Preclinical studies suggest that loss of LKB1 expression renders cancer cells less responsive to radiation partly through NRF2-mediated upregulation of antioxidant enzymes protecting against ...radiation-induced DNA damage. Here we investigated the association of an alteration in this pathway with radio-resistance in lung cancer patients. Patients with locally advanced non-small cell lung cancer (LA-NSCLC) who were treated with chemoradiotherapy (CRT) and analyzed for LKB1 expression using semiquantitative immunohistochemistry. Clinical characteristics and expression of LKB1 were analyzed for association with radiotherapy outcomes. We analyzed 74 available tumor specimens from 178 patients. After a median follow-up of 40.7 months, 2-year cumulative incidence of locoregional recurrence (LRR) in patients who had LKB1
expression was significantly higher than those with LKB1
expression (68.8% vs. 31.3%, P = 0.0001). LKB1
expression was found significantly associated with a higher incidence of distant metastases (DM) (P = 0.0008), shorter disease-free survival (DFS) (P = 0.006), and worse overall survival (OS) (P = 0.02) compared to LKB1
expression. Moreover, patients with LKB1
expression showed a significantly higher 2-year cumulative incidence of LRR (77.6% vs. 21%; P = 0.02), higher DM recurrence (P = 0.002), and shorter OS (P < 0.0001) compared with the EGFR-mutant group. For all patients with LKB1
who had LRR, these recurrences occurred within the field of radiation, in contrast to those with LKB1
expression having both in-field, marginal, and out-of-field failures. LKB1 expression may serve as a potential biomarker for poor outcomes after receiving radiation in LA-NSCLC patients. Further studies to confirm the association and application are warranted.
Despite the development of predictive biomarkers to shape treatment paradigms and outcomes, de novo EGFR TKI resistance advanced non-small cell lung cancer (NSCLC) remains an issue of concern. We ...explored clinical factors in 332 advanced NSCLC who received EGFR TKI and molecular characteristics through 65 whole exome sequencing of various EGFR TKI responses including; de novo (progression within 3 months), intermediate response (IRs) and long-term response (LTRs) (durability > 2 years). Uncommon EGFR mutation subtypes were significantly variable enriched in de novo resistance. The remaining sensitizing EGFR mutation subtypes (exon 19 del and L858R) accounted for 75% of de novo resistance. Genomic landscape analysis was conducted, focusing in 10 frequent oncogenic signaling pathways with functional contributions; cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGF-β, p53 and β-catenin/Wnt signaling. Cell cycle pathway was the only significant alteration pathway among groups with the FDR p-value of 6 × 10
. We found only significant q-values of < 0.05 in 7 gene alterations; CDK6, CCNE1, CDK4, CCND3, MET, FGFR4 and HRAS which enrich in de novo resistance range 36-73% compared to IRs/LTRs range 4-22%. Amplification of CDK4/6 was significant in de novo resistance, contrary to IRs and LTRs (91%, 27.9% and 0%, respectively). The presence of co-occurrence CDK4/6 amplification correlated with poor disease outcome with HR of progression-free survival of 3.63 95% CI 1.80-7.31, p-value < 0.001. The presence of CDK4/6 amplification in pretreatment specimen serves as a predictive biomarker for de novo resistance in sensitizing EGFR mutation.
Most immune-related adverse event (irAE) patterns and treatment guidelines are based on western clinical data. We evaluated the incidence and patterns of irAEs in patients treated with ...immune-checkpoint inhibitors (ICI) in Thailand.
All solid tumor patients treated with ICIs were retrospectively reviewed in a multicenter analysis. The study aims to evaluate the incidence of irAEs and their characteristics, treatments, outcomes, and impact on survival. All irAEs were graded using the CTCAE version 4.0. Characteristics of irAEs including time to onset, duration of irAEs, specific treatments, and outcomes of irAEs were reviewed. The Chi-square or Fisher's exact test was used to compare variables. Overall survival (OS) was estimated by the Kaplan-Meier method, and compared by the log-rank test. A p-value < 0.05 was considered statistically significant.
irAEs of any grade were observed in 98 of 414 patients (24%), whereas grades 3-4 irAEs were observed in 5.6%. The majority of patients (78%) were treated with monotherapy ICI (anti-PD1/PD-L1 92%). The most common all-grade irAEs were hypothyroidism (7.5%), hepatitis (6.5%), and rash (4.8%). Median onset of overall irAEs was 63 days. Pancreatitis and pneumonitis had the earliest onset at 30 and 34 days, respectively. ICIs were rechallenged in 68 of 98 patients with irAE. Eleven of sixty-eight patients (11.2%) with initial irAE had reoccurrence after ICI rechallenge. Based on a multivariate analysis, pre-existing hypothyroidism, ICI used in a clinical trial setting, and combinations of ICI/ICI were independent factors predicting irAE occurrence. Patients with irAE had a statistically significant longer overall survival (OS) when compared to patients without irAE (p = 0.019). A multivariate analysis revealed that occurrence of irAE was an independent prognostic factor for OS (HR 0.70, 95% CI 0.51-0.96; p = 0.028).
irAE was commonly observed in Thai cancer patients treated with ICIs. Most irAEs were low-grade and manageable. Re-occurrence of irAE after re-challenging ICI was not uncommonly observed. Patients who experienced irAEs might have significantly longer OS compared to patients without irAEs. However, OS in this study should be interpreted with caution since it might be affected by various tumor types, treatment settings, dosing schedule, and ICI combinations.
The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma ...were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status.
In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS.
OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio HR, 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation-positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation-negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation-positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09).
EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.
Summary Background The results of FASTACT, a randomised, placebo-controlled, phase 2 study, showed that intercalated chemotherapy and erlotinib significantly prolonged progression-free survival (PFS) ...in patients with advanced non-small-cell lung cancer. We undertook FASTACT-2, a phase 3 study in a similar patient population. Methods In this phase 3 trial, patients with untreated stage IIIB/IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio by use of an interactive internet response system with minimisation algorithm (stratified by disease stage, tumour histology, smoking status, and chemotherapy regimen) to receive six cycles of gemcitabine (1250 mg/m2 on days 1 and 8, intravenously) plus platinum (carboplatin 5 × area under the curve or cisplatin 75 mg/m2 on day 1, intravenously) with intercalated erlotinib (150 mg/day on days 15–28, orally; chemotherapy plus erlotinib) or placebo orally (chemotherapy plus placebo) every 4 weeks. With the exception of an independent group responsible for monitoring data and safety monitoring board, everyone outside the interactive internet response system company was masked to treatment allocation. Patients continued to receive erlotinib or placebo until progression or unacceptable toxicity or death, and all patients in the placebo group were offered second-line erlotinib at the time of progression. The primary endpoint was PFS in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT00883779. Findings From April 29, 2009, to Sept 9, 2010, 451 patients were randomly assigned to chemotherapy plus erlotinib (n=226) or chemotherapy plus placebo (n=225). PFS was significantly prolonged with chemotherapy plus erlotinib versus chemotherapy plus placebo (median PFS 7·6 months 95% CI 7·2–8·3, vs 6·0 months 5·6–7·1, hazard ratio HR 0·57 0·47–0·69; p<0·0001). Median overall survival for patients in the chemotherapy plus erlotinib and chemotherapy plus placebo groups was 18·3 months (16·3–20·8) and 15·2 months (12·7–17·5), respectively (HR 0·79 0·64–0·99; p=0·0420). Treatment benefit was noted only in patients with an activating EGFR gene mutation (median PFS 16·8 months 12·9–20·4 vs 6·9 months 5·3–7·6, HR 0·25 0·16–0·39; p<0·0001; median overall survival 31·4 months 22·2–undefined, vs 20·6 months 14·2–26·9, HR 0·48 0·27–0·84; p=0·0092). Serious adverse events were reported by 76 (34%) of 222 patients in the chemotherapy plus placebo group and 69 (31%) of 226 in the chemotherapy plus erlotinib group. The most common grade 3 or greater adverse events were neutropenia (65 29% patients and 55 25%, respectively), thrombocytopenia (32 14% and 31 14%, respectively), and anaemia (26 12% and 21 9%, respectively). Interpretation Intercalated chemotherapy and erlotinib is a viable first-line option for patients with non-small-cell lung cancer with EGFR mutation-positive disease or selected patients with unknown EGFR mutation status. Funding F Hoffmann-La Roche.
Angiosarcoma (AS) is a rare disease with a dismal prognosis. The treatment landscape and prognostic factors for advanced AS, including locally advanced, unresectable, and metastatic disease remain ...elusive. The Asian Sarcoma Consortium is an international collaborative effort to understand the sarcoma treatment landscape in Asia. We undertook a retrospective chart review of AS patients seen in 8 sarcoma academic centers across Asia. Patients with complete clinical, treatment, and follow‐up data were enrolled. Overall, 276 advanced AS patients were included into this study; 84 (30%) of the patients had metachronous metastatic AS. The median age was 67 y; primary sites of AS was cutaneous in 55% and visceral in 45% of patients. In total, 143 (52%) patients received at least 1 line of systemic chemotherapy. The most common first‐line chemotherapy regimen used was paclitaxel (47.6%) followed by liposomal doxorubicin (19.6%). The median overall survival (OS) was 7.8 mo. Significant prognostic factors for OS included age > 65 (hazard ratio (HR) 1.54, P = .006), male gender (HR 1.39, P = .02), and a cutaneous primary AS site (HR 0.63, P = .004). The median progression‐free survival (PFS) for first‐line chemotherapy was 3.4 mo. PFS for single vs combination or paclitaxel vs liposomal doxorubicin chemotherapy regimens were comparable. This study provides an insight into the treatment patterns and prognostic factors of advanced AS patients in Asia. Prognosis of advanced AS remains poor. Data from this study serve as a benchmark for future clinical study design.
With a total of 276 advanced angiosarcoma patients, we provided the complete clinicopathological demographics, treatment patterns, and prognostic outcomes of advanced angiosarcoma in Asia.
The Blood First Assay Screening Trial is an ongoing open-label, multicohort study, prospectively evaluating the relationship between blood-based next-generation sequencing (NGS) detection of ...actionable genetic alterations and activity of targeted therapies or immunotherapy in treatment-naive advanced or metastatic NSCLC. We present data from the ALK-positive cohort.
Patients aged more than or equal to 18 years with stage IIIB or IV NSCLC and ALK rearrangements detected by blood-based NGS using hybrid capture technology (FoundationACT) received alectinib 600 mg twice daily. Asymptomatic or treated central nervous system (CNS) metastases were permitted. Primary end point was investigator-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors version 1.1). Secondary end points were independent review facility-assessed ORR, duration of response, progression-free survival (PFS), overall survival, and safety. Exploratory end points were investigator-assessed ORR in patients with baseline CNS metastases and relationship between circulating biomarkers and response.
In total, 2219 patients were screened and blood-based NGS yielded results in 98.6% of the cases. Of these, 119 patients (5.4%) had ALK-positive disease; 87 were enrolled and received alectinib. Median follow-up was 12.6 months (range: 2.6–18.7). Confirmed ORR was 87.4% (95% confidence interval CI: 78.5–93.5) by investigator and 92.0% (95% CI: 84.1–96.7) by independent review facility. Investigator-confirmed 12-month duration of response was 75.9% (95% CI: 63.6–88.2). In 35 patients (40%) with baseline CNS disease, investigator-assessed ORR was 91.4% (95% CI: 76.9–98.2). Median PFS was not reached; 12-month investigator-assessed PFS was 78.4% (95% CI: 69.1–87.7). Safety data were consistent with the known tolerability profile of alectinib.
These results reveal the clinical application of blood-based NGS as a method to inform clinical decision-making in ALK-positive NSCLC.
Background:
The objectives of this phase II study were to determine the clinical activity of the MET tyrosine kinase inhibitor capmatinib (INC280) in patients with MET-dysregulated advanced ...hepatocellular carcinoma (HCC) and to assess the safety, pharmacokinetics, and correlation of biomarkers with the response.
Methods:
This phase II, open-label, single-arm study evaluated twice daily (BID) oral capmatinib in a dose-determining stage, utilizing a Bayesian Logistic Regression Model (BLRM) subject to Escalation with Overdose Control criteria, safety, pharmacokinetics, and pharmacodynamic information to determine a recommended dose for expansion (RDE) evaluating efficacy in patients with MET-dysregulated HCC.
Results:
A total of 38 patients received treatment. In the dose-determining stage, patients received capmatinib 300 mg BID capsules (n = 8), and in the expansion, patients received 600 mg BID capsules (n = 28) or 400 mg BID tablets (n = 2) based on the BLRM and other relevant clinical data. No predefined qualifying adverse events (AEs) were observed during the first 28 days of treatment, and the RDE was 600 mg BID capsules (equivalent pharmacokinetics to 400 mg BID tablets). The most common any causality AEs were nausea (42%), vomiting (37%), and diarrhea (34%). In the expansion stage, in a subgroup of 10 patients with MET-high HCC, the overall response rate was 30%, including 1 durable complete response (>600 days) and 2 partial responses 1 durable (>600 days).
Conclusions:
Single agent capmatinib at the RDE is tolerable with a manageable safety profile. Antitumor activity was seen in a subset of patients with MET-dysregulated (MET-high) HCC.
Trial registration:
ClinicalTrials.gov: NCT01737827. https://clinicaltrials.gov/ct2/show/NCT01737827
Genome-wide losses of DNA methylation have been regarded as a common epigenetic event in malignancies and may play crucial roles in carcinogenesis. Limited information is available on the global ...methylation status in normal tissues and other cancer types beyond colonic carcinoma. Here we applied the combined bisulfite restriction analysis PCR to evaluate the methylation status of LINE-1 repetitive sequences in genomic DNA derived from microdissected samples from several human normal and neoplastic tissues. We found that methylation of LINE-1 in leukocytes was independent of age and gender. In contrast, normal tissues from different organs showed tissue-specific levels of methylated LINE-1. Globally, most carcinomas including breast, colon, lung, head and neck, bladder, esophagus, liver, prostate, and stomach, revealed a greater percentage of hypomethylation than their normal tissue counterparts. Furthermore, DNA derived from sera of patients with carcinoma displayed more LINE-1 hypomethylation than those of noncarcinoma individuals. Finally, in a colonic carcinogenesis model, we detected significantly greater hypomethylation in carcinoma than those of dysplastic polyp and histological normal colonic epithelium. Thus, the methylation status is a unique feature of a specific tissue type and the global hypomethylation is a common epigenetic process in cancer, which may progressively evolve during multistage carcinogenesis.
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