Comprehensive genomic profiling in multiple cancer types: A comparative analysis of the National Biobank Consortium of Taiwan and clinical practice cohorts.

BACKGROUND: This retrospective study analyzed tumor tissue profiling data to assess the potential of comprehensive genomic profiling (CGP) for patient care across diverse solid tumors. MATERIAL AND METHODS: Patients with newly diagnosed or recurrent stage IIIB or IV lung adenocarcinoma with a null immunophenotype and esophageal, gastric, pancreatic, or bile duct cancer between January 2020 and July 2023 at two medical centers in Taiwan were included. One cohort was a part of the National Biobank Consortium of Taiwan project, whereas the other consisted of patients undergoing routine clinical practice. Tumor samples were subjected to CGP using FoundationOne®CDx, with therapeutic implications determined using OncoKB classification. RESULTS: FoundationOne®CDx testing of 574 patients was successful in 456 (79.4%) patients. Clinically actionable genomic alterations were detected in 21.1% (96/456) of the patients, including 17.5%, 2.9%, and 0.7% of patients with evidence levels 1, 2, and 3, respectively. Lung adenocarcinoma accounted for the largest proportion of samples with at least one actionable gene alteration (63.2%), followed by bile duct (26.9%), gastric (17.6%), esophageal (4.0%), and pancreatic (3.1%) cancers. Based on CGP results, 43 patients (9.4%) received matched targeted therapy. The median overall survival of patients who received matched therapy or not was 26.1 months (95% confidence interval (CI), 16.7-35.5 months) and 10.6 months (95% CI, 8.1-13.1 months; hazard ratio, 0.28, 95% CI, 0.14-0.55, p < 0.001), respectively. CONCLUSIONS: This study provides comprehensive insights into the genomic profiles of diverse cancers in Taiwan, highlighting the crucial role of CGP in identifying actionable genomic alterations and guiding effective therapeutic strategies in real-world practice.

Clinical characteristics and genetic HLA marker for patients with oxaliplatin-induced adverse drug reactions.

BACKGROUND: Oxaliplatin is commonly used to treat gastrointestinal malignancies. However, its applications are limited due to potential adverse drug reactions (ADRs), particularly severe anaphylactic shock. There is no method to predict or prevent ADRs caused by oxaliplatin. Therefore, we aimed to investigate the genetic HLA predisposition and immune mechanism of oxaliplatin-induced ADRs. METHODS: A retrospective review was performed for 154 patients with ADRs induced by oxaliplatin during 2016-2021 recorded in our ADR notification system. HLA genotyping was conducted for 47 patients with oxaliplatin-induced ADRs, 1100 general population controls, and 34 oxaliplatin-tolerant controls in 2019-2023. The in vitro basophil activation test (BAT) was performed and oxaliplatin-specific IgE levels were determined. RESULTS: The incidence of oxaliplatin-induced ADRs and anaphylactic shock in our cohort was 7.1% and 0.15%, respectively. Of the 154 patients, 67.5% suffered rash/eruption; 26.0% of the patients who could not undergo oxaliplatin rechallenge were considered to show oxaliplatin-induced immune-mediated hypersensitivity reactions (HRs). The genetic study found that the HLA-DRB∗12:01 allele was associated with oxaliplatin-induced HRs compared to the general population controls (sensitivity = 42.9%; odds ratio [OR] = 3.4; 95% CI = 1.4-8.2; P = 0.008) and tolerant controls (OR = 12; 95% CI = 2.3-63.7; P = 0.001). The in vitro BAT showed higher activation of CD63+ basophils in patients with oxaliplatin-induced HRs compared to the tolerant controls (P < 0.05). Only four patients (8.5%) with oxaliplatin-induced ADRs were positive for oxaliplatin-specific IgE. CONCLUSIONS: This study found that 26.0% of patients with oxaliplatin-induced ADRs could not undergo oxaliplatin rechallenge. HLA-DRB∗12:01 is regarded as a genetic marker for oxaliplatin-induced hypersensitivity.

Effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with epidermal growth factor receptor-mutated advanced non-small-cell lung cancer: a multi-institute retrospective study.

BACKGROUND: In real-world practice, most patients with lung cancer are diagnosed when they are aged ≥65 years. However, clinical trials tend to lack data for the elderly population. Therefore, we aimed to describe the effectiveness and safety of afatinib, gefitinib, and erlotinib for elderly patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: Treatment-naïve patients with EGFR-mutated advanced NSCLC were enrolled at many hospitals in Taiwan. Patient characteristics and the effectiveness and safety of afatinib, gefitinib, and erlotinib were compared. RESULTS: This study enrolled 1,343 treatment-naïve patients with EGFR-mutated advanced NSCLC, of whom 554 were aged <65 years, 383 were aged 65-74 years, 323 were aged 75-84 years, and 83 were aged ≥85 years. For elderly patients, afatinib was more effective, with a median progression-free survival (PFS) of 14.7 months and overall survival (OS) of 22.2 months, than gefitinib (9.9 months and 17.7 months, respectively) and erlotinib (10.8 months and 18.5 months, respectively; PFS: p = 0.003; OS: p = 0.026). However, grade ≥3 adverse events, including skin toxicities, paronychia, mucositis, and diarrhea, were more frequently experienced by patients receiving afatinib than those receiving gefitinib or erlotinib. CONCLUSIONS: This large retrospective study provides real-world evidence of the effectiveness and safety of EGFR-TKIs for elderly patients with EGFR-mutated advanced NSCLC, a population that is often underrepresented in clinical trials and real-world evidence. Afatinib was more effective as a first-line treatment than gefitinib or erlotinib for elderly patients with EGFR-mutated advanced NSCLC.

Real-world evidence of lorlatinib therapy in Taiwanese patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer.

BACKGROUND: Lorlatinib is a brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) inhibitor indicated for ALK-positive metastatic non-small cell lung cancer (NSCLC). In a global phase II study, patients who experience disease progression despite prior treatment with ALK tyrosine kinase inhibitors (TKIs) was assessed. Herein, we report real-world clinical outcomes of lorlatinib-treated patients with ALK-positive advanced NSCLC who were heavily pretreated and progressed on first- and second-generation ALK-TKIs, in a Taiwanese population under the lorlatinib expanded access program (EAP). METHODS: This multicenter observational study examined the effectiveness and safety of ALK-positive advanced NSCLC patients that progressed from previous second-generation ALK-TKI therapy and received lorlatinib treatment subsequently. Patients who received lorlatinib treatment under EAP between Jul 2017 and Sep 2019 were eligible. Patients were followed for at least one year from the first lorlatinib treatment until study completion. RESULTS: Sixty-three patients were eligible for safety analysis (male: 46.0 %; median age: 52.8 [27.5-78.3] years; brain metastases: 81.0 %). Fifty-four patients with more than one-month lorlatinib treatment were included in the effectiveness analysis. Prior to lorlatinib treatment, 10 patients (18.5 %) received one ALK-TKI, 27 (50.0 %) received two ALK-TKIs, and 17 (31.5 %) received three or more ALK-TKIs. The overall median rwPFS was 9.2 months (95 % confidence interval: 5.3-21.1). The best overall response rate (n = 51) was 13.7 %, with a disease control rate of 80.4 %. CONCLUSION: Lorlatinib exhibits substantial activity and tolerability when used clinically in a later-line setting in a Taiwanese population with ALK-positive advanced NSCLC.

Gut microbiota and clinical response to immune checkpoint inhibitor therapy in patients with advanced cancer.

BACKGROUND: There is currently no well-accepted consensus on the association between gut microbiota and the response to treatment of immune checkpoint inhibitors (ICIs) in patients with advanced cancer. METHODS: Fecal samples were collected before ICI treatment. Gut microbiota was analyzed using 16 S ribosomal RNA sequencing. We investigated the relationship between the α-diversity of fecal microbiota and patients' clinical outcomes. Microbiota profiles from patients and healthy controls were determined. Pre-treatment serum was examined by cytokine array. RESULTS: We analyzed 74 patients, including 42 with melanoma, 8 with kidney cancer, 13 with lung cancer, and 11 with other cancers. Combination therapy of anti-PD1 and anti-CTLA-4 was used in 14 patients, and monotherapy in the rest. Clinical benefit was observed in 35 (47.3 %) cases, including 2 complete responses, 16 partial responses, and 17 stable diseases according to RECIST criteria. No significant difference in α-diversity was found between the benefiter and non-benefiter groups. However, patients with α-diversity within the range of our healthy control had a significantly longer median overall survival (18.9 months), compared to the abnormal group (8.2 months) (p = 0.041, hazard ratio = 0.546) for all patients. The microbiota composition of the benefiters was similar to that of healthy individuals. Furthermore, specific bacteria, such as Prevotella copri and Faecalibacterium prausnitzii, were associated with a favorable outcome. We also observed that serum IL-18 before treatment was significantly lower in the benefiters, compared to non-benefiters. CONCLUSIONS: The α-diversity of gut microbiota is positively correlated with more prolonged overall survival in cancer patients following ICI therapy.

Distinct changes to pancreatic volume rather than pancreatic autoantibody positivity: insights into immune checkpoint inhibitors induced diabetes mellitus.

BACKGROUND: Immune checkpoint inhibitors (ICI) are promising treatment options for various cancers. However, their use is associated with immune-related adverse events (irAEs), including ICI-induced diabetes mellitus (ICI-DM). This study aimed to investigate the clinical features of ICI-DM, with a particular focus on alterations to pancreatic volume. METHODS: We conducted a retrospective review of 2829 patients who received ICI treatment at the Chang Gung Memorial Hospital, Linkou, between January 2014 and December 2021. New-onset diabetes or diabetic ketoacidosis (DKA) was identified in ten patients receiving ICI therapy. Pancreatic volumes were assessed by manual segmentation of computed tomography (CT) images before and after ICI-DM diagnosis. RESULTS: Among these ten patients, nivolumab was the most commonly used ICI (50.0%), followed by pembrolizumab (30.0%) and atezolizumab (20.0%). One patient received combination therapy with nivolumab and ipilimumab. The median age was 63.01 years (range: 40.1 - 87.8). ICI-DM developed after a median of 13.5 cycles (range: 2 - 42) of ICI treatment or 9.85 months (range:1.5 - 21.3) since ICI initiation. The initial presentation was DKA in 60.0% of patients. All patients had low or undetectable C-peptide levels (range: <0.033 - 0.133 nmol/L) and were negative for most type 1 diabetes mellitus (T1DM)-related autoantibodies; only one patient tested positive for glutamic acid decarboxylase antibodies. CT imaging revealed significant pancreatic atrophy, with a median pancreatic volume decrease of 19.92% (P = 0.038) from baseline and sustained significant decline at last follow-up (median - 37.14%, P = 0.012). CONCLUSIONS: ICI-DM is often accompanied by pancreatic atrophy and approximately two-thirds of patients initially present with DKA. Although the majority of ICI-DM patients lack T1DM-related autoantibodies, identifying diminished pancreatic volumes through CT imaging provides valuable clues into the subclinical aspects of ICI-DM development, aiding in the prevention of diabetic emergencies. TRIAL REGISTRATION: Not applicable.

Personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against metastatic ovarian cancer.

Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.

Generation and validation of a predictive model for estimating survival among patients with EGFR-mutant non-small cell lung cancer.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC), treatment outcomes vary significantly. Previous studies have indicated that concurrent mutations may compromise the effectiveness of first-line EGFR-TKIs. However, given the high cost of next-generation sequencing, this information is often inaccessible in routine clinical practice. A prediction model based on pre-treatment clinical characteristics may thus offer a more practical solution. This study established a nomogram based on pretreatment clinical characteristics to stratify patients according to optimal treatment strategies. We retrospectively reviewed 761 patients with EGFR-mutant NSCLC who received first- or second-generation EGFR-TKIs at a tertiary referral center between 2010 and 2019. The pretreatment clinical characteristics and progression-free survival data were collected. Using COX proportional hazard regression analysis, we constructed a nomogram based on seven clinically significant prognostic factors: sex, Eastern Cooperative Oncology Group performance status, histology subtype, mutation subtype, stage, and metastasis to the liver and brain. Our nomogram could stratify patients into three groups with different risks for disease progression and was validated in a patient cohort from other hospitals. This risk stratification can provide additional information for determining the optimal first-line treatment strategy for patients with EGFR-mutant NSCLC.

Genomic and tumour microenvironmental biomarkers of immune checkpoint inhibitor response in advanced Taiwanese melanoma.

Objective: Genomic biomarkers predicting immune checkpoint inhibitor (ICI) treatment outcomes for Asian metastatic melanoma have been rarely reported. This study presents data on next-generation sequencing (NGS) and tumour microenvironment biomarkers in 33 cases. Methods: Thirty-three patients with advanced melanoma, who underwent ICI treatment at the Chang Gung Memorial Hospital in Taiwan, were recruited. The study evaluated clinical outcomes, including response rate, disease control rate, progression-free survival (PFS) rate and overall survival (OS) rate. Archived tissue samples from 33 cases were subjected to NGS by ACTOnco, and ACTTME was employed in 25 cases. Results: The most prevalent driver mutations were BRAF mutations (24.2%), followed by NRAS (15.2%), KIT (12.1%), KRAS (9.1%) and NF1 (9.1%) mutations. Acral/mucosal melanomas exhibited distinct mutation patterns compared to non-acral melanomas. Tumour mutational burden estimated using ACTOnco was not associated with ICI efficacy. Notably, genetic alterations in the p53 pathway (CDKNA2 loss, MDM2 gain/amplification and TP53 mutation) accounted for 36.4% and were significantly associated with unfavourable PFS (median PFS 2.7 months vs. 3.9 months, P = 0.0394). Moreover, 26 genes were identified as differentially expressed genes that were upregulated in patients with clinical benefits compared to those without benefits. Four genes, GZMH, GZMK, AIM2 and CTLA4, were found to be associated with both PFS and OS. Conclusion: Genetic alterations in the p53 pathway may be critical in Asian patients with melanoma undergoing ICI treatment. Further investigation is required to explore this mechanism and validate these findings.

Comprehensive assessment of pretreatment sarcopenia impacts on patients with EGFR-mutated NSCLC treated with afatinib.

BACKGROUND: This study aimed to comprehensively evaluate the efficacy and toxicity of afatinib in patients with sarcopenia, an important prognostic factor for treatment efficacy and toxicity in patients with cancer. METHODS: The clinical features of patients with advanced NSCLC treated with frontline afatinib between 2014 and 2018 at a medical center in Taiwan were retrospectively reviewed. Sarcopenia was evaluated based on the total cross-sectional area of skeletal muscles assessed by computed tomography (CT) imaging at the L3 level. Baseline characteristics, response rates, survival rates, and adverse events (AEs) were compared between sarcopenic and nonsarcopenic patients. RESULTS: A total of 176 patients evaluated for sarcopenia by CT and treated with afatinib were enrolled in the current study. Sarcopenia was significantly associated with good performance status, low body mass index (BMI), low body surface area (BSA), and low total mass area (TMA). Sarcopenia did not influence the response rate (69.2% vs. 72.0%, p = 0.299), progression-free survival (median 15.9 vs. 14.9 months, p = 0.791), or overall survival (median 26.5 vs. 27.2 months, p = 0.441). However, BSA ≤ 1.7 and the 40 mg afatinib dose were associated with dose reduction. TMA was the only independent factor for afatinib discontinuation due to AEs. CONCLUSION: Sarcopenia was not associated with treatment efficacy or toxicity among patients with NSCLC harboring common mutations treated with afatinib, indicating sarcopenic patients should not be excluded from afatinib treatment. Other factors, such as BSA and TMA, were associated with dose reduction and afatinib discontinuation, respectively, which may require additional evaluations in future studies.

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer harboring uncommon EGFR mutations: Real-world data from Taiwan.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study aimed to evaluate the efficacy of EGFR-TKIs and prognostic factors for patients with NSCLC harboring uncommon EGFR mutations, which account for 10% of EGFR mutations. METHODS: A total of 230 treatment-naive patients with NSCLC harboring uncommon EGFR mutations treated with first-line EGFR-TKIs between 2011 and 2018 at four hospitals (belonging to four institutions, Linkou, Kaohsiung, Keelung, and Chiayi, of the Chang Gung Memorial Hospital) in Taiwan were retrospectively reviewed. Their clinicopathological characteristics, adverse events (AEs), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors for PFS. RESULTS: Overall, patients who received afatinib (n = 62) had better PFS (median: 6.4 vs. 5.9 months, p = 0.022) and OS (median: 13.4 vs. 13.0 months, p = 0.008) than those who received gefitinib/erlotinib (n = 124), although no significant differences were observed for ORR (46.8% vs. 35.5%, p = 0.137) or DCR (59.7% vs. 58.9%, p = 0.916). Patients who received afatinib showed significantly higher ORR (58.3% vs. 31.3%, p = 0.027) but not DCR compared with gefitinib/erlotinib for major uncommon mutations. Afatinib trended toward better PFS and OS for major uncommon mutations and compound mutations. No EGFR-TKIs were effective for most NSCLC patients with exon 20 insertions. Performance status, metastasis of the liver and pleura, and dose reduction were independent prognostic factors for PFS. CONCLUSION: Afatinib demonstrated better survival outcomes than gefitinib/erlotinib for NSCLC patients harboring major EGFR uncommon mutations and compound mutations. Performance status and metastatic sites may be useful for predicting PFS for major uncommon mutations and compound mutations.

The survival after discontinuation of EGFR-TKIs due to intolerable adverse events in patients with EGFR-mutated non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard treatments for advanced non-small cell lung cancer (NSCLC) patients harboring the EGFR mutation. Patients experiencing intolerable adverse events (AEs) would discontinue EGFR-TKIs. This study aimed to evaluate the impact of intolerable AEs and subsequent treatment on the survival of patients who discontinued EGFR-TKIs. PATIENTS: The data of advanced NSCLC patients treated with EGFR-TKIs as frontline treatment at Chang Gung Memorial Hospitals from June 2014 to March 2018 were retrospectively reviewed. RESULTS: A total of 2190 patients were enrolled and treated with frontline EGFR-TKIs. In August 2021, 114 (5.2%) patients experienced intolerable AEs requiring discontinuation of EGFR-TKIs. The time median of EGFR-TKIs discontinuation was 2.56 months. Age >65 years, females, body weight, and body surface area were associated with the occurrence of intolerable AEs for patients treated with afatinib. Patients experiencing skin/paronychia/mucositis and abnormal liver function test had favorable survivals results. Patients who received subsequent EGFR-TKIs treatment, experienced better progression-free survival (PFS), total PFS (from frontline line EGFR-TKIs), and overall survival (OS) compared to patients receiving chemotherapy or no treatment. Patients undergoing subsequent EGFR-TKIs had better total PFS (median, 14.9 vs. 11.3 months, p = 0.013) and OS (median, 31.3 vs. 20.1 months, p = 0.001) than patients who did not discontinue because of AEs. Favorable OS was validated by propensity score matching. CONCLUSION: Patients experiencing intolerable AEs during EGFR-TKI treatment should consider switching to an alternative EGFR-TKI, which increase the survival results as compared to those patients who did not experience intolerable AEs.

Impact of T790M Mutation Status on Later-Line Osimertinib Treatment in Non-Small Cell Lung Cancer Patients.

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) designed to overcome acquired T790M resistance mutations in non-small cell lung cancer (NSCLC). However, the efficacy of osimertinib in patients without acquired T790M mutations has not been well studied. This study aimed to evaluate the efficacy of osimertinib in patients treated with first- and second-generation EGFR-TKIs followed by later-line osimertinib treatment. Patients: The clinical data and survival outcomes of 172 patients with advanced NSCLC treated with osimertinib following frontline EGFR-TKIs at Chang Gung Memorial Hospital from 2014 to 2018 were retrospectively reviewed. T790M mutations were detected using tissue sequencing and/or liquid biopsy. Results: A total of 172 EGFR-mutated NSCLC patients treated with frontline EGFR-TKI therapy followed by later-line osimertinib were enrolled in the current study and divided into three groups based on the T790M status (positive, negative, or unknown T790M). Patients with NSCLC harboring acquired T790M mutation treated with osimertinib had the best objective response rate (ORR) (52.6%, 25.0%, and 32.0%, p = 0.044), disease control rate (DCR) (79.3%, 41.7%, and 68.0%, p = 0.011), and progression-free survival (PFS, median PFS, 12.6, 3.1, 10.4 months, p = 0.001) among the three groups (positive, negative, and unknown T790M, respectively). However, a marked difference was found between positive and negative T790M mutations but not between positive and unknown T790M mutations. Univariate analysis was performed to identify potential prognostic factors for PFS in 172 patients treated with osimertinib. Lung metastasis (p < 0.001), brain metastasis (p < 0.009), number of metastatic sites (p < 0.001), PFS with frontline EGFR-TKIs (p = 0.03), and T790M status (p = 0.006) were identified as prognostic factors for PFS with osimertinib. Multivariate analysis showed that lung metastasis (p < 0.001) and PFS with frontline EGFR-TKIs and T790M status were independent prognostic factors. Conclusion: This study confirmed the greater efficacy of later-line osimertinib for NSCLC with acquired T790M mutation than for NSCLC without acquired T790M mutation. Detection of the T790M mutation after frontline treatment (first- and second-generation EGFR-TKI) is crucial for prolonging the survival of NSCLC patients harboring EGFR mutation. Osimertinib may be considered an option for NSCLC with unknown T790M mutations, as a certain subpopulation may benefit from osimertinib.

Sequential treatment in advanced non-small cell lung cancer harboring EGFR mutations.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatments for advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients. Osimertinib is an effective therapy for NSCLC patients with acquired resistance due to T790M mutation after first- and second-generation EGFR-TKI treatment. This study aimed to analyze the clinical outcomes of sequential therapy following first-line EGFR-TKIs and the predictive factors of an acquired T790M mutation. METHODS: Between January 2014 and December 2018, data from 2190 advanced NSCLC patients with common EGFR mutations (exon 19 deletion and L858R) receiving first- and second-generation EGFR-TKIs in Linkou, Kaohsiung, Chiayi and Keelung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed. RESULTS: Until August 2021, among 1943 patients who experienced progressive disease, 526 underwent T790M mutation tests, and their T790M-positive rate was 53.6%. Exon 19 deletion mutation and progression-free survival (PFS) of >12 months were positively associated with secondary T790M mutation. Different first-line first- and second-generation EGFR-TKI therapies did not affect the appearance of acquired T790M mutations. The median overall survival (OS) was 58.3 [95% confidence interval (CI): 49.0-67.5] months among the patients with T790M mutation who received second-line osimertinib therapy compared with 31.0 (95% CI: 27.5-34.5) months among the patients without T790M mutation who received chemotherapy alone. The multivariate analysis showed that a poor performance status (score: >2), nonadenocarcinoma histology, stage IV cancer, liver metastasis, brain metastasis, PFS while on first-line EGFR-TKIs, and subsequent chemotherapy without third-generation EGFR-TKIs were significant independent unfavorable prognostic factors for OS. CONCLUSION: This study demonstrated the efficacy of first-line EGFR-TKIs and sequential osimertinib therapy. The results of our study suggest that T790M mutation tests are important for the use of subsequent osimertinib, which yielded favorable survival outcomes.

In vitro and in vivo study of GSK2830371 and RG7388 combination in liver adenocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct and accounts for the second highest incidence of primary liver cancers after hepatocellular carcinoma. The lack of effective treatment leads to a poor prognosis for advanced iCCA, so new targeted therapy is needed. The impairment of wild-type (WT) p53 tumor suppressor function by its negative regulators frequently occurs in iCCA. Therefore, restoration of WT p53 function by inhibiting its negative regulators is a therapeutic strategy being explored for cancer treatment. Combining an MDM2 inhibitor (MDM2i, RG7388) to stabilize p53 and a WIP1 inhibitor (WIP1i, GSK2830371) to increase p53 phosphorylation enhances p53 function. The combination of MDM2 and WIP1 inhibitors has been reported in several cancer types but in vivo studies are lacking. In the current study, liver adenocarcinoma cell lines, RBE and SK-Hep-1, were treated with RG7388 alone and in combination with GSK2830371. Cell proliferation, clonogenicity, protein and mRNA expressions, and cell cycle distribution were performed to investigate the effect and mechanism of growth suppression. To evaluate the antitumor efficacy of RG7388 and GSK2830371 in vivo, SK-Hep-1 xenografts in NOD-SCID mice were treated with combination therapy for two weeks. The combination of MDM2i and WIP1i significantly increased the growth inhibition, cytotoxicty, p53 protein expression, and phosphorylation (Ser15), leading to transactivation of downstream targets (p21WAF1 and MDM2). The in vivo results demonstrated that the combination treatment can significantly inhibit tumor growth. In this study, the liver adenocarcinoma cell lines responded to combination treatment via reactivation of p53 function evidenced by increased p53 expression, phosphorylation and expression of its downstream targets. This efficacy was also demonstrated in vivo. The current research provides a novel strategy for targeting the p53 pathway in liver adenocarcinoma that warrants further investigation.

Safety of Tepotinib Challenge after Capmatinib-Induced Pneumonitis in a Patient with Non-Small Cell Lung Cancer Harboring MET Exon 14 Skipping Mutation: A Case Report.

The targeted agents capmatinib and tepotinib provide a new treatment for patients with non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutation (METex14). However, drug-induced pneumonitis is an uncommon but threatening adverse effect found in patients treated with both capmatinib and tepotinib. The safety of treating a patient with a MET inhibitor after drug-induced pneumonitis by another MET inhibitor remains unclear. Here, we present a case of a patient with NSCLC harboring a METex14 who was treated with a standard dose of tepotinib after advanced capmatinib-induced pneumonitis and did not present pneumonitis relapse. Tepotinib may be a safe option when medical professionals consider switching MET inhibitors after patients experience pneumonitis.

Radiation Recall Pneumonitis: A Rare Syndrome That Should Be Recognized.

Radiation recall pneumonitis (RRP) is a rare but severe condition which has been mainly detected in the previously irradiated lung of patients with cancer after administering inciting agents, most commonly antineoplastic regimens including chemotherapy, targeted therapy, or immunotherapy. More recently, coronavirus disease vaccines were found to induce RRP. In addition to typical radiation pneumonitis (RP) or drug-induced interstitial lung disease, the management of RRP requires withholding inciting agents and steroid therapy. Thus, the occurrence of RRP could significantly impact cancer treatment, given that inciting agents are withheld temporarily and even discontinued permanently. In the present review, we discuss the current understanding and evidence on RRP and provide additional insights into this rare but severe disease.

Epidermal growth factor receptor tyrosine kinase inhibitors for de novo T790M mutation: A retrospective study of 44 patients.

BACKGROUND: This study aimed to evaluate possible treatment strategies for patients with de novo T790M mutation-positive (T790M+) non-small-cell lung cancer (NSCLC). METHODS: Patients diagnosed with de novo T790M+ NSCLC and treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) between 2011 and 2018 at a regional hospital in Taiwan were retrospectively reviewed. Their clinicopathological characteristics and subsequent treatment information were collected, and potential prognostic factors were identified using univariate and multivariate analyses. RESULTS: All tumors with T790M mutations coexisted with sensitizing mutations. Through the last follow-up in May 2021, afatinib and osimertinib demonstrated better progression-free survival (PFS, p < 0.01) and overall survival (OS, p < 0.01) than gefitinib and erlotinib. Additionally, patients with low T790M ratios had better PFS than those with high T790M ratios, implying that the proportion of T790M+ tumors determined the response to EGFR-TKIs. Multivariate analysis confirmed that both EGFR-TKI treatment (osimertinib hazard ratio [HR] 0.06, 95% confidence interval [CI] 0.01-0.30; afatinib HR 0.09, 95% CI 0.02-0.39) and a low T790M ratio (HR 0.29, 95% CI 0.12-0.69) were independently favorable prognostic factors for patients with de novo T790M+ NSCLC. Median PFS was 6.1 (95% CI 4.4-7.8) months. In addition, patients treated with first-generation (1G)/second-generation (2G) EGFR-TKIs followed by osimertinib (n = 8) demonstrated the best OS compared with patients treated with frontline osimertinib (n = 5) or 1G/2G EGFR-TKIs without osimertinib (n = 28, p < 0.01). CONCLUSION: Sequential TKIs may represent an alternative option for de novo T790M mutation, particularly frontline afatinib and tumors with low T790M ratios.

Real-world Afatinib Outcomes in Advanced Non-small Cell Lung Cancer Harboring EGFR Mutations.

BACKGROUND/AIM: Afatinib is a standard treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib can overcome the treatment resistance-associated EGFR T790M mutation, and the sequence of afatinib followed by osimertinib is an effective therapeutic strategy for NSCLC patients. This study comprehensively evaluated the outcomes of sequential therapy following frontline afatinib and identified predictive factors for T790M mutation acquisition. PATIENTS AND METHODS: Data from patients with advanced NSCLC treated with frontline afatinib at a Taiwanese hospital group from June 2014 to March 2018 were retrospectively reviewed. The EGFR T790M mutation was detected by tissue sequencing or liquid biopsy. The patients' clinicopathological features were collected, and univariate and multivariate analyses were performed to identify potential predictive and prognostic factors. RESULTS: A total of 635 patients treated with afatinib were enrolled in this study. Until August 2021, 553 patients experienced progression, and 225 patients underwent T790M mutation testing. The T790M positive rate was 54.2%. Both exon 19 deletion and progression-free survival were associated with T790M positivity. Osimertinib was found to be effective in T790M-positive but not T790M-negative NSCLC. The median overall survival (OS) was 61.8 months for patients with T790M mutation undergoing later-line osimertinib compared with 30.1 months for patients without T790M mutation undergoing chemotherapy only. Osimertinib independently prolonged OS after afatinib progression. CONCLUSION: This study confirmed the efficacy of sequential afatinib and osimertinib treatment. T790M mutation detection and osimertinib availability are important for prolonging survival in patients with NSCLC harboring EGFR mutations.

Risk Stratification Using a Novel Nomogram for 2190 EGFR-Mutant NSCLC Patients Receiving the First or Second Generation EGFR-TKI.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). This study aimed to create a novel nomogram to help physicians suggest the optimal treatment for patients with EGFRm+ NSCLC. Records of 2190 patients with EGFRm+ NSCLC cancer who were treated with EGFR-TKIs (including gefitinib, erlotinib, and afatinib) at the branches of a hospital group between 2011 and 2018 were retrospectively reviewed. Their clinicopathological characteristics, clinical tumor response, progression-free survival (PFS), and overall survival (OS) data were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors to create a nomogram for risk stratification. Univariate analysis identified 14 prognostic factors, and multivariate analysis confirmed the pretreatment independent factors, including Eastern Cooperative Oncology Group performance status, morphology, mutation, stage, EGFR-TKIs (gefitinib, erlotinib, or afatinib), and metastasis to liver, brain, bone, pleura, adrenal gland, and distant lymph nodes. Based on these factors, a novel nomogram was created and used to stratify the patients into five different risk groups for PFS and OS using recursive partitioning analysis. This risk stratification can provide additional information to clinicians and patients when determining the optimal therapeutic options for EGFRm+ NSCLC.