Growth Factor Receptor Inhibitor Therapy Research Articles

Circulating Tumor DNA Dynamics Fail to Predict Efficacy of Poly(ADP-ribose) Polymerase/VEGFR Inhibition in Patients With Heavily Pretreated Advanced Solid Tumors.

Cell-free circulating tumor DNA (ctDNA) has shown its potential as a quantitative biomarker for longitudinal monitoring of response to anticancer therapies. However, ctDNA dynamics have not been studied in patients with heavily pretreated, advanced solid tumors, for whom therapeutic responses can be weak. We investigated whether changes in ctDNA could predict clinical outcomes in such a cohort treated with combined poly(ADP-ribose) polymerase/vascular endothelial growth factor receptor inhibitor therapy. Patients with metastatic pancreatic ductal adenocarcinoma (PDAC), triple-negative breast cancer (TNBC), small-cell lung cancer (SCLC), or non-small-cell lung cancer (NSCLC) received up to 7 days of cediranib 30 mg orally once daily monotherapy lead-in followed by addition of olaparib 200 mg orally twice daily. Patients had progressed on a median of three previous lines of therapy. Plasma samples were collected before and after cediranib monotherapy lead-in and on combination therapy at 7 days, 28 days, and every 28 days thereafter. ctDNA was quantified from plasma samples using a multigene mutation-based assay. Radiographic assessment was performed every 8 weeks. ctDNA measurements were evaluable in 63 patients. The median baseline ctDNA variant allele fractions (VAFs) were 20%, 28%, 27%, and 34% for PDAC, TNBC, SCLC, and NSCLC, respectively. No association was observed between baseline VAF and radiographic response, progression-free survival, or overall survival (OS). Similarly, no association was found between ctDNA decline and radiographic response or survival. However, an increase in ctDNA at 56 days of combination therapy was associated with disease progression and inferior OS in a landmark analysis. ctDNA levels or dynamics did not correlate with radiographic response or survival outcomes in patients with advanced metastatic malignancies treated with olaparib and cediranib.

Resistance Mechanisms to Anti-Epidermal Growth Factor Receptor Therapy in RAS/RAF Wild-Type Colorectal Cancer Vary by Regimen and Line of Therapy.

Acquired resistance to anti-epidermal growth factor receptor (EGFR) inhibitor (EGFRi) therapy in colorectal cancer (CRC) has previously been explained by the model of acquiring new mutations in KRAS/NRAS/EGFR, among other MAPK-pathway members. However, this was primarily on the basis of single-agent EGFRi trials and little is known about the resistance mechanisms of EGFRi combined with effective cytotoxic chemotherapy in previously untreated patients. We analyzed paired plasma samples from patients with RAS/BRAF/EGFR wild-type metastatic CRC enrolled in three large randomized trials evaluating EGFRi in the first line in combination with chemotherapy and as a single agent in third line. The mutational signature of the alterations acquired with therapy was evaluated. CRC cell lines with resistance to cetuximab, infusional fluorouracil, leucovorin, and oxaliplatin, and SN38 were developed, and transcriptional changes profiled. Patients whose tumors were treated with and responded to EGFRi alone were more likely to develop acquired mutations (46%) compared with those treated in combination with cytotoxic chemotherapy (9%). Furthermore, contrary to the generally accepted hypothesis of the clonal evolution of acquired resistance, we demonstrate that baseline resistant subclonal mutations rarely expanded to become clonal at progression, and most remained subclonal or disappeared. Consistent with this clinical finding, preclinical models with acquired resistance to either cetuximab or chemotherapy were cross-resistant to the alternate agents, with transcriptomic profiles consistent with epithelial-to-mesenchymal transition. By contrast, commonly acquired resistance alterations in the MAPK pathway do not affect sensitivity to cytotoxic chemotherapy. These findings support a model of resistance whereby transcriptomic mechanisms of resistance predominate in the presence of active cytotoxic chemotherapy combined with EGFRi, with a greater predominance of acquired MAPK mutations after single-agent EGFRi. The proposed model has implications for prospective studies evaluating EGFRi rechallenge strategies guided by acquired MAPK mutations, and highlights the need to address transcriptional mechanisms of resistance.

BI02 (P97): Epidermal growth factor receptor inhibitor therapy induces a distinct inflammatory hair follicle response that includes a collapse of immune privilege

BI02 (P97): Epidermal growth factor receptor inhibitor therapy induces a distinct inflammatory hair follicle response that includes a collapse of immune privilege

P97: Epidermal growth factor receptor inhibitor therapy induces a distinct inflammatory hair follicle response that includes a collapse of immune privilege

P97: Epidermal growth factor receptor inhibitor therapy induces a distinct inflammatory hair follicle response that includes a collapse of immune privilege

A survey study of prevention and treatment patterns by academic and community oncologists for papulopustular, acneiform skin rash associated with epidermal growth factor receptor inhibitor (EGFRi) therapy.

e24083 Background: EGFRi’s are associated with dermatologic AEs that include an acneiform skin rash. This rash occurs in up to 80% for all grades and 18% for grades ≥3. Treatments are based on grade and include topical antibiotics or corticosteroids for grades 1 and 2, and EGFRi dose interruption and/or oral corticosteroids for severe grades (i.e., ≥ grade 3). For prevention, topical corticosteroids or oral antibiotics are recommended. This survey was conducted to assess current toxicity management patterns and treatment gaps for EGFRi associated skin rash. Methods: An online survey (MedSurvey) with 5 eligibility & 8 questions related to EGFRi practice patterns was conducted (April 2021). Fifty-one practicing oncologists completed the survey. Results: Among the 51 oncologists, 86% have been practicing ≥ 11 yrs with 37% from an academic and 63% from a community setting. They (percent of respondents) prescribed cytotoxic chemotherapy (91%) and targeted agents (84%) > 10x/week. Prevention of EGFRi skin rash with topical antibiotics (33%), topical steroids (45%), and oral antibiotics (45%) were commonly administered prophylactic treatments, while 26% do not treat prophylactically. EGFRi’s were started at a lower dose always 6%, frequently (≥50%) 26%, sometimes (< 50%) 24%, and never 45% of the time. Skin rash treatment is started by 47% at Grade 1, 33% at Grade 2, and 2% ≥Grade 3, while 18% start treatment prophylactically. The majority (57%) would use a novel agent to treat skin rash, while 26% would use it for patients with a previous occurrence, 13% for those not responding to the standard of care and 2% would use this agent for selected EGFR inhibitors. For Grade 1 skin rash (multiple choices allowed), 33% used observation only for management, whereas 55% prescribed topical antibiotics, 35% prescribed oral antibiotics, and 55% used topical steroids. Dose reduction was implemented 4% of the time. For Grade 2 skin rash (multiple choices allowed) 51% used topical antibiotics, 63% prescribed an oral antibiotic, and 77% used topical steroids. Dose reduction was used 35% of the time. For patients not responding to standard therapy 6% switched to a different anti-cancer regimen, 16% changed to another EGFRi, while 77% interrupted the EGFRi therapy. Conclusions: Treating EGFRi-associated skin rash continues to be a significant challenge with Grade 2/3 toxicity or patients not responding to standard treatment. This often requires a therapeutic dose reduction or interruption that may impact the efficacy of anti-cancer treatment. Effective management (prevention and treatment) for skin toxicities associated with EGFRi inhibitors remains an unmet need for many patients and a treatment challenge for oncologists.

A survey study of prevention and treatment patterns by academic and community oncologists for hand-foot skin reaction associated with vascular endothelial growth factor receptor inhibitor (VEGFRi) therapy.

322 Background: VEGFRi therapies are associated with hand-foot skin reaction (HFSR) that affects up to 69% of patients depending on the VEGFRi administered. The incidence and severity of HFSR are dose-dependent and have been associated with improved clinical outcomes suggesting a direct toxicity mechanism. HFSR significantly diminishes patients’ quality of life and effects optimal treatment. Current HFSR treatments focus on managing symptoms since there are no effective therapies that address the underlying cause of HFSR. Small studies and expert opinion have suggested treating HFSR with topical corticosteroids or urea-based creams. However, the most effective management remains dose reduction/interruption or treatment discontinuation. This survey was conducted to assess current toxicity management patterns and treatment gaps for VEGFRi associated HFSR. Methods: An online survey (MedSurvey) with 5 eligibility & 8 questions related to VEGFRi practice patterns was conducted (April 27 to 30, 2021). Fifty-one (51) practicing oncologists completed the survey. Results: Among the 51 oncologists, 86% have been practicing ≥ 11 yrs with 37% from an academic setting and 63% from a community setting. They (percent of respondents) prescribed cytotoxic chemotherapy (91%) and targeted agents (84%) more than 10 times per week. Prevention of VEGFRi-induced HFSR with urea (57%) or topical steroids (75%) were the commonly administered prophylactic treatments. The majority (53%) would prophylactically use a novel agent to prevent HFSR, while 33% would use it for HFSR prevention in a patient with a previous occurrence, and 12% would use this agent for selected VEGFR inhibitors. Many oncologists (4% always, 61% sometime/frequently) start a VEGFRi at a lower dose and titrate up to prevent HFSR. For grade 1 HFSR (multiple choices allowed), 37% used observation only for management, whereas 51% prescribed urea ointment, and 63% used a topical steroid. Dose reduction was implemented 20% of the time. For grade 2 HFSR (multiple choices allowed) 53% used urea ointment, 84% prescribed a topical steroid and 59% considered dose reduction as a treatment strategy. For patients not responding to standard therapy 2% switched to a different anti-cancer regimen, 18% changed the VEGFRi, while 78% interrupted the VEGFRi therapy. Conclusions: Treating VEGFRi-associated HFSR continues to be a significant challenge with grade 2/3 toxicity or patients not responding to standard treatment. This often requires a therapeutic dose reduction or interruption that may impact the efficacy of anti-cancer treatment. Effective management (prevention and treatment) for skin toxicities associated with targeted-multikinase/VEGFRi inhibitors remains an unmet need for many patients and a treatment challenge for oncologists.

Safety Evaluations of Topical Vitamin K1 for Epidermal Growth Factor Receptor Inhibitor-Induced Rash

Papulopustular rash occurs in 80% of patients receiving Epidermal Growth Factor Receptor Inhibitor therapy for cancer. Topical vitamin K1, a phosphatase inhibitor, could reduce epidermal growth factor receptor inhibitor-induced rash. This preliminary safety study evaluated a novel topical 0.1% vitamin K1product for potential use in patients with epidermal growth factor receptor inhibitor-induced rash. Ten healthy subjects applied topical 0.1% vitamin K1 to healthy and tape stripped skin every 12 hours for five doses. Vitamin K1 levels were measured by ELISA in serum and plasma at 0, 26, and 50 hours. Vitamin K1 levels ranged between 0 to 8.22ng/ml. Bivariate correlative analyses showed no association between mean vitamin K1 concentration and time (r=0.008, p=0.930). Using a range of vitamin K1 concentrations (2.5 to 100ng/ml) that encompassed and exceeded the levels detected in our healthy subjects, we evaluated the ability of vitamin K1 to reverse cetixumab-induced Epidermal Growth Factor Receptor inhibition in A549 lung cancer cells. Vitamin K1 did not significantly change phosphorylated-Epidermal Growth Factor Receptor levels in cetuximab-treated cells (p>0.670). In conclusion, systemic vitamin K1 levels up to 100ng/ml would not interfere with epidermal growth factor receptor inhibitor therapy. Our next step is to test the effectiveness of our 0.1% topical VK1 formulation for Epidermal Growth Factor Receptor Inhibitor-induced rash in patients receiving epidermal growth factor receptor inhibitor therapy in a randomized, placebo-controlled, blinded study.

Clinical impact of uncommon epidermal growth factor receptor exon 19 insertion-deletion variants on epidermal growth factor receptor-tyrosine kinase inhibitor efficacy in non-small-cell lung cancer.

Our study aimed to evaluate the efficacy and resistance mechanisms of first-line epidermal growth factor receptor (EGFR) inhibitor therapy in patients with advanced non-small-cell lung cancer (NSCLC) harbouring uncommon EGFR exon 19 deletion-insertion (19delins) variants. Targeted sequencing data of 2467 treatment-naive patients with NSCLC from January 2015 to August 2018 were retrospectively screened for EGFR exon 19 deletion (19del) variants. Clinical outcomes of 93 patients with uncommon EGFR 19delins and 93 patients with common EGFR 19del were selected through propensity score matching at a ratio of 1:1. We identified 10 previously unreported EGFR 19delins variants. L747_P753delinsS, L747_A750delinsPand E746_S752delinsV were the most frequent variants, accounting for 33.1% (42/127), 23.6% (30/127)and 12.6% (16/127) of the cases, respectively. Despite similar baseline characteristics, treatment historyand response rates, patients with uncommon 19delins had significantly longer median progression-free survival (mPFS) than those with common 19del (19.0 months vs. 13.0 months; p=0.0016). At progression from first-line EGFR inhibitor therapy, patients with uncommon 19delins and common 19del had similar rates of developing resistance mechanisms including the acquisition of EGFR T790M (45.8% vs 57.8%), small-cell transformation (3.4% vs 3.6%)and MET amplification (5.1% vs 4.8%). For patients whose tumours acquired T790M and who received second-line osimertinib, the mPFS was significantly shorter for patients with uncommon 19delins (n=27) than those with common 19del (n=47, 5.0 months vs. 12.0 months; p<0.0001). Our results suggest that patients with uncommon EGFR 19delins have improved clinical outcomes with first-generation EGFR inhibitor treatment, but inferior outcomes upon the development of T790M resistance mutations.

Efficacy of non-surgical larynx-preservation comprehensive treatment in advanced laryngeal carcinoma.

Efficacy of non-surgical larynx-preservation comprehensive treatment in advanced laryngeal carcinoma.

Efficacy of topical beta-blockers in the management of EGFR-inhibitor induced paronychia and pyogenic granuloma-like lesions: case series and review of the literature.

Nail toxicities, such as paronychia and pyogenic granuloma-like lesions, are well-recognized side effects of epidermal growth factor receptor inhibitor (EGFR-I) therapy that can significantly impair patient’s quality of life and compliance to anticancer treatment. Numerous therapeutic options are available, with variable rates of success. Recently, topical β-blockers have emerged as a novel, non-invasive treatment strategy. We tested the effectiveness of topical timolol 0.5% gel, twice daily, under occlusion for 30 days, on paronychia and periungual pyogenic granuloma-like lesions in 9 patients being treated with EGFR-I. We also reviewed the available literature on this topic, which is the use of topical β-blockers in the management of EGFR-I-induced nail toxicities. We assessed 25 lesions consistent with the diagnosis of EGFR-I-induced pyogenic granuloma-like lesions and paronychia (21 diagnosed as pyogenic granuloma-like, and four as paronychia). Thirteen of the 25 lesions achieved complete resolution, 9/25 reached at least improvement, and only 3/25 did not respond to the intervention. As for the review, four papers met the scope of our research. The results confirmed at least partial benefit in the majority of treated patients. Among current strategies, high-potency topical corticosteroids are a well-known treatment option especially for paronychia, targeting the inflammatory component of such lesions; nevertheless, the management of pyogenic granuloma-like lesion is often more complex and the success rate is variable. Nail plate avulsion and phenol chemical matricectomy are not highly effective and display some degree of invasiveness. Topical β-blockers seem to be promising alternatives, especially in fragile cancer patients who may be unsuitable candidates for an invasive procedure.

Capmatinib for the treatment of non-small cell lung cancer

ABSTRACTIntroduction: Activation of the MET pathway through MET amplifications or mutations is present in 3–4% of stage IV non-squamous non-small cell lung cancers (NSCLC). High MET amplifications and exon 14 skipping mutations are associated with poor prognosis: new treatments are needed for these patients. Capmatinib is a highly selective, potent small-molecule MET inhibitor with antitumor activity in NSCLC in vitro and in vivo.Areas covered: This article provides an overview of the capmatinib clinical development program in NSCLC, both as monotherapy in NSCLC with a dysregulated MET pathway, and in combination with epidermal growth factor receptor (EGFR) inhibitor therapy in EGFR-mutant NSCLC with MET-based acquired resistance to previous EGFR inhibition.Expert opinion: In the GEOMETRY Mono-1 study, treatment with capmatinib resulted in high response rates in stage IV NSCLC with MET exon 14 skipping mutations, particularly in first line, supporting testing for this biomarker at the time of diagnosis. Durable responses have been reported and results in MET-amplified NSCLC are eagerly anticipated. In EGFR-mutant NSCLC, notable responses have been observed in combination with an EGFR-tyrosine kinase inhibitor (TKI) in case of acquired resistance to EGFR-TKIs based on high MET amplification.

Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer

Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization. Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China. ClinicalTrials.gov Identifier: NCT02314819.

Exosome-Based Detection of EGFR T790M in Plasma from Non–Small Cell Lung Cancer Patients

Purpose: About 60% of non-small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third-generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a noninvasive option to detect the mutation; however, sensitivity is low as many patients have too few detectable copies in circulation. Here, we have developed and validated a novel test that overcomes the limited abundance of the mutation by simultaneously capturing and interrogating exosomal RNA/DNA and cfDNA (exoNA) in a single step followed by a sensitive allele-specific qPCR.Experimental Design: ExoNA was extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) and T790M-negative (N = 108) samples. The T790M mutation status was determined using an analytically validated allele-specific qPCR assay in a Clinical Laboratory Improvement Amendment laboratory.Results: Detection of the T790M mutation on exoNA achieved 92% sensitivity and 89% specificity using tumor biopsy results as gold standard. We also obtained high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), for whom detection by liquid biopsy has been particularly challenging.Conclusions: The combination of exoRNA/DNA and cfDNA for T790M detection has higher sensitivity and specificity compared with historical cohorts using cfDNA alone. This could further help avoid unnecessary tumor biopsies for T790M mutation testing. Clin Cancer Res; 24(12); 2944-50. ©2018 AACR.

Abstract LB-B03: Exosome-based Detection of EGFR T790M in Plasma from Non-Small Cell Lung Cancer Patients

Abstract About 60% of non-small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Although these patients respond well to third generation tyrosine kinase inhibitors like osimertinib, obtaining tissue biopsies for mutation profiling poses risks and is often not feasible. Detecting the mutation in a liquid biopsy from plasma has emerged as a viable alternative to biopsy, however existing liquid biopsy tests using cell-free DNA (cfDNA) often suffer from low sensitivity due to the low copy number of mutant molecules in circulation. As an example, the Food and Drug Adminstration (FDA) approved companion diagnostic for T790M mutation status in plasma (cobas® EGFR mutation Test version 2) only has a 58% sensitivity at a specificity of 80%. In this study we aimed to achieve a higher performance by combining the mutated alleles on cfDNA as well as exosomal RNA and DNA (exoNA) . ExoNA and cfDNA were extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) or T790M-negative (N = 108) samples. The T790M mutation status in plasma exoNA and cfDNA was determined using an analytically validated allele-specific qPCR assay in a CLIA laboratory. The training cohort consisted of 105 samples (51 positives, 54 negatives). The validation cohort consisted of 105 samples (51 positives, 54 negatives), where ~40% of the patients had intrathoracic disease(M0/M1a). Detection of the T790M mutation in exoNA and cfDNA achieved 92% sensitivity and 89% specificity when compared to tumor biopsy results in the validation cohort. We also observed a very high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), patients for whom detection by liquid biopsy has been proven particularly challenging. The combination of exoNA and cfDNA for EGFR T790M detection has a higher sensitivity and specificity compared to historical cohorts using ctDNA alone. This is especially important as it could aid giving the right treatment to patients where biopsy is not available or avoid unnecessary tumor biopsies for T790M mutation testing. Citation Format: Elena Castellanos, Dominik G. Grimm, Vasisht Tadigotla, Stefan Bentink, James Hurley, John Healy, Patricia L. Neal, Mia Sher, Dan Baughman, Chris Karlovich, Mitch Raponi, Anne Krug, Mikkel Noerholm, Luis E. Raez, Johan Skog. Exosome-based Detection of EGFR T790M in Plasma from Non-Small Cell Lung Cancer Patients [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B03.

A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer

BackgroundHead-to-head trials comparing first-line epidermal growth factor receptor inhibitor (EGFRI) versus vascular endothelial growth factor inhibitor (bevacizumab) therapy yielded differing results, and debate remains over optimal first-line therapy for patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). MethodsA PubMed search identified first-line mCRC trials comparing EGFRI plus chemotherapy versus bevacizumab plus chemotherapy; data were subsequently updated using recent congress presentations. This study-level meta-analysis estimated the overall survival (OS) treatment effect of first-line chemotherapy plus EGFRIs or bevacizumab in patients with RAS WT mCRC. Secondary end-points were progression-free survival (PFS), objective response rate (ORR), resection rate and safety. Early tumour shrinkage (ETS) of ≥20% at week 8 was an exploratory end-point. ResultsThree trials comprising data from 1096 patients with RAS WT mCRC were included. OS (hazard ratio [HR]: 0.80 [95% confidence interval: 0.68–0.93]), ORR (odds ratio [OR]: 0.57) and ETS (OR: 0.48) favoured EGFRIs plus chemotherapy versus bevacizumab plus chemotherapy. PFS (HR: 0.98) and resections (OR: 0.93) were similar between treatments. For patients with KRAS exon 2 WT/‘other’ RAS mutant mCRC the OS HR was 0.70. A safety meta-analysis was not possible due to a lack of data; in the individual studies, skin toxicities and hypomagnesaemia were more common with EGFRIs, nausea and hypertension were more common with bevacizumab. ConclusionsThis meta-analysis supports a potential benefit for first-line EGFRI plus chemotherapy versus bevacizumab plus chemotherapy with respect to OS, ORR and ETS in patients with RAS WT mCRC. A patient-level meta-analysis is awaited.

Management of Skin Reactions During Cetuximab Treatment in Association With Chemotherapy or Radiotherapy: Update of the Italian Expert Recommendations.

Cetuximab was shown in phase III clinical trials to improve chemotherapy efficacy in patients with advanced colorectal and head-neck cancer. Appropriate management of skin reactions associated with epidermal growth factor receptor inhibitor therapy is necessary to allow adequate drug compliance and to improve patient quality of life and outcomes. The RAND/UCLA Appropriateness Method was used by a group of experts to produce new Italian recommendations on the management of skin reactions in this setting. Statements were generated on the basis of an updated systematic review of the literature and rated twice by a panel of 38 expert physicians. A meeting of the panel was held after the first rating session. Skin reactions included acneiformic rash, skin dryness (xerosis), pruritus, paronychia, hair abnormalities, mucositis, and increased growth of eyelashes or facial hair. Updates of the previous recommendations on the prevention and treatment of each type of reaction were proposed. This updated Expert Opinion focuses on how to assess and correctly grade skin reactions according to the latest National Cancer Institute Common Terminology Criteria for Adverse Events and on how to manage these adverse events in clinical practice.

Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression.

Targeted therapies are effective in subsets of lung cancers with EGFR mutations and anaplastic lymphoma kinase (ALK) translocations. Large-scale genomics have recently expanded the lung cancer landscape with FGFR1 amplification found in 10-20% of squamous cell carcinomas (SCCs). However, the response rates have been low for biomarker-directed fibroblast growth factor receptor (FGFR) inhibitor therapy in SCC, which contrasts to the relatively high rates of response seen in EGFR mutant and ALK-translocated lung cancers treated with epidermal growth factor receptor (EGFR) inhibitors and ALK inhibitors, respectively. In order to better understand the low response rates of FGFR1-amplified lung cancers to FGFR inhibitors, relationships between gene copy number, mRNA expression and protein expression of FGFR1 were assessed in cell lines, tumor specimens and data from The Cancer Genome Atlas. The importance of these factors for the sensitivity to FGFR inhibitors was determined by analyzing drug screen data and conducting in vitro and in vivo experiments. We report that there was a discrepancy between FGFR1 amplification level and FGFR1 protein expression in a number of these cell lines, and the cancers with unexpectedly low FGFR1 expression were uniformly resistant to the different FGFR inhibitors. Further interrogation of the receptor tyrosine kinase activity in these discordant cell lines revealed co-activation of HER2 and platelet-derived growth factor receptor-α (PDGFRα) caused by gene amplification or ligand overexpression maintained phosphoinositide 3-kinase (PI3K) and MEK/ERK signaling even in the presence of FGFR inhibitor. Accordingly, co-inhibition of FGFR1 and HER2 or PDGFRα led to enhanced drug responses. In contrast, FGFR1-amplified high FGFR1 protein-expressing lung cancers are sensitive to FGFR inhibitor monotherapy by downregulating ERK signaling. Addition of a PI3K inhibitor to these high FGFR1 protein-expressing cancers further sensitized them to FGFR inhibitor. These data reveal that biomarker-directed trials for FGFR1-amplified SCC require assessment of FGFR1 protein expression and uncover novel therapeutic strategies for FGFR1-amplified SCC with low FGFR1 protein expression.

Correlation between DPYD gene variation and KRAS wild type status in colorectal cancer

AimsFailure and side effects of combined cytotoxic therapy are challenges in the treatment of metastatic colorectal cancer (CRC). DPYD gene variations can potentially predict toxicity to 5-fluorouracil (FU)-based therapy and...

Long-term survival of a patient with lung cancer metastasis to the spine following surgical treatment combined with radiation and epithelial growth factor receptor inhibitor therapy: A case report.

The prognosis of patients with lung cancer metastasis to the spine is poor, and the choice of surgery is questionable based on the aggressiveness of the disease. The present study describes a case of a 56-year-old male with metastatic spinal cord compression. The patient underwent surgery for posterior decompression and internal fixation, in addition to receiving postoperative radiation and epidermal growth factor receptor (EGFR) inhibitor medication. After 24 months, positron emission tomography-computed tomography scan showed a reduction in the left upper lobe mass in the short axis and inactivation of the neoplasm in the left upper lobe and T9 vertebra. Based on these promising results, it is suggested that orthopedic oncologists consider the combination of radiation and EGFR inhibitor therapy with surgery for the treatment of lung cancer metastasis to the spine.

Early response monitoring with 18F-FDG PET and cetuximab-F(ab')2-SPECT after radiotherapy of human head and neck squamous cell carcinomas in a mouse model.

Only a subset of patients with head and neck squamous cell carcinomas (HNSCCs) benefit from radiotherapy and concurrent epidermal growth factor receptor (EGFR) inhibitor therapy with cetuximab, indicating the need for patient selection. The aim of this study was to visualize the change in systemically accessible EGFR with (111)In-cetuximab-F(ab')2 SPECT before and after radiotherapy, while simultaneously evaluating (18)F-FDG PET uptake. Mice with HNSCC xenografts, cetuximab-sensitive SCCNij202 and cetuximab-resistant SCCNij167, were imaged with SPECT/CT using (111)In-cetuximab-F(ab')2 as a tracer, directly followed by PET imaging with (18)F-FDG. Scans were acquired 7 d before radiotherapy (10 Gy) and 1, 7, and 14 d after treatment. Intratumoral localization of (111)In-cetuximab-F(ab')(2) was evaluated by autoradiography and histologic markers evaluated by immunofluorescence staining in the same tumor sections. Growth of irradiated SCCNij202 and SCCNij167 tumors was significantly delayed, compared with controls (P < 0.05). No changes in uptake of (18)F-FDG were observed in either of the xenografts after radiotherapy. SPECT images of tumor-bearing mice showed a significant increase in uptake of (111)In-cetuximab-F(ab')(2) in the SCCNij202 tumors after irradiation (tumor-to-liver ratio, 4.3 ± 1.1 vs. 10.5 ± 3.3, 7 d before and 14 d after treatment, respectively, P < 0.01) but not in SCCNij167 tumors. Immunohistochemical EGFR staining showed a translocation of the EGFR from the cytoplasm to the cell membrane in irradiated SCCNij202 xenografts. Intratumoral distribution of (111)In-cetuximab-F(ab')(2) as determined by autoradiography correlated well with the distribution of EGFR as determined immunohistochemically (r = 0.85; range, 0.69-0.95). EGFR accessibility can be visualized with (111)In-cetuximab-F(ab')(2). (111)In-cetuximab-F(ab')(2) uptake increased after irradiation only in cetuximab-sensitive SCCNij202 xenografts, implying that the tracer can be used to measure irradiation-induced changes of EGFR expression and can monitor the compensatory response of tumors to radiotherapy.