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

Combination of traditional Chinese medicine and epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of non-small cell lung cancer

Background:In China, traditional Chinese medicine (TCM) is an increasingly important part of the treatment of non-small cell lung cancer (NSCLC), which usually includes a combination of prescription and syndrome differentiation. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been proven to be the first-line drugs for the treatment of advanced EGFR mutation-positive NSCLC. In China, EGFR-TKIs are used in combination with traditional Chinese medicines to reduce side effects and/or enhance effectiveness. Nevertheless, the relationship between TCMs and EGFR-TKIs remain unclear. This meta-review aimed to explore the clinical evidence of TCMs combined with EGFR-TKIs in the treatment of NSCLC.Methods:Related studies were found by searching the databases of EMBASE, PubMed, Web of Science, MEDLINE, Cochrane library database, China Academic Journals (CNKI), Wanfang and Weipu. This study included 57 randomized controlled trials, all of these were processed by Stata software (version 12.0). In the study, all the materials are published articles, patient anonymity and informed consent and ethics Approval/Institutional review board are not necessary.Results:This study demonstrated that the objective response rate was higher in the group of TCMs plus EGFR-TKIs than in the group of EGFR-TKIs alone (risk ratios 1.39, 95% confidence intervals [1.29, 1.50]). Further research of specific herbal medicines showed that Huangqi, Baishu, Fuling, Gancao, Maidong, Baihuashecao, Shashen, Dangshen and Renshen, had significant higher contributions to results.Conclusion:TCMs may improve the efficacy of EGFR-TKIs in the treatment of NSCLC.

Making the case for EGFR TKI sequencing in EGFR mutation-positive NSCLC: a GioTag study US patient analysis.

Aim: To assess time-to-treatment failure (TTF) in US patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) who received sequential afatinib-osimertinib treatment in the global, observational GioTag study. Patients & methods: Patients had EGFR T790M mutation-positive disease after first-line afatinib and subsequently received osimertinib. The primary outcome was TTF. Results: In 129 patients at US centers, median TTF was 28.4 months (90% CI: 27.0-34.1). Median overall survival was 47.6 months (90% CI: 35.5-51.5). Conclusion: Sequential afatinib-osimertinib in this US-treated population was associated with long median TTF and represents an effective, evidence-based treatment option for US patients with EGFR mutation-positive NSCLC not presenting with active brain metastases or de novo T790M. Clinical Trial Registration: NCT03370770 (ClinicalTrials.gov).

Real-world osimertinib for EGFR mutation-positive non-small-cell lung cancer with acquired T790M mutation.

Aim: Osimertinib is a key drug for EGFR mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. Patients & methods: We retrospectively analyzed the clinical courses of EGFR mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Results: Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Conclusion: Osimertinib is active for T790M-driven acquired resistance in EGFR-mutant NSCLC, but the detection of T790M was unsatisfactory. Clinical Trial Registration: UMIN000028989 (UMIN Clinical Trials Registry).

Development, internal validation and calibration of a risk score to predict survival in patients with EGFR-mutant non-small cell lung cancer

AimsEGFR tyrosine kinase inhibitors (TKIs) are first-line molecularly targeted therapies in patients with advanced non-small cell lung cancer (NSCLC) who carry sensitising EGFR mutations, due to its superior survival outcomes...

Real-world disease burden and outcomes of brain metastases in EGFR mutation-positive non-small-cell lung cancer.

Aim: To evaluate the real-world impact of brain metastases (BM) among patients with EGFR mutation-positive (EGFRm) metastatic non-small-cell lung cancer (NSCLC). Materials & methods: This retrospective, observational matched cohort electronic health record study assessed adults with EGFRm metastatic NSCLC with/without BM. Results: Among 402 patients split equally between both cohorts (±BM), the majority were Caucasian (69%), female (65%) and with adenocarcinoma (92%). Overall symptom burden and ancillary support service use were higher and median overall survival from metastatic diagnosis was significantly shorter in BM patients (11.9 vs 16 months; p = 0.017). Conclusion: BM in EGFRm NSCLC patients can negatively impact clinical outcomes. New targeted therapies that can penetrate the blood-brain barrier should be considered for treating these patients.

Final analysis of a phase II, open label, randomized study of osimertinib versus osimertinib plus carboplatin/pemetrexed for patients with locally advanced or metastatic non-small cell lung cancer whose disease has progressed with previous EGFR-TKI and whose tumours harbour a T790M mutation (LOGIK1604/NEJ032A).

e21594 Background: Osimertinib is now available not only as a second line treatment for the patients with EGFR and T790M-mutation positive non-small cell lung cancer (NSCLC) after initial tyrosine kinase inhibitors (TKIs) but as a first line treantment for those who are TKI-naive. The efficacy and the safety of osimertinib plus palatinum-based chemotherapy has not yet been evaluated. Methods: This phase 2, open-label, randomized study enrolled adult patients (pts) with clinical stage IIIB or IV, or postoperative recurrent NSCLC harbouring susceptible EGFR and T790M mutations after preceded EGFR-TKI failure. Pts were randomly assigned to receive either an osimertinib [80 mg/day 1-21; q3w] or a combination of osimertinib [80 mg/day 1-21] with carboplatin/pemetrexed (hereafter combination) [area under the curve (AUC) = 5 and 500 mg/m2 day 1; q3w]. The primary endpoint was progression-free survival (PFS). Secondary endpoints included incidence of adverse events, response rate and overall survival. As indiction of osimertinib was expanded to a first line, we amended the protocol to discontinue the enrollment and perform final analyses. Results: From October 2016 to January 2019, 62 pts were enrolled [31 pts osimertinib; 31 pts combination] (median age 68 (37-80); 53.2% male; 83.3% stage IV; 100% adenocarcinoma; 59.7% exon 19 deletion and 40.3% L858R; 45.2% never smoker). The rate of grade (G) ≥ 3 treatment-related adverse events was 32.2% in the osimertinib group and 83.9% in the combination group. Neutropenia, anemia and thrombocytopenia were more common in the combination group and the rates of G ≥ 3 were 0%, 0% and 6.4% in the osimertinib group and 38.7%, 25.8% and 29.1% in the combination group, respectively. Three episodes (9.7%) of G ≥ 3 infection and one episode (3.2%) of G ≥ 3 febrile neutropenia were uniquely observed in the combination group, however, these were well managed. Two episodes (6.5%) of G ≥ 3 pneumonitis was observed only in the osimertinib group. Exaggeration of adverse events specific for osimertinib or any unknown adverse event was not observed in the combination group. Final PFS analysis is to be demonstrated in the presentation. Conclusions: Combination of osimertinib with carboplatin and pemetrexed demonstrated safety in patients with EGFR and T790M mutation-positive NSCLC and the efficacy should be validated in the future phase 3 study. Clinical trial information: 000024438.

RELAY study of erlotinib (ERL) + ramucirumab (RAM) or placebo (PL) in EGFR-mutated metastatic non-small cell lung cancer (NSCLC): Biomarker analysis using circulating tumor DNA (ctDNA) in Japanese patients (pts).

9527 Background: The phase III RELAY study (NCT02411448) showed significantly improved progression-free survival (PFS) for RAM+ERL vs PL+ERL in 449 pts with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4 mo, HR 0.591 [95% CI 0.461–0.760], p<.0001). To understand baseline genetic mutations and treatment-emergent (TE) resistance mechanisms, this exploratory liquid biopsy substudy examined biomarkers in ctDNA from participating Japanese pts by next-generation sequencing (NGS) and droplet digital PCR (ddPCR). Methods: Plasma samples were collected at baseline, during treatment (Cycle 4, 13, and every 6 cycles to Cycle 53) and post-study treatment discontinuation (30-day follow-up [30d FU]). Mutations were assessed at baseline and 30d FU by NGS (Ion AmpliSeq Colon and Lung Cancer panel). EGFR mutations and MET and ERBB2 copy number (CN) were assessed at all time points by ddPCR. Baseline markers were analyzed in pts with any detectable baseline mutation (to confirm ctDNA presence; NGS N=84, ddPCR N=74). TE mutations were analyzed in pts with any detectable mutation at baseline and 30d FU (NGS N=26, ddPCR N=28). Among these pts, 81% and 57% for NGS and ddPCR, respectively, had progressed by 30d FU. Results: By plasma NGS, baseline EGFR activating mutations (exon 19 deletion or exon 21 [L858R] mutation) were detected in 83.3% of pts. Common co-occurring baseline mutations were TP53 (42.9%), PTEN (7.1%) and KRAS (6.0%). Baseline TP53 mutation rate was higher in men vs women (p=.02). No difference in PFS was detected by baseline TP53 status (interaction predictive p=.45, prognostic p=.33). TE mutations were detected in EGFR (including T790M), FGFR3, KRAS and TP53. Slightly higher rates of TE KRAS (p=.03) and TP53 (p=.07) mutations were detected in RAM+ERL than in PL+ERL. TE total EGFR mutations (p=.65) or TE T790M (p=.69) did not differ by arm. By ddPCR, baseline EGFR activating mutations were detected in all pts. T790M was detected at baseline in 2/37 pts/arm (5.4%) and was TE in 6/11 (55%) RAM+ERL pts and 7/17 (41%) PL+ERL pts. There was a trend (p=.054) for greater ERBB2 CN in RAM+ERL vs PL+ERL at Cycle 4. MET CN decreased slightly at Cycle 4 in both arms (significant in PL+ERL, p=.003). Biomarker levels by ddPCR across all time points will be presented. Conclusions: Though limited by sample size and likely inconsistent tumor shedding, this exploratory study identified potential differences in TP53, KRAS, ERBB2 and MET by demographics, treatment and/or time. Clinical trial information: NCT02411448 .

Observational Study of Treatment Patterns in Patients with Epidermal Growth Factor Receptor (EGFR) Mutation-Positive Non-Small Cell Lung Cancer After First-Line EGFR-Tyrosine Kinase Inhibitors

Epidermal growth factor receptor (EGFR) mutations are observed in approximately 15% of patients with non-small cell lung cancer (NSCLC) in the USA. Little is known about treatment patterns in EGFR mutation-positive NSCLC following progression on or after first-line (1L) treatment with first- or second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs). Osimertinib, a third-generation EGFR-TKI, is a treatment option for patients with EGFR T790M-positive NSCLC following progression on 1L EGFR-TKIs. This study analyzed real-world treatment sequencing of EGFR-TKIs, EGFR T790M testing rates, and disposition of patients with EGFR mutations after 1L EGFR-TKI post-FDA approval of osimertinib in patients with EGFR mutation-positive NSCLC. Adult patients with stageIV NSCLC and documented EGFR mutation-positive status were identified between December 1, 2015 and May 31, 2017 from the US Oncology Network iKnowMed™ electronic health record (EHR). Data were abstracted from the EHR database and supplemented by chart review. Of 308 patients, 302 (98%) received an EGFR-TKI overall, and 246 patients (80%) received a 1L EGFR-TKI. The most common 1L EGFR-TKI was erlotinib (66%); the remaining 1L regimens were predominantly combination chemotherapies with or without an EGFR-TKI. Only 80 patients (26%) received any 2L therapy. The most common EGFR-TKIs used as 2L monotherapy in patients who received 1L EGFR-TKI were afatinib and osimertinib (n = 7 for both). Among all patients treated with 1L EGFR-TKI (n = 246), 47 (19%) were tested for EGFR T790M [16 patients (34%) were positive], 48 (20%) remained on 1L EGFR-TKI, 29 (12%) received subsequent therapy, 38 (15%) had died on or after their 1L EGFR-TKI therapy, and 131 (53%) stopped their EGFR-TKI with no recorded evidence of having received subsequent therapy at follow-up end. Following 1L EGFR-TKI treatment, 19% of patients were tested for EGFR T790M, and most (69%) had no record of receiving any subsequent therapy.

Observational Study of Sequential Afatinib and Osimertinib in EGFR Mutation-Positive NSCLC: Patients Treated with a 40-mg Starting Dose of Afatinib.

IntroductionEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard of care for patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). However, questions remain about the optimal treatment sequence of EGFR TKIs. The global, observational GioTag study demonstrated prolonged time on treatment with sequential afatinib and osimertinib therapy in patients who acquired the T790M mutation. Here, we assessed outcomes in patients who received the approved 40-mg starting dose of afatinib, as used in the clinical trial setting.MethodsIn the non-interventional, global, multicenter GioTag study, patients had T790M-positive disease following first-line afatinib and started osimertinib treatment ≥ 10 months prior to data entry. Primary outcome was time on treatment. This subanalysis assessed outcomes in patients who received afatinib 40 mg.ResultsIn 169 patients who received an afatinib starting dose of 40 mg, median time on treatment was 27.6 months (90% confidence interval [CI] 26.3–31.3). Benefit was seen across patient subgroups, particularly those with Del19-positive disease and Asian patients; median time on treatment was 29.9 months (90% CI 27.6–46.7) in patients with Del19-positive disease and 46.7 months (90% CI 28.4–not reached) in Asian patients. The 2-year overall survival rate was 80%.ConclusionsThese real-world results support the overall study results and demonstrate prolonged time on treatment with sequential afatinib and osimertinib. The results suggest that sequential afatinib and osimertinib is a feasible therapeutic strategy for patients who acquire the T790M mutation, particularly those with Del19-positive disease or Asian patients.Trial Registration NumberNCT03370770.Electronic Supplementary MaterialThe online version of this article (10.1007/s12325-019-01187-y) contains supplementary material, which is available to authorized users.

Impact of coexisting gene mutations in EGFR-mutated non–small cell lung cancer before treatment on EGFR T790M mutation status after EGFR-TKIs

ObjectivesThe T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation–positive non–small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after EGFR-TKI treatment. Materials and methodsA total of 57 EGFR mutation–positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software. ResultsProgression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P = 0.049). ConclusionsCoexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.

481P - Updated survival outcomes of the phase II study of low starting dose of afatinib as first-line treatment in patients with EGFR mutation-positive non-small cell lung cancer (KTORG1402)

BackgroundThe phase II trial evaluated the efficacy and safety of low starting dose of afatinib in patients with advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). In primary analysis, progression free survival (PFS) met the primary endpoint. Here, we report updated survival outcomes. MethodsThis study was a multi-center, single-arm, open-label phase II trial. Treatment-naïve patients with common EGFR mutation-positive NSCLC were treated with afatinib starting at a dose of 20 mg/day. If tolerated, the dose is increased by 10- mg increments up to 50mg/day. PFS and overall survival (OS) were re-evaluated at the final data cut-off point (October 2018). Results46 patients were enrolled. Median age was 73 years (range, 43-86). The median follow-up was 31.9 months. Median PFS of entire population was 15.2 months (95% confident interval (CI), 13.2–21.2), and 2-year PFS rate was 27.7% (95% CI, 17.1-44.7). Median OS was not estimated, and the 2-year overall survival was 76.1% (95% CI, 64.7-89.5). Performance status (PS) and existence of brain metastases at study entry were revealed to have significant impact on the survival with Cox-regression test. Among patients with disease progression on afatinib (n = 36), rebiopsy was performed on 29 patients, and T790M was proved positive on 14 patients. Twelve out of the 14 patients positive for T790M received osimertinib as a second line therapy. Median time from enrollment to progression on the osimertinib (PFS2) was 32.6 months (95%CI: 20.5-NE). ConclusionsLow starting dose afatinib therapy demonstrated promising OS outcome. PS and existence of brain metastases were predictive factors of this therapy. Clinical trial identificationUMIN 000016444. Legal entity responsible for the studyKyoto Thoracic Oncology Research Group. FundingHas not received any funding. DisclosureT. Yokoyama: Honoraria (self): Boehringer Ingelheim Japan; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Ono pharmaceutical; Honoraria (self): MSD. H. Yoshioka: Honoraria (self): Boehringer Ingelheim; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Eli Lilly Japan; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Merck Serono; Honoraria (self): Kyowa Kirin; Honoraria (self): AstraZeneca; Honoraria (self): Ono pharmaceutical; Honoraria (self): Daiichi Sankyo; Honoraria (self): MSD. D. Fujimoto: Honoraria (self), Research grant / Funding (self): AstraZeneca KK; Honoraria (self): Ono Pharmaceutical Co Lt; Honoraria (self): Bristol-Myers Squibb Co Ltd; Honoraria (self): Taiho Pharmaceutical Co ; Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical Co Ltd; Honoraria (self): MSD KK; Honoraria (self): Boehringer Ingelheim Japan Inc; Honoraria (self): Eli Lilly Japan KK. K. Hirano: Honoraria (self): Boehringer Ingelheim Japan. T. Ishida: Honoraria (self): Boehringer Ingelheim Japan. T. Hirai: Research grant / Funding (institution): Boehringer Ingelheim Japan. All other authors have declared no conflicts of interest.

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.

Targeting PKCι-PAK1 in EGFR-mutation positive non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) induce significant responses in EGFR-mutation positive non-small cell lung cancer (NSCLC). However, universal progression is observed. The effect of the anti-rheumatoid agent, auranofin, a selective inhibitor of oncogenic protein kinase C iota (PKCι) signaling and IPA-3, a non-ATP competitive p21-activated kinase 1 (PAK1) inhibitor in treatment-naïve and EGFR TKI-resistant EGFR-mutation positive NSCLC cell lines was investigated. PC9 and HCC827 cells were used. The four EGFR-TKI resistant cell lines were established from PC9. Cell viability assays, drug combination studies, and western blotting were performed. The combination index, and RTK or non-RTK expression were performed. The combination of IPA-3 and auranofin was highly synergistic in all 6 cell lines (combination indexes ranged from 0.37-0.62). The activities on EGFR, CDCP1, AXL, MET, and downstream effector pathways, including PAK1, PKCι, ERK, AKT, STAT3, Src, and YAP1 were abrogated. The combination of auranofin with IPA-3 could be a potential therapy for EGFR-mutation positive NSCLC resistant to EGFR TKIs. Auranofin with IPA-3 could become a therapeutic solution for EGFR-mutation positive NSCLC patients resistant to EGFR TKIs.

1471P - EGFR inhibitor versus chemotherapy as adjuvant treatment for locally-advanced EGFR-mutant non-small cell lung cancer

BackgroundCisplatin-based chemotherapy as adjuvant therapy for resected NSCLC has reached its plateau, and was limited by high risk of recurrence and significant toxicities. The clinical value of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in resected non-small cell lung cancer (NSCLC) harboring EGFR mutations remains controversial. In this study, we performed a meta-analysis to evaluate the role of EGFR inhibitors as adjuvant therapy for targeted patients. MethodsStudies were identified via an electronic search on Pubmed, EMBASE, ISI Web of Science, ScienceDirect, SpringerLink, The Cochrane library and so on. Pooled odds ratio (OR) for disease-free survival (DFS) and overall survival (OS) were calculated for meta-analysis. Registration number: PROSPERO (CRD42018093144). ResultsThere were 11 trials (1,152 resected NSCLC patients with EGFR sensitive mutations) in this meta-analysis. Results showed that adjuvant treatment with EGFR-TKIs can prolong both OS and DFS when compared to treatment without TKIs as adjuvant therapy (OS: Figure 1, OR, 0.63; 95% CI, 0.46 to 0.87, P=0.004; heterogeneity I2=61%, P=0.008; DFS: OR, 0.56; 95% CI, 0.43 to 0.72, P<0.00001; heterogeneity I2=37%, P=0.1). Results of predefined subgroup analyses in this meta-analysis suggested a greater DFS with EGFR-TKI mono compared with chemotherapy, whereas the OS benefit failed to show a similar difference between the two arms (p=0.3). And we also find that treatment with EGFR-TKI plus chemotherapy was associated with significantly longer DFS as well as OS than chemotherapy mono in patients with completely resected EGFR-mutant NSCLC. ConclusionsAdjuvant EGFR-TKIs may be a potential treatment option compared to adjuvant chemotherapy in completed resected patients with EGFR mutation-positive NSCLC. This project was supported by the National Natural Science Foundation of China (Grant No. 81502667), Key Research and Development Plan of Shandong, China (Grant No. 2016GSF201167). Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

PC03.01 Adjuvant Therapy for Resected NSCLC Harboring EGFR Mutation, Chemotherapy or Targeted Therapy - PROs

Lung cancer is so far the leading cause of cancer death worldwide. Complete surgical resection remains the most effective approach for patients with early-stage non-small cell lung cancer (NSCLC). Patients with completely resected stage I NSCLC could have a 5-year survival of ∼80%, whereas it fails to ∼30%. Since 2003, adjuvant chemotherapy became the standard of care showing 4% absolute 5-year survival benefit compared to surgery alone [1]. Following randomized control trials revealed similar results [2-4], yet limited survival benefit, low therapeutic completed rate plus high toxicities rate may somehow hinder its clinical applicability. In the past decade, targeted therapies had achieved tremendous success in oncogene-driven advanced NSCLC showing both high efficacy and low toxicities [5]. As a matter of course, targeted therapy had its baby steps in early-stage NSCLC. However, no positive results were found in these trials which should probably be blame for large proportion of stage IB patients and incorrect detection methods for EGFR mutation. Besides, conservative trial design without head to head comparison could not fully address toxicities issues caused by chemotherapy. Precise target population seemed to be an essential key point to adjuvant targeted therapies and ADJUVANT as well as EVAN trial came into being [6, 7]. Although overall survival (OS) was not mature enough to measure, significantly prolonged disease-free survival (DFS) was observed in both trials along with better tolerability. Indeed, questioning around adjuvant targeted therapy has never been adjourned such as the optimal duration of targeted therapies, study design and lack of OS data. Ross et al brought up with an informative comment for ADJUVANT trial bringing the concept of MRD (molecular residual disease) into adjuvant treatment [8]. Based on the ctDNA testing after standard of care adjuvant chemotherapy, patients of high risk of recurrence will be given further treatments while observation for the others. It highlighted the significant role of discriminating beneficiaries from adjuvant targeted therapies instead of simply providing more efficient treatment modalities. Previous biomarker-based studies regarding adjuvant treatment among different tumor types [9, 10] had provided inspirational examples, and as well shown clinical feasibility and urgent need for personalized adjuvant treatment after complete surgical resection. For ADJUVANT trial, we established a comprehensive signature of genetic-features (MEDUSA) to guide personalized adjuvant treatment in EGFR-mutant stage II-III NSCLC. Results would be unleashed in upcoming ESMO meeting. Through utilizing multi-omics data, we could predict whether additional treatments, adjuvant chemotherapy only or observation would be adequate for each individual and provide optimal sequential treatments. Further translational researches and corresponding trials regarding resectable NSCLC should decipher the issues. Fortunately, several trials regarding dynamic monitoring postoperative ctDNA or genomic profile of primary cancer to guide sequential treatments are ongoing and the results should be expected. 1. Arriagada R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350: 351-360. 2. Winton T, Livingston R, Johnson D et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352: 2589-2597. 3. Strauss GM, Herndon JE, 2nd, Maddaus MA et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26: 5043-5051. 4. Douillard JY, Rosell R, De Lena M et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7: 719-727. 5. Hirsch FR, Scagliotti GV, Mulshine JL et al. Lung cancer: current therapies and new targeted treatments. Lancet 2017; 389: 299-311. 6. Zhong WZ, Wang Q, Mao WM et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol 2018; 19: 139-148. 7. Yue D, Xu S, Wang Q et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med 2018; 6: 863-873. 8. Ng TL, Camidge DR. Lung cancer's real adjuvant EGFR targeted therapy questions. Lancet Oncol 2018; 19: 15-17. 9. Sparano JA, Gray RJ, Makower DF et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2015; 373: 2005-2014. 10. Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. J Clin Oncol 2015; 33: 1787-1796. Adjuvant therapy, EGFR-TKI, Lung cancer

1521P - Osimertinib in epidermal growth factor receptor (EGFR) T790M advanced non-small cell lung cancer (NSCLC): Analysis of patients with central nervous system (CNS) metastases in a real-world study (ASTRIS)

BackgroundApproximately 20%–30% of patients (pts) with EGFR mutation-positive NSCLC present with CNS metastases at the time of diagnosis of advanced disease. CNS metastases are associated with a poor prognosis. Osimertinib is a third-generation, irreversible, oral EGFR-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitising (EGFRm) and EGFR T790M mutations and in clinical trials has demonstrated efficacy in NSCLC CNS metastases. ASTRIS is the largest ongoing, international, real-world study of osimertinib in EGFR T790M positive advanced NSCLC (NCT02474355). We report a subset analysis of pts with CNS metastases. MethodsEligible pts with stage IIIB/IV EGFR T790M positive NSCLC previously treated with an EGFR-TKI received osimertinib 80mg once-daily. Investigator-assessed (IA) progression-free survival (PFS), clinical response and time to treatment discontinuation (TTD) were analysed in a subset of pts with CNS (leptomeningeal and/or brain) metastases at baseline (BL). Follow-up brain imaging was not mandatory. ResultsFrom 18 September 2015 to 15 October 2018, 3015 pts across 16 countries had received ≥1 dose of osimertinib (full analysis set [FAS]); 882 (29%) pts presented with CNS metastases at BL. BL demographics were similar between this subset and the FAS (female: 63%/64%; Asian: 69%/69%; median age (range): 61 (27–88) years/62 (27–92); WHO performance status 2: 15%/11%). IA response rates were consistent across the two groups, while median PFS and TTD appeared to be slightly lower in the CNS subset (Table). Overall survival data are immature. ConclusionsIn a real-world setting, over half of pts with EGFR T790M positive advanced NSCLC and CNS metastases responded to treatment with osimertinib 80mg. These findings support previous clinical research showing clinically meaningful CNS efficacy with osimertinib in advanced NSCLC.Table1521P Clinical outcomes for pts with EGFR T790M advanced NSCLC and CNS metastases at BLTableClinical outcomesFAS Osimertinib 80mg (N=3015)CNS subset Osimertinib 80mg (N=882)Response rate*, % (95% CI)57 (55, 59)59 (55, 62)Best overall response†, n (%) Responding Stable disease Progressive disease Unknown1655 (55) 1043 (35) 202 (7) 115 (4)485 (55) 274 (31) 66 (7) 57 (6)Median PFS, months (95% CI)11.1 (11.0, 12.0)9.7 (9.2, 10.5)Median TTD, months (95% CI)13.5 (12.6, 13.9)11.1 (10.1, 12.1)CI, confidence interval*Response rate is defined as the percentage of pts with a best response of ’Responding’ by investigator assessment, based on pts with ≥1 documented response assessment. 95% CI is defined by Clopper-Pearson method †Best overall response is defined as the best response by investigator assessment. Pts with no assessments were considered as ’Unknown’ Clinical trial identificationNCT02474355. Editorial acknowledgementBernadette Tynan, MSc, of iMed Comms, Macclesfield, UK, an Ashfield Company, part of UDG Healthcare plc, funded by AstraZeneca. Legal entity responsible for the studyAstraZeneca. FundingAstraZeneca. DisclosureM. Provencio: Advisory / Consultancy: BMS, MSD, AstraZeneca, BI; Travel / Accommodation / Expenses: MSD, AstraZeneca. D. Kim: Research grant / Funding (institution): Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan. B.C. Cho: Honoraria (institution): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Boehringer Ingelheim, Roche, BMS, Pfizer, Eli Lilly, Takeda, TheraCanVac Inc.; Advisory / Consultancy: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Boehringer Ingelheim, Roche, BMS, Pfizer, Eli Lilly, Takeda, TheraCanVac Inc.; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (institution): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc.; Licensing / Royalties: Champions Oncology. K. Park: Advisory / Consultancy: AMGEN, AstraZeneca, Astellas, BluePrint, Eli Lilly, Hanmi, KHK, MSD, Boehringer Ingelheim, Roche, Merck KGaA, Ono; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Research grant / Funding (self): AstraZeneca. R. Migliorino: Advisory / Consultancy: AstraZeneca, MSD, BI, Pfizer, Roche, BMS; Speaker Bureau / Expert testimony: AstraZeneca, MSD, BI, Pfizer, Roche, BMS; Travel / Accommodation / Expenses: AstraZeneca, MSD, BI, Pfizer, Roche, BMS. M. Tiseo: Advisory / Consultancy: AstraZeneca, BMS, MSD, Boehringer Ingelheim, Takeda; Research grant / Funding (institution): AstraZeneca. Q. Zhou: Honoraria (self): AstraZeneca, Roche. A. Santo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca, Roche. A. Ardizzoni: Honoraria (self): MSD, BMS, Pfizer, Eli Lilly; Advisory / Consultancy: MSD, Roche; Research grant / Funding (institution): BMS, Celgene, Roche. Y. Wu: Honoraria (self): AstraZeneca, Roche, Eli Lilly, Pfizer, MSD, BMS, Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca, Roche, Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Roche. S. Kim: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. M. Miranda: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca PLC. A. Fernandes: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. F. de Marinis: Honoraria (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Roche, Celgene, MSD, BMS, AstraZeneca, Takeda, Pfizer; Research grant / Funding (self): Boehringer Ingelheim, MSD. All other authors have declared no conflicts of interest.

1528P - Effectiveness of sequencing TKIs in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC): A French national medical-administrative claim database analysis

BackgroundTreatment of EGFR mutation-positive NSCLC has been revolutionized with the development of EGFR tyrosine kinase inhibitors (TKIs). Three generations of TKIs are now available (1st: erlotinib, gefitinib; 2nd: afatinib, dacomitinib; 3rd: osimertinib). Osimertinib has been developed as second-line treatment after a first-line TKI 1G or 2G when patients progressed with T790M-positive tumors, the most frequent mechanism of resistance. While osimertinib may also be given as first-line treatment, limited data exists on the real life effectiveness of the TKIs sequencing approach: TKI 1G or 2G followed by osimertinib. The French National medico administrative claim database (SNDS) offers the opportunity to estimate the effectiveness parameters for these patients in France. MethodsBased on SNDS, a historic cohort of patients with a diagnosis of EGFR-mutated NSCLC treated, after a first-line with a TKI 1G or 2G, with osimertinib in second-line between 2015 and 2017 was extracted. Follow-up was conducted until December 31st 2017. Patients’ characteristics, Time on treatments and Overall survival were analysed. Results1,404 NSCLC patients have been treated with osimertinib in the database between 2015 and 2017. Among them, 509 had a previous treatment with TKI 1G or 2G without any other anticancer drug before osimertinib initiation, and constitute the analysed population. Mean age was 70.9 (29.1% were above 80 years old), 25.7% were males. Median time on TKI treatment (between the beginning of the first TKI 1G or 2G until discontinuation of osimertinib) was not reached but the percentages of patients still treated were: 83.8% at 24 months and 75.5% at 36 months. Median overall survival was not reached but the percentages of patients still alive were: 79.6% at 24 months and 70.3% at 36 months. Updated data will be presented at the meeting. ConclusionsOur cohort confirms the prolonged time on TKI treatment and survival rates of patients receiving TKI 1G or 2G followed by osimertinib in a real life setting. Legal entity responsible for the studyThe authors. FundingBoehringer Ingelheim. DisclosureN. Girard: Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): GlaxoSmithKline; Honoraria (self): Hoffmann La Roche; Honoraria (self): Lilly; Honoraria (self): Merck Sharp Dohme; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Takeda. S. Bouee: Full / Part-time employment: CEMKA. D. Moro-Sibilot: Honoraria (self), Honoraria (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Honoraria (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Honoraria (institution): Roche; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: AbbVie. C. Emery: Full / Part-time employment, CEMKA received a grant from Boehringer Ingelheim to perform the statistical analysis of this study : CEMKA. K. Le Lay: Full / Part-time employment: Boehringer Ingelheim. L. Luciani: Full / Part-time employment: Boehringer Ingelheim. C. Maritaz: Full / Part-time employment: 4. Boehringer Ingelheim. C. Chouaid: Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): GlaxoSmithKline; Honoraria (self): Roche; Honoraria (self): Sanofi; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Takeda; Honoraria (self): Bayer; Honoraria (self): Amgen.

P2.14-15 Impact of Coexisting Gene Mutations in EGFR-Mutated Non–Small Cell Lung Cancer Before Treatment on EGFR T790M Mutation Status After EGFR-TKIs

The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation–positive non–small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after treatment. A total of 57 EGFR mutation–positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software. Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P = 0.024). Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.

P1.16-36 Treatment Patterns Among Patients with EGFRm NSCLC Treated in the US Community Oncology Setting

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is associated with improved outcomes in patients with EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Despite initial responses, most patients develop resistance. Little is known about treatment following first-line (1L) TKIs. This study aimed to understand real world treatment patterns, T790M testing rates, and disposition of EGFRm patients following availability of newer TKIs. Adult patients with EGFRm stage IV NSCLC treated between Dec 1, 2015 and Aug 31, 2017, were retrospectively identified from the US Oncology Network’s iKnowMedSM (iKM) electronic health record. Patient characteristics, treatment patterns, and T790M testing data were obtained via programmatic database abstraction and supplemented with chart review. 308 patients were identified during the study period. Median age at diagnosis was 69 years, 67% were female, 63% Caucasian, 49% never smokers and 59% with ECOG performance status 0–1. Nearly all patients (n=302; 98%) received treatment with a TKI, 80% (n=246) with a TKI as 1L therapy. The most frequently used TKIs as 1L monotherapy were erlotinib (n=204; 66%), afatinib (n=27; 9%), and gefitinib (n=3; 1%). Combination chemotherapy with or without a TKI was used in 24% of patients. Among all patients treated with a 1L TKI, 19% (n=47) were tested for the T790M mutation after 1L TKI, and 34% (n=16) were positive. The most common 2L therapies in patients who received a 1L TKI (n=44 patients) were pemetrexed-based chemotherapy (n=20; 45%), afatinib (n=7; 16%), and osimertinib (n=7; 16%). Among all patients who received a 1L TKI, 15% (n=41) had died, 18% (n=51) were still alive and on TKI therapy, 12% (n=29) went on to receive subsequent therapy, and 53% (n=149) stopped their TKI and received no subsequent therapy at the end of the follow-up period. The majority of patients with EGFRm advanced NSCLC received 1L TKI therapy, most often with erlotinib. Following 1L TKI, less than 20% of patients were tested for T790M, and most did not receive any subsequent therapy following TKI. As understanding of resistance mechanisms in mutation-driven lung cancer is rapidly evolving, and as ongoing studies evaluate optimal treatments, it is imperative to integrate this information into clinical practice.

Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer: A multicentric retrospective French study

ObjectivesThe understanding of histo-molecular mechanisms associated with resistance to osimertinib is a critical step to define the optimal treatment strategy in advanced EGFR-mutated Non-Small-Cell-Lung-Cancer (NSCLC). Materials and methodsWe performed a multicentric retrospective analysis on a cohort of consecutive patients treated with osimertinib for an advanced EGFR-mutated NSCLC and collected histo-molecular data from plasma and tumor samples at the time of progression. Next-generation sequencing (NGS) was performed for all samples. Best Overall Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS) and data on treatment post-progression efficacy were also collected. ResultsTwo-hundred and twenty-six patients were included from 9 Academic French Hospitals between April 2015–October 2018. Osimertinib was given in second-line or more in 219 patients (97%). Best ORR was 52% and best central nervous system ORR was 56%. Median PFS and OS were 9.5 months (IQR 4.0-17.2) and 24 months (IQR 12.4-NR) respectively. At the time of analysis, 150 patients (66%) had tumor progression. Among them, 73 contributive samples (56 tumor biopsies) were available. The most frequent molecular alterations were C797S mutation (n = 9 (13%)) and MET amplification (n = 8 (11%)). Histologic transformation occurred in 5 patients (9% of tumor biopsies). In T790M + NSCLC, loss of T790 M occurred in 68% of cases. Median PFS and OS with treatment beyond progression were 6.0 months (IQR 2.0-10.4) and 15.1 months (IQR 6.7-NR) respectively and longer in case of osimertinib continuation beyond progression. ConclusionWe confirmed the efficacy of osimertinib in patients with advanced EGFR mutation positive NSCLC. At progression, the most frequent molecular alterations were MET amplification and C797S mutation.