A Randomized Phase 2 Study of Gefitinib With or Without Pemetrexed as First-line Treatment in Nonsquamous NSCLC With EGFR Mutation: Final Overall Survival and Biomarker Analysis

IntroductionClinical studies have shown that a combination of a tyrosine kinase inhibitor (TKI) and pemetrexed overcame acquired resistance to epidermal growth factor receptor (EGFR) TKI in NSCLC. Previously, pemetrexed+gefintib (P+G) had improved progression-free survival (PFS) compared with gefitinib. We present OS, updated PFS, biomarker analysis, and safety of P+G versus gefitinib.MethodsThis was a phase 2, multicenter, randomized study conducted in East Asian patients with advanced nonsquamous NSCLC with EGFR mutations. Patients were randomized (2:1) to receive P+G (500 mg/m² intravenously 3-weekly + 250 mg/day orally) or gefitinib.ResultsIn total, 191 patients (P+G, n=126; gefitinib, n=65) comprised the intent-to-treat and safety populations. Median OS was 43.4 months in P+G versus 36.8 months in gefitinib arm; adjusted HR 0.77 (95% CI, 0.5-1.2); one-sided P=0.105. Median PFS was significantly longer in the P+G (16.2 months) versus gefitinib arm (11.1 months); adjusted HR 0.67 (95% CI, 0.5-0.9); one-sided P=0.009. In the P+G and gefitinib arms, median PFS was 22.6 and 11.0 months, respectively, in patients with low thymidylate synthase (TS) expression, and 12.6 and 9.9 months, respectively, in patients with high TS expression. Common second-line post-discontinuation systemic therapies were EGFR-TKIs and chemotherapy. Most patients experienced at least one adverse event.ConclusionsAddition of pemetrexed to EGFR TKI gefitinib resulted in significantly improved PFS and numerically longer OS compared with gefitinib in treatment-naïve patients with EGFR-mutated advanced nonsquamous NSCLC. Low TS expression appeared to be a good predictor for treatment outcomes.     

Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial

BackgroundIn LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data.Patients and methodsLUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases.ResultsTwo-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.ConclusionIn LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.Clinicaltrials.gov identifierNCT01466660.     

Gefitinib With Concurrent Thoracic Radiotherapy in Unresectable Locally Advanced NSCLC With EGFR Mutation; West Japan Oncology Group 6911L

IntroductionAbout 10% of patients with locally advanced NSCLC (LA-NSCLC) harbor EGFR mutation and recent reports suggested the declined benefit with an immune checkpoint inhibitor in this population. The attempt that introduces EGFR tyrosine kinase inhibitor into the treatment of LA-NSCLC with EGFR mutation has been warranted.MethodsChemotherapy-naive patients with unresectable LA-NSCLC with sensitive EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were enrolled. Patients were treated with gefitinib (250 mg/d for 2 y) plus concurrent thoracic radiotherapy (64 Gy/32 fractions). The primary end point was progression-free survival (PFS) at 2 years (trial identifier, UMIN000008366).ResultsBetween August 2012 and November 2017, a total of 28 patients were enrolled and 27 were eligible. The median age was 67 years (range: 45–74); never/current or former smoker in 15/12 patients, respectively; Eastern Cooperative Oncology Group performance status of 0/1 in 19/8; EGFR exon 19 deletion/exon 21 L858R in 13/14; and c-stage IIIA/IIIB in 14/13. The PFS rate at 2 years by independent review was 29.6% (one-sided 95% confidence interval [CI]: 17.6%–). The overall response rate was 81.5% (95% CI: 63.3%–91.3%), median PFS was 18.6 months (95% CI: 12.0–24.5 mo), and median overall survival was 61.1 months (95% CI: 38.1 mo–not reached). Approximately half of the patients exhibited solitary brain metastasis as their first site of relapse. Adverse events greater than or equal to grade 3 were fatigue, skin reaction, and appetite loss (3.7% each).ConclusionsThis prospective study revealed the tolerability and the possible efficacy of gefitinib plus concurrent thoracic radiotherapy in patients with LA-NSCLC having EGFR mutation.     

Tumor Burden is Predictive of Survival in Patients With Non–Small-Cell Lung Cancer and With Activating Epidermal Growth Factor Receptor Mutations Who Receive Gefitinib

BackgroundAlthough activating epidermal growth factor receptor (EGFR) mutations are excellent predictors of gefitinib outcome in non–small-cell lung cancer (NSCLC), most patients become resistant to gefitinib. Despite our knowledge of the molecular basis of acquired resistance, clinical predictors have not been well elucidated. This study was undertaken to evaluate predictors of clinical outcome in patients with NSCLC and with EGFR mutations treated with gefitinib.Patients and MethodsA total of 170 patients with NSCLC and with EGFR mutations received gefitinib as a first-line (n = 50) and a second-line or more (n = 120) treatment at Seoul National University Hospital. Treatment outcomes were compared between groups based on clinicopathologic factors, such as treatment line, metastatic site, and mutation subtype.ResultsSurvival outcomes were similar between first-line and second-line or greater gefitinib treatment (overall response rate, 2P = .832; progression-free survival [PFS], 2P = .373; and overall survival [OS], 2P = .290). When the number of metastatic sites was at least 3, significantly reduced survival was observed (median PFS 8.5 vs. 14.0 months, 2P < .001; median OS 21.4 vs. 25.6 months, 2P = .002). In addition, the presence of at least 3 organs with metastases was an independent predictor of PFS (hazard ratio [HR] 1.97 [95% CI, 1.37-2.85]; 2P < .001) and OS (HR 2.00 [95% CI, 1.18-3.39]; 2P = .010). Patients who failed to respond to gefitinib within 6 months of treatment had more lymph node metastases and more sites of metastasis than those who responded later.ConclusionsTumor burden, expressed as the number of metastatic sites, is predictive of inferior survival in patients with NSCLC and with activating EGFR mutations who are treated with gefitinib.     

EGFR Mutation Subtypes Influence Survival Outcomes following First-Line Gefitinib Therapy in Advanced Asian NSCLC Patients

IntroductionActivating mutations in the EGFR gene have been shown to confer sensitivity to EGFR tyrosine kinase inhibitors in patients with advanced NSCLC. However, wide interpatient variability in treatment outcomes in response to EGFR tyrosine kinase inhibitors in these patients remains unaccounted for. This study aimed to evaluate the influence of EGFR mutation types and subtypes on survival outcomes in advanced Asian patients with NSCLC receiving first-line gefitinib therapy.MethodsPatients with stage IIIB or IV NSCLC who were harboring EGFR mutations, receiving first-line gefitinib treatment, and of Asian descent (N = 383) were evaluated. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Log-rank tests and Cox proportional hazards models were implemented to evaluate the differences in PFS and OS.ResultsSignificant differences in PFS were observed between patients carrying EGFR mutations in exons 18, 19, 20, and 21, with patients carrying EGFR exon 19 mutations having the longest median PFS (overall p = 8.88 × 10^-15). Comparison of PFS among the five different exon 19 mutation subtypes and among the two exon 19 deletion start codons did not reveal any significant differences. No significant difference was observed in OS among patients carrying EGFR mutations on different exons (overall p = 0.054); however, OS was found to be significantly different among the various subtypes of exon 19 mutations, with the 15–nucleotide deletion “non-ELREA” group having the shortest OS of 11.3 months (overall p = 0.025).ConclusionsEGFR mutation types and subtypes significantly influence survival outcomes in patients with advanced NSCLC who are receiving first-line gefitinib treatment.     

Brief Report: Durvalumab After Chemoradiotherapy in Unresectable Stage III EGFR-Mutant NSCLC: A Post Hoc Subgroup Analysis From PACIFIC

IntroductionConsolidation durvalumab (the “PACIFIC regimen”) is standard of care for patients with unresectable stage III NSCLC who have not progressed after chemoradiotherapy, on the basis of data from the phase 3 placebo-controlled PACIFIC study (NCT02125461). Nevertheless, the benefit of immunotherapy in patients with stage III EGFR-mutant (EGFRm) NSCLC is not well characterized. Here, we report a post hoc exploratory efficacy and safety analysis from a subgroup of patients with EGFRm NSCLC from the PACIFIC.MethodsPatients with stage III unresectable NSCLC and no progression after more than or equal to two cycles of platinum-based concurrent chemoradiotherapy were randomized (2:1) to receive durvalumab (10 mg/kg intravenously every 2 weeks [wk], for up to 1 y) or placebo; stratified by age, sex, and smoking history. Enrollment was not restricted by oncogenic driver gene mutation status or programmed death-ligand 1 expression. Patients with NSCLC with an EGFR mutation, determined by local testing only, were included in this subgroup analysis. The primary end points were progression-free survival (PFS; assessed by blinded independent central review) and overall survival (OS). Secondary end points included objective response rate and safety. Statistical analyses for the subgroup of patients with EGFRm NSCLC were post hoc and considered exploratory.ResultsOf 713 patients randomized, 35 had locally confirmed EGFRm NSCLC (durvalumab, n = 24; placebo, n = 11). At data cutoff (January 11, 2021), median duration of follow-up for survival was 42.7 months (range: 3.7–74.3 mo) for all randomized patients in the subgroup. Median PFS was 11.2 months (95% confidence interval [CI]: 7.3–20.7) with durvalumab versus 10.9 months (95% CI: 1.9–not evaluable [NE]) with placebo; hazard ratio = 0.91 (95% CI: 0.39–2.13). Median OS was 46.8 months (95% CI: 29.9–NE) with durvalumab versus 43.0 months (95% CI: 14.9–NE) with placebo; hazard ratio = 1.02 (95% CI: 0.39–2.63). The safety profile of durvalumab was generally consistent with the overall population and known profile for durvalumab.ConclusionsPFS and OS outcomes with durvalumab were similar to placebo for patients with EGFRm tumors, with wide CIs. These data should be interpreted with caution owing to small patient numbers and lack of a prospective study that evaluates clinical outcomes by tumor biomarker status. Further research to determine the optimal treatment for unresectable stage III EGFRm NSCLC is warranted.     

Central Nervous System Efficacy of Furmonertinib (AST2818) Versus Gefitinib as First-Line Treatment for EGFR-Mutated NSCLC: Results From the FURLONG Study

IntroductionFurmonertinib (AST2818) is a pan-EGFR tyrosine kinase inhibitor with central nervous system (CNS) antitumor activity. We report the CNS efficacy of furmonertinib compared with gefitinib in untreated EGFR-sensitizing mutation-positive NSCLC from the FURLONG study.MethodsFURLONG was a randomized, double-blind, phase 3 study conducted in 55 hospitals in the People’s Republic of China. Patients 1:1 randomly received furmonertinib 80 mg once daily or gefitinib 250 mg once daily treatment. At screening, all the patients underwent brain imaging examination. Patients with asymptomatic steady CNS metastases at baseline constituted this preplanned CNS subgroup analysis.ResultsA total of 358 patients were enrolled in the FURLONG study. In the 133 (37%) patients who had measurable or nonmeasurable CNS lesions, CNS progression-free survival was 20.8 months (95% confidence interval [CI]: 15.2–25.3) in the furmonertinib group and 9.8 months (95% CI: 7.2–18.0) in the gefitinib group (hazard ratio = 0.40 [95% CI: 0.23–0.71], p = 0.0011). In the 60 patients (17%) who had measurable CNS lesions, CNS objective response rate was 91% (95% CI: 72–99) with furmonertinib and 65% (95% CI: 48–80) with gefitinib (OR = 6.82 [95% CI: 1.23–37.67], p = 0.0277). The least-square mean of CNS depth of response was 62% (95% CI: 51–72) in the furmonertinib group and 39% (95% CI: 30–47) in the gefitinib group, the mean difference was 23% (95% CI: 10–37, p = 0.0011).ConclusionsFurmonertinib first-line treatment was found to have superior efficacy in CNS progression-free survival, CNS objective response rate, and CNS depth of response compared with gefitinib in patients with EGFR-mutated NSCLC with CNS metastases.     

Pemetrexed versus gefitinib as a second-line treatment in advanced nonsquamous nonsmall-cell lung cancer patients harboring wild-type EGFR (CTONG0806): a multicenter randomized trial

BackgroundCTONG0806 assessed the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced nonsquamous nonsmall-cell lung cancer (NSCLC) harboring wild-type epidermal growth factor receptor (EGFR).Patients and methodsPatients with locally advanced or metastatic nonsquamous NSCLC harboring wild-type EGFR, detected by direct sequencing, and previously treated with platinum-based chemotherapy were randomized to receive gefitinib (250 mg/day) orally or pemetrexed (500 mg/m²) i.v. on day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). The Independent Review Committee (IRC) evaluated all pictorial data.ResultsFrom February 2009 to August 2012, 161 patients were enrolled, and 157 were assessable (81 in the gefitinib arm, 76 in the pemetrexed arm). Baseline characteristics were balanced between the two arms. The median PFSs were 4.8 versus 1.6 months in the pemetrexed and gefitinib arms, respectively [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.40–0.75, P < 0.001] as confirmed by IRC evaluation (5.6versus 1.7 months, HR 0.53, 95% CI 0.38–0.75, P < 0.001). The median overall survival (OS) showed a trend of superiority in the pemetrexed arm (12.4 versus 9.6 months, HR 0.72, 95% CI 0.49–1.04, P = 0.077). Quality-of-life assessment showed no marked difference between the arms. No unexpected adverse events were found. Of 108 patients with sufficient DNA samples, EGFR mutation status was re-tested by Scorpion amplification refractory mutation system (ARMS); 32 (29.6%) tested positive (19 in the pemetrexed arm, 13 in the gefitinib arm; median PFS: 8.1 versus 7.0 months, HR 0.94, 95% CI 0.43–2.08, P = 0.877).ConclusionsCTONG0806 is the first trial to show significant improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment of EGFR wild-type advanced nonsquamous NSCLC. ARMS is superior to direct sequencing in excluding false-negative patients.ClinicalTrials.gov IdentifierNCT00891579.     

Activity of EGFR Tyrosine Kinase Inhibitors in NSCLC With Refractory Leptomeningeal Metastases

IntroductionLeptomeningeal metastases (LMs) are associated with dismal prognosis in NSCLC. Optimal management remains unknown in patients with EGFR-mutated NSCLC after initial tyrosine kinase inhibitor (TKI) failure.MethodsWe conducted a multicenter retrospective study including patients with EGFR-mutated NSCLC and LM. TKI failure was defined as diagnosis of LM on TKI, or progression of known LM on TKI.ResultsNinety-two patients were included, median age of 60 years, predominantly female (68%), never-smokers (74%). EGFR mutations included L858R (45%), exon 19 deletions (28%), or other mutations (14%). Median time to LM diagnosis was 18.5 months after initial diagnosis of advanced NSCLC. LM was diagnosed after a median of 2 (range: 0–9) systemic therapies. Median overall survival from LM diagnosis was 6.1 months (95% confidence interval [CI]: 4.2–7.6 months). Among 87 patients with TKI failure, patients rechallenged with TKI (n = 50) had a median LM overall survival of 7.6 months (95% CI: 5.7–10.9) compared to 4.2 months (95% CI: 1.6–6.7) in patients without further therapy. Overall, 60% of patients rechallenged with TKI experienced clinical benefit (clinical response or stable disease >2 months), and 23% were treatment failure-free at 6 months. Clinical benefit was reported in 11 of 20 (55%) patients treated with erlotinib after afatinib or gefitinib. Strategies based on increasing dose intensity (n = 17) yielded clinical benefit in 59% of patients. All four patients who received osimertinib after first- and second-generation TKI experienced clinical benefit.ConclusionsTKI rechallenge strategies, including dosing intensification, may improve clinical outcomes of patients with LM from EGFR-mutated NSCLC after initial TKI failure.     

Gefitinib Versus Adjuvant Chemotherapy in Patients With Stage II-IIIA Non–Small-Cell Lung Cancer Harboring Positive EGFR Mutations: A Single-Center Retrospective Study

Background

The superior efficacy of first-line treatment with gefitinib over that of standard chemotherapy was demonstrated in patients with advanced non–small-cell lung cancer (NSCLC) harboring sensitive mutation of epidermal growth factor receptor (EGFR). However, scarce evidence showing the superiority of gefitinib to chemotherapy exists regarding the postoperative adjuvant therapy of EGFR mutation–positive patients with stage II-IIIA NSCLC. To address this important gap, we undertook a retrospective study to assess the efficacy of adjuvant gefitinib versus adjuvant chemotherapy (AC) in patients with completely resected EGFR-mutant stage II-IIIA NSCLC.

Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III,randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC)

BackgroundThe OPTIMAL study found that erlotinib improved progression-free survival (PFS) versus standard chemotherapy in Chinese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). This report describes the quality of life (QoL) and updated PFS analyses from this study.Patients and methodsChinese patients ≥18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received erlotinib (150 mg/day; n = 82) or gemcitabine–carboplatin (n = 72). The primary efficacy end point was PFS; QoL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire, Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS).ResultsPatients receiving erlotinib experienced clinically relevant improvements in QoL compared with the chemotherapy group in total FACT-L, TOI and LCS (P < 0.0001 for all scales). Erlotinib scored better than chemotherapy for all FACT-L subscales from baseline to cycles 2 and 4 (non-significant). In the updated analysis, PFS was significantly longer for erlotinib than chemotherapy (median PFS 13.7 versus 4.6 months; HR = 0.164, 95% CI = 0.105–0.256; P < 0.0001), which was similar to the previously reported primary analysis.ConclusionErlotinib improves QoL compared with standard chemotherapy in the first-line treatment of patients with EGFR mutation-positive advanced NSCLC.     

Approval summary: erlotinib maintenance therapy of advanced/metastatic non-small cell lung cancer (NSCLC)

On April 16, 2010, the U. S. Food and Drug Administration (FDA) approved erlotinib tablets (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY) for maintenance treatment of patients with stage IIIB/IV non-small cell lung cancer (NSCLC) whose disease had not progressed after four cycles of platinum-based first-line chemotherapy.In total, 889 patients received either erlotinib (150 mg) or placebo once daily. Progression-free survival (PFS), in all patients and in patients with epidermal growth factor receptor (EGFR)⁺ tumors by immunohistochemistry (IHC), was the primary efficacy endpoint. Overall survival (OS) was a secondary sponsor endpoint but was the primary regulatory endpoint.Median PFS times were 2.8 months and 2.6 months in the erlotinib and placebo arms, respectively (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.62–0.82; p < .001). Median OS times were 12.0 months and 11.0 months, favoring erlotinib (HR, 0.81; 95% CI, 0.70–0.95). The PFS and OS HRs in patients with EGFR⁺ tumors by IHC were 0.69 (95% CI, 0.58–0.82) and 0.77 (95% CI, 0.64–0.93), respectively. The PFS and OS HRs in patients with EGFR⁻ tumors by IHC were 0.77 (95% CI, 0.51–1.14) and 0.91 (95% CI, 0.59–1.38), respectively.Following disease progression, 57% of placebo-treated patients received additional chemotherapy, compared with 47% of erlotinib-treated patients. Fourteen percent of placebo-treated patients received erlotinib or gefitinib, 31% received docetaxel, and 14% received pemetrexed. In total, 59% of placebo-treated patients who received treatment received FDA approved second-line NSCLC drugs.The most common adverse reactions in patients receiving erlotinib were rash and diarrhea.     

Mechanisms of Resistance to First-Line Osimertinib in Hispanic Patients With EGFR Mutant Non-Small Cell Lung Cancer (FRESTON-CLICaP)

IntroductionOsimertinib is a third generation EGFR-TKI inhibitor approved in the first-line setting for patients with advanced non-small cell lung cancer (NSCLC). Additionally, it represents the treatment of choice in patients who present with T790M mutations and evidence of relapse of the disease. Effectiveness and safety of this drug have been studied in multiple clinical trials and observational studies, however, information regarding outcomes among Hispanic patients treated with Osimertinib is scarce. The objective of this study was to examine real-world effectiveness and safety of first-line Osimertinib in a cohort of Hispanic patients with NSCLC, emphasizing post-progression outcomes.MethodsThis is a multicenter, multinational, retrospective cohort study of Hispanic patients treated with Osimertinib as first-line for EGFR-mutated NSCLC. Patients with a confirmed diagnosis of metastatic EGFR-mutated NSCLC who received Osimertinib (80mg/day until evidence of disease progression or presence of intolerable adverse effects) were identified and included. NGS was performed in tumor samples or liquid biopsies among patients who had disease progression. The primary outcome was progression-free survival, and the secondary outcome was post-progression survival.ResultsA total of 94 patients from Mexico, Argentina, Costa Rica, Colombia, Panama, Chile and the USA were included, with a median age of 59 years. Identified mutations included EGFR Exon 19 deletions and EGFR pL858R point mutations. Median progression-free survival (PFS) was 14.4 months (95%CI 12.4–18.2 months). Lung/pleura and lymph nodes were the most common sites of progression. Median post-progression survival was 7.73 months (95%CI 4.07 months-Not reached). Factors which negatively affected PFS included presence of liver metastases at diagnosis and a tumor mutational burden > 5 mut/Mb.ConclusionTreatment with first line osimertinib represents an effective and safe option for Hispanic patients with metastatic NSCLC. Liver metastases and a higher tumor mutation burden were associated with a lower PFS. Despite effectiveness, different mechanisms of resistance were identified among the patients in this cohort, including mutations which can be targeted by other therapeutic options.     

Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG–0803)

BackgroundThis phase II, open-label study evaluated the efficacy and safety of erlotinib as second-line therapy in non-small-cell lung cancer (NSCLC) patients with brain metastases (BM).Patients and methodsForty-eight patients aged 18–75 years with Eastern Cooperative Oncology Group performance status 0–2, confirmed adenocarcinoma or activating epidermal growth factor receptor (EGFR) mutation-positive NSCLC, and asymptomatic BM without extracranial progressive disease after first-line platinum-doublet chemotherapy were recruited. Treatment comprised erlotinib 150 mg/day. The primary end point was progression-free survival (PFS) determined by RECIST.ResultsThe median PFS was 10.1 months [95% confidence interval (CI) 7.1–12.3] for intracranial progression and 9.7 months (95% CI 2.5–17.8) for intracranial and systemic progression. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease [15.2 months (95% CI 8.3–22.2) versus 4.4 months (95% CI 0.0–11.6); P = 0.02]. The median overall survival was 18.9 months (95% CI 14.4–23.4); 6-month and 1-year survival rates were 85% and 73%, respectively. Overall response rate was 58.3%. Most common adverse events were rash (77.1%), paronychia (20.8%), hyperbilirubinemia (16.7%), and diarrhea (14.6%); these were predominantly of grade 1/2.ConclusionsSingle-agent erlotinib was active and well tolerated in NSCLC patients with BM. Further studies are warranted.     

First-line erlotinib and bevacizumab in patients with locally advanced and/or metastatic non-small-cell lung cancer: a phase II study including molecular imaging

BackgroundBoth bevacizumab and erlotinib have clinical activity in non-small-cell lung cancer (NSCLC). Preclinical data suggest synergistic activity.Patients and methodsChemonaive patients with stage IIIb or IV non-squamous NSCLC were treated with bevacizumab 15 mg/kg every 3 weeks and erlotinib 150 mg daily until progression. Primary end point was non-progression rate (NPR) at 6 weeks. Tumor response was measured with computed tomography, 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG–PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). KRAS and EGFR mutations were assessed in tumor samples.ResultsForty-seven patients were included. Median follow-up was 15.2 months. NPR at 6 weeks was 75%. Median progression-free survival (PFS) was 3.8 [95% confidence interval (CI) 2.3–5.4] months and median overall survival (OS) was 6.9 (95% CI 5.5–8.4) months. Toxicity was mainly mild. The presence of KRAS (n = 10) or EGFR mutations (n = 5) did not influence outcome. After 3 weeks of treatment, >20% decrease in standard uptake value as measured with positron emission tomography predicted for longer PFS (9.7 versus 2.8 months; P = 0.01) and >40% decrease in K^trans as assessed by DCE-MRI did not predict for longer PFS.ConclusionsFirst-line treatment with bevacizumab and erlotinib in stage IIIb/IV NSCLC resulted in an NPR of 75%. OS was however disappointing. Early response evaluation with FDG–PET is the best predictive test for PFS.     

Efficacy and Safety of Rezivertinib (BPI-7711) in Patients With Locally Advanced or Metastatic/Recurrent EGFR T790M-Mutated NSCLC: A Phase 2b Study

IntroductionRezivertinib (BPI-7711) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) targeting both EGFR-sensitizing mutations and EGFR T790M mutation. This study aimed to evaluate the efficacy and safety of rezivertinib in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC.MethodsPatients with locally advanced or metastatic/recurrent NSCLC with confirmed EGFR T790M mutation who progressed after first-/second-generation EGFR TKI therapy or primary EGFR T790M mutation were enrolled. Patients received rezivertinib at 180 mg orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR) assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival, and safety. This study is registered with Clinical Trials.gov (NCT03812809).ResultsA total of 226 patients were enrolled from July 5, 2019, to January 22, 2020. By the data cutoff date on January 24, 2022, the median duration of follow-up was 23.3 months (95% confidence interval [CI]: 22.8–24.0). The ORR by blinded independent central review was 64.6% (95% CI: 58.0%–70.8%), and DCR was 89.8% (95% CI: 85.1%–93.4%). The median duration of response was 12.5 months (95% CI: 10.0–13.9), and median PFS was 12.2 months (95% CI: 9.6–13.9). The median overall survival was 23.9 months (95% CI: 20.0–not calculated [NC]). Among 91 (40.3%) patients with central nervous system (CNS) metastases, the median CNS PFS was 16.6 months (95% CI: 11.1–NC). In 29 patients with more than or equal to one brain target lesion at baseline, the CNS ORR and CNS DCR were 69.0% (95% CI: 49.2%–84.7%) and 100% (95% CI: 88.1%–100%), respectively. Time to progression of CNS was 16.5 months (95% CI: 9.7–NC). Of 226 patients, 188 (83.2%) had at least one treatment-related adverse event, whereas grade more than or equal to 3 occurred in 45 (19.9%) patients. No interstitial lung disease was reported.ConclusionsRezivertinib was found to have promising efficacy and favorable safety profile for patients with locally advanced or metastatic/recurrent NSCLC with EGFR T790M mutation.     

A phase III,randomized, open-label study of ASP8273 versus erlotinib or gefitinib in patients with advanced stage IIIB/IV non-small-cell lung cancer

BackgroundASP8273, a novel, small molecule, irreversible tyrosine kinase inhibitor (TKI) specifically inhibits the epidermal growth factor receptor (EGFR) in patients with activating mutations or EGFR T790M resistance mutations. The current study examines the efficacy, safety, and tolerability of ASP8273 versus erlotinib or gefitinib in patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations not previously treated with an EGFR inhibitor.Patients and methodsThis global, phase III, open-label, randomized study evaluated ASP8273 versus erlotinib/gefitinib in patients with locally advanced, metastatic, or unresectable stage IIIB/IV NSCLC with activating EGFR mutations. They were ineligible if they received prior chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS), and secondary end points included overall survival, investigator-assessed PFS, best overall response rate (ORR), disease control rate, duration of response (DoR), and the safety/tolerability profile.ResultsPatients (n = 530) were randomized 1 : 1 to receive ASP8273 (n = 267) or erlotinib/gefitinib (n = 263). Patient demographics between both treatment groups were generally balanced. Median PFS was 9.3 months (95% CI 5.6–11.1 months) for patients receiving ASP8273 and 9.6 months (95% CI 8.8–NE) for the erlotinib/gefitinib group, with a hazard ratio of 1.611 (P = 0.992). The ORR in the ASP8273 group was 33% (95% CI 27.4–39.0) versus 47.9% (95% CI 41.7–54.1) in the erlotinib/gefitinib group. Median DoR was similar for both groups (9.2 months for ASP8273 versus 9.0 months for erlotinib/gefitinib). More grade ≥3 treatment-emergent adverse events (TEAEs) occurred in patients receiving ASP8273 than in those receiving erlotinib/gefitinib (54.7% versus 43.5%). An independent data monitoring committee carried out an interim safety analysis and recommended discontinuing the study due to toxicity and limited predicted efficacy of ASP8273 relative to erlotinib/gefitinib.ConclusionsFirst-line ASP8273 did not show improved PFS or equivalent toxicities versus erlotinib/gefitinib.ClinicalTrial.gov numberNCT02588261.     

Addition of Bevacizumab to Erlotinib as First-Line Treatment of Patients With EGFR-Mutated Advanced Nonsquamous NSCLC: The BEVERLY Multicenter Randomized Phase 3 Trial

IntroductionAdding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC.MethodsEligible patients were randomized 1:1 to erlotinib plus bevacizumab or erlotinib alone. Investigator-assessed PFS and blinded independent centrally reviewed PFS were coprimary end points. With 80% power in detecting a 0.60 hazard ratio and two-sided α error of 0.05, 126 events of 160 patients were needed. The trial was registered as NCT02633189 and EudraCT 2015-002235-17.ResultsFrom April 11, 2016, to February 27, 2019, a total of 160 patients were randomized to erlotinib plus bevacizumab (80) or erlotinib alone (80). At a median follow-up of 36.3 months, median investigator-assessed PFS was 15.4 months (95% confidence interval [CI]: 12.2–18.6) with erlotinib plus bevacizumab and 9.6 months (95% CI: 8.2–10.6) with erlotinib alone (hazard ratio = 0.66, 95% CI: 0.47–0.92). Blinded independent centrally reviewed PFS analysis confirmed this result. A statistically significant interaction with treatment effect was found for smoking habit (p = 0.0323), with PFS prolongation being clinically significant only among current or previous smokers. Hypertension (grade ≥3: 24% versus 5%), skin rash (grade ≥ 3: 31% versus 14%), thromboembolic events (any grade: 11% versus 4%), and proteinuria (any grade: 23% versus 6%) were more frequent with the combination.ConclusionsThe addition of bevacizumab to first-line erlotinib prolonged PFS in Italian patients with EGFR-mutated NSCLC; toxicity was increased with the combination but without unexpected safety issues.     

EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment: a systematic review and meta-analysis in non-small-cell lung cancer

IntroductionWe conducted a systematic review and meta-analysis to assess epidermal growth factor receptor (EGFR) gene copy number as a potential biomarker of survival for patients with advanced non-small-cell lung cancer (NSCLC) receiving single-agent treatment with EGFR tyrosine kinase inhibitors (TKIs).MethodsWe systematically identified articles investigating EGFR gene copy number by fluorescent or chromogenic in situ hybridization in patients with advanced or recurrent NSCLC treated with the TKIs erlotinib or gefitinib, (last search: 31 June 2009). Eligible studies had to report on overall survival (OS), progression-free survival (PFS) or time-to-progression (TTP), stratified by EGFR gene copy number. Summary hazard ratios (HRs) were calculated using random-effects models.ResultsAmong 255 identified studies, 20 (1689 patients, 594 with increased gene copy number), 10 (822 patients, 290 with increased gene copy number) and 5 (294 patients, 129 with increased gene copy number) were eligible for the OS, PFS and TTP meta-analyses, respectively. Increased EGFR gene copy number was associated with increased OS (HR = 0.77; 95% CI 0.66–0.89; P = 0.001), PFS (HR = 0.60; 95% CI 0.46–0.79; P<0.001) and TTP (HR = 0.50; 95% CI 0.28–0.91; P = 0.02). Among predominantly white populations, increased EGFR gene copy number was strongly associated with improved survival (HR = 0.70; 95% CI 0.59–0.82; P<0.001), whereas it did not influence survival in East Asians (HR = 1.11; 95% CI 0.82–1.50; P=0.50). This difference was statistically significant (P=0.02).ConclusionAmong TKI-treated patients, increased EGFR gene copy number appears to be associated with improved survival outcomes. The effect on OS appears to be limited to patients of non-Asian descent.     

EGFR Tyrosine Kinase Inhibitor (TKI) Combined With Concurrent or Sequential Chemotherapy for Patients With Advanced Lung Cancer and Gradual Progression After First-Line EGFR-TKI Therapy: A Randomized Controlled Study

IntroductionContinuing tyrosine kinase inhibitor (TKI) therapy may be beneficial when patients with non–small-cell lung cancer and EGFR mutations experience gradual disease progression after initial EGFR-TKI treatment. We aimed to compare the efficacy of simultaneous EGFR-TKI and chemotherapy with that of sequential treatment after patients’ disease gradually progressed after first-line EGFR-TKI treatment.Patients and MethodsPatients with gradual progression who were EGFR-T790M mutation negative were randomly divided into two groups. In the concurrent group, patients were treated with pemetrexed plus cisplatin along with the same EGFR-TKI. In the sequential group, patients continued with EGFR-TKI until the disease progressed again, according to RECIST, then switched to chemotherapy. We evaluated the patients’ progression-free survival (PFS) and overall survival times.ResultsNinety-nine patients were enrolled: 49 in the concurrent group and 50 in the sequential group. The median PFS (mPFS) was 7.7 months (95% confidence interval [CI], 3.6-11.7) in the concurrent group and 5.7 months (95% CI, 3.5-7.9) in the sequential group (hazard ratio = 0.66; 95% CI, 0.44-1.00; P = .026), respectively. For the sequential group, the mPFS1 and mPFS2 were 1.8 months (95% CI, 1.4-2.3) and 3.8 months (95% CI, 3.1-4.5), respectively. The median overall survival of the concurrent group was longer than that of the sequential group (20.0 vs. 14.7 months; hazard ratio = 0.52; 95% CI, 0.32-0.85; P = .038).ConclusionFor patients with advanced non–small-cell lung cancer and gradual progression who are EGFR-T790M mutation negative after initial EGFR-TKI therapy, EGFR-TKI combined with chemotherapy confers longer PFS and overall survival than sequential EGFR-TKI and chemotherapy does.