Irreversible EGFR-TKI Research Articles

The difference between dacomitinib and afatinib in effectiveness and safety in first-line treatment of patients with advanced EGFR-mutant non-small cell lung cancer: a real-world observational study

ObjectivesThe irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) afatinib and dacomitinib are approved for first-line treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and dacomitinib in this setting.Materials and methodsBetween September 2020 and March 2023, we retrospectively recruited patients diagnosed with advanced-stage EGFR-mutant NSCLC who were treated with first-line irreversible EGFR-TKIs. The enrolled patients were assigned to two groups based on whether they received afatinib or dacomitinib.ResultsA total of 101 patients were enrolled in the study (70 to afatinib and 31 to dacomitinib). The partial response rates (PR) for first-line treatment with afatinib and dacomitinib were 85.7 and 80.6% (p = 0.522). The median progression-free survival (PFS) (18.9 vs. 16.3 months, p = 0.975) and time to treatment failure (TTF) (22.7 vs. 15.9 months, p = 0.324) in patients with afatinib and dacomitinib treatment were similar. There was no significant difference observed in the median PFS (16.1 vs. 18.9 months, p = 0.361) and TTF (32.5 vs. 19.6 months, p = 0.182) between patients receiving the standard dose and those receiving the reduced dose. In terms of side effects, the incidence of diarrhea was higher in the afatinib group (75.8% vs. 35.5%, p < 0.001), while the incidence of paronychia was higher in the dacomitinib group (58.1% vs. 31.4%, p = 0.004). The PFS (17.6 vs. 24.9 months, p = 0.663) and TTF (21.3 vs. 25.1 months, p = 0.152) were similar between patients younger than 75 years and those older than 75 years.ConclusionThis study showed that afatinib and dacomitinib had similar effectiveness and safety profiles. However, they have slightly different side effects. Afatinib and dacomitinib can be safely administered to patients across different age groups with appropriate dose reductions.

Development and validation of an LC-MS/MS method for simultaneous determination of SH-1028, an irreversible third-generation EGFR TKI, and two of its metabolites in human plasma: application in clinical pharmacokinetics

SH-1028 is a novel, potent, and highly selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) developed for the treatment of T790M Mutation-positive non-small cell lung cancer (NSCLC). The objective was to develop an LC-MS/MS method for the simultaneous determination of SH-1028 and its metabolites, Imp2 and Imp3, in human plasma. The plasma samples were extracted through protein precipitation with acetonitrile on wet ice conditions. A rapid, sensitive, and specific method was developed and successfully applied to evaluate the pharmacokinetic (PK) properties of SH-1028 in patients with advanced NSCLC following single and multiple doses of SH-1028 (60 mg). After single-dose administration, the C max of SH-1028, Imp2, and Imp3 was 11.2, 50.2, and 7.99 ng/mL, respectively. The mean AUC0–24 h was 138, 602, and 76.7 h*ng/mL, respectively. And the terminal half-life time was 19.9, 14.4, and 26.1 h, respectively. After multiple-dose administration, SH-1028 exhibited a slight accumulation, with a mean accumulation ratio (R AUC) of 2.00. The study assessed the PK properties of SH-1028 following single and multiple doses in patients with advanced NSCLC and would provide meaningful information for the further development of SH-1028.

Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferential options for advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. Osimertinib is a potent irreversible third-generation EGFR-TKI targeting EGFR mutations but has little effect on wild-type EGFR. In view of its remarkable efficacy and manageable safety, osimertinib was recommended as the standard first-line treatment for advanced or metastatic NSCLC patients with EGFR mutations. However, as the other EGFR-TKIs, osimertinib will inevitably develop acquired resistance, which limits its efficacy on the treatment of EGFR-mutated NSCLC patients. The etiology of triggering osimertinib resistance is complex including EGFR-dependent and EGFR-independent pathways, and different therapeutic strategies for the NSCLC patients with osimertinib resistance have been developed. Herein, we comprehensively summarized the resistance mechanisms of osimertinib and discuss in detail the potential therapeutic strategies for EGFR-mutated NSCLC patients suffering osimertinib resistance for the sake of the improvement of survival and further achievement of precise medicine.

Abstract 3259: TAS3351 is a 4th-generation EGFR-TKI overcoming T790M and C797S-mediated resistance in NSCLC with EGFR common mutations

Abstract Background: Common mutations (exon 19 deletion; ex19del or L858R point mutation; L858R) of the epidermal growth factor receptor (EGFR) are found in patients with non-small cell lung cancer (NSCLC) and are sensitive to EGFR-tyrosine kinase inhibitors (TKIs), including osimertinib, a third-generation, irreversible EGFR-TKI. Although osimertinib is widely utilized as the standard of care in first-line therapy of NSCLC, resistance inevitably occurs during the treatment. Among EGFR-dependent/on-target resistant mechanisms of osimertinib, the C797S mutation is reported to emerge as the most frequent alteration. The cysteine residue at position 797 of EGFR is covalently bound with osimertinib, and its alteration to serine causes an inability to form a covalent bond, making osimertinib resistant to NSCLC with a C797S mutation. While first-generation, reversible EGFR-TKIs (gefitinib and erlotinib) might be effective for patients with C797S mutation, the T790M mutation is reported to emerge in almost half of patients with EGFR common mutations during treatment with first-generation EGFR-TKIs. Here, we report TAS3351 as a novel, next-generation EGFR-TKI designed to overcome C797S and T790M-mediated resistance in NSCLC patients. Methods: The inhibitory potency of TAS3351 on cellular phospho-EGFR was analyzed by In-cell western assay. In addition, inhibition of cell viability in Ba/F3 cells transformed by human wild type or mutated EGFR, as well as in human NSCLC cell lines whose EGFR harbors common mutations, was tested. Anti-tumor activity of TAS3351 was evaluated in NIH/3T3-EGFR allograft models and human NSCLC xenograft models. Results: TAS3351 exhibited almost comparable inhibitory potency against cellular phosphorylation of EGFR harboring ex19del or L858R with or without C797S and/or T790M while sparing wild type EGFR activity. TAS3351 also showed similar trends in the cell viability assay for Ba/F3-EGFR cells and human NSCLC cell lines. Finally, TAS3351 demonstrated favorable anti-tumor activity in NIH/3T3 allografts transformed by human EGFR harboring ex19del/C797S/T790M. Conclusion: TAS3351 is a fourth-generation EGFR-TKI overcoming T790M and C797S-mediated resistance in NSCLC with common mutations. The present results support the clinical development of TAS3351 as monotherapy in NSCLC patients with EGFR mutations harboring C797S and/or T790M EGFR-TKI resistance mutations. Citation Format: Hidefumi Kasuga, Yuki Kataoka, Fuyuki Yamamoto, Takashi Mizutani, Shingo Tsuji, Sakiho Tanaka, Shinji Mizuarai. TAS3351 is a 4th-generation EGFR-TKI overcoming T790M and C797S-mediated resistance in NSCLC with EGFR common mutations [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 3259.

Afatinib (AFA) plus bevacizumab (BEV) combination after osimertinib (OSI) resistance in advanced EGFR-mutant NSCLC: A phase II study (ABCD-study).

9117 Background: After OSI failure, various resistant mechanisms such as C797S and uncommon EGFR mutations, or MET amplification have been reported. AFA is an irreversible EGFR-TKI with a potency as pan-HER inhibitor, including high sensitivity to uncommon EGFR mutations. Many clinical studies have also shown a synergy of EGFR-TKIs and VEGF inhibitors. Methods: ECOG PS 0-1 patients (pt) with EGFR-mutant NSCLC were enrolled after OSI resistance. AFA was prescribed at 30-40 mg QD, and BEV was administered at 15 mg/kg tri-weekly until progression. Plasma/histologic rebiopsied samples taken after OSI failure but before enrollment were analyzed to examine resistant mechanisms including gene alterations/copy-number gain using cancer personalized profiling by deep sequencing. Results: Between January 2018 and October 2020, 28 pts were enrolled. Mutation subtypes were: 9 (32%) Del-19; 5 (18%) Del-19+T790M; 5 (18%) L858R; 7 (25%) L858R+T790M; 1 (4%) Del-19+L858R+T790M; and 1 (4%) G719S. Median line of prior OSI was 2 (range, 1-9). CR/PR was obtained by prior OSI in 24 (86%) pts. Regarding AFA+BEV efficacy, one (4%) CR, 4 (14%) PR, and 17 (61%) SD were confirmed, resulting in response rate of 17.9% and disease control rate of 78.6%. Median DoR was 9.0 (range, 4.2-22.3) months. Median PFS and OS were 2.7 (95% CI, 2.0-4.6) months and not reached, respectively. Twenty-eight (100%) plasma and/or 21 (75%) histologic rebiopsies identified: 17 (61%) TP53; 15 (54%) T790M; 9 (32%) uncommon EGFR; 9 (32%) MET; 6 (21%) C797S; 3 (11%) BRAF; 2 (7%) HER2; 2 (7%) KRAS; and 2 (7%) PI3K mutations; or 14 (50%) EGFR; 6 (21%) MET; and 2 (7%) HER2 amplifications. One (4%) small cell transformation was found. Among 6 C797S pts, 1 CR, 4 SD, and 1 PD were confirmed. Three (33%) of 9 uncommon EGFR and 1 (50%) of 2 HER2 mutation positive pts achieved radiographic response. All 15 T790M-positive pts showed no response, but 5 (38%) of 13 T790M-negative pts responded to AFA+BEV. None (0%) of six pts with EGFR downstream signaling mutations such as BRAF, KRAS, or PI3K responded. Five (50%) of 10 pts without T790M/BRAF/KRAS/PIK3 mutations exhibited confirmed response. FAT1 mutation was found in two (40%) of 5 responded pts. Dose reduction/interruption of AFA was performed in 15 (54%) pts. Median number of BEV administrations was 4 (range, 1-32). There were neither TRD nor ILD. Adverse events ≥grade 3: hypertension (29%); proteinuria (7%); diarrhea (7%); and rash (4%) were observed. One (4%) grade 4 duodenal perforation was reported. Conclusions: AFA+BEV after OSI resistance demonstrated moderate efficacy and favorable safety. A small portion of C797S pts exhibited the sensitivity. Higher potency was suggested in T790M/BRAF/KRAS/PIK3 mutation-negative and uncommon EGFR/HER2 mutation-positive pts. Selected population could obtain clinical benefit from AFA+BEV, based on rebiopsy results after OSI resistance. Clinical trial information: UMIN000030545.

122TiP Phase III study of durvalumab with SBRT for unresected stage I/II, lymph-node negative NSCLC (PACIFIC-4/RTOG 3515)

Stereotactic body radiation therapy (SBRT) is a standard treatment for pts with unresectable (UR) stage I/II, lymph-node negative NSCLC, with excellent safety and high rates of primary tumor control. Despite predominant regional and distant failure that increases with tumor size, no adjuvant therapy is approved for these pts. Durvalumab (D) is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1/CD80. In the placebo (pbo)-controlled phase (ph) 3 PACIFIC trial of pts with stage III UR-NSCLC without progression on/after concurrent chemoradiotherapy, D improved PFS and OS with manageable safety (Antonia et al, 2017; 2018), leading to its approval in stage III UR-NSCLC. Osimertinib (O) is a 3rd-generation, irreversible CNS-active EGFR-TKI that selectively inhibits NSCLC tumors with EGFR-sensitizing mutations (EGFRm). In the recent pbo-controlled ph 3 ADAURA trial, O demonstrated statistically significant and clinically meaningful improvement in DFS (HR, 0.20 [99.12% CI, 0.14–0.30], P<0.001) in pts with resected stage IB-IIIA EGFRm NSCLC (Wu et al, 2020), leading to its approval in an adjuvant setting. Based on data for D and O in the early-stage setting, PACIFIC-4 is designed to assess the efficacy and safety of D combined with SBRT in pts with stage I/II UR-NSCLC and O after SBRT in pts with stage I/II EGFRm UR-NSCLC. PACIFIC-4 (NCT03833154) is an international ph 3 study with 2 independent cohorts. Eligible pts are ≥18 years with stage T1-T3, N0, M0 unresected NSCLC and ECOG PS 0–2. The main cohort of ∼630 pts will be randomized (1:1) in a double-blind manner, stratified by tumor size and location, to receive D (1500 mg IV) or pbo Q4W for up to 26 cycles with concurrent SoC SBRT. The primary endpoint in this cohort is PFS (BICR; RECIST v1.1); other endpoints include OS, health-related QoL and safety. The protocol was amended (v4) to exclude pts with an identified EGFRm from the main cohort and add a separate cohort of ∼60 pts with EGFRm (L858R or Ex19del) who will receive O 80 mg PO QD, following SoC SBRT, for up to 36 months. The primary endpoint in this cohort is 4-year PFS (ICR; RECIST v1.1); secondary endpoints include PFS, OS and safety. Trial recruitment is ongoing. NCT03833154. Medical writing support, under the direction of the authors, was provided by Nina Kratky of Ashfield MedComms (Manchester, UK), an Ashfield Health Company, and was funded by AstraZeneca. AstraZeneca.

EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios.

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of approved EGFR-TKIs. We sought to characterize variants involving EGFR-D770 to EGFR-G770 position equivalence changes that structurally allow for response to irreversible 2nd generation EGFR-TKIs. Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. EGFR-D770>GY and other EGFR insertions with a G770 equivalence were identified at a frequency of 3.96% in separate cohorts of EGFR exon 20 insertion mutated lung cancer (n = 429). Cells driven by EGFR-D770>GY were insensitive to erlotinib and osimertinib, displayed sensitivity to poziotinib and dacomitinib and were uniquely sensitive to afatinib and dacomitinib in comparison with other more typical EGFR exon 20 insertion mutations using proliferation and biochemical assays. Clinical cases with EGFR-G770 equivalence from the literature and our center mirrored the preclinical data, with radiographic responses and clinical benefits restricted to afatinib, dacomitinib, poziotinib and mobocertinib, but not to erlotinib or osimertinib. Although they are rare, at <4% of all exon 20 insertion mutations, EGFR-G770 equivalence exon 20 insertion mutations are sensitive to approved 2nd generation EGFR TKIs and EGFR exon 20 insertion mutant-active TKIs (mobocertinib and poziotinib). EGFR-D770>GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration.

Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model.

Furmonertinib (AST2818) is a novel third-generation irreversible EGFR TKI and recently has been approved in China for the treatment of non-small cell lung cancer (NSCLC) with EGFR-sensitizing and T790M resistance mutations. In the current study, we developed a semi-mechanistic population pharmacokinetic model to characterize the nonstationary pharmacokinetics (PK) of the furmonertinib and its active metabolite AST5902 simultaneously. The PK data of furmonertinib and AST5902 were obtained from 38 NSCLC patients and 16 healthy volunteers receiving 20-240 mg furmonertinib in three clinical trials. A nonlinear mixed-effects modeling approach was used to describe the PK data. The absorption process of furmonertinib was described by a transit compartment model. The disposition of both furmonertinib and AST5902 was described by a two-compartment model. An indirect response model accounted for the autoinduction of furmonertinib metabolism mediated by CYP3A4. The model-based simulation suggested that furmonertinib clearance was increased in one cycle of treatment (orally once daily for 21 days) compared to baseline, ranging from 1.1 to 1.8 fold corresponding to the dose range of 20-240 mg. The concentration of furmonertinib was decreased over time whereas that of AST5902 was increased. Interestingly, the concentration of the total active compounds (furmonertinib and AST5902) appeared to be stable. The food intake, serum alkaline phosphatase and body weight were identified as statistically significant covariates. The mechanism of food effect on PK was investigated, where the food intake might increase the bioavailability of furmonertinib via increasing the splanchnic blood flow. Overall, a population PK model was successfully developed to characterize the nonstationary PK of furmonertinib and AST5902 simultaneously. The concentrations of total active compounds were less affected by the autoinduction of furmonertinib metabolism.

Current Therapeutic Strategies and Prospects for EGFR Mutation-Positive Lung Cancer Based on the Mechanisms Underlying Drug Resistance.

The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene and the development of EGFR tyrosine kinase inhibitors (TKIs) have led to a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). EGFR mutation-positive NSCLC is common in East Asia, and approximately 50% of adenocarcinomas harbor EGFR mutations. Undoubtedly, EGFR-TKIs, with their promising efficacy, are the mainstay of primary therapy. However, even if tumor shrinkage is achieved, most patients become resistant to EGFR-TKIs and relapse; hence, EGFR-TKIs do not achieve a radical cure. The problem of the development of resistance to targeted drugs has been a persistent challenge. After the role of EGFR T790M mutation in acquired drug resistance was reported, osimertinib, a third-generation irreversible EGFR-TKI, was designed to overcome the resistance conferred by T790M mutation. In addition, some studies have reported the mechanism of drug resistance caused by mutations other than the T790M mutation and strategies to overcome them. Elucidating the mechanism underlying drug resistance development and combining therapeutic approaches are expected to further improve NSCLC prognosis.

P47.08 A Phase II, Single-arm, Multicenter, Efficacy of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With EGFR Mutated NSCLC

Leptomeningeal metastases (LM) are severe, an aggressive complication of cancer, characterized by tumor cell spread to the cerebrospinal fluid (CSF) and leptomeninges. The higher incidence of LM in EGFR mutated non-small cell lung cancer (NSCLC) has been observed, especially after treated with 1st or 2nd generation EGFR TKI. The Osimertinib, the third generation irreversible EGFR TKI, has been developed to target T790M mutation. Unlike other EGFR TKIs, Osimertinib showed homogenous distribution to the brain suggesting high penetration of blood-brain barrier, and clinical efficacy in intracranial lesions has been demonstrated from the retrospective analyses.

An Observational Study to Assess the Molecular Epidemiology and Direct Medical Costs of Epidermal Growth Factor Receptor (EGFR) Mutations in Patients with Advanced EGFR Mutation-Positive Non-Small Cell Lung Cancer Treated with Afatinib in Real-World Clinical Settings in Greece.

PurposeEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line option for patients with advanced, EGFR-mutant non-small cell lung cancer (NSCLC). Afatinib, a second-generation irreversible EGFR-TKI, has been extensively used in Greece in this setting; however, real-world data regarding molecular epidemiology and financial implications of afatinib use are lacking.Materials and MethodsThis was an observational, non-interventional, multicenter, retrospective cohort study, based on real-world data collected from the medical charts/records of patients treated with afatinib between 15/03/2015 and 25/06/2020 and were recorded on a web-based data capture system. Cox models were used to assess the prognostic significance of clinicopathological parameters with respect to clinical outcomes of interest. Cost analysis was conducted from a public third-payer perspective, and only direct medical costs reimbursed by the payer were considered.ResultsA total of 59 patients were treated with afatinib for their EGFR mutation-positive advanced NSCLC; the median age was 61 years (range: 37–91). Performance status was zero in 61%, and brain metastases were present in 13.6%. Forty-four patients (74.6%) had a deletion in exon 19 only, while nine (15.3%) had a mutation in exon 21, 8 of them in L858R and one in L861Q. At a median follow-up of 41.8 months (95% CI 35.9–51.4), the median PFS was 14.3 months (95% CI 12.2–16.4), and the median OS was 29 months (95% CI 25.6–33.4). Corresponding values for patients with deletion 19 only were 14.3 months (95% CI 11.5–18.5) and 28.1 months (95% CI 21.1–32.6), respectively. The mean expenditure for the treatment of each patient equals €25,333.68; with €21,865.06 being attributed to drug acquisition costs, €3325.35 to monitoring costs and €143.27 to adverse event treatment-related costs.ConclusionLong-term data in the real-world setting in Greece confirm activity, tolerability and cost-effectiveness of afatinib as first-line treatment of patients with advanced EGFR-mutant NSCLC.Clinical Trial RegistrationClinicaltrials.gov NCT04640870.

The real-life efficacy and safety of osimertinib in pretreated advanced non-small cell lung cancer patients with T790M mutation: a Turkish Oncology Group Study.

Osimertinib, an irreversible third-generation EGFR-TKI, is the standard of care for second-line treatment of T790M-mutant advanced NSCLC patients whose disease progressed after first-line EGFR-TKI therapy. In this multicenter study, we aimed to determine the real-life efficacy and safety of Osimertinib in pretreated advanced NSCLC patients with T790M mutation. This retrospective trial included advanced T790M-mutant pretreated NSCLC patients who received Osimertinib from 24 different centers in Turkey. Primary endpoint was time-to-treatment discontinuation (TTD). Secondary endpoints were objective response rate (ORR), overall survival (OS), and safety. Of 163 patients, 68.7% had EGFR exon 19 deletion and 22.7% had exon 21 L858R mutation. Osimertinib was given as second-line treatment in 96 patients (58.9%) and third-line in 48 patients (29.4%). After median of 13-month follow-up, median TTD was 21.6months with an 82.2% ORR. Estimated median OS was 32.1months. Grade 3-4 adverse events were seen in 11.7% of the patients. Osimertinib is a highly effective option in second- or third-line treatment of NSCLC patients with T790M mutation, with a favorable safety profile.

Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer.

The pyrimidine core-containing compound Osimertinib is the only epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the third generation that has been approved by the U.S. Food and Drug Administration to target threonine 790 methionine (T790M) resistance while sparing the wild-type epidermal growth factor receptor (WT EGFR). It is nearly 200-fold more selective toward the mutant EGFR as compared to the WT EGFR. A tertiary cystein 797 to serine 797 (C797S) mutation in the EGFR kinase domain has hampered Osimertinib treatment in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). This C797S mutation is presumed to induce a tertiary-acquired resistance to all current reversible and irreversible EGFR TKIs. This review summarizes the molecular mechanisms of resistance to Osimertinib as well as different strategies for overcoming the EGFR-dependent and EGFR-independent mechanisms of resistance, new challenges, and a future direction.

Abstract 2423: Discovery of ZN-e4, an irreversible EGFR-TKI with potent anti-tumor activity in EGFR mutant non-small-cell lung cancer

Abstract Small molecule tyrosine kinase inhibitors against the epidermal growth factor (EGFR) have made significant impact in the treatment of advanced non-small-cell lung cancer (NSCLC) with activating EGFR mutations. Although the first and second-generation EGFR inhibitors have remarkably improved survival in advanced EGFR mutant NSCLC patients, most of the patients develop acquired resistance. The gatekeeper mutation (T790M) is the most common acquired resistance mechanism to the first and second-generation EGFR inhibitors. To overcome the T790M acquired resistance, third-generation EGFR inhibitors, such as osimertinib, were developed. However, additional mutant selective EGFR inhibitors with improved toxicity profile are still needed as osimertinib treatment produced incidence of adverse events, such as diarrhea and skin rush. Here, we describe the identification and characterization of ZN-e4, an orally bioavailable, selective, irreversible third generation EGFR inhibitor. ZN-e4 selectively inhibited the kinase activity of several mutated forms of EGFR, including L858R, T790M/L858R, and Exon19 del in biochemical assay. In cell-based assays, ZN-e4 demonstrated a 20-40-fold selectivity ratio for mutant EGFR forms over the wild-type form thus minimizing the potential for on target toxicity. ZN-e4 potently inhibited the proliferation of NSCLC cell lines harboring EGFR activating and T790M mutation and induced tumor regression in small and large tumors with activating EGFR mutations in preclinical human NSCLC xenograft models. Taken together, our data suggest that ZN-e4 is a potent and selective third generation EGFR inhibitor. Currently, ZN-e4 is in a Phase I clinical trial in patients with EGFR mutant NSCLC showing clinical activity and encouraging toxicity profile. Citation Format: Jiali Li, Sunny Abraham, Jianhui Ma, Peter Q. Huang, Kevin D. Bunker, Fernando Doñate, Ahmed A. Samatar. Discovery of ZN-e4, an irreversible EGFR-TKI with potent anti-tumor activity in EGFR mutant non-small-cell lung cancer [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 2423.

Lazertinib: First Approval

Lazertinib (LECLAZA®) is an oral, third-generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) being developed by Yuhan and Janssen Biotech for the treatment of non-small cell lung cancer (NSCLC). It is a brain-penetrant, irreversible EGFR-TKI that targets the T790M mutation and activating EGFR mutations Ex19del and L858R, while sparing wild type-EGFR. In January 2021, lazertinib received its first approval for the treatment of patients with EGFR T790M mutation-positive locally advanced or metastatic NSCLC who have previously received EGFR-TKI therapy. This article summarizes the milestones in the development of lazertinib leading to this first approval.

Phase II, noncomparative, open label, multicenter, study of osimertinib, in patients with locally advanced or metastatic EGFR mutated, T790M undetectable or unknown non-small cell lung cancer (Stage IIIB-IV) after no immediate prior EGFR TKI (OSIRIS study).

e21116 Background: Osimertinib (OSI) is a potent irreversible EGFR TKI approved for 1st line therapy advanced EGFR+ NSCLC and for 2nd line T790M+ pts. The AURA trial showed promising results even in pts with T790M- NSCLC after no immediate prior OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI and subsequent chemotherapy. Methods: This phase II trial was performed to investigate the role OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI (1 or 2 generation) and subsequent chemotherapy. Eligible pts (M or F, &gt; 18 years, ECOG 0-2) received OSI (80 mg/day) until disease progression or unacceptable toxicity. Objective response rate (ORR) was the primary endopoint. Assuming a 10% attrition rate, 90 pts were planned to be enrolled according to the Optimal Simon’s 2 stage design. In the first stage, 32 pts were planned to be accrued, and if ≤ 3 responses were observed the study would be stopped. Otherwise, 49 additional pts were planned to be accrued. The null hypothesis would have been rejected if ≥ 12 responses were observed. This design yields a type I error rate of 0.05 and 80% power. Results: From May 2017 to October 2020, a total of 54 pts were enrolled (17 M and 37 F, mean age 66 years). The study was stopped early due to an extremely slow enrolment rate. However, the ORR of 31.5% (95% CI 19.5% - 45.5%) was significantly higher than the null hypothesis of 9% (p&lt;0.0001). 17 pts obtained a partial response and 20 a stable disease with an overall disease control rate of 68.5%. Median PFS was 9 mos and median OS was 15 mos. Forty-one pts experienced at least 1 adverse event (51.8% treatment related), more than 90% Grade 1 or 2, the most common being diarrhea. Conclusions: Despite early termination and incomplete recruitment, the treatment with OSI in pts with undetectable or unknown T790M showed a significant ORR and a PFS in line with results in T790M+. Currently, OSI represents the preferred option in naïve pts with EGFR+ NSCLC, regardless of T790M status and for pts who progress the recommended subsequent therapies include local therapy, continuing OSI or chemotherapy; in this new scenario, our results confirm that OSI rechallenge in subsequent line after chemotherapy should be explored. This research was conducted with support from AstraZeneca. Clinical trial information: 2016-002555-17.

SH-1028, An Irreversible Third-Generation EGFR TKI, Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer.

SH-1028 is an irreversible third-generation EGFR TKI. Both SH-1028 and osimertinib have a pyrimidine structure (a typical mutant-selective EGFR TKI structure). Compared with osimertinib, SH-1028 is modified on the indole ring, thus resulting in a more stable 6,7,8,9-tetrahydro-pyrrolo [1, 2-a] indol structure. In this study, we explored the anti-tumor effect of SH-1028 in vitro and in vivo, the inhibition of cell signal, such as EGFR and ERK phosphorylation, and verified the relationship between the pharmacokinetics and pharmacodynamic responses. Firstly, SH-1028 selectively inhibited EGFR sensitive and resistant mutations, with up to 198-fold more effective compared with wild-type EGFR cells. Then, in mouse xenograft models, oral administration of SH-1028 at a daily dose of 5 mg/kg significantly inhibited proliferation of tumor cells with EGFR sensitive mutation (exon 19 del) and resistant mutation (T790 M) for consecutive 14 days, with no TKI-induced weight loss. Moreover, SH-1028 exhibited good bioavailability, and was distributed extensively from the plasma to the tissues. The main metabolite of SH-1028, Imp3, was tested and showed no wild-type EGFR inhibition or off-target effects. In conclusion, SH-1028 is a new third-generation EGFR inhibitor that exhibits potent activity against EGFR sensitive and resistant (T790 M) mutations.

DDRE-17. INITIAL CLINICAL EXPERIENCE USING OSIMERTINIB IN PATIENTS WITH RECURRENT MALIGNANT GLIOMAS WITH EGFR ALTERATIONS

Abstract EGFR alterations are commonly observed in malignant gliomas (MG), especially glioblastomas, making this pathway an appealing therapeutic target. Unlike other EGFR tyrosine kinase inhibitors (TKIs), osimertinib (osi), a third-generation, irreversible EGFR-TKI commonly used to treat EGFR-mutant lung cancer, is able to effectively penetrate the blood brain barrier (BBB) and achieve therapeutic concentrations in brain tissue. METHODS: A retrospective chart review identified six patients (pts) aged 46–74 years with recurrent MG and known EGFR alterations identified by next generation sequencing who received at least one dose of osi between 1/1/2018 and 5/26/2020. Patients received osi 80 mg by mouth once daily and continued treatment until disease progression, the development of unacceptable side effects, medical complications, or death. RESULTS: All patients had EGFR amplification. Other EGFR alterations identified included EGFRvIII (1 pt), deletion of introns 1–7 (3 pts) and deletion of introns 13–15 (2 pts). Four of the six patients were evaluable for response. Three patients (75.0%) had stable disease (SD) as best response and one patient (25.0%) was refractory to treatment. One patient with an EGFRvIII mutation achieved stable disease on osi and remained on treatment for 236 days. Thrombocytopenia developed in 2 patients (grade 2 (1), grade 3 (1) in patient also on concurrent bevacizumab) and 1 patient developed grade 1 diarrhea and pneumonia. Overall, this heavily pretreated patient population tolerated osi therapy and half of the patients had a best response of SD which lasted from 77 to 236 days. CONCLUSIONS: Osi has a tolerable safety profile in this heavily pretreated brain tumor population, and it may benefit selected patients with recurrent MG containing EGFR alterations. Further clinical investigations are needed, particularly in patients whose tumors express an EGFRvIII mutation, to identify which EGFR alterations may sensitize tumors to this BBB penetrant EGFR-TKI.

HCC-derived EGFR mutants are functioning, EGF-dependent, and erlotinib-resistant

BackgroundEpidermal growth factor receptor (EGFR) has emerged as an important therapeutic target. Overexpression of EGFR is frequently observed in hepatocellular carcinoma (HCC) and EGFR activation has been proven to be a potential determinant of primary resistance of HCC cells to sorafenib. In our previous study, we found 13 missense mutations in EGFR exon 19–23 from hepatocellular carcinoma (HCC) tissues, but the functions of these mutations have not been determined. This study aims to determine the kinase activity and sensitivity to erlotinib, a 1st-generation EGFR-tyrosine kinase inhibitor (TKI), of seven HCC-derived mutants (K757E, N808S, R831C, V897A, P937L, T940A, and M947T).ResultsUsing transduction of pBabe-puro retroviral vector with or without EGFR, we constructed and determined the function of EGFRs in NIH-3T3 cells stably harboring each of the seven mutants, as well as the erlotinib-sensitive L858R-mutant, the erlotinib-resistant T790M-mutant, and EGFR wild type (WT). Our results indicate that the seven mutants are functioning, EGF-dependent, EGFRs. Cells harboring six of the seven mutants could generate some level of EGFR phosphorylation in the absence of EGF, indicating some constitutive kinase activity, but all of the seven mutants remain primarily EGF-dependent. Our results demonstrate that erlotinib induces differential degree of apoptosis and autophagy among cells harboring different EGFRs: complete apoptosis and autophagy (cleavage of both caspase-3 and PARP, and marked LC3-II increment) in L858R-mutant; partial apoptosis and autophagy (only cleavage of caspase-3, and moderate LC3-II increment) in WT and HCC-derived mutants; and no apoptosis and minimal autophagy (no cleavage of caspase-3 and PARP, and minimal LC3-II increment) in T790M-mutant. The seven HCC-derived mutants are erlotinib-resistant, as treatment with erlotinib up to high concentration could only induce partial inhibition of EGFR phosphorylation, partial or no inhibition of AKT and ERK phosphorylation, and partial apoptosis and autophagy.ConclusionThe seven HCC-derived EGFR mutants in this study are functioning, EGF-dependent, and erlotinib-resistant. Erlotinib induces differential degree of apoptosis and autophagy among cells harboring different EGFRs. The degree of inhibition of EGFR phosphorylation by erlotinib is the determining factor for the degree of apoptosis and autophagy amongst cells harboring EGFR mutants. This study paves the way for further investigation into the sensitivity of these HCC-derived mutants to the 3rd-generation irreversible EGFR-TKI, osimertinib.

Naquotinib exerts antitumor activity in activated B-cell-like diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell non-Hodgkin lymphoma (NHL), is categorized into two major subtypes, activated B-cell-like (ABC) and germinal center B-cell-like (GCB). The ABC subtype is associated with worse prognosis than the GCB subtype using currently available therapies such as combination treatment with rituximab plus standard cytotoxic chemotherapy. The B-cell receptor (BCR) pathway is activated in ABC DLBCL, suggesting that inhibition of this pathway could provide an alternative strategy for treatment. Naquotinib is an irreversible tyrosine kinase inhibitor (TKI) originally designed to target the epidermal growth factor receptor (EGFR). As sequence alignment analysis indicates that irreversible EGFR-TKIs also inhibit Bruton's tyrosine kinase (BTK), here, we characterized the inhibitory effects of naquotinib against BTK in comparison to ibrutinib, acalabrutinib, tirabrutinib and spebrutinib. Naquotinib inhibited BTK kinase activity with similar potency to that for EGFR activating mutations. In vivo, naquotinib induced tumor regression and suppressed tumor recurrence in TMD8 and OCI-Ly10, ABC DLBCL cell line xenograft models, at a lower dose than the clinically relevant dose. Compared to other BTK inhibitors, naquotinib showed faster onset and comparable inhibition of BTK following incubation with cell lines for 3 and 20 h. In addition, naquotinib showed longer continuous inhibition of BTK following removal of the compound, lasting for at least 26 h after removal. Pharmacokinetics studies in the TMD8 xenograft model showed higher concentration and slower elimination of naquotinib in tumors than other BTK inhibitors. These data suggest that naquotinib may have therapeutic potential in ABC DLBCL patients.