• Pharmacist-led outpatient clinic
• duration of treatment
• non-small cell lung cancer
• osimertinib
• tyrosine kinase inhibitor

• Amivantamab
• FDA Adverse Event Reporting System
• lung tumors
• reporting odds ratio method
• safety profile

• ARCHER 1050
• biomarker
• dacomitinib
• non-small-cell lung cancer
• skin disorders

• Humans
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/mortality
• Carcinoma, Non-Small-Cell Lung/pathology
• Quinazolinones/adverse effects
• Quinazolinones/therapeutic use
• Quinazolinones/administration & dosage
• ErbB Receptors/antagonists & inhibitors
• Lung Neoplasms/drug therapy
• Lung Neoplasms/mortality
• Lung Neoplasms/pathology
• Female
• Male
• Aged
• Middle Aged
• Aged, 80 and over
• Adult
• Protein Kinase Inhibitors/therapeutic use
• Protein Kinase Inhibitors/adverse effects
• Progression-Free Survival
• Treatment Outcome
• Mutation
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/adverse effects

• SFJ Pharmaceuticals
• Pfizer

• acneiform eruption
• afatinib
• erlotinib
• molecular‐targeting agent
• skin disorder

• Humans
• Animals
• Mice
• Afatinib/therapeutic use
• Erlotinib Hydrochloride/adverse effects
• Adapalene/therapeutic use
• ErbB Receptors/metabolism
• Skin Diseases/chemically induced
• Inflammation/chemically induced
• Protein Kinase Inhibitors/adverse effects
• Lung Neoplasms/pathology

• KAKENHI 16K19452 Japan Society for the Promotion of Science
• Japan Society for the Promotion of Science

• FAERS
• cutaneous toxicity
• data mining
• epidermal growth factor receptor inhibitors
• pharmacovigilance

• biochemistry
• cancer
• drug discovery
• immunology
• health care

• Humans
• Ligands
• Vitamin K/metabolism
• Chemokines
• ErbB Receptors
• Chemokine CCL5

• 20K16066 Japan Society for the Promotion of Science

• Extracellular signal-regulated inhibitor
• Fibroblast growth factor receptor inhibitor
• Mitogen-activated protein kinase inhibitor
• Retina

• P30 CA008748 NCI NIH HHS

• MET ex14 skipping mutation
• MET inhibitor
• NSCLC

Cutaneous squamous cell carcinoma (cSCC) is an increasingly prevalent and morbid cancer worldwide. Management of this cancer has changed significantly in the last decade through improved risk stratification and new therapies offering patients with locally advanced and metastatic disease more effective, less toxic, and more durable treatment options. Ongoing clinical trials are assessing new therapeutic options as well as optimizing existing regimens in efforts to better manage this cancer. The recent developments highlight the need for multidisciplinary care, especially for those with locally advanced and metastatic disease.

cSCC is increasing in prevalence due to increased lifespans and improvements in survival for conditions that increase the risk of cSCC. The absolute mortality of cSCC exceeds melanoma in the United States and approaches that of melanoma worldwide. This review presents significant changes in the management of cSCC, focusing on improvements in risk stratification, new treatment options, optimization of existing treatments, and prevention strategies. One major breakthrough in cSCC treatment is the advent of immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1), which have ushered in a renaissance in the treatment of patients with locally advanced and metastatic disease. These agents have offered patients with advanced disease decreased therapeutic toxicity compared to traditional chemotherapy agents, a more durable response after discontinuation, and improved survival. cSCC is an active field of research, and this review will highlight some of the novel and more developed clinical trials that are likely to impact cSCC management in the near future.

• cancer
• personalized medicine
• therapeutic drug monitoring
• tyrosine kinase inhibitors

Molecular targeted therapies (MTTs) cause skin disorders in patients with cancer, and moisturizers are useful treatments; however, their actual use and costs are unknown. Our purpose was to examine the use and costs of moisturizers prescribed for xerosis (asteatosis) in patients with cancer treated with MTTs.

We used data from a Japanese hospital-based claims database. The index date was the first date of MTT prescription from October 2011 to April 2018 (selection period), and the follow-up period was 1 year from the index date. Patients treated with MTTs during the selection period and who were not prescribed moisturizers in the 6 months before the index date were included as the study cohort. Timing, duration, amount, and costs of the prescribed moisturizers and total medical costs were analyzed.

Among the 78,190 patients in the study cohort, 27,906 patients (35.7%) were prescribed moisturizers during follow-up. Moisturizer prescription timing, duration, and volume were inconsistent. The average annual total medical costs for treating patients with MTT who were prescribed moisturizers was JPY 6.165 million (USD 53,797) per patient, and the moisturizer costs were JPY 6033 (USD 53). The number of patients who used moisturizers showed an increasing trend.

No consistent patterns were observed for the timing or duration of moisturizer use, which suggests various developmental patterns of skin disorders. Furthermore, medical costs for moisturizers accounted for only a small proportion of the total medical costs required for cancer treatment.

The online version contains supplementary material available at 10.1007/s13555-022-00712-2.

• Maruho Co., Ltd.

• anti-EGFR agents
• breast cancer
• lapatinib
• neratinib
• pyrotinib
• tyrosine kinase inhibitor

•

Cutaneous toxicities are frequent with targeted therapies.

With the development of molecular targeted therapies, a wide array of dermatologic toxicities is appearing. Their prevention, recognition, and management by dermatologists is critical to ensure antineoplastic treatment continuation. The objective of this study was to provide a literature review of the most common dermatologic toxicities due to targeted therapies in oncologic patients, including their clinical presentation, prevention, and management.

• Molecular targeted therapies
• antineoplastic agents
• dermatological toxicities
• drug-related side effects and adverse events
• supportive care

• MCP-1
• RANTES
• Viscum album
• anti-inflammation
• erlotinib
• mistletoe
• skin rash
• viscumneoside

• advanced cSCC
• cSCC
• cutaneous squamous cell carcinoma
• immunotherapy
• systemic therapies
• tumor response

• cancer
• cutaneous
• immunotherapy
• oncodermatology
• pediatric
• targeted therapy

• immunotherapy
• mCRC
• rechallenge anti-EGFR
• skin toxicity

• (I-Cure Research Project, Grant number: Cup 21C17000030007). Regione Campania

• clinical symptom
• cutaneous toxicity
• incidence
• mechanism
• small-molecule kinase inhibitors

• Concentration-guided dosing
• kinase inhibitors
• precision medicine
• therapeutic drug monitoring

Afatinib is a first-line treatment option for patients with an advanced nonsmall cell lung cancer (NSCLC) expressing an epidermal growth factor receptor (EGFR) activating mutation. This study aimed to evaluate the association between early adverse events induced by afatinib and overall survival (OS) and progression free survival (PFS) in patients with advanced NSCLC.

The study was a pooled post hoc analysis of the randomized trials LUX-Lung 3 and LUX-Lung 6 which evaluated afatinib versus pemetrexed-cisplatin or gemcitabine-cisplatin, respectively. Cox proportional hazard analysis was used to assess the impact of adverse events occurring within the first 28 days of afatinib therapy on the PFS and OS outcomes in treatment-naïve advanced NSCLC patients harbouring an EGFR activating mutation.

There were 468 patients who initiated first-line afatinib therapy within LUX-Lung 3 and LUX-Lung 6. A significant association between early rash and improved OS (hazard ratio (HR 95% CI); grade 1 = 0.74 [0.56–0.97]; grade 2+ = 0.64 [0.46–0.89]) (P = 0.018) was observed, although no significant association with PFS was present (P = 0.732). A significant association was identified between early diarrhoea and improved PFS (grade 1 = 0.83 [0.62–1.12]; grade 2+ = 0.62 [0.44–0.88]) (P = 0. 015), although no significant association with OS was present (P = 0.605). No associations between early stomatitis or paronychia and OS or PFS were identified.

Rash occurring early after the initiation of afatinib was significantly associated with improved OS, an indicator that rash may be a surrogate of patients likely to achieve long-term survival. Consideration of using rash as a dose adjustment target may be warranted for future prospective trials aiming to optimise outcomes with afatinib therapy.

Objective: Epidermal growth factor receptor inhibitors (EGFRI) are used as targeted cancer therapy. On average 70% of patients treated with EGFRIs suffer from skin toxicity. Studies showed a correlation between overall survival and the appearance of a skin rash, which is used as a biomarker for therapy efficacy. Micro RNAs (miRNA) as tumor or resistance biomarkers for cancer therapy are also highly investigated. In our study, we searched for associations of miRNA expression profiles in serum, with the severity of skin rash, in order to identify tentative therapy predictive biomarkers.

Materials and Methods: Five candidate miRNAs were selected, based on an earlier in vitro next-generation-sequencing-experiment and after literature search. MiR-21, miR-31, miR-17, miR-106b and miR-520e were investigated in serum samples from patients (n = 254) treated with EGFRI. The quantitative expression of miRNA was tested for association with the occurrence/severity of the rash.

Results: In our cohort of patients treated with EGFR inhibiting monoclonal antibodies, miR-21 and miR-520e serum concentrations were negatively correlated with severity of skin rash (p-value 0.000582 and 1.53e-07 linear-trend-test) whereas for miR-31, a positive correlation was observed (p-value 9.01e-06 linear-trend-test).

Conclusions: This suggests that miR-21, miR-31 and miR-520e expression might be a treatment dependent marker for EGFRI induced skin rash.

• EGFR
• EGFRI
• cancer
• miRNA
• skin toxicity

• Cutaneous toxicities
• MASCC
• Supportive care
• Supportive oncodermatology

• adenoma
• apc
• colorectal cancer
• fap
• pirc

• Adenomatous Polyposis Coli/drug therapy
• Adenomatous Polyposis Coli/genetics
• Adenomatous Polyposis Coli/metabolism
• Adenomatous Polyposis Coli/pathology
• Animals
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/standards
• Colonic Neoplasms/genetics
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/pathology
• Colonic Neoplasms/prevention & control
• Colonic Polyps/genetics
• Colonic Polyps/metabolism
• Colonic Polyps/pathology
• Colonic Polyps/prevention & control
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Erlotinib Hydrochloride/administration & dosage
• Genes, APC
• Intestinal Neoplasms/genetics
• Intestinal Neoplasms/metabolism
• Intestinal Neoplasms/pathology
• Intestinal Neoplasms/prevention & control
• Male
• Mutation
• Rats
• Sulindac/administration & dosage

• HHSN261201500018C NCI NIH HHS
• P01 CA090890 NCI NIH HHS
• P30 CA016672 NCI NIH HHS
• R01 CA122959 NCI NIH HHS

• Administration, Cutaneous
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Dose-Response Relationship, Drug
• Drug Eruptions/drug therapy
• Drug Eruptions/etiology
• Drug Eruptions/pathology
• Drug Resistance, Neoplasm
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/metabolism
• Humans
• MAP Kinase Signaling System/drug effects
• Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
• Mitogen-Activated Protein Kinase Kinases/metabolism
• Molecular Targeted Therapy/adverse effects
• Molecular Targeted Therapy/methods
• Neoplasms/drug therapy
• Protein Kinase Inhibitors/administration & dosage
• Proto-Oncogene Proteins B-raf/antagonists & inhibitors
• Proto-Oncogene Proteins B-raf/metabolism
• Skin/drug effects
• Skin/pathology
• Treatment Outcome

• ZIA BC011930 Intramural NIH HHS

• Kampo medicine
• cetuximab
• epidermal growth factor receptor inhibitor
• paronychia skin toxicities

•

A total of 346 patients were enrolled in this study.

Rash is a well-known predictor of survival for patients with gefitinib therapy with non-small cell lung cancer (NSCLC). However, whether patients with more severe rash obtain the more survival benefits from gefitinib is still unknown, and predicted model for severe rash is needed.

The relationship between gefitinib-induced rash and progression free survival (PFS) was primarily explored in the retrospective cohort. The association between rash and gefitinib/metabolites concentration and genetic polymorphisms were determined by pharmacometabolomic and pharmacogenomics methods in the exploratory cohort and validated in an external cohort.

The survival for patients with rash was significantly higher than that of patients without rash (p = 0.0002, p = 0.0089), but no difference was found between grade 1/2 or grade 3/4. Only the concentration of gefitinib, but not its metabolites, was found to be associated with severe rash, and the cutoff value of gefitinib was 204.6 ng/mL conducted by ROC curve analysis (AUC=0.685). A predictive model for severe rash was established: gefitinib concentration (OR = 11.523, 95% CI = 2.898-64.016, p = 0.0016), SLC22A8 rs4149179(CT vs CC, OR = 3.156, 95% CI = 0.958–11.164, p = 0.0629), SLC22A1 rs4709400(CG vs CC, OR = 10.267, 95% CI = 2.067–72.465, p = 0.0087; GG vs CC, OR = 5.103, 95% CI = 1.032–33.938, p = 0.061). This model was confirmed in the validation cohort with an excellent predictive ability (AUC = 0.749, 95% CI = 0.710–0.951).

Our finding demonstrated that the incidence, not the severity, of gefitinib-induced rash predicted improved survival, the gefitinib concentration and polymorphisms of SLC22A8 and SLC22A1 were recommended to manage severe rash.

• Gefitinib
• Metabolites
• Non-small cell lung cancer
• Pharmacometabolomic
• Polymorphisms
• Rash

Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/MEKi) are beneficial for the treatment of solid cancers but are frequently associated with severe therapy-limiting acneiform skin toxicities. The underlying molecular mechanisms are poorly understood. Using gene expression profiling we identified IL-36γ and IL-8 as candidate drivers of EGFRi/MEKi skin toxicity. We provide molecular and translational evidence that EGFRi/MEKi in concert with the skin commensal bacterium Cutibacterium acnes act synergistically to induce IL-36γ in keratinocytes and subsequently IL-8, leading to cutaneous neutrophilia. IL-36γ expression was the combined result of C. acnes–induced NF-κB activation and EGFRi/MEKi–mediated expression of the transcription factor Krüppel-like factor 4 (KLF4), due to the presence of both NF-κB and KLF4 binding sites in the human IL-36γ gene promoter. EGFRi/MEKi increased KLF4 expression by blockade of the EGFR/MEK/ERK pathway. These results provide an insight into understanding the pathological mechanism of the acneiform skin toxicities induced by EGFRi/MEKi and identify IL-36γ and the transcription factor KLF4 as potential therapeutic targets.

• Cytokines
• Dermatology
• Inflammation
• Molecular biology
• Skin

The bioavailability of lapatinib is affected by food, even following the 1 hour fast recommended by the package insert. We hypothesized that overnight fasting would minimize food‐drug interactions. Here, we investigated if lapatinib administration timing is associated with its tolerability, efficacy, and pharmacokinetics.

This is a retrospective cohort study utilizing the medical records of patients enrolled in the JBCRG‐16/Neo‐LaTH randomized phase 2 trial for breast cancer patients treated with lapatinib. Lapatinib administration timing was divided into three groups: before breakfast (BB), between meals (BM), and at bedtime (AB). Side effects (SE), treatment discontinuation rate (TDR), relative dose intensity (RDI), pathological complete response (pCR) rate, and lapatinib serum trough concentration were compared between groups.

About 140 patients were included in this study: BB 15, BM 51, and AB 74. A reduced risk of diarrhea {adjusted hazard ratio (HR), 0.51, 95% confidence interval (CI), 0.27‐0.89, p = 0.018}, and rash {adjusted HR, 0.37; 95% CI, 0.17‐0.70, p = 0.002} was seen in BB versus AB. Fewer patients with low RDI (< 0.85/<0.6) were in the BB group (BB 13% / 0%, BM 22% / 3.9%, AB 24% / 14%, p = 0.70 / 0.11). pCR was not diminished (p = 0.75). BB group had the lowest serum lapatinib concentration and variability (mean ±SD were 0.35 ± 0.15, 0.65 ± 0.32, 0.96 ± 0.43 µg/ml).

Compared to bedtime administration, lapatinib administration after overnight fasting reduces its toxicity without diminishing its therapeutic efficacy.

• Tyrosine kinase inhibitors
• breast cancer
• drug discovery and delivery
• medical oncology
• quality of life

• KRAS
• Pancreatic adenocarcinoma
• SHP2
• Targeted therapy

• Erlotinib
• Gastrointestinal toxicity
• Non-small cell lung cancer

• Aged
• Carcinoma, Non-Small-Cell Lung/diagnostic imaging
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Erlotinib Hydrochloride/adverse effects
• Female
• Humans
• Lung Neoplasms/diagnostic imaging
• Lung Neoplasms/drug therapy
• Mutation
• Retrospective Studies
• Treatment Outcome

• combination therapy
• efficacy
• pancreatic cancer

• Biomarker
• Fibroblast growth factor receptor
• Hyperphosphatemia
• Infigratinib
• Pharmacodynamics
• Pharmacokinetics
• Response rate
• Urothelial carcinoma

• Autoimmunity
• Immune checkpoint inhibitors
• Immunotherapy
• Toxicity and irAEs

• Animals
• Autoimmune Diseases/etiology
• Autoimmune Diseases/pathology
• Autoimmunity/immunology
• Biomarkers, Tumor/antagonists & inhibitors
• Biomarkers, Tumor/immunology
• Humans
• Immunologic Factors/adverse effects
• Immunotherapy/adverse effects
• Neoplasms/immunology
• Neoplasms/pathology
• Neoplasms/therapy

• K24 CA201543 NCI NIH HHS

• erlotinib
• older patients
• population pharmacokinetics
• therapeutic drug monitoring

Background: This study aimed to investigate the impact of early adverse events (AE) following the initiation of lapatinib plus capecitabine on the progression-free survival (PFS) and overall survival (OS) outcomes of human epidermal growth factor receptor 2 (HER2) positive advanced breast cancer (ABC) patients.

Methods: A secondary analysis of participants treated with lapatinib plus capecitabine, or ado-trastuzumab emtansine in the clinical trial EMILIA was conducted. Cox proportional hazard analysis was used to assess the impact of AE occurring within the first 42 days of lapatinib plus capecitabine therapy on the PFS and OS outcomes of ABC patients.

Results: The study included 488 HER2-positive (ABC) patients initiated on lapatinib plus capecitabine. Rash (Hazard Ratio (HR) [95% Confidence Interval (CI)]: Grade 1 = 0.67 [0.46-0.98], Grade 2+ = 0.71 [0.42-1.19]; p = 0.046) and hand-foot syndrome (HR [95% CI]: Grade 1 = 0.58 [0.43-0.80], Grade 2+ = 0.61 [0.43-0.86]; p = <0.001) occurring within the first 42 days of lapatinib plus capecitabine therapy were significantly associated with improved OS. Conversely, nausea and vomiting occurring within the first 42 days of lapatinib plus capecitabine therapy was significantly associated with worsened OS (HR [95% CI]: Grade 1 = 1.08 [0.82-1.42], Grade 2+ = 1.52 [1.13-2.03]; p = 0.027).

Conclusions: Rash and hand-foot syndrome occurring early after the initiation of on lapatinib plus capecitabine were significantly associated with improved OS, while early nausea and vomiting was associated with worse OS. In HER2-positive ABC patients initiating lapatinib plus capecitabine, consideration should be given to more closely monitoring patients at risk of nausea and vomiting, while rash and hand foot syndrome are AE associated with improved survival.

• adverse events
• breast neoplasms
• capecitabine
• hand-foot syndrome
• lapatinib
• survival analysis

• Epidermal growth factor receptor
• exon 19 deletion mutation
• exon 21 point mutation
• non-small cell lung cancer
• skin rash
• tyrosine kinase inhibitor