Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer.

BACKGROUND: Early detection and management of treatment-related adverse events (TRAEs) in patients receiving immune checkpoint inhibitors may improve outcomes. In CheckMate 142, nivolumab (3 mg/kg) plus low-dose ipilimumab (1 mg/kg) provided durable clinical benefit (objective response rate [ORR] 55%, median duration of response not reached, 12-month overall survival [OS] rate 85%) and manageable safety for previously treated microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). In-depth safety and additional efficacy outcomes from CheckMate 142 are presented. MATERIALS AND METHODS: Safety assessments included frequency of TRAEs, select TRAEs (sTRAEs), and immune-mediated adverse event incidences; time to onset (TTO); time to resolution (TTR); immune-modulating medication (IMM) use; dose delay; and sTRAE occurrence after resuming therapy. Efficacy assessments included ORR and survival analyses in patients with sTRAEs with or without concomitant IMM treatment and patients without sTRAEs. RESULTS: Among 119 patients, 25%, 23%, 19%, 5%, 5%, and 29% experienced an endocrine, gastrointestinal, hepatic, pulmonary, renal, or skin sTRAE, respectively; the majority (57%) were grade 1/2. sTRAEs occurred early (median TTO, 5.2-12.6 weeks). Nonendocrine sTRAEs resolved in most (>71%) patients (median TTR, 1.5-9.0 weeks). IMMs were used to manage sTRAEs in 22%-56% of patients (most resolved). Of patients with dose delay because of sTRAEs, 25 of 29 resumed treatment. Patients with or without sTRAEs had comparable ORR (57% vs. 52%) and 12-month OS rates (93% vs. 75%). Similar results were observed in patients with or without sTRAEs regardless of IMM use (ORR 52% vs. 57%; OS rates 87% vs. 82%). CONCLUSION: The benefit-risk profile of nivolumab plus low-dose ipilimumab provides a promising treatment option for patients with previously treated MSI-H/dMMR mCRC. IMPLICATIONS FOR PRACTICE: Nivolumab (NIVO) plus low-dose (1 mg/kg) ipilimumab (IPI) received U.S. Food and Drug Administration approval for patients with microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on results from CheckMate 142. In this safety analysis, the majority of select treatment-related adverse events (sTRAEs) occurred early, were managed using evidence-based treatment algorithms, and resolved. Efficacy outcomes were comparable between patients with or without sTRAEs regardless of the use of concomitant immune-modulating medications. The benefit-risk profile of NIVO + low-dose IPI provides a promising treatment option for MSI-H/dMMR mCRC.

CCR5 and CCL5 gene expression in colorectal cancer: comprehensive profiling and clinical value.

BACKGROUND: The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5/CCL5 expression in CRC and to determine whether CCR5/CCL5 levels could impact treatment outcomes. METHODS: 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. RESULTS: CCR5/CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5/CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5/CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5/CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone. CONCLUSIONS: Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.

Pharmacogenomics in colorectal cancer: current role in clinical practice and future perspectives.

The treatment scenario of colorectal cancer (CRC) has been evolving in recent years with the introduction of novel targeted agents and new therapeutic strategies for the metastatic disease. An extensive effort has been directed to the identification of predictive biomarkers to aid patients selection and guide therapeutic choices. Pharmacogenomics represents an irreplaceable tool to individualize patients treatment based on germline and tumor acquired somatic genetic variations able to predict drugs response and risk of toxicities. The growing knowledge of CRC molecular characteristics and complex genomic makeup has played a crucial role in identifying predictive pharmacogenomic biomarkers, while supporting the rationale for the development of new drugs and treatment combinations. Clinical validation of promising biomarkers, however, is often an issue. More recently, a deeper understanding of resistance mechanisms and tumor escape dynamics under treatment pressure and the availability of novel technologies are opening new perspectives in this field. This review aims to present an overview of current pharmacogenomic biomarkers and future perspectives of pharmacogenomics in CRC, in an evolving scenario moving from a single drug-gene interactions approach to a more comprehensive genome-wide approach, comprising genomics and epigenetics.

NOS2 polymorphisms in prediction of benefit from first-line chemotherapy in metastatic colorectal cancer patients.

BACKGROUND: Macrophages play a crucial role in the interaction between tumor and immune system, and iNOS is known as a surrogate marker of M1 macrophages activation. The goal of the study was to investigate the role of iNOS polymorphisms as prognostic marker in mCRC patients. MATERIALS AND METHODS: Functional significant polymorphisms in the promoter of INOS gene were analyzed by PCR-based and direct DNA sequencing in 4 cohorts of patients receiving bevacizumab based first-line chemotherapy: two evaluation cohorts (TRIBE ARM A and ARM B) and two validation cohorts (FIRE 3 arm A and MOMA). The relation of the SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test. Subgroup analyses according to RAS status were preplanned. RESULTS: In the exploratory cohort 1 (TRIBE A), patients with CCTTT any>13repeats (N = 57) showed improved median PFS compared with patients carrying the ≤13/≤13 repeats variant (N = 152) (HR, 0.64; 95%CI 0.44-0.92, p = 0.010). Similar results were shown adopting the >26repeats/≤26 repeats (HR, 0.56; 95%CI 0.36-0.87, p = 0.005). In RAS mutant, patient with any>13 repeats (N = 24) had improved PFS results compared with those carrying the ≤13/≤13 repeats variant (N = 81) (HR, 0.51; 95%CI 0.30-0.87, p = 30.009). Similar results were found adopting the >26 repeats/≤26 repeats cut off: (HR, 0.52; 95%CI 0.27-0.98, p = 0.035). These data were partially confirmed in the exploratory cohort 2 (TRIBE B): a better median PFS was observed in patients with >26 repeats vs ≤26 repeats (N = 205) patients. However, these data were not confirmed in the two validation cohorts. CONCLUSION: We failed to replicate the exploratory findings in both validation sets. The CCTTT polymorphic region of the INOS gene does not predict outcome in mCRC receiving bevacizumab based first line chemotherapy. Further investigations are needed to reveal mechanisms between tumor, immune system and chemotherapy response.

Administration of anti-EGFR therapy: a practical review.

OBJECTIVES: To highlight key issues in the administration of cancer therapies that target the EGFR. DATA SOURCES: Published clinical trials of anti-EGFR therapy, secondary literature on the administration of anticancer drugs, and illustrative case study reports. CONCLUSION: Anti-EGFR agents represent a new class of therapy. It is important for nurses to acquire familiarity with the specific issues related to the administration of anti-EGFR agents. Preparedness and active patient monitoring can minimize the impact of toxicities (including interstitial lung disease, infusion reactions, and metabolic alterations) and help ensure the delivery of full treatment courses. IMPLICATIONS FOR NURSING PRACTICE: Nurses familiar with the administration issues and the severe adverse events associated with anti-EGFR therapy will be better equipped to manage them effectively.

Adverse event management strategies: optimizing treatment with regorafenib in patients with metastatic colorectal cancer.

Patients with metastatic colorectal cancer (mCRC) frequently experience treatment-related adverse events (AEs), which may lead to nonadherence or discontinuation from their treatment regimen. In the phase 3 CORRECT study, the addition of regorafenib to best supportive care (BSC) significantly increased overall survival and progression-free survival compared with placebo plus BSC in patients with mCRC who had progressed on all approved standard care therapies. Although regorafenib showed an acceptable safety profile, patients experienced treatment-related AEs such as hand-foot skin reaction, hypertension, oral mucositis, diarrhea, fatigue, and liver abnormalities. The goal of this article is to help oncology nurses implement a strategic, proactive approach to AE management in patients mCRC treated with regorafenib. The article reviews the most common AEs associated with regorafenib in patients who participated in the CORRECT study and provides a strategy and practical measures that nurses can apply to AE management. In addition, the article provides direction and guidance for educating patients and their caregivers on recognizing and managing potential side effects of regorafenib.