Epidermal Growth Factor Receptor Mutation-positive Non-small Cell Lung Cancer Research Articles

Afatinib as First-Line Treatment in Asian Patients with EGFR Mutation-Positive NSCLC: A Narrative Review of Real-World Evidence.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are a standard of care in the first-line treatment of patients with EGFR mutation-positive metastatic non-small-cell lung cancer (NSCLC). EGFR mutations are relatively common in Asian patients with NSCLC, and there is an increasing number of studies supporting the effectiveness of the second-generation TKI afatinib in routine clinical practice in Asia. This article reviews these real-world studies investigating afatinib as first-line treatment for EGFR mutation-positive NSCLC in Asian patients. Evidence from real-world studies with afatinib in this patient population supports findings from randomized controlled trials (RCTs) showing that afatinib is associated with more favorable outcomes compared with the first-generation EGFR TKIs. The effectiveness of afatinib has also been shown in real-world studies in Asian patients with poor prognostic factors, who are often under-represented or excluded from RCTs, such as those with uncommon EGFR mutations, brain metastases, or poor performance status, and elderly patients. The tolerability profile of afatinib in the real-world setting reflects that seen in RCTs, with no new safety signals reported in real-world studies in Asian patients with EGFR mutation-positive NSCLC. Dose-modification strategies also seem to be effective in the real world, with results of the RealGido study, which included 44% Asian patients, confirming findings from prospective clinical trials showing that tolerability-guided afatinib dose modifications can reduce the incidence of adverse events without adversely affecting clinical outcomes. While further research, including clinical trial data, is needed, real-world data have also demonstrated the feasibility of sequential afatinib followed by the third-generation TKI osimertinib in T790M-positive EGFR mutation-positive patients, which showed longer overall survival. Together, these real-world results demonstrate the real-world clinical effectiveness of afatinib as first-line treatment for patients with EGFR mutation-positive NSCLC.

Predicting Survival Duration With MRI Radiomics of Brain Metastases From Non-small Cell Lung Cancer.

Background: Brain metastases are associated with poor survival. Molecular genetic testing informs on targeted therapy and survival. The purpose of this study was to perform a MR imaging-based radiomic analysis of brain metastases from non-small cell lung cancer (NSCLC) to identify radiomic features that were important for predicting survival duration.Methods: We retrospectively identified our study cohort via an institutional database search for patients with brain metastases from EGFR, ALK, and/or KRAS mutation-positive NSCLC. We segmented the brain metastatic tumors on the brain MR images, extracted radiomic features, constructed radiomic scores from significant radiomic features based on multivariate Cox regression analysis (p < 0.05), and built predictive models for survival duration.Result: Of the 110 patients in the cohort (mean age 57.51 ± 12.32 years; range: 22–85 years, M:F = 37:73), 75, 26, and 15 had NSCLC with EGFR, ALK, and KRAS mutations, respectively. Predictive modeling of survival duration using both clinical and radiomic features yielded areas under the receiver operative characteristic curve of 0.977, 0.905, and 0.947 for the EGFR, ALK, and KRAS mutation-positive groups, respectively. Radiomic scores enabled the separation of each mutation-positive group into two subgroups with significantly different survival durations, i.e., shorter vs. longer duration when comparing to the median survival duration of the group.Conclusion: Our data supports the use of radiomic scores, based on MR imaging of brain metastases from NSCLC, as non-invasive biomarkers for survival duration. Future research with a larger sample size and external cohorts is needed to validate our results.

The role of EGFR-TKIs as adjuvant therapy in EGFR mutation-positive early-stage NSCLC: A meta-analysis.

BackgroundThe role of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) is not clear in early‐stage nonsmall‐cell lung cancer (NSCLC) patients. This meta‐analysis aims to compare the efficacy and safety of EGFR‐TKIs as adjuvant therapy with chemotherapy or placebo in NSCLC patients harboring EGFR mutations.Patients and MethodsPubmed, Embase, and Cochrane databases were searched for randomized controlled trials. The hazard ratio (HR) of disease‐free survival (DFS) and overall survival (OS) as well as the risk ratio (RR) of severe adverse events were merged.ResultsSeven articles from five studies from 1843 records, a total of 1227 patients, were included in the analysis. The HR for DFS was 0.38 (95% confidence interval [CI] 0.22–0.63), in favor of EGFR‐TKIs. However, no significant benefit of OS was seen (HR = 0.61, 95% CI 0.31–1.22). Treatment benefit was more pronounced in patients with advanced disease stage and longer duration of medication, EGFR exon 19 deletion mutation, and treatment with third‐generation EGFR‐TKIs. Adjuvant targeted therapy may cause few adverse events compared with chemotherapy (RR = 0.28, 95% CI 0.09–0.94). The possibility of severe adverse events for the first‐generation drugs was significantly lower than for third‐generation drugs.ConclusionIn EGFR mutation‐positive patients with stage IB–IIIA NSCLC, compared with adjuvant chemotherapy or placebo, adjuvant EGFR‐TKIs should effectively improve the patient's DFS, but not effectively improve OS. Disease stage, treatment duration, mutation types, and therapeutic drugs could affect the degree of benefit. Adjuvant EGFR‐TKIs had more favorable tolerability than chemotherapy, especially with the usage of first‐generation drugs.

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).

P76.68 The Impact of Eligibility for Anti-Angiogenic Treatment to the Prognosis of Patients with Non-Small Cell Lung Cancer Harboring EGFR Mutations

Previous studies described the efficacy of erlotinib plus angiogenesis inhibitors (bevacizumab/ramucirumab) combination therapy compared with erlotinib monotherapy in epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC), regardless of EGFR activating mutation subtype. However, the impact of angiogenesis inhibitors’ eligibility criteria to progression free survival (PFS) and overall survival (OS) is still unclear. Hence, we evaluated the impact of angiogenesis inhibitors’ criteria in patients with NSCLC harboring EGFR activating mutation. We retrospectively collected data of patients with EGFR mutation positive NSCLC who were treated with EGFR tyrosine kinase inhibitor (EGFR-TKI) monotherapy at Shizuoka Cancer Center between 2002 and 2019. Patients whose performance status (PS) was over 3, and those with symptomatic brain metastasis, were excluded from this study. Angiogenesis inhibitors ineligibility was defined as having at least one following conditions; 1) a history of bloody sputum or an exposure of tumor in bronchus, 2) radiologically identified major vessel invasion, 3) a history of cardiovascular disease and 4) history of chemoradiotherapy prior to EGFR-TKI treatment. They were divided into two groups, angiogenesis inhibitors eligible group (AI fit group) and ineligible group (unfit group). A total of 452 patients with NSCLC harboring EGFR activating mutation were included in this study. Among 452 patients, 207 patients had L858R mutation, and 245 patients had exon19 deletion. Median age of all patients was 71 years old (range 31-92), 35.0% were male, 43.1% had history of smoking, and majority of the patients were treated with gefitinib or erlotinib as a first EGFR-TKI (60.3% and 18.8%). AI fit group included 339 patients; 152 patients (44.8%) had L858R and 187 patients (55.2%) had exon19 deletion. In baseline characteristics, patients with PS 2 were more frequently observed in AI unfit group compared with AI fit group. The median PFS of AI fit and unfit group were 12.9 month and 9.6 months (HR 0.72, 95%CI 0.57-0.92, p=0.007), and multivariate analysis indicated PS 2 and AI unfit were associated with shorter PFS. Also, OS was significantly longer in AI fit groups than in unfit group; median OS were 33.0 months and 18.5months, respectively (HR 0.58, 95%CI 0.45-0.74, p<0.001). Multivariate analysis indicated PS 2, AI unfit, EGFR exon 19 deletion, and age ≥75 as significant prognostic factors. Out of four AI eligibility definitions, bloody sputum or exposure of tumor in bronchus were significantly associated with poor PFS (HR 1.43, 95%CI 1.07-1.98 p=0.017) and OS (HR 1.67, 95%CI 1.18-2.36 p=0.004). There was no significant difference in PFS between EGFR mutation subtypes in AI fit group; median PFS were 11.5months in L858R mutation and 13.8months in exon19 deletion (HR 0.85, 95%CI 0.67-1.07 p=0.17). In EGFR mutation positive NSCLC patients, the eligibility of AI was associated with longer PFS and OS, and resulted in insignificance of PFS between L858R and exon19 deletion group. Since these selection bias may have affected previous clinical trials data showing the efficacy of AI plus EGFR-TKI, the results of clinical trials should be carefully considered of its benefits.

A Phase II Study to Assess the Efficacy of Osimertinib in Patients With EGFR Mutation-positive NSCLC Who Developed Isolated CNS Progression (T790M-negative or Unknown) During First- or Second-generation EGFR-TKI or Systemic Disease Progression (T790M-negative) After Treatment With First- or Second-generation EGFR-TKI and Platinum-based Chemotherapy (WJOG12819L)

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has recently been established as a standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non–small-cell lung cancer (NSCLC). However, only about one-half of patients who have received prior treatment with a first- or second-generation EGFR-TKI are eligible for osimertinib therapy because its indication in the second-line setting is limited to metastatic NSCLC positive for the T790M resistance mutation of EGFR. The dose-escalation part of a study in which patients received osimertinib at doses of 20 to 240 mg once daily after the development of resistance to first- or second-generation EGFR-TKIs revealed a response rate of 21% and a median progression-free survival of 2.8 months for individuals whose tumors were negative for EGFR T790M. We have now designed a phase II study of osimertinib for patients with EGFR mutation–positive NSCLC who develop isolated central nervous system progression (T790M-negative or unknown) after first- or second-generation EGFR-TKI therapy (cohort 1) or who develop systemic disease progression (T790M-negative) after first- or second-generation EGFR-TKI therapy and platinum-based chemotherapy (cohort 2). A total of 70 patients (cohort 1, n = 17; cohort 2, n = 53) will be enrolled in this study, which originated from a suggestion of a dedicated network for patients with lung cancer in Japan.

The cost-effectiveness of dacomitinib in first-line treatment of advanced/metastatic epidermal growth factor receptor mutation-positive non-small-cell lung cancer (EGFRm NSCLC) in Sweden

Aims Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) over chemotherapy in EGFR mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC) has been demonstrated in clinical trials, the optimal treatment sequence remains unclear. The objective of our study was to evaluate the cost-effectiveness of dacomitinib in Sweden vs afatinib and osimertinib in first-line treatment of EGFRm NSCLC. Materials and methods A partitioned survival model was developed with three health states: progression-free, post-progression, and death. Progression-free and overall survival curves were used to inform movements between states. Clinical data were taken from randomized trials, compared via a network meta-analysis (NMA). Utility data were taken from published studies and costs from national Swedish sources. The model used a 15-year time horizon and a Swedish healthcare payer perspective. Sensitivity and scenario analyses were performed. Results The base-case analysis showed that dacomitinib accrued a total of 2.10 quality-adjusted life-years (QALYs) at a total cost of Swedish krona (SEK) 874,615. The incremental cost-effectiveness ratio (ICER) for dacomitinib vs afatinib was SEK 461,556 per QALY gained. The ICER of osimertinib vs dacomitinib, where the small QALY gains of the former came at a high additional cost, was SEK 11,444,709. Deterministic and probabilistic sensitivity analyses confirmed the robustness of these results; changes to drug and medical resource use costs and overall survival had the greatest impact on ICER estimates. Limitations This model is subject to uncertainty associated with extrapolating long-term treatment effects from shorter trial follow-up periods, although this would also be a limitation when using direct comparison or time-dependent hazard ratios. The NMA was limited by the use of indirect comparison, although sensitivity analyses supported the robustness of our findings. Conclusions Our model demonstrated that dacomitinib is cost-effective for first-line EGFRm NSCLC treatment in Sweden vs afatinib and osimertinib.

A Phase II study of nab-Paclitaxel (nab-P) in patients with advanced non-small cell lung cancer with EGFR mutations after frontline tyrosine kinase inhibitor therapy

BackgroundPatients with metastatic non-small cell lung cancer (NSCLC) harboring a sensitizing EGFR mutation have effective targeted therapy options initially but most patients eventually progress and receive cytotoxic chemotherapy. In this single-institution phase II study, we evaluated the role of nab-paclitaxel monotherapy in this patient population. Patients and MethodsPatients with metastatic NSCLC with an activating EGFR mutation whose disease progressed after frontline tyrosine kinase inhibitor therapy and who were chemotherapy naïve received nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint was response rate per RECIST 1.1 and secondary endpoints were duration of response, progression free survival, toxicity and overall survival. ResultsA total of 27 patients were enrolled and 21 patients were evaluable for response. Median age was 65 (range 52–81), 69% of patients were women, 42% of patients did not having a smoking history. 31% of patients had central nervous system (CNS) metastatic disease at baseline. Confirmed partial response was documented in 9 of 26 patients (35%, 95% CI 17–56) and disease control rate was 58% (95% CI 35–73). CNS was a common first site of progression. Median progression free survival was 4.0 months (95% CI 1.8–5.2). No new safety signals were observed. ConclusionSingle agent nab-paclitaxel showed modest antitumor activity in patients with EGFR mutation positive NSCLC and may be an option in patients who are platinum ineligible. Patients often progressed in the CNS and the results underscores the importance of CNS activity of systemic therapies in this patient population.

Treatment patterns, testing practices, and outcomes in the pre-FLAURA era for patients with EGFR mutation-positive advanced NSCLC: a retrospective chart review (REFLECT).

Introduction:For epidermal growth factor receptor mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC), EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the preferred first-line (1 L) treatment in the advanced setting. Osimertinib, a third-generation EGFR-TKI, received full approval in 2017 for second-line (2 L) treatment of EGFR T790M-positive NSCLC. The REFLECT study characterizes real-world treatment/testing patterns, attrition rates, and outcomes in patients with EGFRm advanced NSCLC treated with 1 L first-/second-generation (1G/2G) EGFR-TKIs before 1 L osimertinib approval.Methods:Retrospective chart review (NCT04031898) of European/Israeli adults with EGFRm unresectable locally advanced/metastatic NSCLC, initiating 1 L 1G/2G EGFR-TKIs 01/01/15–30/06/18 (index date).Results:In 896 patients (median follow-up of 21.5 months), the most frequently initiated 1 L EGFR-TKI was afatinib (45%). Disease progression was reported in 81%, including 10% (86/896) who died at 1 L. By the end of study, most patients discontinued 1 L (85%), of whom 33% did not receive 2 L therapy. From index, median 1 L real-world progression-free survival was 13.0 (95% confidence interval (CI): 12.3–14.1) months; median overall survival (OS) was 26.2 (95% CI: 23.6–28.4) months. 71% of patients with 1 L progression were tested for T790M; 58% were positive. Of those with T790M, 95% received osimertinib in 2 L or later. Central nervous system (CNS) metastases were recorded in 22% at index, and 15% developed CNS metastases during treatment (median time from index 13.5 months). Median OS was 19.4 months (95% CI: 17.1–22.1) in patients with CNS metastases at index, 24.8 months (95% CIs not available) with CNS metastases diagnosed during treatment, and 30.3 months (95% CI: 27.1, 33.8) with no CNS metastases recorded.Conclusion:REFLECT is a large real-world study describing treatment patterns prior to 1 L osimertinib availability for EGFRm advanced NSCLC. Given the attrition rates highlighted in the study and the impact of CNS progression on outcomes, offering a 1 L EGFR-TKI with CNS penetration may improve patient outcomes in this treatment setting.

A prospective phase II study of multimodal prophylactic treatment for afatinib-induced adverse events in advanced non-small cell lung cancer (Niigata Lung Cancer Treatment Group 1401).

BackgroundAfatinib has shown clinical benefits in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Many patients treated with afatinib experience skin or gastrointestinal toxicity. However, an effective management strategy has not been established. This prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity.MethodsThis single-arm prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity in patients with EGFR mutation positive advanced NSCLC who planned to receive a 40 mg dose of afatinib. Eligible patients were treated with oral loperamide (2 mg twice per day), prophylactic minocycline (100 mg once per day), topical medium-class steroids, and gargling with sodium azulene. The primary endpoint was the ability of prophylactic loperamide to prevent severe or intolerable diarrhea during the 4 weeks after the initial administration of afatinib. The incidence, severity and time to occurrence of diarrhea, rash, oral mucositis and paronychia were evaluated based on a daily patient questionnaire.ResultsForty-six patients were enrolled. The primary endpoint analysis was performed in 35 patients as the per-protocol (PP) population. The 4-week successful prophylaxis rate for severe or intolerable diarrhea was 82.9% (90% confidence interval: 70.1–91.9%). In the total population, the incidences of grade 3 or higher rash, oral mucositis and paronychia within 4 weeks were 4%, 2% and 4%, respectively.ConclusionsProphylactic loperamide administration was not effective in preventing severe or intolerable diarrhea during afatinib treatment. Adequate dose reduction will be a better approach to manage afatinib-induced diarrhea. Multimodal prevention using minocycline, topical steroids and gargling with sodium azulene may be helpful to maintain compliance with afatinib treatment (UMIN000016167).

Survival benefit and toxicity profile of adjuvant icotinib for patients with EGFR mutation-positive non-small cell lung carcinoma: a retrospective study.

BackgroundAdjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are increasing considered for the tailored management of resectable non-small cell lung cancer (NSCLC). This study aimed to analyze the survival and toxicity profile of patients with EGFR mutation-positive NSCLC treated with adjuvant icotinib.MethodsThis was a single-center retrospective study of patients with EGFR mutation-positive NSCLC who underwent R0 (microscopically margin-negative) resection and received adjuvant icotinib between November 2011 and December 2017. The outcomes included 2-year disease-free survival (DFS) rate, 3-year overall survival (OS) rates, DFS, OS, and adverse events (AEs).ResultsA total of 86 patients receiving adjuvant icotinib were included. Their mean age was 59.7±10.0 years, and 26 (30.2%) patients were male. The 2-year DFS rate was 86.7%, and the 3-year OS rate was 95.3% with adjuvant icotinib. DFS (P=0.044) and OS (P=0.003) are better in stage I/II disease than in stage III disease. There seems no differences in DFS and OS between patients with low or high preoperative CEA levels (cutoff of 5 ng/mL), patients with exon 19 or 21 EGFR mutation or patients with or without smoking history. The most common AEs with adjuvant icotinib were rash (83.7%) and diarrhea (19.8%). One (1.2%) patient-reported grade ≥3 AEs. No treatment-related death occurred.ConclusionsFor patients with EGFR mutation-positive NSCLC, adjuvant icotinib might be associated with a promising survival benefit, with an acceptable toxicity profile.

Effect of Dose Adjustments on the Safety and Efficacy of Afatinib in Chinese Patients with EGFR-Mutated Non-Small Cell Lung Cancer Who Participated in the LUX-Lung Clinical Trial Program.

BackgroundPost hoc analysis of the LUX-Lung 3 and 6 (LL3/6) Phase III trials showed that tolerability-guided dose-adjustments of afatinib reduced treatment-related adverse events (TRAEs) without affecting progression-free survival (PFS) in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). The current post hoc analysis evaluated outcomes of tolerability-guided dose adjustments of afatinib in patients enrolled in the LL3/6/7 trials in Chinese centers.Patients and MethodsPatients enrolled in LL3/6/7 had advanced EGFR mutation-positive NSCLC. LL3 and LL7 recruited patients globally (including China) and LL6 enrolled Asian patients from China, Thailand, and South Korea. In LL3 and LL6, patients were randomized to afatinib 40 mg/day or cisplatin-based chemotherapy. In the Phase IIb LL7 trial, patients were randomized to afatinib 40 mg/day or gefitinib. Tolerability-guided dose adjustments were permitted for TRAEs, and PFS was the primary endpoint. This post hoc analysis pooled data from patients enrolled in Chinese centers in LL3/6/7 and analyzed the frequency and severity of TRAEs before and after afatinib dose reductions during the first 6 months. PFS and overall survival (OS) were compared for patients who had a dose reduction in the first 6 months and those who did not.ResultsOverall, 299 patients were enrolled in Chinese centers; 68 (23%) had afatinib dose reductions to <40 mg/day in the first 6 months. Prior to dose reduction, 55/68 patients (81%) experienced grade ≥3 TRAE versus 13/68 (19%) after dose reduction. Grade ≥3 TRAEs were much more common in patients with than in those without dose reduction. Median PFS was 11.0 months in both groups, and median OS did not differ significantly: 23.1 months in patients with a dose reduction and 26.9 months in those without a dose reduction.ConclusionTolerability-guided afatinib dose adjustment is an effective strategy to reduce TRAEs without affecting efficacy in Chinese patients.

Osimertinib in Resected EGFR-Mutated Non–Small-Cell Lung Cancer

BackgroundOsimertinib is standard-of-care therapy for previously untreated epidermal growth factor receptor (EGFR) mutation–positive advanced non–small-cell lung cancer (NSCLC). The efficacy and safety of osimertinib as adjuvant therapy are unknown.MethodsIn this double-blind, phase 3 trial, we randomly assigned patients with completely resected EGFR mutation–positive NSCLC in a 1:1 ratio to receive either osimertinib (80 mg once daily) or placebo for 3 years. The primary end point was disease-free survival among patients with stage II to IIIA disease (according to investigator assessment). The secondary end points included disease-free survival in the overall population of patients with stage IB to IIIA disease, overall survival, and safety.ResultsA total of 682 patients underwent randomization (339 to the osimertinib group and 343 to the placebo group). At 24 months, 90% of the patients with stage II to IIIA disease in the osimertinib group (95% confidence interval [CI], 84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive and disease-free (overall hazard ratio for disease recurrence or death, 0.17; 99.06% CI, 0.11 to 0.26; P<0.001). In the overall population, 89% of the patients in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free at 24 months (overall hazard ratio for disease recurrence or death, 0.20; 99.12% CI, 0.14 to 0.30; P<0.001). At 24 months, 98% of the patients in the osimertinib group (95% CI, 95 to 99) and 85% of those in the placebo group (95% CI, 80 to 89) were alive and did not have central nervous system disease (overall hazard ratio for disease recurrence or death, 0.18; 95% CI, 0.10 to 0.33). Overall survival data were immature; 29 patients died (9 in the osimertinib group and 20 in the placebo group). No new safety concerns were noted.ConclusionsIn patients with stage IB to IIIA EGFR mutation–positive NSCLC, disease-free survival was significantly longer among those who received osimertinib than among those who received placebo. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.)

Treatment and Outcomes of Metastatic Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: Are They Different from Those with Common EGFR Mutations?

Simple SummaryThe present study showed the comprehensive analysis of disease characteristics and treatment patterns in uncommon EGFR mutation-positive NSCLC at a major cancer center. This study showed the efficacy of 1G or 2G EGFR-TKIs as the 1L treatment, and subsequent therapy including 3G EGFR-TKIs in the real-world setting.Approximately 10% of the epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are uncommon EGFR mutations. Although the efficacy of second (2G) or third generation (3G) EGFR tyrosine kinase inhibitors (EGFR-TKIs) in the patients with uncommon EGFR mutation has been proven, further studies are warranted to define the optimal treatment approach for uncommon EGFR mutation-positive NSCLC. This study retrospectively investigated the treatment patterns and outcomes of patients with uncommon EGFR mutation-positive NSCLC from January 2011 to December 2019 at the Samsung Medical Center, Seoul, Korea. During the study, 2121 patients with EGFR mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. Of this, 135 (6.4%) patients harbored uncommon EGFR mutations. Of 135, 54 (40%, 54/135) patients had overlapping mutations with major EGFR mutations. The objective response rate (ORR) for the 1L EGFR-TKI was 63.3%. The median progression-free survivals (PFSs) were 8.6 months (95% CI: 3.8–13.5), 11.7 months (95% CI: 6.6–16.7), 7.7 months (95% CI: 4.9–17.4), and 5.0 months (95% CI: 3.7–6.1) for major uncommon EGFR mutation (G719X, L861Q), compound mutation with major EGFR mutation (Del 19 or EGFR exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The median overall survivals (OSs) were 25.6 months (16.9–34.2), 28.8 (95% CI: 24.4–33.4), 13.5 months (95% CI: 7.4–27.8), and 9.4 months (95% CI: 3.4–10.5) for major uncommon EGFR mutation (G719X), compound mutation with major EGFR mutation (Del 19 or EGFR exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The response rate, median PFS, and OS were 63.3%, 16.3 months (95% CI: 15.6–16.9), and 37.5 months (95% CI: 35.4–39.6) for common EGFR mutation-positive NSCLC. After failing 1L EGFR-TKI, repeated tissue or liquid biopsy were carried out on 44.9% (35/78) of patients with T790M detected in 10/35 (28.6%) patients. With subsequent 3G EGFR-TKI after failing the first-line EGFR-TKI, the ORR and PFS for 3G EGFR-TKI were 80% and 8.9 months (95% CI: 8.0–9.8). These patients showed a median OS of 34.6 months (95% CI: 29.8–39.4). The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common EGFR mutations. T790M was detected in 28.6% of the uncommon EGFR mutation-positive patients for whom prior 1G/2G EGFR-TKIs failed and underwent repeat biopsy at the time of progression.

Optimal sequencing strategies in the treatment of EGFR mutation-positive non-small cell lung cancer: Clinical benefits and cost-effectiveness.

PurposeTo 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.ConclusionPreliminary 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.

1365P A prospective, phase II trial of low-dose afatinib monotherapy for patients with EGFR, mutation-positive, non-small cell lung cancer (TORG1632)

Afatinib is an effective treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC), however, its toxicities often require dose modifications. The aim of this study was to assess the efficacy and safety of low dose afatinib monotherapy in patients with EGFR mutation-positive NSCLC.

Sequential afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: final analysis of the GioTag study.

Aim: Final overall survival (OS) and time on treatment analysis of patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) who received sequential afatinib and osimertinib. Patients & methods: Patients (n=203) had T790M-positive disease following first-line afatinib and started osimertinib treatment ≥10 months before data entry. Primary outcome was time on treatment; OS analysis was exploratory. Results: Median time on treatment with afatinib and osimertinib was 27.7months (90% CI: 26.7-29.9). Median OS was 37.6months (90% CI: 35.5-41.3); median OS was 41.6 and 44.8months in Del19-positive patients and Asian patients, respectively. Conclusion: In real-world clinical practice, sequential afatinib and osimertinib was associated with encouraging outcomes in patients with EGFR mutation-positive NSCLC, especially in Del19-positive patientsand Asian patients. Clinical Trial Registration: NCT03370770(ClinicalTrials.gov).

Abstract 5279: HSP72 expression and suppression of resistance is associated with survival in EGFR mutated NSCLC

Abstract Background: Patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations initially respond favorably to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Acquired resistance develops in most patients, usually due to new DNA mutations. Our previous work has shown that EGFR-TKI therapy blocked phosphorylation of Hsp72, leading to degradation and suppression of polymerase α error editing and base excision repair, causing an increase in the overall mutation rate. This study evaluated baseline Hsp72 expression in EGFR mutated NSCLC and assessed Hsp72 ability to suppress EGFR-TKI resistance and improve overall survival (OS) of patients with EGFR mutated NSCLC. Methods: A retrospective cohort of patients was identified with known EGFR mutation positive NSCLC and available tissue from the City of Hope Comprehensive Cancer Center seen between 2008 and 2016. Patients were classified into two groups based on HSP72 levels: less than the mean HSP72 level (low expression, n = 40) and greater than or equal to the mean HSP72 level (high expression, n = 22), and examined OS. A chi-square test for categorical data and multivariate logistic regression analyses was used to study the relation between HSP72 expression and other clinical and demographic data. In vitro, HSP72 overexpression was induced by BPG-15 and degradation was blocked with bortezomib. We analyzed resistance in EGFR mutant NSCLC with osimertinib alone, and in combination with osimertinib and BPG-15 or bortezomib. Results: Sixty-three patients with EGFR mutated NSCLC and available tissue were identified. Median survival of high and low HSP72 expression were 51.5 and 28.8 months respectively (p = 0.003, log-rank test), with HR of 0.47 (95% CI 0.29-0.77). When stratifying by stage (removal of stage I and II patients), the HR associated with a high HSP72 expression remained 0.47 (95% CI 0.29-0.77). In vitro studies showed that in the absence of bortezomib or BGP-15, time to resistance to osimertinib in HCC827 cells was 13 days. In the presence of bortezomib or BGP-15, time to resistance was 29 and 25 days, respectively. A similar phenomenon was observed with the EGFR-TKI, erlotinib. Conclusions: In EGFR mutated NSCLC, a high level of HSP72 expression is associated with improved survival. Furthermore, HSP72 inducing drugs delays the development of resistance in EGFR-mutated NSCLC cancer cells, and mechanisms are under investigation. Supported by R01 CA073764 (BHS), R50 CA211397 (LZ), the William and Anna Tenenblatt Foundation (BHS, KR) and the STOP Cancer Carrie Scott Seed grant (KR). Citation Format: Li Zheng, Angel R. Baroz, Erminia Massarelli, Joy Huang, Ravi Salgia, Binghui Shen, Karen L. Reckamp. HSP72 expression and suppression of resistance is associated with survival in EGFR mutated NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5279.

Abstract CT303: The effect of savolitinib plus osimertinib on ctDNA clearance in patients with EGFR mutation positive (EGFRm) MET-amplified NSCLC in the TATTON study

Abstract MET-amplification is a resistance mechanism seen in &amp;gt;25% of pts with EGFRm non-small cell lung cancer (NSCLC) and progression on osimertinib (1st/later line), a 3rd gen, irreversible, oral EGFR-TKI. Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent and highly selective MET-TKI. In Phase 1b TATTON (NCT02143466) expansion cohorts (Parts B and D), pts with MET-amplified EGFRm advanced NSCLC and progression on a prior EGFR-TKI received osimertinib 80 mg + savolitinib 600/300 mg. Part B was split into cohorts (B1, B2 and B3) by prior therapy and T790M status. Pts in Part D (no prior 3rd gen EGFR-TKI, T790M negative; savolitinib 300 mg) had similar response rates and progression-free survival (PFS) to pts in cohort B2 (analogous cohort; savolitinib 600 mg). In osimertinib-treated pts with EGFRm NSCLC (AURA3, FLAURA), circulating tumor (ct)DNA clearance has been shown to correlate with PFS. We report EGFRm (Ex19del/L858R) ctDNA clearance at two doses of savolitinib + osimertinib 80 mg in TATTON Parts B and D. For this next generation sequencing-based analysis (Resolution Bioscience), ctDNA samples were collected pre-dose, cycle (C) 1 day (D) 1 and at least every 3-8 weeks until discontinuation. Part B pts evaluable for efficacy and with a baseline plus ≥1 longitudinal ctDNA sample at/before C6D1 were included. Data from ctDNA evaluable Part B pts (n=49) identified ctDNA clearance correlates with longer PFS and C3D1/C4D1 as optimal time points for PFS prediction, thus the first 20 pts from Part D with available plasma samples at C1D1 and C4D1 were included. The proportion of pts with detectable EGFRm at baseline was similar across groups (Table). ctDNA clearance was comparable at C3D1/C4D1 for cohort B2 and Part D. ctDNA clearance was similar between the two doses of savolitinib, suggesting efficacy is maintained at the lower dose (300 mg). These data also indicate that ctDNA clearance may be predictive of PFS in EGFRm MET-amplified NSCLC. TATTON Part B and Part D ctDNA analysisPart B: osimertinib 80 mg QD + savolitinib 600 mg QD (n=107)*Part D: osimertinib 80 mg QD + savolitinib 300 mg QD (n=42)#All Part BCohort B2 No prior third-generation EGFR-TKI (T790M negative)All Part D No prior third-generation EGFR-TKI (T790M negative)Number of patients492020Detectable EGFRm at baseline, n (%)38 (78)15 (75)16 (80)ctDNA clearanceNumber of pts evaluable at C3D1/C4D1451820ctDNA clearance at C3D1/C4D1, n (%)22 (45)10 (50)13 (65)‡*Interim data cut-off: 28 Feb 2018 #Interim data cut-off: 29 Mar 2019 ‡ctDNA clearance for patients at Part D was only assessed at C4D1 Citation Format: Ryan Hartmaier, Ji-Youn Han, Myung-Ju Ahn, Byoung Chul Cho, Mireille Cantarini, Paul Frewer, Melanie M. Frigault, Geoffrey Oxnard. The effect of savolitinib plus osimertinib on ctDNA clearance in patients with EGFR mutation positive (EGFRm) MET-amplified NSCLC in the TATTON study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT303.

Abstract 1864: Generation of a triple-mutation (T790M/C797S/L858R) NSCLC cell line for relevant drug discovery and development

Abstract Epidermal Growth Factor Receptor (EGFR) overexpression is observed in a large subset of patients with non-small-cell lung cancer (NSCLC) and correlated with poor prognosis. Current approved treatment for EGFR mutation-positive NSCLC has been revolutionized with three generations of EGFR tyrosine kinase inhibitors (TKIs): the first- and second-generation TKIs, such as gefitinib, erlotinib and afatinib, selectively targeting EGFR activating mutations existing in exon 19 and 21; and the third-generation EGFR-wild-type sparing, irreversible activating mutations/T790M inhibitor, osimertinib. Patients with somatic activating mutations in the EGFR gene have dramatic response initially, but would eventually develop resistance to these TKIs. One leading evidence of osimertinib resistance is mediated by occurrence of the point mutation C797S. There are no effective therapeutic strategies to overcome this triple-mutation (activating mutations/T790M/C797S) mediated resistance. Therefore, it is urged to develop new drug to target this particular mutant. There is still lack of triple-mutation in vitro model for the new generation drug discovery. In this study, a triple-mutation NSCLC model was generated in the NCI-H1975 lung cancer cell line, which harbors other naturally occurring EGFR genomic aberrations - double-mutation (T790M/L858R) - inherent in NSCLC. We utilized the CRISPR/Cas9 genome editing tool to target endogenous loci in human NSCLC cell line NCI-H1975 and created the intend point mutation, resulting in the triple mutation cell line (T790M/C797S/L858R). Further phenotypic analysis demonstrated that the triple-mutation cell line was resistant to the third generation inhibitors in contrast to the parental double-mutation cell line. This newly developed triple-mutation lung cancer cell line provided a very useful tool for oncology drug discovery for NSCLC. Citation Format: Huiying Ma, Peixue Li, Peiran Zhang, Fuyun Sun, Qing Lin. Generation of a triple-mutation (T790M/C797S/L858R) NSCLC cell line for relevant drug discovery and development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1864.