nintedanib versus placebo. Analysis and interpretation of HRQoL endpoints should consider symptom type and severity and course of disease.

Topics: Antineoplastic Agents; Colonic Neoplasms; Follow-Up Studies; Humans; Indoles; Prognosis; Quality of Life; Sickness Impact Profile; Surveys and Questionnaires; Survival Rate

Immunotherapy-related adverse events (irAEs) are common immunotherapy-associated diseases. Severe pulmonary fibrosis with hypercytokinaemia has not been reported with programmed cell death 1 (PD-1) inhibitors. We describe a case of sintilimab-induced pulmonary fibrosis with cytokine storm induced in a 50-year-old patient with colon cancer refractory to second-line systemic chemotherapy.. Our patient developed hypercytokinaemia with elevated levels of interleukin (IL)-6 and IL-10 and pulmonary fibrosis, which differed from other irAEs. The patient benefited from a back-titrated regimen of methylprednisolone with the initial dosage of 2 mg/kg and anti-fibrotic effect of nintedanib and was successfully weaned from the ventilator.. This is the first report that a PD-1 inhibitor may have caused pulmonary fibrosis and a cytokine storm. This case indicates that the addition of nintedanib and glucocorticoid might possibly have potentially therapeutic effects of PD-1 induced pulmonary fibrosis and hypercytokinaemia.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Colonic Neoplasms; Cytokine Release Syndrome; Glucocorticoids; Humans; Immunotherapy; Indoles; Male; Methylprednisolone; Middle Aged; Pulmonary Fibrosis