EGFR T790M-positive NSCLC Research Articles

Efficacy and Safety of SH-1028 in Patients With EGFR T790M-Positive NSCLC: A Multicenter, Single-Arm, Open-Label, Phase 2 Trial

IntroductionAs a novel third-generation EGFR tyrosine kinase inhibitor (TKI), SH-1028 (formerly oritinib) is developed to inhibit both sensitizing EGFR mutations and EGFR T790M mutation. MethodsThis was a multicenter, single-arm, open-label, phase 2 trial (NCT03823807). Eligible patients were those with advanced NSCLC with centrally confirmed EGFR T790M mutation who progressed after first- or second-generation EGFR TKIs or with primary EGFR T790M mutations. Each patient received SH-1028 tablets orally at 200 mg/d until disease progression or intolerable toxicity. Tumor response was evaluated every 6 weeks per the Response Evaluation Criteria in Solid Tumors, version 1.1. The primary end point was objective response rate by an independent review committee. The secondary end points were progression-free survival, overall survival (OS), disease control rate, safety, and so on. ResultsA total of 286 patients with EGFR T790M-positive advanced NSCLC were enrolled in this study, including 59 patients in part A (dose-verification study) and 227 patients in part B (second-line registration study). By data cutoff on September 17, 2021, the independent review committee–assessed objective response rate was 55.9% (95% confidence interval [CI]: 42.4–68.8) in part A and 60.4% (95% CI: 53.7–66.8) in part B. The median progression-free survival was 12.4 months (95% CI: 8.3–20.8) in part A and 12.6 months (95% CI: 9.7–15.3) in part B. The median OS was 26.0 months (95% CI: 23.3–not reached) in part A, and OS was immature in part B. Among the 286 patients, 44 of them experienced at least one grade 3 or higher treatment-related adverse event, with the most common ones as increased serum creatinine phosphokinase level (13 [4.5%]), diarrhea (six [2.1%]), and prolonged QT interval (three [1.0%]). Treatment-related skin rash was reported in 26 patients (9.1%), all grade 1 or 2. There was no interstitial lung disease reported in this study. ConclusionsSH-1028 is efficacious and tolerable in second-line treatment of patients with advanced NSCLC with positive EGFR T790M.

7MO Oritinib (SH-1028) a third-generation EGFR tyrosine kinase inhibitor in locally advanced or metastatic NSCLC patients with positive EGFR T790M: Results of a single-arm phase II trial

Oritinib (SH-1028) is a third-generation EGFR-TKI selectively targeting both sensitive EGFR and EGFR T790M mutations. Herein, we report the efficacy and safety of oritinib in EGFR T790M-positive advanced NSCLC patients from the phase II study (NCT03823807). Eligible patients were locally advanced or metastatic NSCLC patients aged ≥ 18 years, with centrally confirmed EGFR T790M mutation. Patients with asymptomatic, stable CNS metastases were eligible into the study. Oritinib 200 mg was given orally once daily until disease progression or unacceptable toxicity. Primary efficacy endpoint was objective response rate (ORR). Secondary efficacy endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Between December 2019 and March 2021, 228 patients were enrolled and 227 patients received at least one dose of oritinib. The median age of 227 patients was 62 years old, 57.3% of patients were female and 24.7% received systemic chemotherapies. At data cutoff (September 17, 2021), 137 of 227 patients achieved confirmed partial responses with ORR of 60.4% (95% CI: 42.4%, 68.8%) by IRaC. The DCR was 92.5% (88.3%, 95.6%), the mPFS was 12.6 months (95% CI: 9.7, 15.3), the mDOR was 12.5 months (95% CI: 11.2, NA) and the mOS was immature. The most common (≥10%) treatment-emergent adverse events (TEAEs) included diarrhea (45.4%), increased blood creatine phosphokinase (26.0%), anaemia (20.3%), decreased white blood cell count (15.4%), decreased appetite (15.0%), increased blood creatine phosphokinase isoenzyme (13.2%), nausea (13.2%), vomiting (13.2%), increased serum creatine (12.8%), upper respiratory tract infection (12.3%), increased aspartate aminotransferase (11.9%), cough(11.9%), decreased platelet count (11.0%), constipation (10.6%). Grade≥3 TEAEs included increased blood creatine phosphokinase (4.0%), hypertension (3.1%), death (2.6%), diarrhea (2.2%). No interstitial lung disease were reported. Oritinib demonstrated potential clinical benefit and tolerable in advanced NSCLC patients with EGFR T790M mutation.

A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors

IntroductionThis integrated analysis of a phase 1/2 study (NCT03046992) evaluated the efficacy and safety of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), in patients with advanced EGFR T790M-positive NSCLC after previous EGFR TKI therapy. MethodsAdults with EGFR mutation-positive NSCLC that progressed after prior EGFR-directed TKIs received once daily oral lazertinib 240 mg continuously until disease progression. Prior TKIs to treat T790M-positive NSCLC were prohibited. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included progression-free survival, overall survival, and intracranial ORR. ResultsA total of 78 patients received lazertinib 240 mg at 17 centers in South Korea. Among patients with T790M-positive tumors at baseline (N = 76), one (1.3%) had a complete response and 41 (53.9%) had partial responses, giving an ORR of 55.3% (95% confidence interval [CI]: 44.1–66.4). Median progression-free survival was 11.1 months (95% CI: 5.5–16.4). Median overall survival was not reached (median follow-up = 22.0 mo). In patients with measurable intracranial lesions (n = 7), one (14.3%) had a complete intracranial response and five (71.4%) had partial responses, giving an intracranial ORR of 85.7% (95% CI: 59.8%–100.0%). The most common treatment-emergent adverse events were rash (37.2%), pruritus (34.6%), and paresthesia (33.3%); most were mild to moderate in severity. Serious drug-related adverse events occurred in three patients (gastritis, pneumonia, pneumonitis). The major mechanism of resistance was EGFR T790M loss. ConclusionsLazertinib 240 mg/d has a manageable safety profile with durable antitumor efficacy, including brain metastases, in patients with advanced T790M-positive NSCLC after previous EGFR TKI therapy.

Efficacy of Aumolertinib (HS-10296) in Patients With Advanced EGFR T790M+ NSCLC: Updated Post-National Medical Products Administration Approval Results From the APOLLO Registrational Trial

IntroductionAumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) with revealed activity against EGFR-sensitizing mutations and EGFR T790M mutation. MethodsPatients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy were enrolled in this registrational phase 2 trial of aumolertinib at 110 mg orally once daily (NCT02981108). The primary end point was objective response rate (ORR) by independent central review. ResultsA total of 244 patients with EGFR T790M-positive NSCLC were enrolled. The ORR by independent central review was 68.9% (95% confidence interval [CI]: 62.6–74.6). The disease control rate was 93.4% (95% CI: 89.6–96.2). The median duration of response was 15.1 months (95% CI: 12.5–16.6). The median progression-free survival was 12.4 months (95% CI: 9.7–15.0). Among 23 patients with assessable central nervous system (CNS) metastases, the CNS-ORR and CNS-disease control rate were 60.9% (95% CI: 38.5–80.3) and 91.3% (95% CI: 72.0–98.9), respectively. The median CNS-duration of response was 12.5 months (95% CI: 5.6–not reached). Treatment-related adverse events of more than or equal to grade 3 occurred in 16.4% of the patients, with the most common being increased blood creatine phosphokinase level (7%) and increased alanine aminotransferase level (1.2%). The relative dose density of aumolertinib was 99.2% in this study. ConclusionsAumolertinib is an effective and well-tolerated third-generation EGFR TKI for patients with EGFR T790M-positive advanced NSCLC after disease progression on first- and second-generation EGFR TKI therapy. On the basis of these findings, aumolertinib was approved in the People’s Republic of China for patients positive for EGFR T790M NSCLC.

MO37-6 Longitudinal disease monitoring with ctDNA during osimertinib treatment in EGFR T790M positive NSCLC patients (WJOG8815L)

MO37-6 Longitudinal disease monitoring with ctDNA during osimertinib treatment in EGFR T790M positive NSCLC patients (WJOG8815L)

Integrated histological and molecular analyses of rebiopsy samples at osimertinib progression improve post-progression survivals: A single-center retrospective study

BackgroundThis single-center retrospective cohort study sought to investigate the impact of rebiopsy analysis after osimertinib progression in improving the survival outcomes. MethodsEighty-nine patients with EGFR T790M-positive advanced NSCLC who received second- or further-line osimertinib between January 2017 and July 2019 were included in this study. The co-primary study endpoints were post-progression progression-free survival (pPFS), defined as the time from osimertinib progression until progression from further-line treatment, and post-progression overall survival (pOS), defined as the time from osimertinib progression until death or the last follow-up date. ResultsPairwise analysis revealed that receiving targeted therapy as further-line treatment after osimertinib progression did not statistically improve the pPFS (P = 0.285) or the pOS (P = 0.903) compared to chemotherapy. However, patients who submitted rebiopsy samples at osimertinib progression for histological and molecular analyses, particularly those who had actionable markers and received highly matched therapy, had significantly longer pPFS and pOS as compared to those who received low-level matched therapy (pPFS = 10.0 m vs. 4.1 m, P = 0.005; pOS = 19.4 m vs. 10.0 m, P = 0.023), unmatched therapy (pPFS = 10.0 m vs. 4.7 m, P = 0.009; pOS = 19.4 m vs. 7.0 m, P = 0.001), and those without rebiopsy data (Rebiopsy vs Non-rebiopsy; pPFS = 6.1 m vs. 3.3 m, P = 0.014; pOS = 11.7 m vs. 6.8 m, P = 0.011). ConclusionOur real-world cohort study demonstrates that integrated histological and molecular analyses of rebiopsy specimens after osimertinib progression could provide more opportunities for individualized treatments to improve the post-progression survival of patients with advanced NSCLC. Our findings provide clinical evidence that supports the inclusion of NGS-based analysis of rebiopsy specimens as standard-of-care after osimertinib progression and warrants further prospective evaluation.

Serial Plasma Cell-Free Circulating Tumor DNA Tests Identify Genomic Alterations for Early Prediction of Osimertinib Treatment Outcome in EGFR T790M–Positive NSCLC

IntroductionRecent advances in the detection of genomic DNA from plasma samples allow us to follow tumor DNA shedding in plasma during systemic treatment. Osimertinib is the standard of care for patients with NSCLC with acquired EGFR T790M mutations. We assessed changes in serial plasma cell-free circulating tumor DNA (ctDNA) genomic alterations to predict osimertinib efficacy. MethodsWe prospectively collected plasma from patients having EGFR-mutated advanced NSCLC previously treated with EGFR tyrosine kinase inhibitor therapy and with acquired EGFR T790M mutation detected by standard methods. Plasma samples were collected before starting osimertinib treatment, 4 weeks after osimertinib treatment, and on progression. ctDNA was analyzed using the Guardant360 assay. ResultsA total of 15 eligible patients received osimertinib. Before starting treatment, EGFR-activating mutations were detected in the ctDNA of all patients, and EGFR T790M was detected in 93% of the cases. Osimertinib treatment was associated with an objective response rate of 53% and a median progression-free survival of 7.3 months. A total of 12 of the 15 patients had undetectable plasma T790M and decreased activating mutation allelic frequency (AF) at week 4. None of the 12 patients had disease progression within 16 weeks. For the remaining three patients, with detectable plasma T790M (n = 2) or increased activating mutation AF (n = 1) at week 4, two had progressive disease within 16 weeks (p = 0.03). ConclusionsIn patients with EGFR-mutated advanced NSCLC, persistent EGFR T790M or increasing activating mutation AF as detected in ctDNA 4 weeks after the start of osimertinib treatment may predict disease progression within 16 weeks.

Real-World Evaluation of Factors for Interstitial Lung Disease Incidence and Radiologic Characteristics in Patients With EGFR T790M–positive NSCLC Treated With Osimertinib in Japan

Using real-world Japanese postmarketing data, we characterized interstitial lung disease (ILD) development during the second- or later-line osimertinib treatment for EGFR mutation-positive NSCLC. Retrospective radiologic image evaluation of patients developing ILD was also performed. Patients who had ILD events reported as an adverse drug reaction by their physicians and who were assessed as having developed ILD as assessed by an ILD expert committee in Japan were included. Among 3578 patients, 252 ILD events were reported in 245 patients (6.8%) by their attending physicians. The median (range) time to the first onset of ILD after osimertinib treatment initiation was 63.0 (5-410) days, and 29 patients with a fatal outcome were reported. The ILD expert committee assessed 231 of 3578 patients (6.5%) as having ILD. A previous history of nivolumab therapy (adjusted OR: 2.84; 95% confidence interval: 1.98-4.07) and a history or concurrence of ILD (3.51; 2.10-5.87) were identified as factors potentially associated with ILD onset during osimertinib treatment. In patients who had received a previous nivolumab treatment, the number and proportion of patients developing ILD were highest for patients who discontinued nivolumab treatment within the first month before initiating osimertinib; trends for decreasing incidence and proportion were observed, with an increasing duration between the end of nivolumab treatment and the initiation of osimertinib treatment. The frequency of ILD was consistent with the known osimertinib safety profile in the Japanese population. A history or concurrence of ILD and history of previous nivolumab therapy are factors potentially associated with ILD onset during osimertinib treatment.

Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance

BackgroundNon-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors; however, the efficacy of these drugs is limited by acquired resistance driven by the EGFR T790M mutation. The discovery of third-generation EGFR inhibitors overcoming EGFR T790M and their new resistance mechanisms have attracted much attention.MethodsWe examined the antitumor activities and potential resistance mechanism of a novel EGFR third-generation inhibitor in vitro and in vivo using ELISA, SRB assay, immunoblotting, flow cytometric analysis, kinase array, qRT-PCR and tumor xenograft models. The clinical effect on a patient was evaluated by computed tomography scan.ResultsWe identified compound ASK120067 as a novel inhibitor of EGFR T790M, with selectivity over EGFR WT. ASK120067 exhibited potent anti-proliferation activity in tumor cells harboring EGFR T790M (NCI-H1975) and sensitizing mutations (PC-9 and HCC827) while showed moderate or weak inhibition in cells expressing EGFR WT. Oral administration of ASK120067 induced tumor regression in NSCLC xenograft models and in a PDX model harboring EGFR T790M. The treatment of one patient with advanced EGFR T790M-positive NSCLC was described as proof of principle. Moreover, we found that hyperphosphorylation of Ack1 and the subsequent activation of antiapoptotic signaling via the AKT pathway contributed to ASK120067 resistance. Concomitant targeting of EGFR and Ack1 effectively overrode the acquired resistance of ASK120067 both in vitro and in vivo.ConclusionsOur results idenfity ASK120067 as a promising third-generation EGFR inhibitor and reveal for the first time that Ack1 activation as a novel resistance mechanism to EGFR inhibitors that guide to potential combination strategy.

Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis.

Osimertinib has shown promising activity in patients with leptomeningeal metastases (LMs) of EGFR-positive NSCLC at 160 mg once daily (qd) (BLOOM; NCT02228369). We report LM activity with osimertinib (80 mg qd) in a retrospective analysis of studies across the AURA program (AURA extension, AURA2, AURA17, and AURA3). Patients with EGFR T790M-positive advanced NSCLC and progression after previous EGFR-tyrosine kinase inhibitor therapy received osimertinib (80 mg qd). Patients with central nervous system (CNS) metastases (including LMs) were eligible if the lesions were neurologically asymptomatic and stable. Patients with evidence of LMs at the study entry were retrospectively included for the analysis; brain scans were assessed for radiologic LM response by neuroradiologically blinded, independent central review per the modified Response Assessment in Neuro-Oncology LM criteria. LM objective response rate, duration of response, progression-free survival, and overall survival were assessed. A longitudinal analysis was performed to investigate the relationship between changes from the baseline in non-CNS tumor sizes and LM responses at each visit of patients in AURA LM and BLOOM studies. For the 22 patients included in the analysis, LM objective response rate was 55% (95% confidence interval [CI]: 32-76). Median LM duration of response was not reached (95% CI: 2.8-not calculable [NC]). Median LM progression-free survival and overall survival were 11.1 months (95% CI: 4.6-NC) and 18.8 months (95% CI: 6.3-NC), respectively. The longitudinal analysis revealed similar non-CNS and LM responses between the patients in AURA LM and BLOOM programs. Patients with EGFR T790M-positive NSCLC and radiologically detected LM obtained clinical benefit from osimertinib (80 mg qd).

PD2.05 Overall Survival in Pts with EGFRm+ NSCLC Receiving Sequential Afatinib and Osimertinib: Updated Analysis of the GioTag Study

While the superiority of second- and third-generation EGFR tyrosine kinase inhibitors (TKIs) over first-generation agents has been clearly demonstrated, the optimal sequence of EGFR TKIs is less clear, especially as there is no established targeted therapy after osimertinib failure. In the observational GioTag study (NCT03370770), patients with EGFRm+ NSCLC were treated with sequential afatinib and osimertinib in a ‘real-world’ clinical setting, including patients with poor prognosis (ECOG PS ≥2: 15%; stable brain metastases: 10%).1 Encouraging time to treatment failure (TTF) was seen in the primary analysis (overall: 27.6 months; Del19-positive patients: 30.3 months; Asian patients: 46.7 months). In this analysis, we report OS and updated TTF. Data were retrospectively collected between Dec 2017 and June 2018 for 204 patients with EGFRm+ (Del19, L858R) NSCLC who were T790M-positive after first-line afatinib and received subsequent osimertinib. TTF was the primary outcome; OS analysis was exploratory. Data were collected from electronic health records (EHRs; n=126) or medical charts (n=77). For logistical reasons, this interim analysis includes updated data (as at April 2019) from patients with available EHRs (all USA; n=94). After a median follow-up of 30.3 months, median OS was 41.3 months (90% CI: 36.8–46.3) in the overall dataset (n=203) and 45.7 months (90% CI: 45.3–51.5) in Del19-positive patients (n=149). At 2 years, OS was 80%; OS in Asian patients was immature. Updated median TTF was 28.1 months (90% CI: 26.8–30.3) in the overall dataset, and 30.6 months (90% CI: 27.6–32.0) in Del19-positive patients. Outcomes were not affected by afatinib starting dose. Median TTF with osimertinib was 15.6 months (90% CI: 13.8–17.1) in the overall dataset, and 16.4 months (90% CI: 14.9–17.9) in Del19-positive patients. Encouraging OS and TTF were seen with sequential afatinib and osimertinib in patients with EGFR T790M-positive NSCLC, especially in Del19-positive patients, supporting the use of this regimen. Prior treatment with afatinib did not preclude prolonged TTF with second-line osimertinib (15.6 months overall; 16.4 months in Del19-positive patients). The final analysis, incorporating updated data from manual chart reviews and anticipated in early 2020, will provide further insights into the long-term OS of patients treated with sequential afatinib–osimertinib. 1. Hochmair MJ, et al. Future Oncol. 2018;14:2861–74.

489P - Overall survival in patients with EGFRm+ NSCLC receiving sequential afatinib and osimertinib: Updated analysis of the GioTag study

BackgroundIdentifying the optimal sequence of EGFR TKIs is important to maximise survival in EGFR mutation-positive (EGFRm+) NSCLC. The observational GioTag study (NCT03370770) investigated outcomes in patients (pts) with EGFRm+ NSCLC who were treated with sequential afatinib and osimertinib in a ‘real-world’ clinical setting, including pts with poor prognosis (ECOG PS ≥ 2: 15%; stable brain metastases: 10%).1 In the primary analysis, time to treatment failure (TTF) was 27.6 months in the overall population, 30.3 months in Del19-positive pts, and 46.7 months in Asians. Here we report overall survival (OS) and updated TTF. MethodsData were retrospectively collected from Dec 2017–June 2018 for 203 pts with EGFRm + (Del19, L858R) NSCLC who were T790M positive after first-line afatinib and subsequently received osimertinib. TTF was the primary outcome; OS analysis was exploratory. Data were collected from electronic health records (EHRs; n = 126) or medical charts (n = 77). For logistical reasons, this interim analysis includes updated data (at April 2019) from pts with available EHRs (all USA; n = 94); final analysis with updated data from manual chart reviews is anticipated in early 2020. ResultsAfter median follow-up of 30.3 months, median OS was 41.3 months (90% CI: 36.8–46.3) in the overall dataset (n = 203) and 45.7 months (90% CI: 45.3–51.5) in Del19-positive pts (n = 149); 2-year OS was 80%. OS in Asians was immature. Updated median TTF was 28.1 months (90% CI: 26.8–30.3) in all pts, and 30.6 months (90% CI: 27.6–32.0) in Del19-positive pts. Median TTF with osimertinib was 15.6 months (90% CI: 13.8–17.1) in the overall dataset, and 16.4 months (90% CI: 14.9–17.9) in Del19-positive pts. Median time from osimertinib discontinuation to death was 8 months. In 168 pts starting on afatinib 40 mg, median OS was 45.3 months (90% CI: 37.6–47.6); median TTF was 28.1 months (90% CI: 26.8–30.6). ConclusionsEncouraging OS and TTF was seen in pts with EGFR T790M-positive NSCLC with sequential afatinib and osimertinib, especially Del19-positive pts. Of note, prior afatinib treatment did not preclude prolonged TTF with second-line osimertinib. 1. Hochmair MJ, et al. Future Oncol. 2018;14:2861–74. Clinical trial identificationNCT03370770. Editorial acknowledgementLynn Pritchard of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the studyBoehringer Ingelheim. FundingBoehringer Ingelheim. DisclosureM.J. Hochmair: Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self): Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis. A. Morabito: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp and Dohme. D. Hao: Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca. R.A. Soo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Ignyta; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Yuhan. J.C-H. Yang: Honoraria (self): Merck Sharp and Dohme; Advisory / Consultancy: Merck Serono; Honoraria (self): Novartis; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Yuhan Pharmaceuticals; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Ono pharmaceuticals; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Hansoh Pharmaceuticals; Advisory / Consultancy: Takeda Pharmaceuticals; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: G1 Therapeutics; Honoraria (self): Pfizer. B. Halmos: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp and Dohme; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Advisory / Consultancy: Genentech; Advisory / Consultancy: Spectrum; Advisory / Consultancy: Ignyta; Research grant / Funding (self): Takeda; Research grant / Funding (self): Guardant Health; Research grant / Funding (self): Mirati; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Novartis; Research grant / Funding (self): GSK; Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Guardant Health. L. Wang: Full / Part-time employment: Boehringer Ingelheim. A. Märten: Full / Part-time employment: Boehringer Ingelheim. T. Cufer: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

MA21.10 Phase II Study of 160mg of Osimertinib in EGFR T790M Positive NSCLC with Brain or Leptomeningeal Metastases Who Progressed on Prior EGFR TKI

MA21.10 Phase II Study of 160mg of Osimertinib in EGFR T790M Positive NSCLC with Brain or Leptomeningeal Metastases Who Progressed on Prior EGFR TKI

P2.14-55 Real-World Safety and Efficacy Data of Osimertinib in Patients from Japan with EGFR T790M-Positive NSCLC

P2.14-55 Real-World Safety and Efficacy Data of Osimertinib in Patients from Japan with EGFR T790M-Positive NSCLC

Exon 16-Skipping HER2 as a Novel Mechanism of Osimertinib Resistance in EGFR L858R/T790M-Positive Non-Small Cell Lung Cancer.

Osimertinib is the current recommended treatment for EGFR T790M-positive NSCLC after EGFR tyrosine kinase inhibitor therapy. However, resistance to osimertinib therapy is inevitably acquired after a period of effective treatment. We had a patient with EGFR L858R/T790M-positive NSCLC who initially responded to osimertinib therapy but eventually experienced development of resistance. Plasma cell-free DNA analysis revealed the occurrence of exon 16-skipping HER2, which may have resulted in the erb-b2 receptor tyrosine kinase 2 gene (HER2) splice variant HER2D16. HER2D16 has never been reported in lung cancer, and HER2D16-driven signaling is known to be regulated by Src kinase in breast cancer. We investigated the role of HER2D16 as an osimertinib-resistant mechanism. We constructed and established H1975 cells stably expressing HER2D16. The dimeric formation of HER2D16 was tested by using nonreducing polyacrylamide gel electrophoresis. The effects of the study drugs on signaling transduction were examined by using Western blot. Synergistic effect was assessed by using the Chou-Talalay method. We found that HER2D16 can form a homodimer in NSCLC cells. HER2D16-expressing H1975 cells were resistant to osimertinib treatment. We also found that mutant EGFR and HER2D16 cooperated to activate downstream signaling for osimertinib resistance. In addition, cotreatment with osimertinib and an Src kinase inhibitor failed toreverse resistance, indicating that HER2D16-driven signaling in NSCLC did not occur through a canonical pathway. Finally, we revealed that the combination of osimertinib with the pan-HER small-molecule inhibitor afatinib could synergistically repress cell growth and signaling in H1975-HER2D16 cells. HER2D16 can contribute to osimertinib resistance through an Src-independent pathway. HER2D16 should be included in the molecular diagnosis panel for lung cancer.

Effectiveness and safety of osimertinib in patients with metastatic EGFR T790M-positive NSCLC: An observational real-world study.

Osimertinib showed encouraging efficacy in patients with advanced EGFR T790M-positive NSCLC in previous randomized controlled trials. This real-world study aimed to evaluate the effectiveness and safety of osimertinib in a real-world setting. This observational study (NCT03133234) included 74 patients with metastatic EGFR T790M-positive NSCLC who progressed on prior EGFR TKI therapy and received osimertinib between May 2016 and April 2018 at the Kiang Wu Hospital in Macau. Response rate (RR) and other endpoints (progression-free survival [PFS], overall survival [OS], disease control rate [DCR], stable disease rate, and adverse events) were assessed. Survival data were estimated using the Kaplan-Meier method. All patients had stage IV lung adenocarcinoma and 25.6% had brain metastases; median age was 58 years (range 28–84 years) and 83.8% of patients had received at least three prior lines of treatment. The median duration of osimertinib treatment was 8 months (range, 1–25 months). RR and DCR were 67.5% (95% CI 56.9–78.1) and 79.8% (95% CI 70.7–88.9), respectively, while 12.1% had stable disease. The median PFS was 9.0 months (95% CI 6.7–11.2 months), and the median OS was 12.0 months (95% CI 8.8–15.1 months). Nausea (25.8%) and decreased appetite (20.2%) were the most common adverse events associated with osimertinib treatment. Even though most patients had at least three lines of prior treatment, real-world RR and PFS with osimertinib in this study were consistent with those from randomized controlled trials; no new safety signals were observed.

Abstract 4752: Exon-16-skipping HER2 contributes to osimertinib-resistance through Src-independent manner in EGFRL858R/T790M-positive non-small-cell lung cancer

Abstract Osimertinib is current recommended treatment for EGFR T790M-positive NSCLC following progression on prior EGFR tyrosine kinase inhibitor therapy. However, acquired resistance to osimertinib therapy inevitably developed after a period of effective treatment. We had a patient of EGFR L858R/T790M-positive NSCLC who initially responded to osimertinib therapy but eventually developed resistance. Plasma cell-free DNA analysis disclosed exon-16-skipping HER2 (HER2Δ16) in one osimertinib treated patient. HER2Δ16 was regarded as an oncogenic driver in breast cancer and has never been reported in lung cancer before. Therefore, it’s intriguing to investigate the role of HER2Δ16 in osimertinib resistance in NSCLC. The purpose of this study is to explore the mechanism of HER2Δ16-mediated resistance to osimertinib and to explore strategies to overcome the resistance. We constructed and established H1975 cells stably expressing either vehicle, WT-HER2 or HER2Δ16. We observed that without osimertinib treatment, there was no difference in cell growth and the response to EGF-stimulation. However, when treated with osimertinib, H1975-HER2Δ16 cells were more resistant under normal and EGF-stimulating conditions compared to vehicle or WT-HER2 expressing cells. Moreover, osimertinib treatment in H1975-HER2Δ16 cells had less inhibitory effect on phosphor-ERK and phosphor-AKT compared to vehicle or H1975-WT-HER2 cells. Interestingly, co-treatment of osimertinib with Src-kinase inhibitor, dasatinib, failed to reverse the resistance, indicating that HER2Δ16-driven osimertinib-resistance was independent of Src-kinase. Finally, we revealed that combination of osimertinib with the HER2 small molecular inhibitor, afatinib, can suppress cell growth in H1975-WT-HER2 and H1975-HER2Δ16 cells. In summary, we have shown that HER2Δ16, may be a resistance mechanism to osimertinib in EGFR mutated NSCLC and that HER2Δ16-driven resistance was Src-kinase independent. Moreover, we found the HER2Δ16-driven resistance could be rescued by combination of osimertinib with afatinib. Citation Format: Chia-Chi Hsu, Bin-Chi Liao, Wei-Yu Liao, Aleksandra Markovets, Daniel Stetson, Kenneth Thress, Chih-Hsin Yang. Exon-16-skipping HER2 contributes to osimertinib-resistance through Src-independent manner in EGFRL858R/T790M-positive non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4752.

Chemoimmunotherapy combination: Potential option for metastatic NSCLC patients with EGFR mutation resistant to osimertinib.

e20618 Background: Osimertinib has been emerged as the standard selection in EGFR T790M-positive NSCLC patients who failed prior treatment with EGFR TKIs. However, acquired resistance to osimertinib is a growing clinical challenge. Despite the significant antitumor activity of Chemoimmunotherapy (CIT) combinations in NSCLC, clinical benefit in patients with EGFR mutations has not been shown obviously. Our objective was to assess the effectiveness and tolerability of CIT for metastatic EGFR-mutant NSCLC patients with acquired resistance to Osimertinib. Methods: We conducted a retrospective study in patients with sensitizing EGFR-mutant NSCLC who were resistant to Osimertinib and received anti-PD1 immunotherapy combined with chemotherapy at Chinese PLA General Hospital. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and toxicities were examined. Results: Between Oct 2015 and Nov 2018, 11 patients were available for analysis, 45.5% male, 45.5% ECOG PS 0-1, median age 54 years, all pts who failed treatment with Osimertinib had received previously targeted therapies. In this CIT combination group, 6 [54.5%] of 11 pts received pembrolizumab and 5[54.5%] of 11 pts received Nivolumab anti-PD1 therapy, 8 [72.7%] of 11 pts received mono-chemotherapy and 3 [27.3%] of 11 pts received platinum-based doublet chemotherapy. The median PFS was 7.47 months (95% CI 3.04 to 11.89). Despite Median OS was not reached, the OS rate at one year was 6 [54.5%] of 11. The ORR was 5 [45.5%] of 11. Treatment-related adverse events (TRAE) of grade 3 or higher were reported in 6 [54.5%] of 11 patients. The most common grade 3 or worse TRAEs were fatigue (3 [27.3%] of 11) and anemia (3 [27.3%] of 11); The following ≥Grade 3 TRAEs occurred once: decreased neutrophil count, acute kidney injury, gastrointestinal bleeding. One patient discontinued treatment because of immune-associated gastroenteritis. Conclusions: In metastatic NSCLC patients with activating EGFR mutation resistant to Osimertinib, our single institution real-world experience in Chemoimmunotherapy combination shows promising activity and acceptable toxicity profile. Given the small number of patients studied, further clinical trials are warranted.

425P - Effectiveness and safety of osimertinib in patients with metastatic EGFR T790M-positive NSCLC: An observational real-world study

425P - Effectiveness and safety of osimertinib in patients with metastatic EGFR T790M-positive NSCLC: An observational real-world study

1354P - Osimertinib in Asia-Pacific patients (pts) with EGFR T790M-positive advanced NSCLC: Updated Phase II study results including progression-free survival (PFS)

1354P - Osimertinib in Asia-Pacific patients (pts) with EGFR T790M-positive advanced NSCLC: Updated Phase II study results including progression-free survival (PFS)