Prognostic Value of Thyroid Hormone Ratios in Patients With Advanced Metastatic Colorectal Cancer Treated With Regorafenib: The TOREADOR Study

Background

The impact of free triiodothyronine (FT₃)/free thyroxine (FT₄) ratio on survival in hospitalized geriatric patients was recently described. Up today, there are no data regarding the prognostic role of FT₃/FT₄ ratio in patients with advanced cancer. We evaluated the impact of FT₃/FT₄ ratio on survival in patients with refractory colorectal cancer (CRC) treated with regorafenib.

EGFR Gene Polymorphism Predicts Improved Outcome in Patients With EGFR Mutation-positive Non–small cell Lung Cancer Treated With Erlotinib

BackgroundPatients with advanced-stage non–small cell lung cancer with epidermal growth factor receptor (EGFR) mutations are successfully treated with tyrosine kinase inhibitors (TKIs). However, treatment outcome varies significantly. Previously, we found the polymorphism 181946C>T (rs2293347) located in exon 25 of the EGFR gene to be a predictor of improved outcome. However, these data were based on a subgroup analysis. Furthermore, other minor studies have found conflicting data. Thus, the aim of this study was to demonstrate the association of 181946C>T with clinical outcome in an independent cohort of EGFR-mutated patients treated with erlotinib.Patients and MethodsSeventy-five patients were prospectively enrolled. Blood samples were collected, and genotype for 181946C>T was determined by allele-specific polymerase chain reaction. Genotype was correlated with outcome.ResultsIn 73 patients, 181946C>T was successfully measured. Patients harboring the 181946CT genotype had a significantly longer median progression-free survival compared with patients harboring the 181946CC genotype (49.9 months [95% confidence interval (CI), 5.9-93.9 months] versus 11.1 months (95% CI, 7.4-14.9 months); P = .020). Moreover, a significantly longer median overall survival of 65.6 months (95% CI, 11.0-120.3 months) versus 31.2 months (95% CI, 10.9-51.6 months) was found (P = .019). Both results remained significant in a multivariate analysis adjusting for potential confounders.ConclusionWe demonstrate that the 181946C>T polymorphism is a significant predictor of prolonged progression-free survival and overall survival in an independent cohort of EGFR mutation-positive patients treated with erlotinib. The polymorphism could be an important predictor of treatment response in these patients. A large multicenter cohort study involving other concurrent genetic alterations is warranted.     

Polymorphisms in the Von Hippel–Lindau Gene Are Associated With Overall Survival in Metastatic Clear-Cell Renal-Cell Carcinoma Patients Treated With VEGFR Tyrosine Kinase Inhibitors

Background

Clear-cell renal-cell carcinoma (ccRCC) is characterized by loss of a functional Von Hippel–Lindau (VHL) protein. We investigated the potential of 3 single nucleotide polymorphisms (SNPs) in VHL as biomarkers in metastatic ccRCC (m-ccRCC) patients treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs).

A Phase II Study of Regorafenib With a Lower Starting Dose in Patients With Metastatic Colorectal Cancer: Exposure–Toxicity Analysis of Unbound Regorafenib and Its Active Metabolites (RESET Trial)

BackgroundRegorafenib demonstrated survival benefits as salvage therapy for patients with metastatic colorectal cancer. However, severe toxicities frequently occurred early in the treatment with the standard dose (160 mg/day), resulting in a dose reduction or interruption. To improve the tolerability and maintain sufficient efficacy, we conducted a phase II study of regorafenib with a lower starting dose (120 mg/day).Patients and MethodsRegorafenib was initiated at 120 mg/day, and the dosage was increased to 160 mg/day on day 15 of the first cycle for patients who had met the dose escalation criteria. The primary endpoint was the disease control rate (DCR). The pharmacokinetics of the total and unbound regorafenib and its active metabolites (M2, M5) were assessed.ResultsA total of 70 patients were enrolled from September 2016 to December 2017. Only 6 patients achieved dose escalation to 160 mg on day 15 as planned. For the 68 evaluable patients, the DCR was 32.4% (95% confidence interval, 21.5%-44.8%), which was less than the threshold (30%) of our statistical hypothesis. The serum concentrations of total regorafenib for patients whose dose was escalated to 160 mg/day were significantly lower than those of the patients whose dose was not escalated (median, 3978 vs. 7244 nM; P = .027). The serum unbound concentrations of the sum of regorafenib and the active metabolites correlated significantly with the maximum grade of regorafenib-related symptomatic adverse events in the first cycle (11,138 vs. 19,096 pM; P = .035).ConclusionRegorafenib with a low starting dose of 120 mg/day did not achieve the expected DCR. A relationship of unbound exposure with toxicity was found.     

Alternative Treatment Options in Colorectal Cancer Patients With 5–Fluorouracil- or Capecitabine-Induced Cardiotoxicity

Most chemotherapy regimens in colorectal cancer treatment are 5-fluorouracil (5-FU)/leucovorin or capecitabine-based. Cardiotoxicity is a less common but potentially lethal complication of 5-FU or capecitabine treatment, and some physicians might be unfamiliar with treatment alternatives. Rechallenging should be avoided because it carries a high risk of recurrence of the cardiac symptoms and prophylactic treatment is not always protective. Possible alternative treatment options to be considered are to replace the oral capecitabine or intravenous 5-FU by a 5-FU bolus regimen, by uracil-tegafur or tegafur/gimeracil/oteracil, both oral fluoropyrimidines combining a 5-FU prodrug with a dihydropyrimidine dehydrogenase (DPD) inhibitor, or by raltitrexed, a thymidilate synthase inhibitor whose metabolism is independent of DPD. Patients with advanced colorectal cancer and fluoropyrimidine-induced cardiotoxicity can be treated with other non-fluoropyrimidine related chemotherapy, either as a single agent, combined, or in combination with biological agents. In this report we discuss the different alternative treatment options.     

Correlation of DNA Repair Gene Polymorphisms With Clinical Outcome in Patients With Locally Advanced Non–Small-Cell Lung Cancer Receiving Induction Chemotherapy Followed by Surgery

ObjectiveThe aim of this study was to evaluate whether xeroderma pigmentosum group D (XPD) and ribonucleotide reductase subunit M1 (RRM1) polymorphisms influenced clinical outcome in patients with stage IIIA-B non–small-cell lung cancer (NSCLC) treated with neoadjuvant gemcitabine/cisplatin/docetaxel followed by surgery.Materials and MethodsA total of 109 patients with stage IIIA and IIIB NSCLC were prospectively genotyped to examine a potential association between XPD 312 (aspartic acid [Asp]/asparagine [Asn]), XPD 751 (lysine [Lys]/glutamine [Gln]), and RRM1 (−37 C/A) polymorphisms with response and survival.ResultsThe median survival was 32.14 months for carriers of XPD 312 Asp/Asp and 12.04 months for those with the variant Asn allele (P = .05). In addition, event-free survival was longer for patients with the XPD 312 Asp/Asp genotype compared with patients with Asp/Asn or Asn/Asn (P = .03). A similar but nonsignificant trend was observed for the XPD 751 genotype. In a multivariate analysis, complete resection and age emerged as prognostic factors for overall survival; in patients with incomplete resection or exploratory thoracotomy, XPD 312 was the most significant prognostic factor (P = .03).ConclusionThe XPD 312 single nucleotide polymorphism is a prognostic factor for survival in patients with locally advanced NSCLC receiving induction chemotherapy followed by surgery. The Asn allele is associated with unfavorable outcome and could be used for better stratification of patients.     

Patients With Metastatic Breast Cancer Using Bevacizumab as a Treatment: Is There Still a Role for it?

OPINION STATEMENT: Over the last few decades, the angiogenesis mechanism has increasingly been studied and implicated in cancer pathophysiology. At present, it is known that angiogenesis plays a relevant role in tumor growth, and more importantly many new molecules exists can potentially interfere with this process. Bevacizumab, a humanized monoclonal antibody targeting the vascular endothelial growth factor A (VEGF-A) now commonly used in the treatment of colorectal, renal cell, and brain cancer, is the first anti-angiogenesis drug delivered in combination with chemotherapy that has consistently shown clinical efficacy in the treatment of breast cancer. Since the ECOG 2100 trial has shown that bevacizumab added to paclitaxel as a first-line treatment for advanced breast cancer nearly doubled the time to progression and tumor response rate, its approval was granted almost worldwide. However, other phase III trials revealed a smaller absolute improvement in progression-free survival (PFS) and response rates, and no trials yet have demonstrated survival enhancement which led to a great controversy and debate over the use of bevacizumab. The discrepancy between PFS and overall survival also raises the question of whether or not bevacizumab has been applied sub-optimally in some of the studies, if a predictive biomarker(s) exists to select the group of patients whom would receive the greatest benefit and what is the appropriate clinical end-point for approval and funding of new targeted agents. In this article we will review the bevacizumab mechanism of action and the clinical trials that assessed its benefit in the treatment of metastatic breast cancer (MBC).     

Efficacy and Safety of Regorafenib With 2/1 Schedule for Patients ≥ 75 Years With Metastatic Colorectal Cancer (mCRC) After Failure of 2 Lines of Chemotherapy

Background

In the CORRECT (patients with metastatic COloRectal Cancer treated with REgorafenib or plaCebo after failure of standard Therapy) trial, regorafenib was proven to extend survival of patients with metastatic colorectal cancer (mCRC) that progressed after all available therapies. Grade 3 to 4 toxicity occurred in 54% of patients, and data on the activity and tolerability of regorafenib in elderly patients were scarce. The aim of this study was to evaluate the efficacy and safety of an alternative schedule, 2-week-on treatment and 1 week-off (2/1 schedule), of regorafenib for elderly patients with mCRC.

RAS Amplification as a Negative Predictor of Benefit from Anti-EGFR–Containing Therapy Regimens in Metastatic Colorectal Cancer

Background RAS short variant (SV) mutations in colorectal cancer (CRC) are associated with lack of benefit from epidermal growth factor receptor (EGFR) monoclonal antibody (EGFRmAb). However, the clinical implications for RAS amplification (RASa) as a biomarker for anti‐EGFR therapy in CRC remain ill defined.MethodsGenomic analysis was performed using the Foundation Medicine (FM) comprehensive genomic profiling database of 37,233 CRC cases. Clinical outcomes were assessed using two independent cohorts: the City of Hope (COH) cohort of 338 patients with metastatic CRC (mCRC) and the Flatiron Health–FM real‐world clinicogenomic database (CGDB) of 3,904 patients with mCRC.Results RASa was detected in 1.6% (614/37,233) of primarily mCRC. RASa 6–9 (n = 241, 39%), 10–19 (n = 165, 27%), and ≥ 20 (n = 209, 34%) copy number subsets had co‐RAS SV/BRAF V600E in 63%/3%, 31%/0.6%, and 4.8%/0% of cases, respectively. In the COH cohort, six patients with RASa (13–54 copies) received EGFRmAb, four of six had progressive disease, two had stable disease, and median time to treatment discontinuation (TTD) was 2.5 months. Of the CGDB EGFRmAb‐treated patients, those with RASa (n = 9) had median TTD of 4.7 months and overall survival (OS) of 11.4 months, those with RAS SV (n = 101) had median TTD and OS of 5.3 and 9.4 months, and those with RAS/BRAF wild‐type (n = 608) had median TTD and OS of 7.6 and 13.7 months.ConclusionPatients with RASa without RAS mutations (1.1% of mCRC) may have poor outcomes on EGFRmAb, although numbers herein were small, and interpretation is confounded by combination chemotherapy. Larger independent studies are warranted to determine if RASa, including degree of amplification, may act similarly to RAS mutation as a resistance mechanism to EGFRmAb therapies.Implications for PracticeGenomic data suggest that RAS amplification occurs as the sole RAS/RAF alteration in >1% of colorectal cancer cases and that degree of amplification inversely correlates with co‐occurring MAPK pathway alterations. Preliminary clinical evidence suggests that RAS amplification may function similarly to RAS mutation as a negative predictor of benefit from anti‐epidermal growth factor receptor therapies in colorectal cancer. More clinical data are needed, and comprehensive genomic profiling, including detection of RAS amplification, should be used in trial design to inform therapy selection.     

Personalized Dosing via Pharmacokinetic Monitoring of 5-Fluorouracil Might Reduce Toxicity in Early- or Late-Stage Colorectal Cancer Patients Treated With Infusional 5–Fluorouracil-Based Chemotherapy Regimens

IntroductionTherapeutic plasma 5-fluorouracil (5-FU) levels are achieved in only 20% to 30% of patients with the current practice of administering 5-FU doses based on body surface area (BSA). Alternatively, 5-FU doses can be adjusted based on 5-FU pharmacokinetic (PK) monitoring. Although benefits of PK monitoring of 5-FU in metastatic colorectal cancer (CRC) have been reported, its utility among patients with early stage disease has not been reported.Patients and MethodsWe retrospectively examined the effect of 5-FU PK monitoring in 84 CRC patients (49 stage IV and 35 stage II/III) receiving mFOLFOX6 (modifiedFOLFOX6; modified 5-fluorouracil, leucovorin, oxaliplatin protocol) or mFOLFIRI (modified 5-fluorouracil, leucovorin, irinotecan protocol). Forty-six of the 84 patients received 5-FU doses based on BSA and 38 received doses that were adjusted with PK monitoring. 5-FU plasma levels were measured using a nanoparticle immunoassay method.Results5-fluorouracil PK monitoring significantly improved disease-free survival in stage II/III patients (P = .0429). There was also a trend towards improved progression-free survival among stage IV patients who had their 5-FU levels PK-monitored (P = .16). Moreover, 5-FU PK monitoring significantly reduced (P = .0437) and delayed (P = .0144) adverse effects in stage II/III patients. Toxicity occurred after the second 5-FU dose in the BSA group and after the sixth to seventh dose in the PK monitoring group. In stage IV patients, the onset of toxicities was also delayed with PK monitoring (P = .0605).ConclusionWe provide evidence that PK monitoring of 5-FU is potentially beneficial for late stage and early stage CRC. These results contribute to the growing body of evidence regarding patient benefit when treatment decisions are based on the individual patient characteristics, in this case, a patients' 5-FU levels.     

Effect of Coexisting KRAS and TP53 Mutations in Patients Treated With Chemotherapy for Non–small-cell Lung Cancer

BackgroundKRAS and TP53 are common mutations in non–small-cell lung cancer (NSCLC). The Lung Adjuvant Cisplatin Evaluation Biological Program group found adjuvant chemotherapy to be deleterious in patients with coexisting KRAS/TP53 mutations.Patients and MethodsTo validate these results, patients with NSCLC tested for KRAS and TP53 mutations and receiving chemotherapy for any stage NSCLC were selected. Mutation status was analyzed using next generation sequencing (Illumina) or multiplex recurrent mutation detection (MassARRAY, Agena Biosciences) assays, and was correlated with clinical and demographic data. Disease-free (DFS) or progression-free survival (PFS) was the main endpoint, and overall survival (OS) was the secondary endpoint.ResultsAmong 218 patients, 28 had coexisting KRAS/TP53 mutations, 77 TP53, 37 KRAS, 76 had neither KRAS nor TP53 mutation (WT/WT). There was no DFS/PFS difference for the KRAS/TP53 group versus all others among 99 patients who received adjuvant chemotherapy (hazard ratio [HR], 1.22; 95% confidence interval [CI], 0.61-2.44; P = .57), 27 stage III patients who received chemo-radiation (HR, 0.87; 95% CI, 0.32-2.38; P = .8), and 63 patients who received palliative chemotherapy (HR, 0.68; 95% CI, 0.31-1.48; P = .33). OS was longer in the WT/WT group compared with any other group (KRAS: HR, 1.87; 95% CI, 1.02-3.43; P = .043; TP53: HR, 2.17; 95% CI, 1.3-3.61; P = .0028; KRAS/TP53: HR, 2.06; 95% CI, 1.09-3.88; P = .026). No OS difference was seen for KRAS/TP53 compared with the other groups (HR, 1.26; 95% CI, 0.75-2.13; P = .38).ConclusionsThere was no significant difference in DFS/PFS between the 4 groups. However, OS was longer for patients with TP53 and KRAS wild-type NSCLC who received chemotherapy for any stage compared with patients with KRAS, TP53 mutation, or double mutant tumors.     

A Randomized Phase II Study of Pemetrexed in Combination With Cisplatin or Carboplatin as First-Line Therapy for Patients With Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

BackgroundPemetrexed plus cisplatin was approved for first-line treatment of non–small-cell lung cancer (NSCLC) in patients with nonsquamous histology after initiation of this study. This phase II study evaluated pemetrexed plus cisplatin and pemetrexed plus carboplatin as first-line treatments for stage IIIB/IV NSCLC.Patients and MethodsThe patients were randomized (1:1) to 2 parallel arms: pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) or pemetrexed (500 mg/m²) plus carboplatin (area under the curve 6) day 1 every 3 weeks (maximum, 6 cycles). Progression-free survival (PFS) was the primary objective; secondary objectives included overall survival (OS), 1-year survival, and safety.ResultsSixty-five patients were randomized to each treatment arm. The patients treated with pemetrexed plus cisplatin had a median age of 64 years and were predominantly men (42 [64.6%]) with nonsquamous histology (53 [81.5%]), stage IV (61 [92.4%]) disease, and a performance status of 0 (40 [61.5%]). Median PFS was 6.0 months, 6-month PFS rate was 50.5%, median OS was 11.7 months, and 1-year survival rate was 47.5%. Drug-related grade 3/4 toxicities included neutropenia (11 [16.9%]), anemia (5 [7.7%]), thrombocytopenia (2 [3.1%]), and nausea (3 [4.6%]). Patients treated with pemetrexed plus carboplatin had a median age of 63 years, were predominantly men (46 [70.8%]) with nonsquamous histology (52 [80.0%]), stage IV (58 [86.6%]) disease, and a performance status of 0 (45 [69.2%]). The median PFS was 4.7 months, the 6-month PFS rate was 34.9%, median OS was 8.9 months, and 1-year survival rate was 39.2%. Drug-related grade 3/4 toxicities included neutropenia (17 [26.2%]), thrombocytopenia (11 [16.9%]), anemia (7 [10.8%]), and nausea (5 [7.7%]).ConclusionsBoth the pemetrexed plus cisplatin and pemetrexed plus carboplatin arms met their primary endpoints and demonstrated efficacy and tolerability as first-line therapy in patients with advanced NSCLC. http://ClinicalTrials.gov: NCT00402051.     

Perspectives: Neutrophil-to-lymphocyte Ratio as a Potential Biomarker in Immune Checkpoint Inhibitor for Non–Small-Cell Lung Cancer

There is a rising need for optimal biomarkers to better tailor treatments for patients with cancer in the era of immunotherapy. In addition to programmed death-ligand 1 (PD-L1) and tumor mutation burden (TMB), neutrophil-to-lymphocyte (NLR) is regaining interest as a biomarker in immunotherapy for its availability, accessibility, and reproducibility. High NLR, according to different thresholds, is consistently reported to correlate with poor prognosis in different treatments in several cancers. Yet, most data come from retrospective analysis, and proof of mechanism and principle evaluations are limited. Prospective studies or adequately sized retrospective analyses of prospectively collected data are required to best assess its role in clinical practice. Moreover, effective myeloid or neutrophil modulators in tumor microenvironment can potentially contribute as a new therapeutic strategy. This perspective will summarize our current knowledge and will discuss where we stand now and propose future directions.     

Pilot Clinical Trial on the Efficacy of Prophylactic Use of Vitamin K1–Based Cream (Vigorskin) to Prevent Cetuximab-Induced Skin Rash in Patients With Metastatic Colorectal Cancer

BackgroundCetuximab is an effective option for the treatment of metastatic colorectal cancer in the first and subsequent lines of treatment; among its side effects, acneiform skin rash is one of the major causes of treatment delay, reduction, or interruption, with a negative effect on quality of life. No effective strategy to prevent skin rash induced by epidermal growth factor receptor inhibitors is available; however, encouraging results have come from vitamin K₁, phytomenadione, applied as a topical formulation. Available studies have been conducted in heterogeneous populations and are mainly focused on the use of vitamin K₁–based cream for the treatment, rather than the prophylaxis, of acneiform rash.Patients and MethodsForty-one consecutive patients from a single center all affected by metastatic colorectal cancer and receiving cetuximab, alone or combined with chemotherapy, applied vitamin K₁–based cream to prevent the occurrence of acneiform skin rash. The cream was applied twice a day on the face and trunk from the first day of administration of cetuximab.ResultsThe application of the cream was well tolerated. No grade 4 rash was reported. The proportion of grade 3 skin rash in the first 8 weeks of treatment in this population was 15%, at the lower limit of values reported in the literature, and the proportion of patients with grade 2 rash was reduced (22.5%).ConclusionThis experience confirms available data in a homogeneous population, suggesting a possible benefit of topical vitamin K₁ as prophylaxis for cetuximab-induced skin rash in patients with metastatic colorectal cancer.