In the global phase III RELAY study, ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression‐free survival (PFS) to placebo plus erlotinib (PL + ERL) in untreated patients with ...epidermal growth factor receptor (EGFR) mutation‐positive metastatic non‐small‐cell lung cancer (NSCLC) (hazard ratio (HR) 95% CI: 0.59 0.46‐0.76). This prespecified analysis assessed RAM + ERL efficacy and safety in the RELAY subset enrolled in East Asia (Japan, Taiwan, South Korea, Hong Kong). Randomized (1:1) patients received oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL Q2W. Primary endpoint was PFS (investigator‐assessed). Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and safety. Exploratory endpoints included biomarker analyses and time to second progression (PFS2). Median PFS was 19.4 vs 12.5 mo for RAM + ERL (n = 166) vs PL + ERL (n = 170) (HR: 0.636 0.485‐0.833; P = .0009). The 1‐y PFS rate was 72.4% vs 52.2%, respectively. PFS benefit was consistent in most subgroups, including by EGFR mutation (Ex19del, Ex21.L858R). ORR and DCR were similar in both arms, but median DoR was longer with RAM + ERL. OS and PFS2 were immature at data cut‐off (censoring rates, 81.2%‐84.3% and 64.1%‐70.5%, respectively). Grade ≥ 3 treatment‐emergent adverse events were more frequent with RAM + ERL (70.7%) than PL + ERL (49.4%). Adverse events leading to treatment discontinuation were similar in both arms (RAM + ERL, 13.3%; PL + ERL, 12.9%), as were post‐progression EGFR T790M mutation rates (43%; 50%). With superior PFS over PL + ERL and safety consistent with the overall RELAY population, RAM + ERL is a viable treatment option for EGFR‐mutated metastatic NSCLC in East Asia.
This RELAY subset analysis of EGFR‐mutated NSCLC patients enrolled in East Asia demonstrated superior progression‐free survival (PFS) for ramucirumab plus erlotinib compared with placebo plus erlotinib (median PFS 19.4 vs 12.5 mo, HR 95% CI: 0.636 0.485‐0.833, P = .0009). The PFS benefit was accompanied by a consistent benefit for ramucirumab plus erlotinib in secondary, exploratory, and subgroup analyses and a manageable safety profile (consistent with the global RELAY study population). These results support the RELAY regimen as an effective and safe treatment option in the East Asian population.
Background The treatment for stage III non-small cell lung cancer (NSCLC) often involves multi-modality treatment. This retrospective study aimed to evaluate whether multidisciplinary team (MDT) ...discussion results in better patient survival. Materials and methods MDT discussion was optional before February 2016 and was actively encouraged by the MDT committee beginning February 2016. We reviewed the medical charts and computer records of patients with stage III NSCLC between January 2013 and December 2018. Results A total of 515 patients were included. The median survival of all the patients was 33.9 months (M). The median survival of patients who were treated after MDT discussion was 41.2 M and that of patients treated without MDT discussion was 25.7 M (p = 0.018). The median survival of patients treated before February 2016 was 25.7 M and that of patients treated after February 2016 was 33.9 M (p = 0.003). The median survival of patients with stage IIIA tumors and those with stage IIIB tumors was 39.4 M and 25.7 M, respectively (p = 0.141). Multivariate analysis showed that MDT or not (p<0.001), T staging (p = 0.009), performance status (p<0.001), and surgery (p = 0.016) to be significant prognostic factors. Conclusion The results of the study show that MDT discussion results in survival benefit in patients with stage III NSCLC. The MDT discussion, performance status, and if surgery was performed were independent prognostic factors for patients with stage III NSCLC.
Abstract
Whether ICIs combined with chemotherapy can improve outcomes in
EGFR
-mutant non-small cell lung cancer (NSCLC) remains uncertain. Patients with EGFR-mutant NSCLC and who progressed on ...first-line EGFR-TKIs treatment were retrospectively collected. We reviewed the outcome of these patients treated with ICIs or ICIs combined chemotherapy (ICI + C). Total 30 patients were included. The ORR were 9.1% and 25.0% for the ICI and ICI + C groups. The ICI + C group showed the trend of longer progression-free survival and overall survival periods. Patients without the T790M mutation had a significantly longer PFS than did those without this mutation (4.23 95% CI: 2.75–5.72 vs. 1.70 95% CI: 0.00–3.51 months, HR:4.45,
p
= 0.019). ICIs combined with chemotherapy tended to be more effective than ICIs alone in pretreated
EGFR
-mutant NSCLC. The T790M mutation may be a potential biomarker.
Abstract
Detection of driver gene mutations is important in advanced NSCLC. The cobas EGFR mutation test is a mutant allele-specific real-time PCR assay with limitation owing to its primer design. ...Next-generation sequencing-based assay has a higher mutation detection coverage; however, its clinical impact remains unclear. We retrospectively collected the records of stage IV NSCLC patients with wild-type EGFR tested by cobas test. FoundationOne CDx was used for comprehensive genomic profiles. We then evaluated the missed EGFR mutations by the cobas test. We studied 62 patients. The median age was 60 (range: 35–86 years). Most patients were male and 58.1% were smokers. 91.9% were adenocarcinomas. Of the 62 samples, 7 (11.3%) were detected with EGFR mutations by NGS. Among these overlooked EGFR mutations, five were exon 20 insertions, and two were exon 19 deletions. Two patients received EGFR TKIs and showed durable response with PFS 5.9 months and 10.1 months, respectively. Using NGS as the standard, the false-negative rate of the cobas EGFR mutation test was 11.3%—in a population with a high prevalence of EGFR mutations. The most overlooked mutations were exon 20 insertions. A comprehensive EGFR mutation assay can provide significant benefits to patients with NSCLC.
Although low-density culture provides an efficient method for rapid expansion of human mesenchymal stem cells (MSCs), MSCs enriched by this method undergo senescence and lose their stem cell ...properties, which could be preserved by combining low-density and hypoxic culture. The mechanism was mediated through direct down-regulation of E2A-p21 by the hypoxia-inducible factor–1α (HIF-1α)–TWIST axis. Expansion under normoxia induced E2A and p21 expression, which were abrogated by overexpression of TWIST, whereas siRNA against TWIST up-regulated E2A and p21 in hypoxic cells. Furthermore, siRNA against p21 in normoxic cells enhanced proliferation and increased differentiation potential, whereas overexpression of p21 in hypoxic cells induced a decrease in proliferation and a loss of differentiation capacity. More importantly, MSCs expanded under hypoxic conditions by up to 100 population doublings, exhibited telomerase activity with maintained telomere length, normal karyotyping, and intact genetic integrity, and did not form tumors. These results support low-density hypoxic culture as a method for efficiently expanding MSCs without losing stem cell properties or increasing tumorigenicity.
MEK/ERK inhibition can overcome acquired resistance to osimertinib in preclinical models. Osimertinib EGFR-tyrosine kinase inhibitor (TKI) plus selumetinib (MEK1/2 inhibitor) was assessed in the ...global TATTON study.
This multicenter, open-label, phase Ib study expansion cohort enrolled patients (aged ≥18 years) with MET-negative, EGFRm advanced NSCLC who had progressed on EGFR-TKIs. Patients were assigned to one of two cohorts by prior first- or second-generation or T790M-directed EGFR-TKI and received osimertinib 80 mg every day and intermittent selumetinib 75 mg twice a day orally. Safety and tolerability (primary objective) and antitumor activity determined by objective response rate (ORR), and progression-free survival (PFS) using RECIST v1.1 were assessed. Data cutoff: March 4, 2020.
Forty-seven patients received treatment (prior first- or second-generation EGFR-TKI, n = 12; prior T790M-directed EGFR-TKI, n = 35). Forty-four (94%) patients were Asian; 30 (64%) had baseline exon 19 deletion. Most common AEs were diarrhea (89%), decreased appetite (40%), and stomatitis (32%); 11/47 patients (23%) had an AE Grade ≥3 possibly causally selumetinib-related. ORR was 66.7% 95% confidence interval (CI), 34.9-90.1 in the prior first- or second-generation EGFR-TKI group, 22.9% (95% CI, 10.4-40.1) in the prior T790M-directed EGFR-TKI group, and 34.0% (95% CI, 20.9-49.3) overall; median PFS was 15.0 (95% CI, 2.7-33.0), 2.8 (95% CI, 1.6-5.5), and 4.2 months (95% CI, 2.7-7.2), respectively.
In this small study, AEs and tolerability of osimertinib plus selumetinib were as expected, on the basis of previous studies. The combination demonstrated antitumor activity supportive of further investigation in patients with MET-negative, EGFRm advanced NSCLC who had progressed on a previous EGFR-TKI.
15-40% of non-small cell lung cancer (NSCLC) patients harbor epidermal growth factor receptor (EGFR)-sensitizing mutations. Tyrosine kinase inhibitors (TKIs) provide significant clinical benefit in ...this population, yet all patients will ultimately progress. Liquid biopsy can reliably identify somatic tumor-associated EGFR mutations in plasma. This study aimed to assess the feasibility and value of the quantitative assessment of EGFR driver mutations in plasma in EGFR-mutated NSCLC patients treated with EGFR-TKIs as a tool to evaluate therapeutic response to TKIs and monitor for disease progression. The study included 136 patients with tissue biopsy-confirmed EGFR-sensitizing, mutation-positive lung adenocarcinoma with plasma collected prior to TKI treatment and at least two post-initiation TKI treatment/follow-up blood samples. Plasma samples were tested with the cobas® EGFR Mutation Test v2 (cobas EGFR Test), and semi-quantitative index (SQI) values for each identified mutation were reported by the assay software. The most common baseline EGFR mutations detected in tissue were L858R (53.7%) and exon 19 deletion (39.7%). Plasma cell-free DNA analysis detected EGFR mutations in 74% of the baseline samples. Objective response rate by RECIST 1.1 was achieved in 72% of patients, while 93% had a molecular response (defined as disappearance of the EGFR mutation from plasma). 83% of patients had molecular progression (MP; 1.5X SQI increase or new T790M mutation), and 82% who had a clinical response had clinical progression. On average, MP occurred 42 days prior to clinical progression. Patients who progressed while on first-line TKI showed MP of the original EGFR-sensitizing mutations prior to the emergence of a T790M mutation, which was detected in 27% of the EGFR plasma-positive patients. Longitudinal monitoring of EGFR mutational load in plasma is feasible and can predict both response and clinical progression in EGFR-mutated NSCLC patients treated with EGFR-TKIs, as well as detect treatment-emergent EGFR mutations.
Expression of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase associated with cell proliferation and survival, is overactive in many tumors of epithelial origin. Blockade of ...the kinase activity of EGFR has been used for cancer therapy; however, by itself, it does not seem to reach maximum therapeutic efficacy. We report here that in human cancer cells, the function of kinase-independent EGFR is to prevent autophagic cell death by maintaining intracellular glucose level through interaction and stabilization of the sodium/glucose cotransporter 1 (SGLT1).
Systemic therapy is the primary treatment for advanced thymic malignancies. However, there is an urgent need to improve clinical outcome. Personalized treatment based on predictive biomarkers is a ...potential approach to address this requirement. In this study, we aimed to show the correlation between drug sensitivity tests on CTCs-derived organoids and clinical response in patients with thymic malignancies. This approach carries the potential to create personalized cancer avatars and improve treatment outcome for patients.
We previously reported potential treatment outcome prediction with patient-derived organoids (cancer avatars) in patients with pancreatic ductal adenocarcinoma. To further investigate the feasibility of this approach in advanced thymic malignancies, we conducted a study in which 12 patients were enrolled and 21 liquid biopsies were performed.
Cancer avatars were successfully derived in 16 out of 21 samples (success rate 76.2%). We found a sensitivity of 1.0 and specificity of 0.6 for drug sensitivity tests on the cancer avatars, and a two-tailed Fisher's exact test revealed a significant correlation between drug sensitivity tests and clinical responses (p = 0.0275).
This study supports the potential of circulating tumor cell-derived organoids to inform personalized treatment for advanced thymic malignancies. Further validation of this proof of concept finding is ongoing.
Never Say No to Never-Smokers Chiu, Chao-Hua; Yang, Pan-Chyr
Journal of thoracic oncology,
June 2023, 2023-06-00, 20230601, Volume:
18, Issue:
6
Journal Article
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