Summary Background Osimertinib (AZD9291) is an oral, potent, irreversible EGFR tyrosine-kinase inhibitor selective for EGFR tyrosine-kinase inhibitor sensitising mutations, and the EGFR Thr790Met ...resistance mutation. We assessed the efficacy and safety of osimertinib in patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), who had progressed after previous therapy with an approved EGFR tyrosine-kinase inhibitor. Methods In this phase 2, open-label, single-arm study (AURA2), patients aged at least 18 years with centrally confirmed EGFR Thr790Met-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC who progressed on previous EGFR tyrosine-kinase inhibitor therapy received osimertinib 80 mg orally once daily; treatment could continue beyond progression if the investigator observed a clinical benefit. Patients with asymptomatic, stable CNS metastases not requiring steroids were allowed to enrol. The primary endpoint was the proportion of patients achieving an objective response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the evaluable for response analysis set (ie, all patients who received at least one dose of osimertinib and had measurable disease at baseline according to blinded independent central review). Other endpoints and safety were assessed in all patients receiving at least one osimertinib dose (full analysis set). The study is ongoing and patients are still receiving treatment. This study is registered with ClinicalTrials.gov , number NCT02094261. Findings Between May 20, 2014, and Sept 12, 2014, 472 patients were screened, of whom 210 started osimertinib treatment between June 13, 2014, and Oct 27, 2014; 11 patients were excluded from the evaluable for response analysis set (n=199) due to absence of measurable disease at baseline by blinded independent central review. At data cutoff (Nov 1, 2015), 122 (58%) patients remained on treatment. The median duration of follow-up was 13·0 months (IQR 7·6–14·2). 140 (70%; 95% CI 64–77) of 199 patients achieved an objective response by blinded independent central review: confirmed complete responses were achieved in six (3%) patients and partial responses were achieved in 134 (67%) patients. The most common all-causality grade 3 and 4 adverse events were pulmonary embolism (seven 3%), prolonged electrocardiogram QT (five 2%), decreased neutrophil count (four 2%), anaemia, dyspnoea, hyponatraemia, increased alanine aminotransferase, and thrombocytopenia (three 1% each). Serious adverse events were reported in 52 (25%) patients, of which 11 (5%) were investigator assessed as possibly treatment-related to osimertinib. Seven deaths were due to adverse events; these were pneumonia (n=2), pneumonia aspiration (n=1), rectal haemorrhage (n=1), dyspnoea (n=1), failure to thrive (n=1), and interstitial lung disease (n=1). The only fatal event assessed as possibly treatment-related by the investigator was due to interstitial lung disease. Interpretation Osimertinib showed clinical activity with manageable side-effects in patients with EGFR Thr790Met-positive NSCLC. Therefore, osimertinib could be a suitable treatment for patients with EGFR Thr790Met-positive disease who have progressed on an EGFR tyrosine-kinase inhibitor. Funding AstraZeneca.
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.
Kirsten rat sarcoma (KRAS) mutation (KRASm) is associated with poor prognosis in non-small cell lung cancer (NSCLC) patients. We have aimed to survey NSCLC patients harboring KRASm in Taiwan, where ...never-smoking lung adenocarcinoma predominates, and analyze the immune checkpoint inhibitor effect on NSCLC harboring KRASm. NSCLC patients with KRASm were enrolled and tested on programmed death-ligand 1 (PD-L1) expression using available tissue. We analyzed their clinical features, PD-L1 status, responses to ICIs, and overall survival (OS). We studied 93 patients with a median age 66.0 years, 23.7% of whom were women, and 22.6% were never-smokers. The results showed that G12C (36.6%) was the most common KRASm. In 47 patients with available tissue for PD-L1 testing, PD-L1 expression was positive in 66.0% of patients, while PD-L1 ≥50% was higher in ever-smokers (P = .038). Among 23 patients receiving ICI treatment, those with PD-L1 ≥50% experience a 45.5% response rate to ICI. There were benefits from ICI treatment on OS compared with no ICI treatment (median OS 35.6 vs 9.8 months, P = .002) for all of our patients, and for patients with PD-L1 ≥50% (median OS not-reached vs 8.4 months, P = .008). There were no differences in survival across different KRAS subtypes (P = .666). Never-smokers composed more than one-fifth of KRASm in NSCLC in Taiwan. A high PD-L1 expression was related to smoking history and responded well to ICI. ICI treatment improved the OS in NSCLC patients with KRASm, particularly those with PD-L1 ≥50%.
Summary Background Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in ...patients with lung adenocarcinoma and EGFR mutations. Methods In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0–2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov , number NCT00525148. Findings 129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 60% of 30 patients at 40 mg vs 61 62% of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 22% of 99 patients for diarrhoea and 28 28% of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two 7% of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease). Interpretation Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC. Funding Boehringer Ingelheim Inc.
Patients with stage III NSCLC represent a very heterogenous group that requires different treatment strategies, especially in patients with N2 (2 nearby lymph nodes having cancer)-positive NSCLC and ...unresectable EGFR-mutant NSCLC. This real-world study may provide more insights into treatment decisions.
The KINDLE study is a large, multinational real-world observational study that assessed different treatment strategies in patients with stage III NSCLC. Progression-free survival (PFS) and overall survival (OS) were estimated and compared using Kaplan-Meier and log-rank testing. Patients were classified on the basis of disease stage, resectability, and treatment modalities.
The Taiwan subgroup enrolled 200 patients. The median PFS and OS values were similar among patients with stage IIIA and stage IIIB disease, but were significantly better in patients who were deemed as a resectable disease than in those who were deemed as an unresectable disease. In patients with N2-positive NSCLC, patients who underwent surgery had better PFS, but not OS, than patients administered with chemoradiotherapy (CRT) (PFS 13.4 vs. 7.3 mo, hazard ratio HR = 0.18, p < 0.001; OS 32.4 vs. 22.0 mo, HR = 0.64, p = 0.215). Among patients with unresectable EGFR-mutant NSCLC, OS was significantly poorer after upfront EGFR–tyrosine kinase inhibitors (TKI) than after upfront CRT with sequential EGFR-TKI (27.4 vs. 49.0 mo, HR = 3.09, p = 0.03).
Our study suggests that surgery could be added as part of therapy for patients with stage III N2-positive NSCLC. Moreover, upfront CRT with sequential EGFR-TKI seems to be appropriate for stage III unresectable EGFR-mutant NSCLC. Further randomized studies are needed to validate these results.
Objectives Our objective was to identify surgical–pathologic factors affecting prognosis in stage IB non–small cell lung cancers. Methods Between 1997 and 2006, a cohort of 272 cases of pT2 N0 M0 ...stage lung cancer were retrospectively analyzed. The patients included 70 women and 202 men with a mean age of 67.0 years. The surgical resections included pneumonectomy in 4, bilobectomy or lobectomy in 217, and limited resections in another 51. The impact of surgical–pathologic characteristics on survival, including cell type, tumor differentiation, tumor size, depth of visceral pleural invasion, type of surgical resection, and extent of lymphadenectomy on patient survival, was compared accordingly. Results Tumor types included adenocarcinoma/bronchioloalveolar carcinoma in 142, squamous cell carcinoma in 100, and others in 30. Cell differentiations were classified as well, moderately, and poorly differentiated in 23, 151, and 92 cases, respectively. The mean tumor size was 3.9 cm in diameter, and the average resected lymph node number was 14.3. Direct visceral pleural or subpleural invasions (<1 mm) were found in 134 and 42 cases, respectively. Angiolymphatic invasions were seen in 26 cases, and positive tumor margins were found in 14 cases. The overall 5-year and 10-year survivals were 59.5% and 41.3%, respectively. Good prognostic factors using univariate analysis included female gender, nonlimited resection, well-differentiated tumor, no angiolymphatic invasion, smaller size (≤3 cm), and numbers of nodes retrieved (>14 nodes). However, the Cox proportional hazard model revealed female gender, well-differentiated tumor, no pleural involvement, no angiolymphatic invasion, and more than 14 nodes retrieved as independent good prognostic factors. Conclusions Stage IB lung cancer can be treated by standard pulmonary resection accompanied by adequate mediastinal lymphadenectomy. Owing to the heterogeneity of stage IB lung cancer and the fact that prognosis can be affected by many surgical–pathologic factors, refinement of the current TNM staging criteria may be needed.
Lorlatinib is a potent, third-generation inhibitor of ALK. In the planned interim analysis of the ongoing, phase 3, randomized, global CROWN trial (NCT03052608), lorlatinib resulted in significantly ...longer progression-free survival than crizotinib in patients with previously untreated, advanced, ALK-positive NSCLC. Here, we present a subgroup analysis of Asian patients in the CROWN study.
Patients received lorlatinib 100 mg once daily or crizotinib 250 mg twice daily. The primary end point was progression-free survival assessed by blinded independent central review. Objective response rate (ORR), intracranial ORR, safety, and select biomarkers were secondary end points.
At data cutoff (September 20, 2021), 120 patients were included in the Asian intention-to-treat subgroup (lorlatinib n = 59; crizotinib n = 61). At 36 months, 61% (95% confidence interval CI: 47–72) and 25% (95% CI: 12–41) of patients in the lorlatinib and crizotinib groups, respectively, were alive without disease progression (hazard ratio for disease progression by blinded independent central review or death: 0.40; 95% CI: 0.23–0.71). ORR was 78% (95% CI: 65–88) versus 57% (95% CI: 44–70) for patients treated with lorlatinib and crizotinib, respectively. In patients with measurable, nonmeasurable, or both measurable and nonmeasurable brain metastases at baseline, intracranial ORR was 73% (95% CI: 39–94) versus 20% (95% CI: 4–48) for patients treated with lorlatinib and crizotinib, respectively. The definition of nonmeasurable brain metastases is: a brain lesion less than 10 mm in MRI scan is defined as nonmeasurable brain metastasi based on RECIST criteria (Clinical trial evaluation criteria). Hypercholesterolemia, hypertriglyceridemia, and edema were the most frequently reported adverse events with lorlatinib.
Lorlatinib efficacy and safety in the Asian subgroup of CROWN were consistent with those in the overall population.
It has been shown that metabolic syndrome is associated with lower levels of plasma N-terminal pro-B-type natriuretic peptide (Nt-proBNP) in the general population. However, there is no study about ...the association between Nt-proBNP and metabolic syndrome in hypertensive patients.
: To elucidate the relationship between Nt-proBNP and components of metabolic syndrome in hypertensive patients.
Fasting blood samples were obtained from 74 hypertensive patients in our institution. Plasma levels of Nt-proBNP and other biochemical data were measured. Metabolic syndrome and its components were defined using diagnostic criteria from the International Diabetes Federation.
Forty-four hypertensive patients met the criteria for metabolic syndrome. We found that plasma Nt-proBNP levels were lower in hypertensive patients with metabolic syndrome attributable to inverse relationships between Nt-proBNP and albumin, triglyceride, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and pancreatic β-cell function (HOMA-β). We further performed a multivariable linear regression analysis. The result showed that HOMA-IR is the independent predictor of plasma Nt-proBNP levels in hypertensive patients.
Plasma Nt-proBNP levels are inversely associated with metabolic syndrome in hypertensive patients. HOMA-IR is the independent predictor of Nt-proBNP in hypertensive patients.
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