3rd Generation EGFR TKI Research Articles

Abstract 5462: BPI-361175, a 4th generation EGFR-TKI for the treatment of non-small cell lung cancer (NSCLC)

Abstract EGFR-activating mutations (Del19 or L858R) are major drivers in NSCLC (~40% in Asian and 10-20% in non-Asian). EGFR-TKIs have brought benefit to NSCLC patients with EGFR mutations, prolonging PFS and increasing quantity of life. Nevertheless, resistance inevitably emerges and leads to disease progression. Acquired EGFR C797S mutation is the most common event underlying resistance to the 3rd generation EGFR-TKIs, and there are no therapies. Herein, we report the discovery of BPI-361175, a 4th generation EGFR-TKI that overcomes EGFR resistant mutations. In vitro, BPI-361175 potently inhibited the activity of a variety of EGFR kinases, including triple (EGFRdel19 or L858R/T790M/C797S), double (EGFRdel19 or L858R/T790M, EGFRdel19 or L858R/C797S) and single (EGFRdel19 or L858R) mutations. Accordingly, BPI-361175 dose-dependently inhibited the phosphorylation of EGFR and the proliferation of cell lines harboring the above-mentioned mutations. Meanwhile, BPI-361175 were not active towards EGFRWT and IGF1R, therefore displayed good selectivity, both in kinase assays and in cell-based assays. In vivo, oral administration of BPI-361175 led to tumor suppression and regression in multiple EGFR mutant models, such as BaF3 EGFRDel19 or L858R/T790M/C797S, BaF3 EGFRDel19/C797S allograft models, and PC9 EGFRDel19/T790M/C797S, NCI-H1975 EGFRDel19/T790M/C797S, NCI-H1975 (EGFRL858R/T790M), HCC827 (EGFRDel19) CDX models, as well as a LDI-0025-200717 (EGFRDel19/T790M/C797S) PDX model. Remarkably, BPI-361175 significantly prolonged the life span of brain orthotropic BaF3 EGFRDel19/T790M/C797S allograft mice, demonstrating activity towards brain metastasis. In conclusion, BPI-361175 is a potent, selective, and orally bioavailable 4th generation EGFR-TKI which can potentially be used to treat NSCLC resistant mutations as well as at front line. Phase I clinical trial of BPI-361175 is enrolling patients in China, and US Phase I trial is expected to initiate in Q1 2022. Citation Format: Lijia Liu, Changyong Qiu, Xiangyong Liu, Yuanyan Lian, Haibo Chen, Xiaodong Song, Qichao Shen, Guolong Du, Jing Guo, Dan Yan, Hong Lan, Lieming Ding, Jiabing Wang. BPI-361175, a 4th generation EGFR-TKI for the treatment of non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5462.

Aumolertinib activity in patients with CNS metastases and EGFR-mutated NSCLC treated in the randomized double-blind phase III trial (AENEAS).

9096 Background: We previously reported (Lu, ASCO 2021, abstract # 9013) that treatment with aumolertinib (Au), a 3rd generation EGFR TKI, led to robust improvement in progression free survival (PFS) (median PFS 19.3 to 9.9 months, HR = 0.46, p < 0.0001) when compared to gefitinib (G) with a predictable and encouraging safety profile. This benefit was maintained across all prespecified stratification factors including the subset of ̃ 27% of patients (pts) with CNS metastases (HR = 0.38). Here we undertook this analysis to more fully characterize the activity and benefit of Au as compared to G in this clinically important subset of EGFR mutant NSCLC pts. Methods: Pts with previously untreated metastatic or locally advanced NSCLC with EGFR sensitizing mutations were enrolled and randomly assigned in a 1:1 ratio to receive either Au (110 mg QD) or G (250 mg QD). Predefined stratification factors were EGFR-mutated status (Ex19del vs L858R) and CNS metastases (yes vs no). Patients with stable, asymptomatic CNS metastases were eligible for enrollment. All pts had baseline brain imaging by magnetic resonance imaging or computed tomography. The primary endpoint was PFS assessed by investigator per RECIST v1.1 in full analysis set (systemic analysis). Independent CNS efficacy was performed both in pts with baseline CNS metastases (CNS full analysis set, cFAS) and in pts with baseline CNS target lesions (CNS evaluable-for-response set, cEFS) by blinded independent central neuroradiology review (BICR) per RECIST v1.1. Results: Of 429 pts, 106 pts (Au, n = 51; G, n = 55) were found to have CNS metastases (cFAS) and 61 pts (Au, n = 29; G, n = 32) had CNS target lesions as defined by RECIST 1.1 (cEFS) at baseline by BICR. At the cutoff date (Aug 6, 2021), based on cEFS, CNS PFS events were observed in 11 pts (38%) treated with Au versus 20 pts (63%) who were randomized to receive G. Treatment with Au significantly prolonged CNS median PFS compared with G (29.0 vs 8.3 months; HR = 0.300; 95% CI, 0.137-0.657; P = 0.0015). Estimated CNS PFS rate at 12 and 18 months were 71% and 62% in Au arm compared with 23% and 0% in G arm. The confirmed CNS ORR were 82.8% and 75.0% in pts treated with Au and G, respectively (odds ratio = 1.600; 95% CI, 0.457-5.597; P = 0.4621). Au also achieved longer CNS median PFS over G in cFAS (29.0 vs 8.3 months; HR = 0.323; 95% CI, 0.181-0.576; P < 0.0001). No new safety findings were observed. Conclusions: Au demonstrated superior clinical efficacy against CNS metastases over G as first-line therapy in EGFR-mutated advanced NSCLC, and the safety profile was consistent with that reported previously. Additional randomized studies of Au in pts with CNS metastases are ongoing (NCT04870190). Clinical trial information: NCT03849768.

Preliminary clinical investigations of high-dose furmonertinib in NSCLC with EGFR Exon 20 insertions (20ins).

e21029 Background: Currently neither chemotherapy nor approved EGFR TKIs have satisfactory efficacy in most EGFR 20ins mutations. Activity of high-dose furmonertinib, a novel 3rd generation EGFR TKI, against EGFR 20ins was assessed in preclinical models and a phase lb study. This study aimed to retrospectively investigate the efficacy of high-dose furmonertinib against EGFR 20ins in the real world. Methods: Retrospective search identified 14 metastatic NSCLC patients (pts) with EGFR 20ins treated with high-dose furmonertinib (160mg qd) in Fudan University Shanghai Cancer Center. The clinical efficacy and safety were investigated. Results: Median age was 60 years old (range 40-75) in this cohort with 28% female. At data cutoff date of January, 2022, 9 pts had ≥1 disease assessment. 5 out of 9 pts achieved PR, and 3 patients achieved SD. No CR was observed and 1 patient PD at first assessment. The most common adverse events (AE, ≥20%) were diarrhea, paronychia, skin fissures, anorexia, pain in extremity, rash and stomatitis. No grade ≥3 AE was observed. Conclusions: High-dose furmonertinib has shown encouraging anti-tumor activity in NSCLC with EGFR 20ins.

The significance of micro-EGFR T790M mutation on EGFR-TKI efficacy in patients with NSCLC: The WJOG13119L study.

e21177 Background: The significance of micro-pretreatment EGFR T790M mutation on EGFR-tyrosine kinase inhibitor (TKI) efficacy in patients with non-small cell lung cancer (NSCLC) remains uncertain. In addition, there has been no method to examine the micro-T790M mutation after excluding formalin-fixed and paraffin-embedded (FFPE)-derived artificial mutations. Therefore, we used a novel method to examine the variant allele frequency (VAF) of T790M mutation in the FFPE samples after excluding the artificial mutations. Subsequently, we retrospectively investigated the association between micro-T790M mutations and time to treatment failure (TTF) in patients treated with 1st, 2nd, or 3rd generation (1G, 2G, 3G) EGFR-TKIs. Methods: We enrolled patients with NSCLC who harbored EGFR exon 19 deletion (Del19) or L858R without T790M mutation using conventional methods. Patients who received 1G or 2G EGFR-TKIs until June 2018 or 3G EGFR-TKI until June 2019 from 31 institutions were included. Droplet digital PCR was performed using pretreatment FFPE tumor samples. We defined cases as micro-T790M positive when the VAF of T790M was higher than that of F795F, owing to the FFPE-derived artificial mutations. The ratio of micro-T790M mutation was calculated as follows: {(VAF of T790M) – (VAF of F795F)} /VAF of (Del19 or L858R). The lowest value was set as 0. Results: A total of 110, 102, and 103 patients received 1G, 2G, and 3G EGFR-TKIs, respectively. Of these patients, 48.1%, 47.0%, and 47.6% were classified as micro-T790M positive, respectively. The ratios of micro-T790M mutation, represented as median (%) (interquartile range), in 1G, 2G, and 3G EGFR-TKI groups were 0.27 (0.12-0.87), 0.28 (0.13-0.47), and 0.42 (0.20-0.68), respectively. The VAF of T790M or F795F in all patients, represented as median (%) (interquartile range), was 0.26 (0.19-0.35) or 0.25 (0.19-0.33), respectively. The TTF was not significantly different between the T790M-positive and negative groups in analysis based on each generation TKIs. In the Del19 group, the TTF of the 1G EGFR-TKI was significantly shorter, while that of the 3G EGFR-TKI was significantly longer in the T790M-positive group than in the negative group ( p= 0.02, 0.04, respectively). In the T790M-positive group, the TTF of the 2G or 3G EGFR-TKI group was significantly longer than that of the 1G EGFR-TKI group ( p= 0.04, 0.01, respectively). This result was observed in the Del19 group but not in the L858 group. Furthermore, TTF did not significantly differ between the 1G, 2G, and 3G EGFR-TKIs in the T790M-negative group. Conclusions: This study showed that micro- EGFR T790M mutations influence the EGFR-TKI efficacy. Detection of micro-T790M mutations will facilitate selection of the optimal EGFR-TKI for patients with EGFR mutated NSCLC.

Gene alternation of cerebrospinal fluid in patients with leptomeningeal metastases of lung adenocarcinoma using next-generation sequencing

BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) provide a better prognosis in EGFR-mutant non-small cell lung cancer (NSCLC). Nevertheless, the outcome of leptomeningeal metastasis (LM) remains poor. In addition, due to limited access to intracranial tumour tissue, gene alterations associated with leptomeningeal metastasis from lung adenocarcinoma (LM-LUAD) are unclear.MethodsForty-five patients with LM-LUAD from May 2019 to June 2021 in Guangdong Sanjiu Brain Hospital were enrolled in this study. Seventy-five percent (34/45) of patients with LM harbored EGFR mutations, and patients with progressive disease (PD) of LM had 3rd-generation EGFR-TKI therapy and were defined as Cohort 1; those without 3rd-generation EGFR-TKI therapy were defined as Cohort 2. Next-generation targeted panel sequencing (NGS) was performed in each cerebrospinal fluid (CSF) sample of the two cohorts, and 9/45 LM-LUAD patients had matched plasma (PLA).ResultsThe common gene alterations discovered in the CSF of LM-LUAD were EGFR mutation (34/45, 75%), TP53 (25/45, 56%), CDKN2A (9/45, 20%), ALK (7/45, 16%), CTNNB1 (6/45, 13%), MET (5/45, 11%), APC (4/45, 9%), FGF4 (4/45, 9%), FGF3 (4/45, 9%), ERBB2 (4/45, 9%), and PIK3CG (4/45, 9%). Cooccurring mutations of TP53 and EGFR were found in 49% (22/45) of patients and correlated with poor prognosis. CDKN2A was identified in 20% (9/45) of patients and presented slightly shorter overall survival (OS) than those without (7.1 versus 8.8 months, p = 0.2). Cohort 1 had more genes associated with poor prognosis, consisting of CDK4, CDKN2A, PIK3CG, or PIK3CA, and YES1 and MET were more likely to be detected in cohort 2. The alteration of EGFR was comparable between CSF and matched PLA. Incidences of gene alterations such as CDK4, CDKN2A, MET, SOX2, JAK2, BRAF, and PIK3CG were more likely to be identified in CSF. All mutant allele frequencies (MAF) were much higher in CSF than in matched PLA.ConclusionsCSF could be a potential candidate for the genetic profiling of LM-LUAD, demonstrating the genetic characteristics of LM in EGFR-mutated lung adenocarcinoma on diverse EGFR-TKI therapies.

Abstract P083: Metastatic NSCLC -Re-challenging with first generation TKI after a drug free holiday after resistance to 3rd generation TKI

Abstract BACKGROUND Lung cancer is the most common cancer worldwide in males & a good number of patients present with metastatic disease. Though EGFR mutated patients respond to EGFR TKIs, resistance develops ultimately. Overcoming 3rd generation EGFR TKI resistance is a big challenge. METHOD 20 patients of metastatic adenocarcinoma, confirmed with core biopsy & IHC (EGFR positive) were offered Erlotinib initially. Osimertinib was offered to those who developed EGFR TKI resistance due to T790M mutation (10 cases). All 10 patients eventually developed resistance to Osimertinib. All patients were given 3 months drug free holiday & then re-challenged with Erlotinib. RESULT 4 out of 10 (40%) patients responded to the therapy. 6 patients had progression & were managed by systemic chemotherapy & radiation. CONCLUSION Literature shows up to 50% metastatic adenocarcinoma, EGFR positive patients who had developed EGFR TKI resistance to 1st & 3rd generation TKIs, responds to re-challenge with first generation TKI after a drug free holiday. In this series 40% patients responded. This approach should be tried & non-responders can be offered systemic chemotherapy & radiation. Citation Format: Suryakanta Acharya. Metastatic NSCLC -Re-challenging with first generation TKI after a drug free holiday after resistance to 3rd generation TKI [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P083.

P48.14 Metastatic NSCLC -Re-Challenging With Fist Generation TKI After a Drug Free Holiday After Resistance to 3rd Generation TKI

Lung cancer is the most common cancer worldwide in males & a good number of patients present with metastatic disease. Though EGFR mutated patients respond to EGFR TKIs, resistance develops ultimately. Overcoming 3rd generation EGFR TKI resistance is a big challenge.

1210P Preclinical and preliminary clinical investigations of furmonertinib in NSCLC with EGFR exon 20 insertions (20ins)

Currently neither chemotherapy nor approved EGFR TKIs have satisfactory efficacy in most EGFR 20ins mutations. Activity of furmonertinib, a novel 3rd generation EGFR TKI, against EGFR 20ins was assessed in preclinical models and a phase Ib study.

1813P Anlotinib plus osimertinib overcomes acquired resistance to osimertinib via FGFR and EGFR signaling in non-small cell lung cancer (NSCLC)

Osimertinib (Osi), a 3rd generation EGFR-TKI, has shown great efficacy in advanced NSCLC patients (pts) with EGFR sensitizing mutations and EGFR T790M resistance mutation, but the acquisition of resistance is inevitable and the treatment regimen is limited. As an oral multi-targeted tyrosine kinase inhibitor, anlotinib effectively inhibits tumor growth and angiogenesis. We found that anlotinib plus Osi showed favorable efficacy in a subset of Osi-resistant NSCLC pts in clinical practice. However, the underlying mechanism remains unclear.

Abstract CT106: Phase I/II study of osimertinib in EGFR exon 20 insertion mutations in non-small cell lung cancer patients: AEX20

Abstract Background EGFR exon 20 insertion gene mutation (ex20ins) accounts for about 4-12% of the total EGFR gene mutations in non-small cell lung cancer (NSCLC) patients. NSCLC patients with EGFR ex20ins is known to be less sensitive to 1st- or 2nd-generation EGFR-TKIs. Although 3rd-generation EGFR-TKI, osimertinib is active against in vitro models of EGFR ex20ins, its efficacy has not yet been fully elucidated. This phase I/II study is conducted to evaluate the clinical efficacy of osimertinib in NSCLC patients with EGFR ex20ins. Method This is a single-arm, multi-center, open-label, non-randomized phase I/II study (UMIN000031929) consisting of stage 1 and stage 2 (Simon's two-stage design). In stage 1, 12 patients receive osimertinib 80mg once daily until they meet the termination criteria, such as, disease progression, severe toxicities, withdrawal etc. In stage 2, 9 patients receive the same dose of osimertinib if more than 1 patient achieve PR or CR in stage 1. At the transition from stage 1 to 2, Independent Data Monitoring Committee (IDMC) will provide recommendation regarding the need for study continuation, termination or dose modification of osimertinib. Patients with advanced or metastatic NSCLC with EGFR ex20ins who have a history of chemotherapy within 0 to 3 regimens are enrolled. Patients with history of EGFR-TKI treatment (gefitinib, erlotinib, afatinib, dacomitinib) can be included if the EGFR-TKI treatment did not show any clinical benefit. Patients with EGFR gene mutations, such as exon 19 deletion, L858R, T790M, G719X, L861Q are excluded. Primary end point is objective response rate (ORR) assessed via Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points are progression-free survival, overall survival, and safety profiles. Blood sampling is obtained at 4-weeks after starting osimertinib to analyze pharmacokinetic parameters. We also perform liquid biopsy for next generation sequencing at before and after acquiring resistance to osimertinib to clarify resistant mechanisms of osimertinib in EGFR ex20ins. We explore the relationship among clinical outcome, side effect, pharmacokinetic parameters and subtype of EGFR ex20ins. Result Recruitment began in June 2018 and by February 2020, 12 patients were enrolled in stage 1 at 6 institutions. Backgrounds of the patients were as follows, the median age was 63 years (range 22-84), female/male 6/6, ECOG PS 0/1 8/4, cStage IIIA/IIIb/IVA/IVB 1/1/2/8. The ORR was 0% (CR/PR 0, SD 8, PD 4), and the DCR was 66.7%. From the result of stage 1, one of the IDMC's recommendations was protocol revision since it is presumed that increasing the dose of osimertinib could be clinically promising. At the conference, the influence of subtype of EGFR ex20ins and blood levels of osimertinib on survival will be evaluated and the results of interim analysis for stage 1 will be presented. Conclusion Regular dose of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. Funding AstraZeneca. Citation Format: Eiki Ichihara, Hiroyuki Yasuda, Yuta Takashima, Yoshitaka Zenke, Shinji Takeuchi, Masahiro Morise, Katsuyuki Hotta, Mineyoshi Sato, Shingo Matsumoto, Azusa Tanimoto, Reiko Matsuzawa, Katsuyuki Kiura, Hideki Terai, Shinnosuke Ikemura, Koichi Goto, Kenzo Soejima. Phase I/II study of osimertinib in EGFR exon 20 insertion mutations in non-small cell lung cancer patients: AEX20 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT106.

MO29-6 Safety and tolerability of lazertinib and in combination with amivantamab in advanced EGFR-mutated Japanese NSCLC

Lazertinib (Laz) is an oral, potent, brain-penetrant 3rd generation EGFR-TKI targeting T790M and activating EGFR mutations while sparing WT EGFR. Amivantamab (Ami) is an EGFR-MET bispecific antibody with immune-cell directing properties. This study (NCT04077463) evaluates the safety, tolerability, PK of Laz (Ph1) or in combinations with Ami (Ph1b combo) in Japan, and to further characterize this combination globally (Ph1b expansion) in advanced EGFR-mutant NSCLC patients (pts). Here, we present the Japanese (JPN) Ph1/1b combo data.

356MO Osimertinib adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) NSCLC (ADAURA): Central nervous system (CNS) disease recurrence

CNS relapse is common in NSCLC, and is a poor prognostic factor. In the resected EGFRm NSCLC setting, the impact of treatment on sites of recurrence, including the CNS, is a key consideration. Osimertinib is a 3rd-generation EGFR-TKI with demonstrated efficacy in NSCLC CNS metastases. In ADAURA, osimertinib demonstrated a highly statistically significant and clinically meaningful improvement in disease-free survival vs placebo (PBO; DFS, hazard ratio [HR]: 0.20 [99.12% CI 0.14, 0.30; p<0.001) in resected stage IB–IIIA EGFRm (ex19del/L858R) NSCLC (Ph III ADAURA; NCT02511106). We report an exploratory analysis of recurrence patterns. Pts with resected stage IB–IIIA EGFRm NSCLC, with/without adjuvant chemotherapy, were randomised 1:1 to receive osimertinib 80 mg once-daily or PBO until recurrence/discontinuation/3 years. Patterns of recurrence and CNS DFS (time to CNS recurrence/death) were exploratory endpoints. An MRI/CT brain scan was mandated at baseline either before surgery or upon enrolment, but was not required in absence of symptoms. Recurrence was categorised as local/regional and/or distant, with sites of relapse recorded. Data cutoff: 17/01/20. Overall, 682 pts were randomised (osimertinib: 339; PBO: 343). Pts treated with osimertinib had fewer recurrence events vs PBO (Table); 45 pts had CNS DFS events (osimertinib: 6; PBO: 39; median follow-up 22 months [mo]). Conditional probability of CNS recurrence at 12 mo (95% CI): <1% (0%, 2%) with osimertinib vs 7% (4%, 10%) with PBO. Median CNS DFS: not reached (95% CI 39.0 mo, not calculable [NC]) with osimertinib vs 48.2 (NC, NC) mo with PBO. CNS DFS HR: 0.18 (95% CI 0.10, 0.33); p<0.0001.Table: 356MOOsimertinib n=339PBO n=343CNS DFS events, pts (%):6 (2)39 (11)CNS recurrence4 (1)33 (10)Death*2 (1)6 (2)DFS events, pts (%):37 (11)159 (46)Disease recurrence37 (11)157 (46)—— Non-CNS recurrence33 (10)123 (36)—— CNS recurrence4 (1)33 (10)—— Disease recurrence with missing location01 (0)Death†02 (1)*Death in absence of CNS disease recurrence, or death within two visits of baseline where the patient has no evaluable assessments or no baseline data. †Death in the absence of disease recurrence (any site), or death within two visits of baseline where the patient has no evaluable assessments or no baseline data. Open table in a new tab *Death in absence of CNS disease recurrence, or death within two visits of baseline where the patient has no evaluable assessments or no baseline data. †Death in the absence of disease recurrence (any site), or death within two visits of baseline where the patient has no evaluable assessments or no baseline data. There was a clinically meaningful improvement in CNS DFS with osimertinib: 82% reduction in risk of CNS disease recurrence or death. Results support that osimertinib reduces risk of CNS recurrence in the resected EGFRm NSCLC setting.

Abstract 5198: JNJ-61186372, a novel EGFR/c-Met bispecific antibody, exhibits potent antitumor activity in broad-spectrum of acquired resistance to EGFR-TKIs

Abstract Background: 1st generation (erlotinib &amp; gefitinib), 2nd generation (afatinib), and 3rd generation (osimertinib) EGFR TKIs have marked efficacy in patient with EGFR-mutant NSCLC. Unfortunately, patients who show T790M (-) mutation after treated with 1st and 2nd generation EGFR TKI or have C797S (+) mutation or other mechanisms of acquired resistance to 3rd generation EGFR TKI have no therapeutic options for curing cancer in clinic. We introduce a potent therapeutics for overcoming acquired resistance to EGFR-TKIs in several EGFR mutant NSCLC models using JNJ-61186372 (JNJ-372), a bispecific antibody that targets the EGFR and c-Met receptors. Methods: We classified PDC and PDX models into two groups: i) 1st and 2nd generation EGFR TKI acquired resistance models with T790M (-) mutation (YU-1093, YU-1152), ii) 3rd generation EGFR TKI acquired resistance models with C797S (+) mutation (YU-1097), and C797S (-) mutation with unknown resistance mechanisms (YU-1095, YU-1089, YU-1096, YUX-1024_YH1R, YHIM-1035, YHIM-1045, and YHIM-1053). We established 7 patient-derived cells (PDC) and 3 patient-derived xenografts (PDX) model from patients with broad-spectrum acquired resistance to EGFR-TKIs. We performed cell viability test and western blot to investigate antitumor activity of JNJ-372. We evaluated then in vivo antitumor activity of JNJ-372 in PDX and PDC-xenograft models. JNJ-372 was administrated i.p. twice a week at 30 mg/kg. Results: We assessed the ability of JNJ-372 to overcome broad-spectrum of EGFR-TKI acquired resistances. JNJ-372 significantly inhibited cancer cell growth in vitro and in vivo in PDC model harboring T790M (-) mutation. JNJ-372 significantly decreased cell proliferation rate and EGFR downstream signaling in BaF3 cell harboring Del19 (L858R)/T790M/C797S mutant and PDC model harboring Del19/T790M/C797S mutant with amplified KRAS and loss of Rb. C797S (-) cases of four PDCs and three PDX models had i) loss of T790M with c-Met amplification or other acquired resistance mutation and ii) T790M (+) with amplified c-Met. In these models we identified dramatic tumor regression and reduction of EGFR and c-Met expression in vitro and in vivo PDX and PDC-xenograft models. Interestingly, we observed combination treatment of JNJ-372 and c-Met inhibitor showed synergistic immune cell mediated cellular cytotoxicity in EGFR-TKI acquired resistance models harboring c-Met amplification. JNJ-372 exhibited potent inhibition of tumor growth in preclinical models through targeting EGFR and c-Met receptor, decreasing EGFR and c-Met receptor level, inhibiting EGFR downstream signaling cascade and activating ADCC effect in vivo. Conclusion: Our results suggest that JNJ-372 will provide potential and effective therapeutic options for patients with no therapeutic option to overcome broad-spectrum of acquired resistance to EGFR-TKIs. Citation Format: SooHwan Lee, Jiyeon Yun, Seo-Yoon Jeong, Chae Won Park, Seok-Young Kim, Min Hee Hong, Hye Ryun Kim, Byoung Chul Cho. JNJ-61186372, a novel EGFR/c-Met bispecific antibody, exhibits potent antitumor activity in broad-spectrum of acquired resistance to EGFR-TKIs [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 5198.

Abstract 3081: SHOC2 is a critical modulator of the sensitivity to EGFR-TKI in non-small cell lung cancer cells

Abstract Epidermal Growth Factor Receptor tyrosine kinase inhibitors (EGFR-TKI) have become the first line treatment for patients with EGFR mutated non-small cell lung cancer (NSCLC) as a result of multiple clinical trials demonstrating superior response and less toxicity as compared to conventional cytotoxic agents. However, despite the clinical experience among nearly two decades, it is well known that EGFR-TKI monotherapy cannot cure EGFR mutation-positive lung cancer patients due to the occurrence of drug resistance. While dramatic initial tumor shrinkage is shown in most patients with EGFR-TKI treatment, therapeutic resistance is often observed in 1-2 years. This is likely caused by the outgrowth of rare pre-existing resistant clones and/or small fraction of drug tolerant persister cells (DTPs) which survive and acquire resistance to EGFR-TKIs. Several previous studies have clarified the acquired resistance mechanisms to EGFR-TKIs, but little is known how the DTPs survive during the initial phase of drug exposure and rapidly adapt to EGFR-TKIs. Utilizing the genome wide CRISPR/Cas9 screening, we have previously reported that DTPs were capable to exploit endoplasmic reticulum stress to survive EGFR-TKI exposure (Terai, et al, Cancer Research 2018). Further analysis of this data identified multiple genes which could affect the initial drug response to EGFR-TKIs, including the scaffold protein coding gene, SHOC2. In our present study we focused on this unique protein and revealed its critical function as a modulator of drug response to EGFR-TKIs in lung cancer cells. We confirmed that depletion/overexpression of SHOC2 in PC9 cells, an EGFR-dependent NSCLC cell line, renders the cells sensitive/resistant to all 1st to 3rd generation EGFR-TKIs. We have also confirmed similar findings with another EGFR dependent NSCLC cell line named H1975. Reduction of phosphorylation levels of ERK1/2 induced by EGFR-TKIs were stronger in PC9 or H1975 cells with SHOC2 knockout, indicating that SHOC2 can facilitate ERK1/2 reactivation during EGFR-TKI treatment. The above data indicate that SHOC2 is essential for DTPs and its function is correlated with MAPK-ERK pathway activity. Celastrol, a candidate SHOC2 inhibitor, inhibited the emergence of DTPs and synergized with EGFR-TKIs. Additionally, we showed that SHOC2 depletion enhanced the growth inhibitory effect of osimertinib in vivo. Lastly, we confirmed the increased expression of SHOC2 in clinical human samples which experienced EGFR-TKI failure. Our findings could offer a new treatment strategy for NSCLC patients with EGFR mutation leading to the increase of the degree and duration of EGFR TKIs response. Citation Format: Hideki Terai, Junko Hamamoto, Tadashi Manabe, Katsura Emoto, Takeshi Masuda, Satoshi Kuronuma, Keigo Kobayashi, Keita Masuzawa, Shinnosuke Ikemura, Sohei Nakayama, Ichiro Kawada, Yusuke Suzuki, Osamu Takeuchi, Yukio Suzuki, Sumio Ohtsuki, Hiroyuki Yasuda, Kenzo Soejima, Koichi Fukunaga. SHOC2 is a critical modulator of the sensitivity to EGFR-TKI in non-small cell lung cancer cells [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 3081.

Clinical implication and usefulness of de novo EGFR T790M mutation in lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutation

ABSTRACT Detection rate of de novo EGFR T790 M mutation was increased up to 80% through recent ultrasensitive detection methods. Here, we investigated the clinical significance and its usefulness of detecting de novo EGFR T790 M using ultrasensitive droplet-digital polymerase chain reaction (ddPCR) method. In total, 102 cases diagnosed as lung adenocarcinoma with EGFR-tyrosine kinase inhibitor (TKI) sensitizing mutations (mEGFR) and had been treated with 1st ~ 2nd generation EGFR-TKI alone were enrolled for this study. De novo T790 M status was tested using the tissues at the initial diagnosis and positivity was defined as the ratio of T790 M/wild-type copies over 0.00294 by ddPCR. Seventy patients (68.6%) harbored the de novo T790 M. De novo T790 M was more frequently detected in cases with EGFR L858 R mutation than those with EGFR exon 19 deletion (E19d) mutations (P = 0.024). Forty-three patients underwent rebiopsy due to disease progression. The cases who experienced progression due to acquired T790 M were more likely to have E19d at initial diagnosis and the presence of de novo T790 M and the ratio of T790 M/wild-type copies did not relate to the emergence of acquired T790 M. On the other hand, the cases with a longer duration of disease-control by EGFR-TKI had higher change to get acquired T790 M mutation (P-value = 0.040). The presence of de novo T790 M has limitation in predicting disease progression by acquired T790 M, suggesting that identifying de novo T790 M through the ultrasensitive methods may not be necessary identifying patients who would be beneficial by 3rd-generation EGFR-TKI as the 1st line treatment.

Nazartinib (EGF816) in patients with treatment-naïve EGFR-mutant non-small cell lung cancer (NSCLC): Updated phase II results.

9574 Background: Prior data from a phase I/II study showed durable responses, including efficacy in brain lesions, and a tolerable safety profile with nazartinib in treatment (tx)-naïve patients (pts) with EGFR-mutant (mut), locally advanced (adv)/metastatic NSCLC. Here we report updated phase II results, including overall survival (OS). Methods: Tx-naïve adult pts with activating EGFR-mut (L858R or ex19del), stage IIIB/IV adv NSCLC with neurologically stable and controlled brain metastasis (BM) received oral nazartinib 150 mg once daily (continuous schedule). Primary endpoint: overall response rate (ORR) by BIRC per RECIST v1.1; secondary endpoints: disease control rate (DCR), duration of response (DOR), time to response, progression-free survival (PFS), OS, and safety. Results: At data cut-off (Nov 1, 2019), 45 pts were enrolled (median [range] age: 64 [28–83] years; 26 pts [58%] ECOG PS 1; 18 pts [40%] had baseline BM). EGFR mutations: 56% ex19del, 40% L858R, 4% other. 26/45 pts (58%) discontinued tx, with the primary reason being progressive disease in 19 pts (42%); 2 pts (4%) discontinued tx due to AEs. Median (range) follow-up for OS: 25 (0–33) months (mo); and for PFS: 17 (0–33) mo. ORR by BIRC: 69%; median PFS by BIRC: 18 mo; median OS was NE and at 33 mo, 56% of pts were alive (Table). BIRC results by baseline BM are shown in the Table. Median (range) duration of exposure: 24 (0–34) mo. Most frequent AEs (≥20% all grade, all causality): diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough and stomatitis (27% each), decreased appetite and pruritus (24% each), and dermatitis acneiform (22%). Most frequent grade 3/4 AEs (≥10%, all causality): maculopapular rash (5 pts [11%]; all grade 3) and increased lipase (5 pts [11%]; 1 pt with grade 4; no clinical pancreatitis AE was observed). Conclusions: After additional follow-up, median OS was still not reached and the safety profile was manageable. Nazartinib is a promising 3rd generation EGFR TKI for tx-naïve pts with adv EGFR-mut NSCLC, including pts with baseline BM. Clinical trial information: NCT02108964 . [Table: see text]

PCN202 LIQUID BIOPSY FOR EGFR+ PATIENTS IN ADVANCED NSCLC: THE IMPACT OF DIFFERENT STRATEGIES

A previous analysis showed the economic sustainability of adding liquid biopsy, whenever possible, to tissue biopsy for the assessment of epidermal growth factor receptor-positive (EGFR+) mutation in patients with advanced non-small cell lung cancer (mNSCLC). The following analysis evaluated the clinical outcome (progression free survival, PFS) when adopting two different diagnostic strategies in the first-line treatment of patients with EGFR+ mNSCLC. A previous decision-analytic model was adopted to compare the two diagnostic strategies: i) tissue strategy and ii) combined strategy (tissue biopsy and, were its outcome unknown, liquid biopsy). We only evaluated the PFS variation between the two diagnostic strategies considered. We assumed that mNSCLC EGFR+ patients were treated with 3rd generation EGFR-TKI (PFS: 18.9 months), while mNSCLC EGFR Wilde Type (WT) patients were treated with chemotherapy (PFS: 5.7 months). Key variables were tested in the sensitivity analysis. A total of 13,030 patients eligible for tissue biopsy in Italy were considered, of whom 2,463 were assumed to be EGFR+. The combined strategy showed an increase of the number of correctly identified EGFR+ patients (2,293 patients) compared to the tissue strategy (1,691 patients). When considering mNSCLC EGFR+ patients treated with 3rd generation EGFR-TKI, the PFS would increase from 14.8 months per patient with the tissue strategy to 18.5 months per patient with the combined strategy. When considering mNSCLC EGFR+ patients treated with other 1st/2nd generation EGFR-TKI, the PFS would increase from 8.8 months per patient with the tissue strategy to 10.1 months per patient with the combined strategy. The choice of a correct diagnostic strategy is crucial in order to optimize cancer therapies in the first-line treatment of mNSCLC EGFR+. The addition to the diagnostic pathway of the liquid biopsy would correctly identify a greater number of cases, supporting the prescription of a more effective oncological therapy.

498P - An observational retrospective study to evaluate the incidence of acquired EGFR T790M resistance in NSCLC patients with EGFR mutation following progression after at least one prior EGFR TKI treatment in Taiwan: ARISE study

BackgroundIn Taiwan, gefitinib, erlotinib, and afatinib are all prescribed as the first-line therapy in NSCLC patients with EGFR sensitizing mutation. Although EGFR mutation-positive patients had favorable treatment response of EGFR TKIs, acquired resistance eventually developed, especially acquired EGFR T790M mutation. The 3rd-generation EGFR TKI, osimertinib, has been approved effectiveness for patients with acquired T790M formation after 1st-and 2nd-generation EGFR TKIs treatment. However, it is unclear whether the incidence of acquired T790M resistance differs as a result of the choice of the first-line EGFR TKI therapy. This study aimed to evaluate the association between the prior EGFR TKI therapy and the incidence of acquired T790M resistance in NSCLC patients who have progressed on EGFR TKI therapy. MethodsEligibility included NSCLC patients who had re-biopsy results for testing EGFR T790M mutation from 7 medical centers in Taiwan after June 1, 2013. The primary endpoint is to compare the incidence of acquired T790M mutation in patients who had been treated with different types of EGFR TKIs. Patients harboring tumor with de novo T790M mutations were excluded. ResultsThere were 410 patients who received re-biopsy for detection EGFR T790M after treating with 1st- or 2nd- generation EGFR TKIs. The overall acquired T790M mutation rate was 52.9%. Patients treated with gefitinib (59.8%) had higher acquired T790M incidence than those treated with erlotinib (45.5%; p = 0.011), but no difference with those treated with afatinib (53.3%; p = 0.236). Patients who had longer time to treatment discontinuation (TTD) of EGFR TKI for more than 18 months had higher T790M incidence than those with other predefined duration categories (p < 0.001). Multivariate logistic regression analysis revealed common EGFR mutations, gefitinib (compared to erlotinib), and longer TTD of EGFR TKI were associated with higher T790M incidence. ConclusionsPatients treated with gefitinib had higher acquired T790M incidence than those treated with erlotinib. Longer TTD of EGFR TKI was also associated with the frequency of acquired T790M mutation. Legal entity responsible for the studyThe authors. FundingAstraZeneca. DisclosureS-G. Wu: Honoraria (self): Roche; Honoraria (self): AstraZeneca. C-L. Chiang: Honoraria (self): Boehringer Ingelheim; Honoraria (self): Roche. J-Y. Shih: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Novartis; Honoraria (self): Eli Lilly. G-C. Chang: Honoraria (self): F. Hoffmann-La Roche, Ltd; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly and Company Oncology; Honoraria (self): Pfizer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.

497P - Real-word efficacy of osimertinib in patients with metastatic EGFRm NSCLC: An interim analysis from a multi-center study in China

BackgroundThe EGFRm rate in metastatic NSCLC is 30%∼40% in China. Osimertinib, 3rd generation EGFR-TKI, is approved as the 1st line treatment for patients with advanced EGFRm NSCLC and 2nd line treatment for patients with EGFR T790M positive advanced NSCLC globally, and only is approved as the 2nd line treatment in China by now. This study is to investigate the efficacy of Osimertinib in patients with metastatic EGFRm NSCLC in the real word clinical setting in China. MethodsThis multi-center study was conducted in 13 medical centers in China from April 2017 to May 2019 (Clinical trial ID: 1800019903). Patients with metastatic EGFRm NSCLC received by Osimertinib were enrolled into this study. All data were collected and analyzed on China Multi-center Lung Cancer Precision Medicine Registry RWE Box. ResultsA total of 346 patients with metastatic EGFRm NSCLC were enrolled in this study (female: 56.5%, male: 43.5%). 95.1% patients were adenocarcinoma, 2.3% patients were squamous carcinoma and 1.7% patients were adenosquamous carcinoma. The percentage of Osimertinib as 1st line, 2nd line, 3rd line, and more than 3rd line therapy was 10.4%, 55.8%, 21.4% and 12.6%, respectively. 42.5% patients were identified as the secondary T790M (+)after failure of the 1st line EGFR-TKI. For patients (N = 145) with T790M (+) metastatic NSCLC treated by Osimertinib as 2nd line therapy, the ORR was 75.1%, the mPFS was 276 days. Subgroup analysis showed that for those with both T790M (+) and CNS metastasis (N = 146), the mPFS was 280 days and CNS ORR was 67.2%. Interestingly, the CNS ORR was 34.4% for those with T790M (-) of CNS metastasis. In patients (N = 193) who had progressed after 2nd line Osimertinib, 78.9% received chemotherapy, 13.4% received bevacizumab combined with chemotherapy, and 7.7% received immunotherapy, respectively. ConclusionsOsimertinib was generally used as 2nd line treatment in patients who were resistance to the 1st line EGFR-TKI in China. Real-word data further demonstrated and validated the similar efficacy of Osimertinib as 2nd line therapy in China as that previously reported clinical trials. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

475O - Overall survival (OS) from the AURA3 phase III study: Osimertinib vs platinum-pemetrexed (plt-pem) in patients (pts) with EGFR T790M advanced non-small cell lung cancer (NSCLC) and progression on a prior EGFR-tyrosine kinase inhibitor (TKI)

475O - Overall survival (OS) from the AURA3 phase III study: Osimertinib vs platinum-pemetrexed (plt-pem) in patients (pts) with EGFR T790M advanced non-small cell lung cancer (NSCLC) and progression on a prior EGFR-tyrosine kinase inhibitor (TKI)