EGFR Mutation-positive Advanced Non-small Cell Research Articles

Longitudinal Analyses of Circulating-Tumor DNA for Detection of EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer Progression During Treatment: Data From FLAURA and AURA3

IntroductionEpidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitizing and -resistance mutations may be detected in plasma via circulating tumor DNA (ctDNA). ctDNA level changes reflect alterations in tumor burden and could be a dynamic indicator of treatment effect. This analysis aimed to determine whether longitudinal EGFR-mutation ctDNA testing could detect progressive disease (PD) before radiologic detection. MethodsThis was a retrospective, exploratory ctDNA analysis in two phase 3 trials (FLAURA, NCT02296125; AURA3, NCT02151981). Patients had treatment-naïve (FLAURA) or EGFR-TKI pre-treated (AURA3) advanced non-small cell lung cancer (NSCLC) with EGFR mutations and on-study PD (RECIST), with a baseline ctDNA result and EGFR-mutation ctDNA monitoring beyond Cycle 3 Day 1. Patients received osimertinib versus comparator EGFR-TKIs (FLAURA) or chemotherapy (AURA3). Outcomes included time from ctDNA PD to RECIST PD, and to first subsequent treatment (FST; FLAURA only).Results: ctDNA PD preceded/co-occurred with RECIST-defined PD in 93/146 (64%) patients in FLAURA and 82/146 (56%) in AURA3. Median time from ctDNA PD to RECIST-defined PD (months) was 3.4 and 2.6 in the osimertinib and comparator EGFR-TKI arms (FLAURA) and 2.8 and 1.5 in the osimertinib and chemotherapy arms (AURA3). In FLAURA, median time from ctDNA PD to FST (months) was 6.0 and 4.7 in the osimertinib (n = 51) and comparator EGFR-TKI arms (n = 70). ConclusionsAmong patients with EGFR mutation-positive advanced NSCLC receiving EGFR-TKI or chemotherapy with ctDNA data and RECIST-defined PD, ctDNA PD preceded/co-occurred with RECIST-defined PD in approximately 60% of cases. Longitudinal ctDNA monitoring may detect PD before radiologic PD.

365P Patterns of progression on first-line osimertinib in patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC): A Swiss cohort study

Osimertinib (osi) is a third-generation EGFR tyrosine kinase inhibitor (TKI) with antitumor activity in non-small cell lung cancer (NSCLC) against activating EGFR and T790M mutation. The incidence of oligo-PD on first-line osi is unknown.

LBA10 A multicenter, randomized, double-blind, phase III study of gefitinib in combination with anlotinib or placebo in previously untreated patients with EGFR mutation-positive advanced non-small cell lung cancer (FL-ALTER)

Anlotinib（Catequentinib） is an oral multi-targeted tyrosine kinase inhibitor that effectively inhibits VEGFRs, FGFRs, PGFRs, c-kit and MET. This phase III study aims to evaluate the efficacy and safety of Anlotinib or placebo plus Gefitinib in patients (pts) with untreated EGFR-mutated metastatic NSCLC.

ES13.04 What Evidence Level is Enough for Approval and Reimbursement of Novel Cancer Drugs? Lessons from Lung Cancer

ES13.04 What Evidence Level is Enough for Approval and Reimbursement of Novel Cancer Drugs? Lessons from Lung Cancer

A multicenter, randomized, double-blind study of gefitinib in combination with anlotinib or placebo in previously untreated patients with EGFR mutation-positive advanced non-small cell lung cancer (FL-ALTER).

TPS9131 Background: Preclinical and clinical evidence has demonstrated that the dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutated advanced NSCLC population. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that effectively inhibits VEGFRs, FGFRs, PDGFRs, c-kit and MET. It has been proved to be safe and effective in advanced lung cancer after second-line standard chemotherapy failure. A cohort study of Anlotinib plus Erlotinib has shown a favorable safety profile and promising antitumor activity with an objective response rate (ORR)92.6%. This phase III study aims to evaluate the efficacy and safety of Anlotinib or placebo plus Gefitinib in patients(pts) with untreated EGFR-mutated metastatic NSCLC. Methods: Eligible pts were aged 18̃75 years old, had stage IIIB or IV NSCLC, with an EGFR 19del or 21L858R mutation, an ECOG PS of 0 or 1, measurable lesion according to RECIST v1.1 and adequate organ function. We randomly assigned eligible pts in a 1:1 ratio to receive oral Gefitinib (250 mg QD) plus either Anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) or matching placebo until progressive disease or unacceptable toxicity. Randomization was done by an interactive web response system with a computer-generated sequence and stratified by EGFR mutation status, gender, ECOG PS and pathological type. The primary endpoint is progression-free survival(PFS). Secondary endpoints include overall survival, ORR, disease control rate, time to progression, duration of response, quality of life and the safety profile. The peripheral blood of the pts will be detected three times by polygenic detection to monitor the resistance mechanism (before treatment, during the first evaluation, during tumor progression, each time 10ml peripheral blood). Independent Data Monitoring Committee and Independent Review Committee will be used in this study. According to previous report (Erlotinib plus Bevacizumab vs. Erlotinib alone: 16.0 vs. 9.7 mos, HR 0.54, Lancet Oncol, 15(11):1236-1244), the sample size was determined based on a median PFS of 15 months for the Anlotinib + Gefitinib group and median PFS of 10 months for the Placebo + Gefitinib group. To achieve 80% power at a two-sided α = 0.05 and an anticipated dropout rate of 20%, 310 patients (with 192 events required for the analyses) were needed. In total, 310 patients will be enrolled in this trial at 16 sites in China. From April 2019, 224 patients have been enrolled. Clinical trial information: NCT04028778.

Dacomitinib as first-line treatment for EGFR mutation-positive non-small cell lung cancer

ABSTRACT Introduction: Dacomitinib is a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). Recent results from ARCHER 1050, the first randomized, open-label, Phase 3 trial of a second-generation vs. a first-generation EGFR TKI, showed that dacomitinib improves progression-free survival and overall survival compared with gefitinib as a first-line treatment in patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). Areas covered: We review the efficacy and safety of dacomitinib as a first-line treatment of EGFR mutation-positive NSCLC, including the management of toxicity, and evaluate the activity of dacomitinib against brain metastases. Additionally, the optimal treatment sequence given EGFR TKI choice, resistance mechanisms, activity against rare mutations, and real-world dosing is discussed. Expert opinion: The introduction of EGFR TKIs has changed the treatment strategy for patients with EGFR mutation-positive NSCLC. The second- and third-generation EGFR TKIs are the result of research elucidating mechanisms of resistance to first-generation EGFR TKIs. There is now more than one treatment option for patients with EGFR mutation-positive advanced NSCLC that improves survival, highlighting the need to more clearly understand the use of the right drug for the right person at the right time and how the appropriate treatment sequence may provide optimal outcomes for these patients.

P86.12 Cardiac Safety Assessment of Lazertinib in Patients with EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer

P86.12 Cardiac Safety Assessment of Lazertinib in Patients with EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer

A phase II study of first-line afatinib for patients aged \u226575 years with EGFR mutation-positive advanced non-small cell lung cancer: North East Japan Study Group trial NEJ027

BackgroundLung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC).MethodsThis was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review.ResultsIn total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75–91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5–19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2–not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported.ConclusionAlthough dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS.Trial registrationThe trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).

P2.16-07 How to Manage Toxicities of EGFR-TKI for Extreme Elderly Lung Cancer Patients: Supportive Care for Patients Aged 85 and Older

In Japan, the population of extreme elderly individuals (85 years and older) was 5.75 million in 2018, and the number of elderly lung cancer patients is increasing. Recently, several elderly-specific trials showed that epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is effective and feasible for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). Nevertheless, there have been few reports on the efficacy and safety of EGFR-TKI therapy in patients aged 85 years and older with EGFR mutation-positive advanced NSCLC. We analyzed the efficacy and safety of EGFR-TKI therapy in patients with EGFR mutated NSCLC who were 85 years and older treated at our hospital, between 2014 and 2019. We assessed complications, prognosis, and supportive care needs. The median age was 87 years (range, 85-93 years) at last checkup, and only one patient was male. The study population included 12 patients with ECOG performance status 0-1 and all patients had adenocarcinoma. Four patients (33%) were diagnosed with cognitive impairment. Nine patients received gefitinib therapy. Treatment-related deaths were not observed in our analysis. Median progression free survival, overall survival from recent TKI therapy was 11.3 months, and 16.0 months. The response rate and disease control rate were 17%, and 100%. The common adverse events were diarrhea (25%), skin toxicities (25%), and liver dysfunction (25%). One patient (8%) experienced grade 2 EGFR-TKI-related interstitial lung disease. The dose of EGFR-TKI was reduced in 5 patients (42%) and EGFR-TKI therapy was discontinued in 3 patients (25%) due to toxicities, digestive disorders and interstitial lung disease. EGFR-TKI therapy is tolerable for extreme elderly patients with EGFR mutation-positive advanced NSCLC. Approximately half of the patients required a dose reduction or focused supportive care, but well tolerated and had similar efficacy compared to those of the younger. It is important for elderly patients to be treated with a personalized management plan and integrated supportive care.

Estimating long-term survival of previously untreated patients with EGFR mutation-positive (EGFRm) advanced non-small cell lung cancer (NSCLC) who received osimertinib in the FLAURA study.

e20560 Background: In the Phase III FLAURA trial (NCT02296125), osimertinib, a third-generation EGFR-TKI, provided clinically and statistically significantly longer progression-free survival versus gefitinib/erlotinib as first-line treatment for patients with EGFRm advanced NSCLC. At the time of analysis, data on overall survival (OS) were immature (25% maturity). To better understand the long-term survival potential of osimertinib beyond the observed trial follow-up period, mathematical parametric survival models were used to estimate clinically plausible survival rates up to 5 years from FLAURA. Methods: Following published best-practice guidelines, candidate parametric survival models were evaluated based on both statistical and visual goodness-of-fit to the observed FLAURA OS data. Two modeling approaches were considered: single models with treatment included as a covariate; and separate models fitted to the osimertinib and gefitinib/erlotinib arms. Point estimates of 5-year survival rates with 95% confidence intervals (CIs) are reported for the best fitting model. Results: The best fitting parametric survival model to the FLAURA OS data was the Weibull model with treatment included as a covariate. Based on this model, estimated median OS was longer with osimertinib than with gefitinib/erlotinib (41.4 months vs 30.6 months). The estimated 3- and 5-year survival rates with osimertinib were 57.3% (95% CI 46.6%, 69.2%) and 31.1% (95% CI 23.7%, 41.8%), respectively. In comparison, the estimated 3- and 5-year survival rates with gefitinib/erlotinib were 41.1% (95% CI 31.9%, 52.9%) and 15.5% (95% CI 11.6%, 22.1%), respectively. Conclusions: Based on the best fitting parametric survival model to FLAURA OS data, the estimated 5-year survival rate with osimertinib was double that with gefitinib/erlotinib (31.1% vs 15.5%) in patients with EGFRm advanced NSCLC. Long-term follow-up data from FLAURA (60% OS maturity) will further validate this finding. Clinical trial information: NCT02296125.

513P - Preventing and treating brain metastases with three first-line EGFR-tyrosine kinase inhibitors in patients with EGFR mutation-positive advanced non-small cell lung cancer

513P - Preventing and treating brain metastases with three first-line EGFR-tyrosine kinase inhibitors in patients with EGFR mutation-positive advanced non-small cell lung cancer

1445P - A phase II study of first-line afatinib for patients aged 75 or older with EGFR mutation-positive advanced non-small cell lung cancer: North East Japan study group trial NEJ027

Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review. In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75–91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5–19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2–not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported. Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS. The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).

Preventing and treating brain metastases with three first-line EGFR-tyrosine kinase inhibitors in patients with EGFR mutation-positive advanced non-small cell lung cancer.

Introduction:Brain metastases (BM) are common in advanced non-small cell lung cancer (NSCLC), and the prognosis is poor with few therapeutic options. This study evaluated the efficacy of three epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) in preventing and treating BM in patients with EGFR mutation-positive advanced NSCLC.Methods:Patients with EGFR mutation-positive advanced NSCLC who visited a tertiary referral center from 1 December 2013 to 30 November 2017 were analyzed retrospectively. They received gefitinib, erlotinib, or afatinib until disease progression, death, or intolerable adverse events. The cumulative incidence of subsequent BM of initial non-BM patients, progression-free survival (PFS), and overall survival (OS) of the BM and non-BM patients were estimated and compared using the Kaplan–Meier and log-rank tests.Results:306 NSCLC patients were enrolled, with 116, 75, and 115 receiving first-line gefitinib, erlotinib, and afatinib, respectively. The afatinib group had a better PFS [12.7 versus 9.8 months; hazard ratio (HR) 0.59, p = 0.001] and OS (39.1 versus 22.0 months; HR 0.64, p = 0.035) than the gefitinib group. Afatinib tended to provide better BM prevention than gefitinib (BM cumulative incidence, HR 0.49; 95% confidence interval 0.34–0.71, p < 0.001) according to a Cox model adjusted for possible confounders. Patients with initial BM had a shorter PFS (p < 0.001) and OS (p = 0.015) than those without initial BM. Among the former, there were no differences in median PFS (p = 0.34) and median OS (p = 0.46) in the three EGFR-TKI groups.Conclusions:Our data suggested that, compared with gefitinib, afatinib provided better benefits significantly in terms of PFS and OS. Both had the same effectiveness in preventing subsequent BM.

1331P - Detection of EGFR T790M in Asia-Pacific patients (pts) with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC): Circulating tumour (ct) DNA analysis across 3 platforms

1331P - Detection of EGFR T790M in Asia-Pacific patients (pts) with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC): Circulating tumour (ct) DNA analysis across 3 platforms

The impact of osimertinib on function and health status for patients with EGFR mutation-positive advanced non-small cell lung cancer.

e20548Background: The impact of osimertinib (AZD9291) on lung cancer symptoms (cough, pain and dyspnea) has been described in phase I and phase II trials (Ryden A et al. Poster P282 European Cancer...

134O_PR: Plasma ctDNA analysis for detection of EGFR T790M mutation in patients (pts) with EGFR mutation-positive advanced non-small cell lung cancer (aNSCLC)

134O_PR: Plasma ctDNA analysis for detection of EGFR T790M mutation in patients (pts) with EGFR mutation-positive advanced non-small cell lung cancer (aNSCLC)

Patient reported outcomes from LUX-Lung 3: first-line afatinib is superior to chemotherapy-would patients agree?

The LUX-Lung 3 trial was an important randomized phase 3 trial in patients with EGFR mutant advanced non-small cell lung cancer (NSCLC). Here, patients were randomized to either afatinib or cisplatin-pemetrexed and the primary endpoint of progression-free survival (PFS) was easily met (HR=0.58, P=0.001). This was the first large-scale trial of this type using a modern chemotherapy comparator, including Asian and non-Asian patients, central radiology review, and utilizing comprehensive patient-reported outcomes. Whilst efficacy for afatinib was markedly superior to chemotherapy, do the patient-reported outcomes reflect this superiority? The symptom control and quality of life (QoL) data from this trial has now been published. Analysis of these demonstrate clear superiority of afatinib over chemotherapy for delay in cough deterioration, and dyspnoea. Notably, given the toxicity profile of afatinib, these improvements translated into significant improvements in global health status, physical, role, and cognitive functioning. The clinical benefits for afatinib over cisplatin-pemetrexed chemotherapy for EGFR mutation-positive advanced non-small cell lung patients seem overwhelming, and are clinically meaningful. These results are also consistent with QoL data from other trials of gefitinib/erlotinib, but much more robust, given the larger patient numbers. Would patients agree that afatinib is superior to chemotherapy? On the basis of data presented, the answer is probably "Yes". However, the key unanswered question remaining is "Which is the best EGFR-tyrosine kinase inhibitor (TKI) to use up front?" and we will have to wait until ongoing trial data can help answer this.