Analysis of genomic alternations in epidermal growth factor receptor (EGFR)-T790M-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib therapy.

BACKGROUND AND OBJECTIVES: Genomic alterations after resistance to osimertinib therapy in advanced T790M-mutated non-small cell lung cancer (NSCLC) are complex and poorly understood. In this study, we aimed to detect these genomic alternations via comprehensive next-generation sequencing (NGS) of tissue and liquid biopsies. PATIENTS AND METHODS: From September 2020 to June 2021, 31 stage IIIB/IV T790M-mutated NSCLC patients who exhibited progressive disease after osimertinib therapy and provided written informed consent were recruited. Liquid and tissue biopsy samples for NGS testing were collected from 31 and 18 patients, respectively. Eighteen study patients had paired NGS data from tissue and liquid biopsies. RESULTS: With respect to the T790M mutation status, the preservation and loss rates were 33% and 67%, respectively, in both liquid and tissue biopsy samples. Five patients (16.1%) had the C797S mutation (4 liquid samples and 1 tissue sample). Two (6.5%) had MET mutations, 3 (9.7%) had BRAF-V600E mutations, and 1 (3.2%) had a KRAS-G12C mutation. Among the 18 patients who underwent tissue rebiopsies, those with preserved T790M mutation had significantly longer progression-free survival (PFS) with osimertinib therapy than those with T790M mutation loss (10.8 vs. 5.0 months, P = 0.045). Among all patients, those with T790M mutation loss in liquid biopsy samples had longer PFS after osimertinib therapy (10.8 vs. 7.5 months, P = 0.209) and postprogression survival (17.7 vs. 9.6 months, P = 0.132) than those with preserved T790M mutation based on liquid biopsies. CONCLUSIONS: NGS using either tissue or liquid biopsy samples from advanced T790M-mutated NSCLC patients with acquired resistance to osimertinib therapy can detect various genomic alternations. Future studies focusing on subsequent tailored therapies on the basis of NGS results are warranted.

Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer.

BACKGROUND: Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy. METHODS: In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded. RESULTS: A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = 0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = 0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group. CONCLUSIONS: Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.).

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.

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.

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.

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.