Oral Epidermal Growth Factor Receptor Research Articles

Impact of pharmacist managed oral epidermal growth factor receptor inhibitors.

Pharmacists are an integral part of medication management, with the positive impact of their clinical services in patient outcomes previously studied and reported in literature. The roles and responsibilities of pharmacists continue to expand, including optimizing patient medication and health outcomes related to complex oral anticancer drugs. To evaluate the impact of a pharmacist-managed oral chemotherapy clinic in patients with non-small cell lung cancer (NSCLC) taking oral epidermal growth factor receptor inhibitor (EGFRi) regimens within an integrated healthcare delivery system. This was an observational cohort study using data from Kaiser Permanente Northern and Southern California regions on adult patients who received oncology pharmacist-managed care compared to patients with usual care. Patients were newly initiated with EGFRi therapy to treat NSCLC between 2017 and 2019. The follow-up period was defined as the time from index date (first sold date of EGFRi) to December 2020 or end of membership or death, whichever occurred first. Primary outcome measures included adherence to EGFRi, frequency of imaging during drug exposure, and presence of imaging prior to treatment change. Outcomes were analyzed with Chi-square test for categorical variables, and Student's t-test or Wilcoxon rank-sum test for continuous variables. There were 613 patients in the pharmacist-managed group and 714 patients in the usual care group. Overall, the mean age was 68.2 ± 11.3 years, and 65.1% were female. In the pharmacist-managed group, there was a significantly higher mean proportion of days covered (PDC) during the first three months of therapy (0.86 ± 0.24 vs 0.82 ± 0.36, p = 0.01) and a higher percentage of patients who were adherent to EGFRi therapy (with PDC ≥0.80) during the drug exposure period (95.8% vs 92.4%, p = 0.01). The rate of computed tomography (CT) and magnetic resonance imaging (MRI) during drug exposure was higher in the pharmacist-managed group compared to the usual care group (31.8% vs 20.7%, p < 0.01) with a higher number of mean scans completed per patient (1.15 ± 2.42 vs 0.62 ± 1.63, p < 0.01) and per patient-year (2.60 ± 7.27 vs 1.58 ± 5.95, p < 0.01). Overall, 66.2% of patients had a treatment change, with a higher percentage of patients in the pharmacist-managed group who completed a CT or MRI scan prior to treatment change (36.3% vs 26.3%, p < 0.01). Additionally, the median time between the scan and treatment change was shorter for patients with pharmacist-managed care (1.8 vs 4 months, p = 0.04). Clinical pharmacy services contributed to improved adherence, higher rates of imaging, and shorter time between imaging and treatment changes in NSCLC patients who were taking EGFRi regimens.

Plasma ctDNA biomarker study in patients with non-small cell lung cancer with EGFR exon 20 insertion mutation treated with sunvozertinib.

8563 Background: There are limited reports on biomarker studies of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutation (exon20ins). Sunvozertinib (DZD9008), an oral, potent, irreversible and selective EGFR tyrosine kinase inhibitor (TKI), has been granted conditional approval in China for the treatment of NSCLC with EGFR exon20ins in the ≥ second-line setting. Here we report biomarker analysis of EGFR exon20ins in large sample size, by pooling data from WU-KONG series of studies. Methods: Serial plasma ctDNA samples were collected from baseline until progressive disease (PD). Next generation sequencing was used to assess EGFR exon20ins in baseline plasma ctDNA, and to analyze genetic alterations in baseline and PD plasma ctDNA to identify potential resistance mechanisms to sunvozertinib. Droplet digital PCR was used to dynamically monitor the quantity of EGFR exon20ins during treatment. In addition, association between baseline EGFR exon20ins and disease characteristics as well as antitumor activity of sunvozertinib was analyzed. Furthermore, in vitro and in vivo experiments were performed to explore potential approach which may overcome the resistance to sunvozertinib. Results: A total of 121 patients were included in this biomarker analysis, among them 81 out of 121 (66.9%) had detectable EGFR exon20ins in baseline plasma ctDNA. There was a positive correlation between detectable EGFR exon20ins and higher number of metastasis sites. In addition, higher EGFR exon20ins abundance was positively correlated with more metastasis sites and brain metastasis. Patients with EGFR exon20ins negative in plasma ctDNA achieved a higher objective response rate (ORR) (68.0% vs. 45.8%) and longer median progression free survival (PFS) (7.4 months vs. 5.5 months) with sunvozertinib treatment. In patients with baseline detectable EGFR exon20ins, the mutant allele decreased over time with treatment in majority of patients (12/14, 85.7%), and the earliest clearance of EGFR exon20ins occurred after one week of treatment. In patients who developed disease progression, 12 of 18 (66.7%) maintained EGFR exon20ins at PD, and among them, 3 concurrently acquired EGFR C797S, all in cis with exon20ins. In addition, EGFR G724S and other genetic aberrations in EGFR downstream signaling pathway, were also detected. Exploratory work on overcoming resistance to sunvozertinib suggests that combination of golidocitinib, a selective JAK1 inhibitor, with chemotherapy could be a potential approach. Conclusions: This study showed that positive EGFR exon20ins in plasma ctDNA is associated with advanced disease characteristics. Sunvozertinib can effectively clear EGFR exon20ins in plasma ctDNA, confirming its direct effect on EGFR pathway. The resistance to sunvozertinib can be through EGFR-dependent and EGFR-independent mechanisms.

Phase 1 study of BDTX-1535, an oral 4th generation covalent EGFR inhibitor, in patients with recurrent glioblastoma: Preliminary dose escalation results.

2068 Background: Epidermal growth factor receptor ( EGFR) gene is the most frequently altered oncogenic driver in glioblastoma (GBM). In-frame deletion alterations (e.g., EGFRvIII) and missense mutations co-occur in the setting of EGFR gene amplification and are characterized as a hallmark of disease pathogenesis in GBM. BDTX-1535 is an oral, highly potent, brain penetrant, selective, irreversible 4th generation tyrosine kinase inhibitor that targets EGFR alterations in GBM and NSCLC. Preliminary results of the Phase 1 dose escalation study (NCT05256290) of patients with recurrent GBM (rGBM) are presented here. Methods: BDTX-1535-101 is a first-in-human study that enrolled patients with either rGBM harboring EGFR alterations following standard of care or patients with locally advanced or metastatic EGFR mutated NSCLC that progressed on prior EGFR TKIs. Using an adaptive Bayesian optimal interval design in the Phase 1 part, patients were enrolled at increasing dose cohorts and were treated daily for 21-day cycles until treatment discontinuation. The primary objective was to determine the BDTX-1535 recommended Phase 2 dose based on the overall safety, PK, pharmacodynamics, and preliminary antitumor activity. Results: Twenty-seven patients with rGBM were enrolled in the Phase 1 cohort that consisted of 54 patients in total including 27 patients with NSCLC. Patients were treated across seven dose levels (15mg – 400mg QD). The mean age of patients with rGBM was 58.7 years (range 41-85) with 96% of patients with previous temozolomide (TMZ) treatment and a median of 2 lines of prior therapy (range 1-4). The most common all-grade treatment-related AEs across all cohorts were rash (78%), diarrhea (41%), fatigue (15%), stomatitis (11%), decreased appetite (11%), nausea (11%) and paronychia (11%). Gr 3 TRAEs ≥ 10% included rash (19%) reported at 300 or 400 mg QD doses. Plasma exposure of BDTX-1535 increased dose proportionally and had a half-life of ~15h, supporting once daily dosing. The maximum tolerated dose (MTD) is 300 mg QD. Among 19 evaluable patients for response based on RANO criteria, 1 confirmed partial response was observed and 8 patients achieved stable disease. Five patients remained on BDTX-1535 with stable disease for an extended period (&gt;5 months) who previously performed poorly on TMZ with short treatment duration, and 1 patient continues on BDTX-1535 after 16 months of treatment. Conclusions: BDTX-1535 was well-tolerated up to 300mg daily, which is the MTD, and promising preliminary clinical activity was observed in patients with rGBM after relapse on standard of care treatment. Given the inability to reconfirm EGFR status at the time of treatment with BDTX-1535 in this Phase 1 trial, further exploration of BDTX-1535 in a “window of opportunity” study is ongoing (NCT06072586). Clinical trial information: NCT05256290 .

A phase 1 study to assess the absolute bioavailability, mass balance, pharmacokinetics, metabolism, and excretion of [14C]-mobocertinib, an oral inhibitor of EGFR exon 20 insertion mutations, in healthy participants

Mobocertinib (TAK-788) is a first-in-class oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that received accelerated approval for the treatment of patients with non-small cell lung cancer with EGFR exon 20 insertion mutations previously treated with platinum-based chemotherapy. This phase 1, 2-period, study was conducted to assess the absolute bioavailability of mobocertinib (Period 1), as well as mass balance, pharmacokinetics, metabolism, and excretion of [14C]-mobocertinib (Period 2) in healthy adult males. In Period 1, participants received a single oral capsule dose of 160 mg mobocertinib, followed by a 15-minute intravenous infusion of 50 µg (~ 2 µCi) [14C]-mobocertinib administered from 3.75 to 4 h after the capsule dose. In Period 2, a single oral dose of 160 mg (~ 100 µCi) [14C]-mobocertinib was administered as an oral solution. The geometric mean absolute bioavailability of mobocertinib was determined to be 36.7%. After oral administration of [14C]-mobocertinib, mobocertinib and its active metabolites, AP32960 and AP32914, were minor components in plasma, accounting for only 0.275% of total plasma radioactivity as the majority of mobocertinib-related material was covalently bound to plasma proteins. The geometric mean percentage of the administered radioactive dose recovered in the urine and feces was 3.57% and 76.0%, respectively. Only 0.39% of the oral dose of [14C]-mobocertinib was recovered in the urine as mobocertinib; thus, indicating that renal excretion of unchanged drug was a very minor pathway of elimination. In both treatment periods, mobocertinib was generally safe and well-tolerated as all adverse events were Grade 1 in severity. (Trial registration number ClinicalTrials.gov NCT03811834. Registration date January 22, 2019).

Mobocertinib: Mechanism of action, clinical, and translational science.

Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations represent ~6%-12% of all EGFR-mutated non-small cell lung cancer (NSCLC) cases. First-, second-, and third-generation tyrosine kinase inhibitors (TKIs) have limited clinical activity against EGFR ex20ins mutations. Mobocertinib is a first-in-class oral EGFR TKI that selectively targets in-frame EGFR ex20ins mutations in NSCLC; accelerated approval in the United States was granted for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations whose disease has progressed on or after platinum-based chemotherapy. Accelerated approval was based on the results from the three-part, open-label, multicenter, pivotal phase I/II nonrandomized clinical trial (NCT02716116) that enrolled 114 patients with locally advanced or metastatic EGFR ex20ins mutation-positive NSCLC who were previously treated with platinum-based chemotherapy and received mobocertinib at the recommended dosage of 160 mg once daily. At the November 1, 2021, data cutoff date, the confirmed objective response rate per independent review committee (IRC) was 28%, median duration of response was 15.8 months, median progression-free survival per IRC was 7.3 months, and median overall survival was 20.2 months. The most common treatment-emergent adverse events were gastrointestinal- and skin-related. The phase III EXCLAIM-2 study evaluated mobocertinib versus chemotherapy as first-line therapy for locally advanced or metastatic EGFR ex20ins-positive NSCLC; however, the primary end point was not met, resulting in initiating voluntary withdrawal of mobocertinib worldwide. This mini-review article summarizes the mechanism of action, pharmacokinetic characteristics, key clinical trials, and clinical efficacy and safety data for mobocertinib.

Abstract B153: Resistance mechanisms to mobocertinib in treating NSCLC with EGFR exon 20 insertion mutations

Abstract Background: Mobocertinib is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that received FDA accelerated approval for non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations, based on data from a pivotal phase 1/2 study of mobocertinib (NCT02716116). In platinum-pretreated patients (pts) with EGFR ex20ins NSCLC (N=114), the overall response rate (ORR) was 28%, median duration of response was 17.5 months, and median progression-free survival was 7.3 months. Despite this encouraging clinical activity, de novo and acquired resistant mechanisms to mobocertinib remain largely unknown. Methods: Tumor samples and circulating tumor DNA (ctDNA) samples were obtained from platinum-pretreated pts with EGFR ex20ins+ NSCLC treated with mobocertinib (NCT02716116) and subjected to next-generation sequencing (NGS) analyses. CtDNA was collected at baseline, cycle 3 day 1 (C3D1) and progression per protocol. Tumor growth assay was performed in BaF3 cells and patient-derived xenograft models to evaluate efficacy of combination therapies to overcome resistance. Results: At baseline, in tumor (n=56), the combined presence of BRAF and PIK3CA mutations alone (n=9) or together with copy number gains (CNV) in EGFR, MYC, CDK4, or CCND1 (n=19) was significantly associated with inferior ORR to mobocertinib with odd ratios of ‘infinity’ (p=0.045) and 13.21 (p=0.0047), respectively. Individual co-occurring gene mutations and CNV were not significantly associated with differential clinical outcomes. Longitudinal analysis of paired tumor-blood samples at baseline and C3D1 showed that 22 out of 55 pts (40%) achieved clearance at C3D1, including 81.2% (13/16) of PR pts, 50% of SD pts, and 20% of PD pts. CtDNA was also used to assess emerging mutations after mobocertinib progression after at least 5 months of treatment (n=18). TP53 (n=11) and acquired secondary EGFR (n=5) were the most common genes with emerging variants, including EGFR T790M (n=4) and D379E (n=1). With this observation, T790M was engineered in Ba/F3 cells in the context of EGFR ex20ins mutations (H773_V774insNPH and 769_D770insASV). T790M did confer resistance to mobocertinib in vitro, and to all EGFR TKIs tested including osimertinib. In patient-derived xenograft models (H773_V774insNPH and 769_D770insASV), the combination of mobocertinib plus the bispecific monoclonal antibody amivantamab demonstrated greater antitumor activity than either agent alone. Conclusions: Our results indicate that bypass pathway alterations are associated with de novo resistance whereas T790M emergence mediates acquired resistance to mobocertinib. Future research is warranted to determine the potential clinical benefits of combination strategies in patients with EGFR ex20ins+ NSCLC. Citation Format: Xiuning Le, Monique Nilsson, Sampurna Chatterjee, Zhenqiang Su, Junqin He, Hibiki Udagawa, Xiaoxing Yu, Alissa Poteete, Qian Huang, John V Heymach, Sylvie Vincent. Resistance mechanisms to mobocertinib in treating NSCLC with EGFR exon 20 insertion mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B153.

Abstract C036: A Phase 1 Study to assess BDTX-1535, an oral EGFR inhibitor, in patients with Glioblastoma or Non-Small Cell Lung Cancer

Abstract Background: Epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in non-small cell lung cancer (NSCLC) and glioblastoma (rGBM). For NSCLC, EGFR tyrosine kinase activity can be driven by classical driver, intrinsic driver, and acquired resistance mutations. BDTX-1535 is an orally available, highly potent, brain penetrant, selective, irreversible small molecule tyrosine kinase inhibitor that targets all 3 classes of EGFR mutations. Preclinical data demonstrated the ability of BDTX-1535 to cross the blood-brain barrier and produce sustained inhibition of EGFR signaling. Methods: BDTX-1535-101 (NCT05256290) is a Phase 1, open-label, multicenter study to assess the safety, tolerability, pharmacokinetics (PK), central nervous system (CNS) activity, and preliminary antitumor activity of BDTX-1535 in locally advanced or metastatic NSCLC with or without CNS disease or recurrent GBM (rGBM). The primary objective is to determine the BDTX-1535 recommended Phase 2 dose (RP2D) based on the overall safety, PK, pharmacodynamic, and preliminary antitumor activity. The monotherapy dose escalation portion evaluates BDTX-1535 in patients with locally advanced/metastatic NSCLC harboring intrinsic driver EGFR mutations following standard of care or with acquired resistance EGFR mutations following a 3rd generation EGFR inhibitor in the 1st line setting, in addition to patients with rGBM expressing EGFR alterations who previously received available standard therapy of surgical resection followed by chemoradiotherapy and/or temozolomide (TMZ). A capsule-to-tablet bridging cohort and a food effect cohort will also be assessed. Following the establishment of a preliminary recommended Phase 2 dose (RP2D), the disease-specific expansion portion of the study will further evaluate the safety, tolerability, and preliminary antitumor effect of BDTX-1535. Cohorts include the following:1) advanced/metastatic NSCLC with intrinsic resistance EGFR mutations following up to 2 lines of therapy, one of which must be an EGFR inhibitor treatment, 2) advanced/metastatic NSCLC with acquired resistance EGFR mutation following a 3rd generation EGFR inhibitor in the first line setting, 3) rGBM with confirmed EGFR alterations with or without amplifications. NSCLC patients may enroll with or without CNS metastases and must not be known to express excluded resistance mutations such as EGFR T790M. BDTX-1535 will also be studied in combination with TMZ to assess safety, tolerability, and a recommended combination dose for the treatment of patients with newly diagnosed GBM harboring EGFR alterations. Enrollment was initiated in 2022 and dose escalation is almost complete. Initiation of the dose expansion cohorts of NSCLC patients with EGFR acquired resistance and intrinsic driver mutations after progression on prior EGFR inhibitor is planned for the second half of 2023. For additional information, please contact ClinicalTrials@bdtx.com. Citation Format: Helena Yu, Melissa Johnson, Jason T Henry, Alex Spira, Ji-Youn Han, Minal Barve, James Battiste, Iyad Alnahhas, DoHyun Nam, Jeffrey Edenfield, Balazs Halmos, Shinkyo Yoon, Tae Min Kim, Sudharshan Eathiraj, Julio Hajdenberg, Sergey Yurasov, Manmeet Ahluwalia, Patrick Wen. A Phase 1 Study to assess BDTX-1535, an oral EGFR inhibitor, in patients with Glioblastoma or Non-Small Cell Lung Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C036.

Comparative cost-effectiveness analysis of oral agents for advanced EGFR mutated and ALK-positive non-small cell lung cancer.

26 Background: The cost of lung cancer treatment and accessibility to the first-line oral targeted therapies is a growing concern worldwide. However, the cost-effectiveness of guideline-directed treatments is not well studied. The aim of this study was to evaluate cost-effectiveness of advanced epidermal growth factor receptor (EGFR) mutated and anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Methods: We calculated the cost of each targeted therapies based on the progress free survival and overall survival as shown in the major studies that led to the therapy approval. The cost-effectiveness of a treatment was measured by its incremental cost-effectiveness ratio (ICER). Lower ICER values indicate better cost-effectiveness, as they represent a lower cost per unit of health benefit. We evaluated the total costs, incremental ICERs and quality-adjusted life years (QALYs) associated with different treatment options. Results: The yearly-cost analysis revealed that Osimertinib, an oral agent targeting EGFR mutations, is the most expensive option. With a total cost of $222,044.10 per year, Osimertinib surpasses the cost of other oral agents, including erlotinib ($113,171.90) and Afatinib ($147,204.50). The ICERs indicate that Osimertinib has a higher ICER compared to other oral agents. Specifically, the ICER for Osimertinib versus erlotinib is calculated at $62,779.22. For each additional QALY gained, the cost of Osimertinib exceeds that of erlotinib by $62,779.22. Despite its higher cost, Osimertinib may offer a greater improvement in QALYs, making it a justifiable choice. In the context of ALK-positive NSCLC, Alectinib compared to Brigatinib, Lorlatinib and Crizotinib, as well as Brigatinib compared to Lorlatinib, and Lorlatinib compared to Crizotinib, are the drugs with lower ICER values, indicating better cost-effectiveness. Alectinib emerges as the most cost-effective oral agent, followed by Ceritinib. While Brigatinib and Lorlatinib are more expensive, they may provide a greater improvement in QALYs. Crizotinib is found to be the least cost-effective agent. Conclusions: The cost-effectiveness analysis presented in this study highlights the economic considerations associated with oral agents. The findings indicate the higher costs of Osimertinib and certain ALK inhibitors, which need to be weighed against the potential improvements in QALYs. By considering both costs and effectiveness, healthcare decision-makers can optimize treatment strategies, allocate resources efficiently and improve patient outcomes.

Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions.

Although several agents targeting epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines. This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day. Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

A phase 1 study to assess BDTX-1535, an oral EGFR inhibitor, in patients with glioblastoma or non–small-cell lung cancer.

TPS9156 Background: The epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in many cancers, including glioblastoma (GBM) and non-small cell lung cancer (NSCLC). EGFR tyrosine kinase activity driven by common EGFR mutations can be inhibited by small molecules, however, resistance to available agents may be driven by mutations in the EGFR active kinase site or other regions. BDTX-1535 is an orally available, highly potent, selective, irreversible inhibitor of EGFR mutations, including extracellular variants and amplifications commonly expressed in GBM and inhibits the common and uncommon EGFR mutations found in NSCLC, including the C797S mutation acquired following 3rd generation EGFR inhibitor therapy. Preclinical data demonstrated the ability of BDTX-1535 to cross the blood-brain barrier and produce sustained inhibition of EGFR signaling. Preclinical studies suggest that BDTX-1535 has the potential to be clinically active in suppressing tumor growth in patients with GBM and NSCLC with or without CNS metastases, including a potential survival benefit. Methods: BDTX-1535-101 (NCT05256290) is Phase 1, open-label, multicenter study to assess the safety, tolerability, PK, CNS activity, and preliminary antitumor activity of BDTX-1535 in recurrent GBM (rGBM) or locally advanced or metastatic NSCLC with or without CNS disease. The Monotherapy Dose Escalation portion will evaluate BDTX-1535 in patients with either rGBM expressing EGFR alterations or locally advanced/metastatic NSCLC harboring sensitizing EGFR mutations with or without CNS disease. Patients with rGBM must have previously received available standard therapy of surgical resection followed by chemoradiotherapy and/or temozolomide (TMZ). Eligible NSCLC patients must have EGFR mutated NSCLC that has progressed following standard of care EGFR inhibitor therapy. Once a provisional recommended Phase 2 dose (RP2D) has been established, BDTX-1535 monotherapy will be explored in the following Dose Expansion cohorts to further evaluate safety, PK, and preliminary assessment of efficacy: 1) rGBM with confirmed EGFR alterations, 2) NSCLC with uncommon EGFR mutations following EGFR inhibitor therapy; 3) NSCLC with acquired EGFR resistance mutation following a 3rd generation EGFR inhibitor in 1L setting. NSCLC patients may enroll with or without CNS metastases and must not be known to express excluded resistance mutations such as EGFR T790M or MET. BDTX-1535 will also be studied in combination with TMZ to assess safety, tolerability, and a recommended combination dose for the treatment of patients with rGBM harboring EGFR mutations or variants. Enrollment was initiated in 2022 and dose escalation is ongoing. Dose Expansion cohorts are expected to open in 2023. For additional information, please contact BDTX_1535_101_Study@bdtx.com . Clinical trial information: NCT05256290 .

Afatinib for the Treatment of NSCLC with Uncommon EGFR Mutations: A Narrative Review.

Afatinib, the world's first irreversible ErbB family (containing four different cancer cell epidermal growth factor receptors, including EGFR, HER2, ErbB3, and ErbB4) inhibitor, is a second-generation oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It can be used as a first-line treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) with an EGFR-sensitive mutation or for patients with locally advanced or metastatic squamous lung cancer whose disease progresses during or after platinum-containing chemotherapy. Currently, with the use of third-generation EGFR-TKIs, afatinib is no longer clinically indicated as the first choice for patients with NSCLC who have EGFR-sensitive mutations. However, afatinib showed a considerable inhibitory effect in NSCLC patients with uncommon EGFR mutations (G719X, S768I, and L861Q) according to a combined post hoc analysis of the LUX-Lung2/3/6 trials. With the development of genetic testing technology, the detection rate of uncommon EGFR mutations is increasing. The aim of this paper is to describe in detail the sensitivity of rare EGFR mutations to afatinib and to provide information and a reference for those suffering from advanced NSCLC who have uncommon EGFR mutations.

Abstract CT127: A phase 1 study to assess BDTX-1535, an oral EGFR inhibitor, in patients with glioblastoma or non-small cell lung cancer

Abstract Background: The epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in many cancers, including glioblastoma (GBM) and non-small cell lung cancer (NSCLC). EGFR tyrosine kinase activity driven by common EGFR mutations can be inhibited by small molecules, however, resistance to available agents may be driven by mutations in the EGFR active kinase site or other regions. BDTX-1535 is an orally available, highly potent, selective, irreversible inhibitor of EGFR mutations, including extracellular variants and amplifications commonly expressed in GBM and inhibits the uncommon EGFR mutations found in NSCLC, including the C797S mutation acquired following 3rd generation EGFR inhibitor therapy. Preclinical data demonstrated the ability of BDTX-1535 to cross the blood-brain barrier and produce sustained inhibition of EGFR signaling. Preclinical studies suggest that BDTX-1535 has potential to be clinically active in suppressing tumor growth in patients with GBM and NSCLC with or without CNS metastases, including a potential survival benefit. Methods: BDTX-1535-101 (NCT05256290) is Phase 1, open-label, multicenter study to assess the safety, tolerability, PK, CNS penetrance, and preliminary antitumor activity of BDTX-1535 in recurrent GBM (rGBM) or locally advanced or metastatic NSCLC with or without CNS disease. The Monotherapy Dose Escalation portion will evaluate BDTX-1535 in patients with either rGBM expressing EGFR alterations or locally advanced/metastatic NSCLC harboring sensitizing EGFR mutations with or without CNS disease. Patients with rGBM must have previously received available standard therapy of surgical resection followed by chemoradiotherapy and/or temozolomide (TMZ). Eligible NSCLC patients must have EGFR mutated NSCLC that has progressed following standard of care EGFR inhibitor therapy. Once a provisional recommended Phase 2 dose (RP2D) has been established, BDTX-1535 monotherapy will be explored in the following Dose Expansion cohorts to further evaluate safety, PK, and preliminary assessment of efficacy: 1) rGBM with confirmed EGFR alterations, 2) NSCLC with uncommon EGFR mutations following EGFR inhibitor therapy; 3) NSCLC with acquired EGFR resistance mutation following a 3rd generation EGFR inhibitor in 1L setting. NSCLC patients may enroll with or without CNS metastases and must not be known to express excluded resistance mutations such as EGFR T790M or MET. BDTX-1535 will also be studied in combination with TMZ to assess safety, tolerability, and a recommended combination dose for the treatment of patients with rGBM harboring EGFR mutations or variants. Enrollment was initiated in 2022 and dose escalation is ongoing. Dose Expansion cohorts are expected to open in 2023. For additional information, please contact BDTX_1535_101_Study@bdtx.com Citation Format: Melissa Johnson, Jason Henry, Alex Spira, James Battiste, Iyad Alnahhas, Manmeet Ahluwalia, Minal Barve, Jeffrey Edenfield, DoHyun Nam, Sudharshan Eathiraj, Julio Hajdenberg, Sergey Yurasov, Helena Yu, Patrick Wen. A phase 1 study to assess BDTX-1535, an oral EGFR inhibitor, in patients with glioblastoma or non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT127.

Indirect comparison of mobocertinib and real-world therapies for pre-treated non-small cell lung cancer with EGFR exon 20 insertion mutations

ObjectivesMobocertinib, a novel oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is available for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations after platinum chemotherapy. We performed an indirect comparison of clinical trial data and real-world data (RWD) to determine the relative efficacy of mobocertinib vs. other treatments for these patients. Materials and methodsData on the efficacy of mobocertinib from a phase I/II trial (NCT02716116) were compared to RWD from a retrospective study in 12 German centers using inverse probability of treatment weighting to adjust for age, sex, Eastern Cooperative Oncology Group score, smoking status, presence of brain metastasis, time from advanced diagnosis, and histology. Tumor response assessment was based on RECIST v1.1. ResultsThe analysis included 114 patients in the mobocertinib group and 43 in the RWD group. The confirmed overall response rate (cORR) according to investigator assessment was 0% for standard treatments and 35.1% (95% confidence interval [CI], 26.4–44.6) for mobocertinib (p < 0.0001). Compared to standard regimens in the weighted population, mobocertinib prolonged overall survival (OS, median [95% CI] = 9.8 [4.3–13.7] vs. 20.2 [14.9–25.3] months; hazard ratio [HR] = 0.42 [0.25–0.69], p = 0.0035), progression-free survival (PFS, median [95% CI] = 2.6 [1.5–5.7] vs. 7.3 [5.6–8.8] months; HR = 0.28 [0.18–0.44], p < 0.0001), and time to treatment discontinuation (median [95% CI] = 2.1 [1.2–3.1] vs. 7.4 [6.4–8.5] months; HR = 0.34 [0.18–0.65], p = 0.0004). ConclusionMobocertinib was associated with an improved cORR and prolonged PFS and OS compared to standard treatments for patients with EGFR ex20ins-positive NSCLC previously treated with platinum-based chemotherapy.

Comparative effectiveness of mobocertinib and standard of care in patients with NSCLC with EGFR exon 20 insertion mutations: An indirect comparison

IntroductionMobocertinib is a novel, first-in-class, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to selectively target in-frame EGFR exon 20 insertions (ex20ins). Comparative effectiveness data for mobocertinib versus real-world treatments are lacking in this rare population. This study compared data for mobocertinib reported in a Phase I/II single-arm clinical trial with an external control group consisting of patients who received available treatment in the real-world setting in the United States (US). Materials and MethodsThe mobocertinib group included platinum-pretreated patients with advanced EGFR ex20ins non-small cell lung cancer (NSCLC) receiving mobocertinib 160 mg QD in an ongoing, single-arm, phase 1/2 clinical trial (NCT02716116; n = 114). The real-world data (RWD) group included platinum-pretreated patients with advanced EGFR ex20ins-mutant NSCLC from the Flatiron Health database (n = 50). Inverse probability treatment weighting based on the propensity score method controlled for potential confounding between groups. Confirmed overall response rate (cORR), progression-free survival (PFS), and overall survival (OS) were compared between groups. ResultsAfter weighting, baseline characteristics were balanced. Patients in the RWD group received EGFR TKI (20 %), immuno-oncology therapy (40 %), or any regimens containing chemotherapy (40 %) in the second- or later-line setting. In the mobocertinib and RWD groups, respectively, cORR was 35.1 % and 11.9 % (odds ratio: 3.75 [95 % confidence interval (CI): 2.05, 6.89]); median PFS was 7.3 and 3.3 months (hazard ratio [HR]: 0.57 [95 % CI: 0.36, 0.90]); and median OS was 24.0 and 12.4 months (HR: 0.53 [95 % CI: 0.33, 0.83]) after weighting. DiscussionMobocertinib showed substantially improved outcomes versus an external control group using available therapies in platinum-pretreated patients with EGFR ex20ins-mutant NSCLC. In the absence of comparative evidence from randomized trials, these findings help elucidate potential benefits of mobocertinib in this rare population.

Erlotinib-induced dry eye.

Erlotinib is a newer, second-line oral antineoplastic drug mainly used in the treatment of non-small cell lung carcinoma, in addition to carcinomas of the pancreas, esophagus, and ovaries.[1] It targets protein tyrosine kinase and inhibits phosphorylation of epidermal growth factor receptor (EGFR), thereby blocking tumor cell proliferation. Other previously reported ocular side effects of erlotinib include trichomegaly, periorbital inflammation, ectropion, and epiphora.[2–4] Case Report A 58-year-old female presented with complaints of persistent irritation and redness in both eyes since a month. She was diagnosed with adenocarcinoma of the lung and had been under treatment with oral EGFR antagonist erlotinib for 6 months. Ocular examination revealed sparse eyelashes, blepharitis, and diffuse conjunctival congestion in both eyes [Fig. 1a]. Fluorescein staining showed punctate epithelial erosions and a tear film breakup time of 9 s [Fig. 1b]. She was diagnosed with erlotinib-induced blepharitis and dry eye; she was started on treatment with topical azithromycin ointment and preservative-free lubricants and was advised lid hygiene and hot fomentation as supportive therapy. Discontinuation of erlotinib was not advised as the tumor was responsive to the therapy and the side effects were tolerable and improved with treatment.Figure 1: (a) Diffuse slit-lamp image showing sparse eyelashes and blepharitis with decreased tear film height. (b) Diffuse slit-lamp image with cobalt blue filter showing punctate epithelial erosions on corneaEGFR receptors are found in the sebaceous glands, hair follicles, capillary system, and basal epidermal cells, and the abundance of these in the periorbital region has been hypothesized to be the reason for the ocular side effects of erlotinib.[2,4] A murine study with topical erlotinib showed it to cause a reduction in goblet cell numbers, ultrastructural changes to the corneal epithelium, and a significant reduction in the tear film breakup time.[5] With foreseeable increase in the use of erlotinib in cancer therapy, it is essential to understand its ocular side effects for appropriate patient education and treatment, which may warrant a concerted management from the ophthalmologist and the oncologist. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Adjuvant Osimertinib vs. Placebo in Completely Resected Stage IA2–IA3 EGFR-Mutated NSCLC: ADAURA2

IntroductionOsimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR mutation-positive (EGFRm) non–small cell lung cancer (NSCLC), including central nervous system (CNS) metastases. Here we present the rationale and study design for ADAURA2 (NCT05120349), which will evaluate adjuvant osimertinib vs. placebo in patients with stage IA2–IA3 EGFRm NSCLC, following complete tumor resection. Patients and MethodsADAURA2 is a phase III, global, randomized, double-blind, placebo-controlled study. Patients will be adults aged ≥18 years with resected primary nonsquamous NSCLC stage IA2 or IA3 and central confirmation of an EGFR exon 19 deletion or L858R mutation. Patients will be stratified by pathologic risk of disease recurrence (high vs. low), EGFR mutation type (exon 19 deletion vs. L858R) and race (Chinese Asian vs. non-Chinese Asian vs. non-Asian), and randomized 1:1 to receive osimertinib 80 mg once daily (QD) or placebo QD until disease recurrence, treatment discontinuation, or a maximum treatment duration of 3 years. The primary endpoint of this study is disease-free survival (DFS) in the high-risk stratum. Secondary endpoints include DFS in the overall population, overall survival, CNS DFS, and safety. Health-related quality of life and pharmacokinetics will also be evaluated. ResultsStudy enrolment began in February 2022 and interim results of the primary endpoint are expected in August 2027.

Phase II trial of icotinib in adult patients with neurofibromatosis type 2 and progressive vestibular schwannoma.

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant syndrome associated primarily with bilateral vestibular schwannomas (VSs). Conventional surgical or radiosurgical treatments for VS in NF2 usually result in high risks of hearing loss and facial nerve impairment, while there is no validated medical option to date. This single-institution phase II study evaluated the efficacy and safety of icotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with NF2 and progressive VS. Icotinib was administered daily at 375 mg orally in a continuous 28-day course for up to 12 courses. The primary endpoint of the study was radiographic response assessed by brain MRI using 3D volumetric tumor analysis and defined as a ≥ 20% decrease in VS volume. Hearing function was evaluated as a secondary endpoint, with response defined as a statistically significant increase in word recognition scores. Ten eligible patients with a mean age of 23.8 years were enrolled. One patient (10%) with bilateral tumors experienced an objective radiographic response (-23.58% and -22.01%). Three (43%) of 7 patients met the hearing response criteria. At 12 months, the estimated progression-free survival was 82.0% (95% CI 42.3%-95.5%) for volumetric progression and 69.2% (95% CI 37.3%-87.2%) for hearing progression. Common mild to moderate adverse events included rash (90%), diarrhea (50%), myalgia (20%), and nausea/gastrointestinal pain (20%). Icotinib carries minor toxicity and is associated with radiographic and hearing responses in patients with NF2 and progressive VS.

Review of epidermal growth factor receptor-tyrosine kinase inhibitors administration to non-small-cell lung cancer patients undergoing hemodialysis.

Non-small-cell lung cancer (NSCLC) causes significant mortality worldwide. Patients with chronic renal failure have an increased risk of developing lung cancer. NSCLC Patients with chronic renal failure undergoing hemodialysis (HD) often exhibit poor performance, and chemotherapy is generally contraindicated. Oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are effective treatment agents for NSCLC patients. However, the benefits and adverse effects of EGFR-TKIs in NSCLC undergoing HD are known. There are no clinical studies on the effects of EGFR-TKIs on NSCLC patients undergoing HD. We reviewed all previous case reports about EGFR-TKIs in NSCLC patients undergoing HD. It is difficult to design studies about the effects of EGFR-TKIs in patients undergoing HD, and this review is quite important. EGFR-TKIs are well tolerated in patients undergoing HD. The main routes of elimination of EGFR-TKIs are metabolism via the liver, and renal elimination is minor. The recommended doses and pharmacokinetics of these EGFR-TKIs for patients undergoing HD are similar to those for patients with normal renal function. The plasma protein binding of EGFR-TKIs is very high, and it is not necessary to adjust the dose after HD. In conclusion, EGFR-TKIs are effective and well tolerated in patients undergoing HD.

Clinical Experience on Use of Oral EGFR-TKIs as First-line Treatment of Advanced NSCLC from a Tertiary Care Centre in North India and Implications of Skin Rash

Limited data are available from India on treatment outcomes with oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in newly diagnosed non-small cell lung cancer (NSCLC). We studied the demographic profile and treatment outcomes of patients with NSCLC, receiving first-line treatment with oral EGFR-TKIs. Retrospective study of newly diagnosed NSCLC patients treated with oral EGFR-TKIs over a 4-year period at a tertiary care institute in North India. Of 76 patients studied, females and non-smokers constituted 32.9% and 48.7%, respectively. Majority of patients had adenocarcinoma (59.2%), stage IV (64.5%) disease and Karnofsky performance status ≤ 70 (74.5%). Gefitinib was the most frequently used EGFR-TKI (92.1%). Most common indication for the use of EGFR-TKIs was poor performance status (65.8%). Among assessable patients, disease control and progressive disease were evident in 66% and 34%, respectively. Most common side effects were skin rash (17%) and diarrhoea (10.6%). Patients with and without skin rash differed significantly in relation to objective response to treatment (100% versus 23.1%) and overall survival (median not reached versus 178 days). On multivariate logistic regression analysis, malignant pleural effusion was associated with occurrence of rash (odds ratio = 0.19; 95% confidence interval = 0.04-0.95; p = 0.04). Oral EGFR-TKIs appear to be useful for the treatment of clinically selected patients with advanced NSCLC. Occurrence of skin rash was independently associated with treatment response and better survival in the current study.

P47.11 COMPEL: Chemotherapy With/Without Osimertinib in Patients With EGFRm Advanced NSCLC and Progression on First-Line Osimertinib

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR TKI-sensitizing and EGFR T790M resistance mutations with demonstrated efficacy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC), including central nervous system (CNS) metastases. Osimertinib is the preferred first-line treatment in EGFRm advanced NSCLC; however, progression eventually occurs. Guidelines recommend that upon systemic progression, osimertinib be discontinued and platinum-based doublet chemotherapy be initiated.