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 treatment-related 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.

Of all 428 resectable stage II and III NSCLC patients included in this study, 25% received neoadjuvant therapy. Perioperative outcomes and 5-year overall survival were similar between patients having received neoadjuvant therapy versus upfront surgery. Establishing a neoadjuvant therapy program for NSCLC is feasible and safe from a surgical perspective. Background: Several regulatory agencies have approved the use of the neoadjuvant chemo-immunotherapy for resectable stage II and III of non -small cell lung cancer (NSCLC) and numerous trials investigating novel agents are underway. However, significant concerns exist around the feasibility and safety of offering curative surgery to patients treated within such pathways. The goal in this study was to evaluate the impact of a transition towards a large-scale neoadjuvant therapy program for NSCLC. Methods: Medical charts of patients with clinical stage II and III NSCLC who underwent resection from January 2015 to December 2020 were reviewed. The primary outcome was perioperative complication rate between neoadjuvant-treated versus upfront surgery patients. Multivariable logistic regression estimated occurrence of postoperative complications and overall survival was assessed as an explorator y secondar y outcome by Kaplan-Meier and Cox -regression analyses. Results: Of the 428 patients included, 106 (24.8%) received neoadjuvant therapy and 322 (75.2%) upfront surgery. Frequency of minor and major postoperative complications was similar between groups ( P = .22). Occurrence in postoperative complication was similar in both cohort (aOR = 1.31, 95% CI 0.73-2.34). Neoadjuvant therapy administration increased from 10% to 45% with a rise in targeted and immuno therapies over time, accompanied by a reduced rate of preoperative radiation therapy use. 1-, 2-, and 5 -year overall survival was higher in neoadjuvant therapy compared to upfront surgery patients (Log -Rank P = .017). Conclusions: No significant differences in perioperative outcomes and survival were observed in resectable NSCLC patients treated by neoadjuvant therapy versus upfront surgery. Transition to neoadjuvant therapy among resectable NSCLC patients is safe and feasible from a surgical perspective.

Dose-intensified radiation has been shown to improve tumor control and survival in Stage I NSCLC, and in Stage III NSCLC radiation-alone studies. However, NRG-RTOG 0617 showed that with concurrent chemo-RT, higher-dose RT paradoxically worsened survival. Here we present the results of a multicenter trial led by NRG Oncology and American College of Radiology Network (ACRIN), which aimed to determine whether adaptive isotoxic radiation dose escalation to mid-treatment FDG-PET provides superior local tumor control compared to a standard uniform dose of 60 Gy in patients with stage III NSCLC.

Background: The purpose of this study was to build radiogenomics models from texture signatures derived from computed tomography (CT) and 18F-FDG PET-CT (FDG PET-CT) images of non-small cell lung cancer (NSCLC) with and without epidermal growth factor receptor (EGFR) mutations. Methods: Fifty patients diagnosed with NSCLC between 2011 and 2015 and with known EGFR mutation status were retrospectively identified. Texture features extracted from pretreatment CT and FDG PET-CT images by manual contouring of the primary tumor were used to develop multivariate logistic regression (LR) models to predict EGFR mutations in exon 19 and exon 20. Results: An LR model evaluating FDG PET-texture features was able to differentiate EGFR mutant from wild type with an area under the curve (AUC), sensitivity, specificity, and accuracy of 0.87, 0.76, 0.66, and 0.71, respectively. The model derived from CT texture features had an AUC, sensitivity, specificity, and accuracy of 0.83, 0.84, 0.73, and 0.78, respectively. FDG PET-texture features that could discriminate between mutations in EGFR exon 19 and 21 demonstrated AUC, sensitivity, specificity, and accuracy of 0.86, 0.84, 0.73, and 0.78, respectively. Based on CT texture features, the AUC, sensitivity, specificity, and accuracy were 0.75, 0.81, 0.69, and 0.75, respectively. Conclusion: Non-small cell lung cancer texture analysis using FGD-PET and CT images can identify tumors with mutations in EGFR. Imaging signatures could be valuable for pretreatment assessment and prognosis in precision therapy.

8548 Background: NRG-RTOG 0617 (R0617) found that non-personalized dose escalation of radiotherapy (RT) with concurrent chemotherapy was deleterious. NRG-RTOG 1106/ACRIN 6697 (R1106) studied adaptive chemoradiotherapy, using tumor and patient individualized RT dose intensification simultaneously with field reduction, based upon mid-treatment FDG-PET. Methods: The control arms of both studies used 60 Gy (+ weekly carboplatin/paclitaxel). The investigational arm of R0617 used 74 Gy in 37 fractions, with no field/dose adaptation, while R1106 used mid-treatment FDG-PET (after ̃40 Gy) to design an individualized dose adaptive RT plan with daily-fraction size 2.2 to 3.8 Gy (up to 80.4 Gy/30 fractions), based upon a model of isotoxic lung risk. Nearly all (93%) patients had IMRT. No patients had consolidation immunotherapy. The primary endpoint for R1106 was local-regional-progression freedom (LRPF) assessed by central review. Other endpoints reported here were survival, toxicity, and institution-defined local/regional control. Results: From 2012-2017, 127 patients were enrolled to R1106 (43 in the standard and 84 in the adaptive arms), with a median follow-up of 3.6 years. The median actual RT dose in the adaptive arm was 71 Gy (Q1-Q3 68-76 Gy). The 2-year LRPF was 59.5% versus 54.6% (p=0.66) for standard versus adaptive RT; the 3-year survival rates were 49.1% versus 47.5% (p=0.80). An exploratory analysis of 2-year in-field local primary tumor control and local-regional tumor control (institution-assessed) were 58.5% and 55.6% for standard RT, and 75.6% and 66.3% for adaptive RT, respectively. As shown in the table, there were no significant differences in cardiac or esophageal adverse events between the two arms; the adaptive RT arm had more Grade 3+ respiratory events (23.8% versus 14.3%). Conclusions: NRG-RTOG1106 did not meet its primary endpoint of demonstrating improved LRPF. Unlike R0617, there was no suggestion of a detrimental effect of adaptive dose-intensified RT on survival and cardiac events. Studies to refine personalized RT, especially in the immunotherapy era, should be considered. Outcome comparison between R0617 and R1106. Clinical trial information: NCT01507428. [Table: see text]

Surgery remains a cornerstone of cure for early stage non-small cell lung cancer (NSCLC). The value of systemic therapy for node negative early stage lung cancer is unclear, yet local and distant recurrence rates remain high after surgery. The advent of immunotherapy for advanced NSCLC has created new opportunities for patients. With better side effect profiles, improved outcomes and prolonged survival, immune checkpoint inhibition (ICI) as a single agent or in combination has become a first-line therapy in advanced NSCLC.

Purpose Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non-small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics. This systematic review evaluates emerging phase III data on the efficacy and safety of checkpoint inhibitor combinations as first-line treatment for advanced NSCLC. Materials and Methods Published and presented literature was searched using the key search terms "non-small cell lung cancer" AND "checkpoint-inhibitors" (OR respective aliases) AND phase III trials. Seven randomized phase III clinical trials reporting outcomes on checkpoint inhibitor combinations in first-line advanced NSCLC were identified. Results Four first-line trials reported outcomes for checkpoint inhibitor combinations in nonsquamous NSCLC. Pembrolizumab-chemotherapy, atezolizumab-chemotherapy, and atezolizumab-bevacizumab-chemotherapy showed significantly improved overall survival compared with controls in patients with advanced nonsquamous epidermal growth factor receptor-negative (EGFR-)/ anaplastic lymphoma kinase gene (ALK)- NSCLC. Two trials reported outcomes for squamous NSCLC, with pembrolizumab-chemotherapy reporting significantly improved overall survival (OS) compared with chemotherapy. The combination of nivolumab-ipilimumab in all-comer histology failed to improve OS compared with histology appropriate chemotherapy in patients regardless of their tumor mutational burden status. Based on improved survival and safety, either pembrolizumab monotherapy or pembrolizumab-chemotherapy administered based on PD-L1 status and histology is a preferred treatment option. Outcomes for atezolizumab-bevacizumab-chemotherapy in EGFR+/ALK+ patients are promising and require further exploration. Conclusion First-line checkpoint inhibitors added to standard therapies improve overall survival for nonsquamous EGFR-/ALK- and squamous advanced NSCLC. Implications for Practice Single-agent immune checkpoint inhibitors are now standard of care for advanced non-small cell lung cancer (NSCLC), and emerging data show that combining these agents with established chemotherapy further improves outcomes. The phase III KEYNOTE-189 and IMPower-130 trials showed significantly improved survival using this strategy for nonsquamous NSCLC, and the phase III KEYNOTE-407 trial showed similar results in squamous disease. Checkpoint inhibitor combinations are therefore an important new treatment option for first-line NSCLC. Programmed death ligand-1 expression may inform the use of checkpoint inhibitor combination therapy, and overall tumor mutation burden is also an emerging biomarker for this new treatment strategy.

Purpose To summarize current understanding of the efficacy, role, and cost-effectiveness of the available epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and to evaluate sequencing strategies based on the available evidence. Summary. EGFR TKIs are the current standard of care for patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Five EGFR TKIs are currently approved in the United States for use in a first-line setting; these TKIs differ in mechanism of action, efficacy, safety, and cost. Most patients develop resistance to first-line EGFR TKIs and require subsequent therapy with additional EGFR TKIs, chemotherapy, and/or other targeted agents. A major consideration when selecting EGFR TKIs, both as first-line or subsequent treatment options, is cost-effectiveness. Although clinical trials have shown that the second- and third-generation EGFR TKIs are superior in efficacy to the first-generation agents, pharmacoeconomic studies suggest that the first-generation agents are the most cost-effective, with the second-generation TKI afatinib also considered cost-effective in some studies. Despite its impressive efficacy, osimertinib appears to be less cost-effective due to substantially higher acquisition costs. Conclusion Preliminary data suggest that first-line afatinib followed by osimertinib may offer promising survival outcomes and, on the basis of efficacy alone, may represent an optimal sequencing strategy in the majority of patients with EGFR mutation-positive NSCLC, in particular Asian patients and those with Del19-positive tumors. However, considerably more research into outcomes and costs associated with consecutive sequencing of EGFR TKIs is needed before any conclusions can be reached.

For more than a decade, there has been no improvement in outcomes for patients with unresectable locally advanced (la) non-small-cell lung cancer (nsclc). The standard treatment in that setting is definitive concurrent chemotherapy and radiation (ccrt). Although the intent of treatment is curative, most patients rapidly progress, and their prognosis is poor, with a 5-year overall survival (os) rate in the 15%–25% range. Those patients therefore represent a critical unmet need, warranting expedited approval of, and access to, new treatments that can improve outcomes. The pacific trial, which evaluated durvalumab consolidation therapy after ccrt in unresectable la nsclc, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (pfs) and a significant improvement in os. Durvalumab thus fills a critical unmet need in the setting of unresectable la nsclc and provides a new option for patients treated with curative intent. Here, we review the treatment of unresectable la nsclc, with a focus on the effect of the clinical data for durvalumab.

INTRODUCTION:This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin (Hb) ceiling. METHODS:Adults with stage IV NSCLC expected to receive two or more cycles of myelosuppressive chemotherapy and Hb less than or equal to 11.0 g/dL were randomized 2:1 to blinded 500 μg darbepoetin alfa or placebo every 3 weeks. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] < 1.15). Secondary endpoints were PFS and incidence of transfusions or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period. RESULTS:The primary analysis set included 2516 patients: 1680 were randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR = 0.92; 95% confidence interval [CI]: 0.83‒1.01) and PFS (stratified HR = 0.95; 95% CI: 0.87‒1.04). Darbepoetin alfa was superior to placebo for transfusion or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period (stratified odds ratio = 0.70; 95% CI: 0.57‒0.86; p < 0.001). Objective tumor response was similar between the groups (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events was 31.1% in both groups. No unexpected adverse events were observed. CONCLUSIONS:Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb less than or equal to 8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.

OBJECTIVES:In patients with advanced epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC), first-line afatinib significantly improved progression-free survival (PFS) and objective response vs. platinum-doublet chemotherapy in the phase III LUX-Lung 3 and LUX-Lung 6 trials, and significantly improved PFS, time to treatment failure and objective response vs. gefitinib in the phase IIb LUX-Lung 7 trial. We report post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in these trials. METHODS:Treatment-naïve patients with stage IIIB/IV EGFRm + NSCLC randomized to afatinib in LUX-Lung 3/LUX-Lung 6/LUX-Lung 7 were included in the analysis. Patients treated with afatinib for ≥ 3 years were defined as LTRs. RESULTS:In LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7, 24/229 (10%), 23/239 (10%) and 19/160 (12%) afatinib-treated patients were LTRs. Baseline characteristics were similar to the study populations, except for the proportions of women (LUX-Lung 3/LUX-Lung 6 only; 92/78% vs. 64% overall) and Del19-positive patients (63-79% vs. 49-58% overall). Median treatment duration among LTRs was 50, 56 and 42 months, and median PFS was 49.5, 55.5, and 42.2 months in LUX-Lung 3/LUX-Lung 6/LUX-Lung 7, respectively. Median overall survival could not be estimated. Frequency of afatinib dose reduction was consistent with the LUX-Lung 3/LUX-Lung 6/LUX-Lung 7 overall populations. PROs were stable in LTRs, with slight improvements after 3 years of afatinib treatment vs. baseline scores. CONCLUSIONS:In the LUX-Lung 3/LUX-Lung 6/LUX-Lung 7 trials, 10-12% of afatinib-treated patients were LTRs. Long-term afatinib treatment was independent of tolerability-guided dose adjustment and had no detrimental impact on safety or PROs.

Purpose In the randomized phase IIb LUX-Lung 7 trial, afatinib significantly improved progression-free survival (PFS) and time-to-treatment failure vs gefitinib in patients with treatment-naïve epidermal growth factor receptor mutation-positive non-small cell lung cancer. We report post hoc analyses of tolerability-guided dose adjustment for afatinib and summarize the clinical characteristics of patients who continued afatinib/gefitinib beyond initial radiological progression in LUX-Lung 7. Methods Patients received afatinib 40 mg/day or gefitinib 250 mg/day until investigator-assessed progression or beyond if beneficial. In case of selected treatment-related adverse events (TRAEs), the afatinib dose could be reduced by 10-mg decrements to minimum 20 mg (only dose interruptions were permitted with gefitinib). Results All …

Les métastases au niveau du SNC sont une complication connue du CBNPC avancé EGFR muté (m+), et les études LUX-Lung (LL) évaluant afatinib autorisaient l'inclusion de patients avec métastases cérébrales (MC). LL3, 6 et 7 ont déjà démontré l'efficacité d'afatinib chez des patients avec MC, avec un niveau d'amélioration de survie sans progression (SSP) pour afatinib vs chimiothérapie ou gefitinib comparable à celui observé chez les patients sans MC (HR 0,54, 0,47, et 0,76 dans LL3, 6 et 7, respectivement) [1], [2]. La SSP a été significativement améliorée avec afatinib vs chimiothérapie dans une analyse combinée de LL3 et 6 chez des patients avec MC asymptomatiques (HR 0,50, p = 0,0297) [1]. Afin d'évaluer la capacité d'afatinib à prévenir une progression/métastases au SNC, des analyses de risques concurrents de progression et le profil des métastases dans le SNC ou hors SNC ont été réalisées chez les patients avec ou sans MC dans LL3, 6 et 7. Des analyses de risques concurrents ont été réalisées chez des patients avec CBNPC EGFR m+ de stade IIIB/IV ayant reçu afatinib 40 mg/j dans LL3, 6 ou 7. Les analyses étaient réalisées séparément pour les patients avec et sans MC à l'inclusion. Le risque de progression au SNC vs progression non-SNC ou décès était calculé sur la base de la fréquence cumulative de l'évènement d'intérêt vs l'évènement de risque concurrent. Chez les patients avec MC à l'inclusion recevant afatinib dans LL3 et 6 (n = 48 ; suivi médian 10,3 mois), 31,3 % ont eu une progression au SNC vs 52,1 % avec progression non-SNC ; l'incidence cumulative (SNC vs non-SNC) était de 15,5 % vs 17,7 % à 6 mois, et 24,5 % vs 24,4 % à 12 mois. Chez les patients sans MC à l'inclusion recevant afatinib dans LL3, 6 et 7 (n = 485 ; suivi médian 13,0 mois), le risque de progression de novo au SNC était très faible (6,4 %) comparé à une progression non-SNC (78,4 %) ; l'incidence cumulative (SNC vs non-SNC) était de 1,3 % vs 17,2 % à 6 mois, et 2,6 % vs 41,2 % à 12 mois. Les analyses de risques concurrents à partir des données de LL3, 6 et 7 s'ajoutent aux preuves existantes soutenant l'utilisation d'afatinib chez les patients CBNPC EGFR m+ avec métastases au niveau du SNC. Ces résultats montrent qu'afatinib retarde l'apparition/progression de MC.

ObjectivesWith the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), sequential therapy could potentially render EGFR mutation-positive non-small cell lung cancer a chronic disease in some patients. In this retrospective analysis of EGFR mutation-positive (Del19/L858R) patients receiving first-line afatinib in LUX-Lung 3, 6, and 7, we assessed uptake of, and outcomes following, subsequent therapies including the third-generation EGFR TKI, osimertinib.MethodsPost-progression therapy data were prospectively collected during follow-up. Molecular testing of tumours at progression/discontinuation of afatinib was not mandatory. Duration of subsequent therapies, and survival following osimertinib, were calculated with Kaplan–Meier estimates.ResultsAmong 553 patients who discontinued first-line afatinib, second-, third- and fourth-line therapy was administered in 394 (71%), 265 (48%), and 156 (28%) patients. The most common post-progression therapy was platinum-based chemotherapy (46%). Thirty-seven patients received subsequent osimertinib, 10 as second-line treatment. Median progression-free survival on afatinib in these 37 patients was 21.9 months. Median duration of osimertinib therapy was 20.2 months; median overall survival was not reached after a median follow-up of 4.7 years.ConclusionsMost patients treated with first-line afatinib received subsequent therapy. Although limited by sample size, enrichment, and a retrospective nature, data from patients who received sequential afatinib and osimertinib are encouraging, warranting further investigation.

In the LUX-Lung 3 and 6 trials, first-line afatinib significantly improved progression-free survival (PFS) versus chemotherapy in patients with EGFR mutation-positive (EGFRm+) NSCLC and baseline brain metastases (hazard ratio [HR], 0.50; P=0.0297).1 In LUX-Lung 7, similar PFS improvement with afatinib versus gefitinib was observed in patients with, and without, brain metastases (HR, 0.76 and 0.74; Pint=0.93).2 The aims of this study were to assess: i) the impact of afatinib on central nervous system (CNS) progression or metastatic spread in LUX-Lung 3, 6, and 7; ii) efficacy of afatinib in patients with brain metastases in a similar setting to ‘real-world’ practice. Competing risk analysis of CNS/non-CNS progression or death was performed in patients who received afatinib in LUX-Lung 3, 6, and 7, based on the cumulative frequency of the event of interest versus the competing risk event. Separate analysis was performed of an Asian phase IIIb study, which assessed afatinib in a broad population of EGFR TKI-naïve patients with EGFRm+ NSCLC (NCT01953913).3 PFS and time-to-symptomatic progression (TTSP) in patients with baseline brain metastases were calculated by Kaplan–Meier methodology. In patients with baseline brain metastases receiving afatinib in LUX-Lung 3 and 6 (n=48; median follow-up: 10.3 months), the risk of CNS progression was 40% lower than the risk of extracranial progression; 31.3%/52.1% of patients had CNS/non-CNS progression, respectively. In patients without baseline brain metastases receiving afatinib in LUX-Lung 3, 6, and 7 (n=485; median follow-up: 13.0 months), the risk of de novo CNS/non-CNS progression was 6.4%/78.4%. Cumulative risk of CNS/non-CNS progression was 1.3%/17.2% at 6 months and 2.6%/41.2% at 12 months. In the Asian phase IIIb study, there was no difference in PFS (median 10.9 vs 12.4 months; P=0.18) or TTSP (median 14.8 vs 15.4 months; P=1.0) between patients with (n=92) or without (n=387) brain metastases. Competing risk analyses of LUX-Lung 3, 6, and 7 suggest that afatinib delays the onset/progression of brain metastases. Real-world data are consistent with LUX-Lung 3, 6, and 7, and support the use of afatinib in patients with EGFRm+ NSCLC and baseline brain metastases. 1. Schuler, M. et al. J Thorac Oncol 2016;11:380‒90 2. Park, K. et al. Lancet Oncol 2016;17:577‒89 3. Wu YL, et al. J Thorac Oncol 2017;12(suppl 2):abstract P3.01-036

In the randomized phase IIb LUX-Lung 7 trial, afatinib significantly improved progression-free survival (PFS) and time-to-treatment failure vs gefitinib in patients with treatment-naïve epidermal growth factor receptor mutation-positive non-small cell lung cancer. We report post hoc analyses of tolerability-guided dose adjustment for afatinib and summarize the clinical characteristics of patients who continued afatinib/gefitinib beyond initial radiological progression in LUX-Lung 7. Patients received afatinib 40 mg/day or gefitinib 250 mg/day until investigator-assessed progression or beyond if beneficial. In case of selected treatment-related adverse events (TRAEs), the afatinib dose could be reduced by 10-mg decrements to minimum 20 mg (only dose interruptions were permitted with gefitinib). All randomized patients were treated (afatinib, n = 160; gefitinib, n = 159). Sixty-three patients had afatinib dose reduction (< 40 mg/day; 47 within first 6 months). Dose reduction decreased TRAE incidence/severity (before vs after; all grade/grade 3: 100.0%/63.5% vs 90.5%/23.8%). There was no evidence of significant difference in PFS for patients who received < 40 mg/day vs ≥ 40 mg/day for the first 6 months [median: 12.8 vs 11.0 months; hazard ratio 1.34 (95% confidence interval 0.90–2.00)]. Twenty-four and 26 patients continued afatinib and gefitinib, respectively, beyond progression in target lesions; median time from nadir of target lesion diameters to initial progression was 6.7 months and 5.6 months. Of these patients, ~ 70% had objective response or non-complete response/non-progressive disease in non-target lesions at initial progression. Protocol-defined dose adjustment of afatinib may allow patients to remain on treatment longer, maximizing clinical benefit even in the presence of radiological progression.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for first-line therapy in patients with EGFR mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC). However, many patients with EGFR M+ NSCLC eventually acquire resistance to first and second generation TKIs, which commonly occurs with the onset of a T790M mutation.1,2,3,4 Due to the different resistance mechanisms caused by first- and second-generation TKIs versus third-generation TKIs, and the subsequent availability of targeted treatment options, the sequence of TKIs in EGFR M+ NSCLC must be considered. Previous studies have shown the effectiveness of afatinib followed by osimertinib in delaying later chemotherapy, but there is not yet agreement on wider use of this sequencing strategy. The aim of this survey was to establish a global expert consensus on TKI sequencing strategies in EGFR M+ NSCLC. The global panel (7 expert oncologists) reached consensus by a modified Delphi approach (e-surveys). The panellists voted on each statement: disagree, agree, agree with changes (consensus defined as ≥85% agree). Statements without consensus were refined as per suggested changes (through freeform answers to the ‘agree with changes’ option) and re-voted on. Voting was electronic. The project was funded by Boehringer Ingelheim, who had no role in the development of the Delphi questions or the voting process. The panel reached consensus that it is important to consider the sequencing of treatments when deciding which EGFR TKI to choose for a patient with advanced EGFR M+ NSCLC, and that optimising TKI sequencing may delay the need for chemotherapy. When choosing the appropriate TKI, the panel reached consensus that a treatment sequence which extends survival, without compromising quality of life, is an important factor when treating patients with advanced EGFR M+ NSCLC. The panel also reached consensus that the sequential strategy of afatinib followed by osimertinib is a viable option to prolong the chemotherapy-free period, in particular for the 75% of patients with an Exon 19 deletion (del19) who acquire T790M mutations after first-line treatment.2,5 The survey confirms the importance of considering the sequencing of treatments when deciding which TKI to choose for patients with advanced EGFR M+ NSCLC, and provides an expert consensus view on the treatment priorities for this patient population. References: 1. Novello S, et al. Ann Oncol 2016;27(Suppl. 5):v1–27. 2. Jenkins S, et al. J Thorac Oncol 2017;12(8):1247–56. 3. Matsuo N, et al. Sci Rep 2016;6:36458. 4. Lau K-S, et al. Poster presented at ESMO 2016 (Poster 1243P) 5. Hochmair M, et al. Targeted Oncology 2019

Background Little evidence has been generated for how best to manage patients with non-small-cell lung cancer (NSCLC) presenting with rarer clinical scenarios, including oligometastases, oligoprogression, and pseudoprogression. In each of those scenarios, oncologists have to consider how best to balance efficacy with quality of life, while maximizing the duration of each line of therapy and ensuring that patients are still eligible for later options, including clinical trial enrolment. Methods An expert panel was convened to define the clinical questions. Using case-based presentations, consensus practice recommendations for each clinical scenario were generated through focused, evidence-based discussions. Results Treatment strategies and best-practice or consensus recommendations are presented, with areas of consensus and areas of uncertainty identified. Conclusions In each situation, treatment has to be tailored to suit the individual patient, but with the intent of extending and maximizing the use of each line of treatment, while keeping treatment options in reserve for later lines of therapy. Patient participation in clinical trials examining these issues should be encouraged.