Does EGFR Mutation Type Influence Patient-Reported Outcomes in Patients with Advanced EGFR Mutation-Positive Non-Small-Cell Lung Cancer? Analysis of Two Large, Phase III Studies Comparing Afatinib with Chemotherapy (LUX-Lung 3 and LUX-Lung 6)

Introduction: In LUX-Lung 3 and LUX-Lung 6, afatinib significantly improved progression-free survival (PFS) versus chemotherapy in patients with tumors harboring common epidermal growth factor receptor (EGFR) mutations (Del19/L858R) and significantly improved overall survival (OS) in patients with tumors harboring Del19 mutations. Patient-reported outcomes stratified by EGFR mutation type are reported. Patients and Methods Lung cancer symptoms and health-related quality of life (QoL) were assessed every 21 days until progression using the EORTC Quality of Life Core Questionnaire C30 and its lung cancer-specific module, LC13. Analyses of cough, dyspnea, and pain were prespecified and included analysis of percentage of patients who improved on therapy, time to deterioration of symptoms, and change over time. Global health status (GHS)/QoL was also assessed. Analyses were conducted for all patients with tumors harboring Del19 or L858R mutations and were exploratory. Results: Compared with chemotherapy, afatinib more commonly improved symptoms of, delayed time to deterioration for, and was associated with better mean scores over time for cough and dyspnea in patients with Del19 or L858R mutations. All three prespecified analyses of pain showed a trend favoring afatinib over chemotherapy. In both Del19 and L858R mutations, afatinib was also associated with improvements in GHS/QoL. Longitudinal analyses demonstrated statistically significant improvements in GHS/QoL for afatinib over chemotherapy for patients with tumors harboring Del19 mutations or L858R mutations. Conclusions: These exploratory analyses suggest first-line afatinib improved lung cancer-related symptoms and GHS/QoL compared with chemotherapy in patients with non-small-cell lung cancer with tumors harboring common EGFR mutations, with benefits in both Del19 and L858R patients. When considered with OS (Del19 patients only) and PFS benefits, these findings substantiate the value of using afatinib over chemotherapy in these patient groups. Electronic supplementary material The online version of this article (10.1007/s40271-017-0287-z) contains supplementary material, which is available to authorized users

การศึกษาต้นทุนอรรถประโยชน์ ยาภูมิคุ้มกันมะเร็งในผู้ป่วยมะเร็งปอดชนิดเซลล์ไม่เล็กที่กลับเป็นซ้ำหลังจากได้รับการรักษายาเคมีบำบัดในประเทศไทย

Doctor of Philosophy (Health Sciences), 2023Introduction: Lung cancer is the most common cancer in males and the fourth most common in females. Although there are many novel effective treatments available on the market, patients are mainly unable to access them. The biggest barrier factor is the cost of treatment which may cause financial toxicity to the patients, family, or even to the healthcare system, especially in low or middle-income countries. This study aims to (1) evaluate the cost-effectiveness of applying immune checkpoint inhibitors (ICI) in second-line non-small cell lung cancer in Thailand., and (2) evaluate the financial toxicity among lung cancer patients in Thailand. Materials and Methods: Economics evaluation using clinical input from published clinical trials data together with the cost and utility information from face-to-face questionnaire interviews. The incremental cost-effectiveness of ICI compared with docetaxel was computed using partition survival and the Markov model. Financial toxicity evaluation using data from the questionnaires in the cross-sectional design. Results: The ICI treatment improved survival by 0.55 to 0.81 life years. The incremental cost of ICI treatment ranged from USD 18,683 for atezolizumab to USD 69,723 for pembrolizumab. The ICI treatment improves QALY of about 0.43-0.62. The ICER for nivolumab, pembrolizumab, and atezolizumab were USD 84,957, USD 115,365, and USD 30,003, respectively. About 66% of the patients with lung cancer experience catastrophic health expenditure (CHE) and 29% of the patients develop medical impoverishment. Conclusion: The ICI treatment provided better survival and QALY but was more costly. Atezolizumab was the most favored regimen compared with the other two ICI. However, the ICER for atezolizumab was higher than Thailand's cost-effectiveness acceptability threshold of USD 5,208. A significant proportion of lung cancer patients in Thailand experienced financial toxicity

Symptom and Quality of Life Improvement in LUX-Lung 6: An Open-Label Phase III Study of Afatinib Versus Cisplatin/Gemcitabine in Asian Patients With EGFR Mutation-Positive Advanced Non–small-cell Lung Cancer

IntroductionIn the phase III, LUX-Lung 6 trial, afatinib prolonged progression-free survival (PFS) versus cisplatin/gemcitabine in Asian patients with epidermal growth factor receptor (EGFR) mutation-positive non–small-cell lung cancer (NSCLC). This article provides detailed assessments of patient-reported outcomes (PROs), a LUX-Lung 6 secondary end point, and explores the relationship between PFS and health-related quality of life (QoL) in these patients.MethodsPatients (n = 364) were randomized (2:1) to oral afatinib (40 mg/day) or up to six cycles of cisplatin/gemcitabine (21-day cycle; cisplatin 75 mg/m2 [d1]; gemcitabine 1000 mg/m2 [d1,8]). QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and its lung cancer-specific module. The relationship between PFS (investigator assessment and independent review) and QoL was evaluated using analysis of covariance and a longitudinal model.ResultsMore patients treated with afatinib versus cisplatin/gemcitabine showed improvements in global health status/QoL (p < 0.0001) and physical (p < 0.0001), role (p = 0.013), and social (p < 0.001) functioning scales. Delayed symptom deterioration and better QoL over time was also observed with afatinib. QoL measured before tumor assessment was considerably poorer for patients with progression than those without progression, with significant differences in mean scores at multiple assessment time points. Results from the longitudinal analysis consistently demonstrated a significant negative impact of progression on QoL (p < 0.0001).ConclusionAfatinib improved PFS and PROs versus chemotherapy in EGFR mutation-positive NSCLC patients. Progression was associated with statistically significant worsening in QoL measured before tumor assessment, underscoring the value of PFS as a clinically relevant end point

P1.33: Afatinib versus chemotherapy for EGFR mutation-positive NSCLC patients aged ≥65 years: Subgroup Analysis of LUX-Lung 3/6: Track: Advanced NSCLC

Background Afatinib, an irreversible ErbB family blocker, significantly improved progression-free survival (PFS) versus platinum-doublet chemotherapy as first-line treatment in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) in the LUX-Lung 3 (LL3; 11.1 vs 6.9 months, HR=0.58, p<0.001) and LUX-Lung 6 (LL6; 11.0 vs 5.6 months, HR=0.28, p<0.0001) trials. Afatinib also significantly improved overall survival (OS) versus chemotherapy in patients with Del19-positive NSCLC (LL3: 33.3 vs 21.1 months, HR=0.54, p=0.0015; LL6: 31.4 vs 18.4 months, HR=0.64, p=0.023). Here were report the efficacy and safety of afatinib versus chemotherapy in patients aged ≥65 years in the LL3 and LL6 trials..

P1.45: Impact of Dose Adjustment on Afatinib Safety and Efficacy in EGFR Mutation-Positive NSCLC: Post-Hoc Analyses of LUX-Lung 3/6

Background Afatinib 40 mg/day is approved for the first-line treatment of pts with EGFR mutation-positive NSCLC. The dose can be adjusted based on individual tolerability. Post-hoc analyses assessed the impact of afatinib dose adjustment on adverse events (AEs), pharmacokinetics (PK) and progression-free survival (PFS) in LL3 and LL6. Methods All afatinib-treated pts in LL3 (n = 229) and LL6 (n= 239) were included. In case of drug-related grade 3 or selected prolonged grade 2 AEs with afatinib 40 mg, the dose could be reduced by 10 mg decrements to a minimum of 20 mg. We analysed the incidence and severity of common AEs before and after dose reduction and compared PK data collected as part of the standard visit schedule on Day 43 in pts who reduced to 30 mg vs those remaining at 40 mg. PFS in pts who dose reduced within the first 6 months of treatment was compared with those who remained on afatinib 40 mg/day. Results Dose reductions occurred in 53% (122/229) and 28% (67/239) of pts in LL3 and LL6, respectively; the majority (86% and 82%, respectively) within the first 6 months of treatment. Dose reduction led to decreases in the incidence and severity of EGFR-mediated drug-related AEs (table). Combined PK analysis of LL3 and LL6 suggested that dose reduction was more likely in pts with higher plasma concentrations of afatinib. On Day 43, pts who had dose reduced to 30 mg (n = 59) had geometric mean plasma afatinib concentrations of 23.3 ng/mL, vs 22.8 ng/mL in pts who remained on the 40 mg dose (n = 284). Median PFS was similar in pts who dose reduced during the first 6 months of treatment vs those who did not in LL3 (11.3 vs 11.0 months [HR = 1.25; 95% CI, 0.91–1.72]) and LL6 (12.3 vs 11.0 months [HR = 1.00; 95% CI, 0.69–1.46]). Conclusions Tolerability-guided dose adjustment of afatinib reduced treatment-related AEs without adversely affecting efficacy

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma With EGFR mutations

Purpose The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). Patients and Methods In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). Results A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Conclusion Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations

First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study

Background The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients. Methods This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cisplatin 75 mg/m(2) or carboplatin AUC 5-6 plus pemetrexed 500 mg/m(2)] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1-2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01828099. Findings Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16.6 months (95% CI 12.6-27.2) in the ceritinib group and 8.1 months (5.8-11.1) in the chemotherapy group (hazard ratio 0.55 [95% CI 0.42-0.73]; p<0.00001). The most common adverse events were diarrhoea (in 160 [85%] of 189 patients), nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotransferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients), vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group. Interpretation First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC

Asian Thoracic Oncology Research Group (ATORG) Expert Consensus Statement on MET Alterations in NSCLC: Diagnostic and Therapeutic Considerations

© 2022Non-small cell lung cancer (NSCLC) is a heterogeneous disease, with many oncogenic driver mutations, including de novo mutations in the Mesenchymal Epithelial Transition (MET) gene (specifically in Exon 14 [ex14]), that lead to tumourigenesis. Acquired alterations in the MET gene, specifically MET amplification is also associated with the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in patients with EGFR-mutant NSCLC. Although MET has become an actionable biomarker with the availability of MET-specific inhibitors in selected countries, there is differential accessibility to diagnostic platforms and targeted therapies across countries in Asia-Pacific (APAC). The Asian Thoracic Oncology Research Group (ATORG), an interdisciplinary group of experts from Australia, Hong Kong, Japan, Korea, Mainland China, Malaysia, the Philippines, Singapore, Taiwan, Thailand and Vietnam, discussed testing for MET alterations and considerations for using MET-specific inhibitors at a consensus meeting in January 2022, and in subsequent offline consultation. Consensus recommendations are provided by the ATORG group to address the unmet need for standardised approaches to diagnosing MET alterations in NSCLC and for using these therapies. MET inhibitors may be considered for first-line or second or subsequent lines of treatment for patients with advanced and metastatic NSCLC harbouring MET ex14 skipping mutations; MET ex14 testing is preferred within multi-gene panels for detecting targetable driver mutations in NSCLC. For patients with EGFR-mutant NSCLC and MET amplification leading to EGFR TKI resistance, enrolment in combination trials of EGFR TKIs and MET inhibitors is encouraged.Y