Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO).

BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

Real-world analysis of afatinib as a first-line treatment for patients with advanced stage non-small-cell lung cancer with uncommon EGFR mutations: a multicenter study in Vietnam.

Background: Afatinib is indicated for advanced-stage non-small-cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) and uncommon mutations. However, real-world studies on this topic are limited. This study aimed to evaluate afatinib as first-line therapy for locally advanced and metastatic NSCLC with uncommon EGFR mutations. Patients and methods: A retrospective study included 92 patients with advanced NSCLC with uncommon and compound EGFR mutations, treated with afatinib as first-line therapy. Patients were followed up and evaluated every 3 months or when symptoms of progressive disease arose. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and adverse events. Results: The G719X EGFR mutation had the highest occurrence rate (53.3% for both monotherapy and the compound). By contrast, the compound mutation G719X-S768I was observed at a rate of 22.8%. The ORR was 75%, with 15.2% of patients achieving complete response. The overall median TTF was 13.8 months. Patients with the G719X EGFR mutation (single and compound) had a median TTF of 19.3 months, longer than that of patients with other mutations, who had a median TTF of 11.2 months. Patients with compound EGFR mutations (G719X and S768I) demonstrated a median TTF of 23.2 months compared to that of 12.3 months for other mutations. Tolerated doses of 20 or 30 mg achieved a longer median TTF of 17.1 months compared to 11.2 months with 40 mg. Median TTF differed between patients with and without brain metastasis, at 11.2 and 16.9 months, respectively. Rash (55.4%) and diarrhea (53.3%) were the most common adverse events, primarily grades 1 and 2. Other side effects occurred at a low rate. Conclusion: Afatinib is effective for locally advanced metastatic NSCLC with uncommon EGFR mutations. Patients with G719X, compound G719X-S768I mutations, and tolerated doses of 20 or 30 mg had a longer median TTF than those with other mutations.

"ACHILLES" Heel No More? Afatinib at 40 Mg Once Daily is Superior to Platinum-Based Chemotherapy in EGFR Uncommon (G719X, S768I, and L861Q) Mutations (ACHILLES/TORG1834).

Afatinib, a second-generation covalent EGFR TKI, has been approved for the treatment of the three "uncommon" EGFR mutations (G719X, S768I, and L861Q) based on one pooled retrospective analysis of three prospective trials (LUX-Lung 2, 3 and 6). The confirmed overall response rate, as assessed by independent radiology review, was 66% (95% confidence interval: 47-81). Among the 21 responders, the proportion of patients with response duration of ≥12 months was 52% and the proportion with response durations of ≥18 months was 33%. Of note, all patients received afatinib at 40 or 50 mg once daily which is higher than the approved dose of 40 mg once daily and the usual 30 mg once daily starting dose by most thoracic oncologists. Given the approval of afatinib for "uncommon" EGFR mutations was based on the limited number of patients analyzed, the retrospective nature of the analysis, lack of randomized phase 2 or 3 trial, there remains uncertainty as to whether afatinib, chemotherapy or other next-generation EGFR TKIs is the optimal treatment. This uncertainty also hinders the development of future treatment of these "uncommon" mutations because of the uncertainty that afatinib is the optimal treatment and hence should be the standard of care control arm in future randomized trials. Finally, the ACHILLES/TORG1834 provided us with the first randomized trial result that afatinib achieved superior progression-free survival over platinum-based chemotherapy (10.6 months vs 5.7 months, HR = 0.42; 95% CI: 0.256-0.694; P = 0.0007). However, ACHILLES should mostly be considered as phase 2 trial given the limited number (N = 109) of patients enrolled. Furthermore, the PFS benefit seemed to be with the 40 mg daily dose (HR = 0.128; 95% CI: 0.050-0.327) and not with the 30 mg daily dose (HR = 0.704; 95% CI: 0.352-1.406). Further investigation of the 30 once daily dosing for the treatment of uncommon EGFR mutations is needed.

Osimertinib in uncommon EGFR exon 21 L861R and EGFR exon 18 deletion-insertion mutant non-small cell lung cancer-case report.

Background: Tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for patients with advanced non-small cell lung cancer (NSCLC) found to have oncogene-driven activating epidermal growth factor receptor (EGFR) mutations. Whilst there have been a handful of case reports of sensitivity to first-generation TKIs in EGFR L861R mutations, the efficacy of the third-generation TKI osimertinib in NSCLC patients with EGFR L861R and EGFR exon 18 deletion-insertion mutations is limited. Case Description: We report two patients from our institution with uncommon EGFR mutations treated with first-line osimertinib. Our first patient, a 72-year-old male with metastatic lung adenocarcinoma was identified to harbour a rare EGFR L861R mutation and was commenced on osimertinib. After a follow-up period of 18 months, the patient is continuing to experience treatment benefit with imaging showing a good partial response. The second patient, a 60-year-old male also with metastatic lung adenocarcinoma and an EGFR exon 18 deletion-insertion mutation achieved a partial response for 6.6 months. Upon progression, he was commenced on carboplatin and pemetrexed chemotherapy however died from subsequent pneumonia. He had an overall survival (OS) from time of diagnosis of 7.6 months. Conclusions: We demonstrate clinical efficacy of first-line osimertinib in the treatment of advanced NSCLC harbouring uncommon EGFR L861R and EGFR exon 18 deletion-insertion mutations. These results may be suggestive of the wider applicability of osimertinib in the treatment of uncommon EGFR mutant NSCLC.

Unveiling the Landscape of Uncommon EGFR Mutations in NSCLC-A Systematic Review.

Uncommon EGFR mutations represent a rare subgroup of NSCLC. Data on the efficacy of different generations of tyrosine kinase inhibitors (TKIs) in these rare mutations are scattered and limited to mostly retrospective small cohorts because these patients were usually excluded from clinical trials. This was a systematic review on the efficacy of TKIs in patients harboring uncommon EGFR mutations, defined as mutations other than exon 20 insertions mutations or T790M. Response rates (RRs) for different generations of TKIs were determined for individual uncommon mutations, compound mutations, and according to classical-like and P-loop alpha helix compressing mutations classes. This study was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 1836 patients from 38 studies were included in the final analysis. Most available data (92.6%) were from patients treated with first- or second-generation TKIs. G719X, S768I, E709X, L747X, and E709-T710delinsD showed RRs ranging from 47.8% to 72.3% to second-generation TKIs, generally higher than for first- or third-generation TKIs. L861Q mutation exhibited 75% (95% confidence interval [CI]: 56.6%-88.5%) RRs to third-generation TKIs. Compound mutations with G719X, E709X, or S768I consistently showed RRs above 50% to second- and third-generation TKIs, although fewer data were available for third generations. For classical-like mutations, RRs were 35.4% (95% CI: 27.2%-44.2%), 51.9% (95% CI: 44.4%-59.3%), and 67.9% (95% CI: 47.6%-84.1%) to first-, second-, and third-generation TKIs, whereas for P-loop alpha helix compressing mutations classes mutations, RRs were 37.2% (95% CI: 32.4%-42.1%), 59.6% (95% CI: 54.8%-64.3%), and 46.3% (95% CI: 32.6%-60.4%), respectively. This systematic review supports the use of second-generation TKI afatinib for G719X, S768I, E709X, and L747X mutations and for compound uncommon mutations. For other uncommon mutations such as L861Q, third-generation TKI, such as osimertinib, could also be considered, given its activity and toxicity profile.

Sintilimab plus anlotinib as second- or third-line therapy in metastatic non-small cell lung cancer with uncommon epidermal growth factor receptor mutations: A prospective, single-arm, phase II trial.

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) and uncommon EGFR alterations typically have worse treatment outcomes than patients with classically EGFR-mutated NSCLC. This study aimed to investigate the efficacy and safety of PD-1 blockade with sintilimab plus anti-angiogenic treatment with anlotinib in patients with NSCLC harboring uncommon EGFR mutations. METHODS: Patients with metastatic NSCLC harboring uncommon EGFR mutations after two previous treatments, including a platinum-based chemotherapy regimen and a targeted treatment (or chemotherapy only for patients harboring EGFR ex20ins), received sintilimab combined with anlotinib. The primary endpoint was objective response rate (ORR). RESULTS: At data cutoff (September 27, 2022), median follow-up was 22.3 months (range, 1.2-37.6). Among 21 enrolled patients, 12 had EGFR ex20ins and nine had other uncommon EGFR mutations such as L861Q, G719A, and G709X. Overall, eight patients (38.1%) achieved an objective response, and 18 (85.7%) achieved disease control. Median (95% CI) progression-free survival (PFS) was 7.0 (5.4-8.6) months, and median overall survival (OS) was 20.0 (15.6-24.4) months. The 12-month PFS rate (95% CI) was 22.2% (7.4-42.0), and the 12-month OS rate was 66.7% (42.5-82.5). Patients harboring EGFR ex20ins had similar ORR and PFS to those with other mutations. Six patients (28.6%) experienced grade 3 treatment-related adverse events (TRAEs); hand-foot syndrome was the most common grade 3 TRAE (2 patients; 9.5%). No grade ≥4 TRAEs were observed. CONCLUSIONS: The combination of sintilimab and anlotinib demonstrated durable efficacy and was generally well tolerated in patients with NSCLC and uncommon EGFR mutations who had received prior standard-of-care treatments. (ClinicalTrials.gov identifier: NCT04790409).

Antitumor activity of aumolertinib, a third-generation EGFR tyrosine kinase inhibitor, in non-small-cell lung cancer harboring uncommon EGFR mutations.

Uncommon epidermal growth factor receptor (EGFR) mutations account for 10%-20% of all EGFR mutations in non-small-cell lung cancer (NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors (TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC. Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models (V769-D770insASV and L861Q mutations) and a patient-derived xenografts model (H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.

CNS efficacy of afatinib as first-line treatment in advanced non-small cell lung cancer patients with EGFR mutations.

Background: Afatinib is a potent, irreversible second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor which has demonstrated efficacy in advanced non-small cell lung cancer (NSCLC) patients harboring either common or uncommon EGFR mutations. However, data on its activity against brain metastases are limited. This study aimed to retrospectively evaluate the efficacy and safety of afatinib as first-line treatment for EGFR-mutant NSCLC patients with brain metastases. Methods: Treatment-naive advanced NSCLC patients harboring EGFR mutations and brain metastases treated with afatinib were retrospectively reviewed to assess the central nervous system (CNS) efficacy and also the systematic benefits. Results: Totally 43 patients with measurable or non-measurable brain metastases were enrolled in the CNS full analysis (cFAS) set. Among them, 23 patients with measurable brain metastases were included in the CNS evaluable for response (cEFR) set. The CNS ORR was 48.8% (95% CI, 33.3 - 64.5%) in the cFAS set and 82.6% (95% CI, 61.2 - 95.0%) in the cEFR set, respectively. CNS mDoR was 8.9 months (95% CI, 4.7 - 13.1 months) and CNS mPFS was 12.7 months (95% CI, 6.9 - 18.5 months) in the cFAS set. In the subgroup analysis stratified by EGFR mutation types, CNS ORR of cEFR set in the common mutation cohort was 100% (95% CI, 75.3 - 100%) and 60% (95% CI, 26.2 - 87.8%) in the uncommon mutation cohort (p = 0.024); CNS ORR of cFAS set was 57.7% (95% CI, 36.9 - 76.6%) and 35.3% (95% CI, 14.2 - 61.7%), respectively (p = 0.151). CNS mPFS was 14.4 months in patients with common mutations and 6.1 months in patients with uncommon mutations (hazard ratio, 0.47; 95% CI, 0.22 - 1.00; p = 0.045). Patients with common mutations showed a significantly lower cumulative incidence of CNS failure than uncommon mutation cohort (p = 0.0026). Most of patients experienced grade 1/2 treatment-related adverse events. Conclusions: First-line afatinib demonstrated encouraging efficacy on brain metastases in NSCLC patients harboring either common or major uncommon EGFR mutations in a real-world setting, with manageable toxicities. Patients with common mutations showed better CNS outcomes than those with uncommon mutations.

A single-arm, multicenter, phase II trial of osimertinib in patients with epidermal growth factor receptor exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations.

BACKGROUND: For patients with stage IV non-small-cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions and exon 21 L858R mutations, osimertinib is the standard of care. Investigating the activity and safety of osimertinib in patients with EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations is of clinical interest. PATIENTS AND METHODS: Patients with stage IV non-small-cell lung cancer with confirmed EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations were eligible. Patients were required to have measurable disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were required to be EGFR tyrosine kinase inhibitor-naive. The primary objective was objective response rate, and secondary objectives were progression-free survival, safety, and overall survival. The study used a two-stage design with a plan to enroll 17 patients in the first stage, and the study was terminated after the first stage due to slow accrual. RESULTS: Between May 2018 and March 2020, 17 patients were enrolled and received study therapy. The median age of patients was 70 years (interquartile range 62-76), the majority were female (n = 11), had a performance status of 1 (n = 10), and five patients had brain metastases at baseline. The objective response rate was 47% [95% confidence interval (CI) 23% to 72%], and the radiographic responses observed were partial response (n = 8), stable disease (n = 8), and progressive disease (n = 1). The median progression-free survival was 10.5 months (95% CI 5.0-15.2 months), and the median OS was 13.8 months (95% CI 7.3-29.2 months). The median duration on treatment was 6.1 months (range 3.6-11.9 months), and the most common adverse events (regardless of attribution) were diarrhea, fatigue, anorexia, weight loss, and dyspnea. CONCLUSIONS: This trial suggests osimertinib has activity in patients with these uncommon EGFR mutations.

Antitumor activity of aumolertinib, a third-generation EGFR tyrosine kinase inhibitor, in non-small-cell lung cancer harboring uncommon EGFR mutations

Uncommon epidermal growth factor receptor (EGFR) mutations account for 10%-20% of all EGFR mutations in non-small-cell lung cancer (NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors (TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC. Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models (V769-D770insASV and L861Q mutations) and a patient-derived xenografts model (H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.

Afatinib and Dacomitinib Efficacy, Safety, Progression Patterns, and Resistance Mechanisms in Patients with Non-Small Cell Lung Cancer Carrying Uncommon EGFR Mutations: A Comparative Cohort Study in China (AFANDA Study).

(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.

Spotlight on Furmonertinib (Alflutinib, AST2818). The Swiss Army Knife (del19, L858R, T790M, Exon 20 Insertions, "uncommon-G719X, S768I, L861Q") Among the Third-Generation EGFR TKIs?

Osimertinib, a third-generation (3G) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is now considered the standard of care for the first-line (1L) treatment of advanced EGFR+ NSCLC due to statistically significant improved progression-free survival (PFS) and overall survival (OS) compared with first-generation (1G) treatment from the FLAURA trial. Recently two other 3G EGFR TKIs (aumolertinib and furmonertinib) have been approved in China for treatment of EGFR T790M+ NSCLC. Randomized Phase 3 trials of these two 3G EGFR TKIs have also demonstrated PFS over gefitinib respectively. Among these two Chinese home-grown, 3G EGFR TKIs, furmonertinib seems to most closely resemble osimertinib in terms of dosing regimen, efficacy and adverse events profile. In this article, we reviewed the clinical activity and adverse events of furmonertinib at 80 mg daily (approved dose), potential usage of 160 mg daily for CNS metastasis in EGFR+ NSCLC, and usage of 160 mg or 240 mg daily in EGFR exon20 insertion positive (EGFRex20ins+) NSCLC patients.

Osimertinib in non-small cell lung cancer with uncommon EGFR-mutations: a post-hoc subgroup analysis with pooled data from two phase II clinical trials.

Background: Osimertinib is standard of care for EGFR-mutated non-small cell lung cancer (NSCLC) patients. The efficacy of the drug in patients with mutations other than the common deletion in exon 19 and L858R in exon 21 is largely unknown. Methods: We identified patients with uncommon EGFR-mutations from two prospective clinical phase II, single-arm studies for previously treated patients and untreated patients, respectively, and pooled data for this analysis. All patients received treatment with osimertinib 80 mg daily until radiological progression or death. The primary endpoint of both trials was objective response rate (ORR), with progression-free survival (PFS), overall survival (OS) and intracranial efficacy as key secondary endpoints. Circulating tumour DNA (ctDNA) was analysed before and two weeks after treatment initiation in the first line cohort. Results: Of 299 enrolled patients in the two trials, 21 patients with uncommon mutations were identified; 12 patients had a single mutation (G719X or L861Q), one patient had L861Q and an exon 20 insertion, and 8 patients had compound mutations with G719X and either L861Q or S768I. Three of the 10 pretreated patients had the T790M resistance mutation. ORR was 47.6% and disease control rate (DCR) 85.7%. The median duration of response (DoR) was 7.9 months. Among 11 patients treated with osimertinib in first line, ORR was 63.6% vs. 30.0% of 10 previously treated patients. The median PFS was 5.5 months in both groups. Patients with G719X-compound mutations had a higher response rate (62.5% vs. 38.5%), a longer median PFS (13.7 vs. 3.5 months) and median OS (29.3 vs. 7.5 months) than patients with other mutations. Most first line treated patients (81.8%) displayed a reduction in ctDNA after two weeks of treatment. Conclusions: Osimertinib demonstrates activity in patients with uncommon EGFR-mutations, and especially for G719X-compound mutations.

Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China.

Objective: Dacomitinib has been approved for non-small-cell lung cancer (NSCLC) patients harboring classical epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on major uncommon EGFR mutations is currently limited. Materials and methods: This was a dual-center, single-arm, ambispective cohort study in China. Patients with histologically confirmed metastatic or recurrent NSCLC harboring major uncommon EGFR mutations were eligible for the study. The objective response rate and disease control rate were determined by RECIST 1.1 every 1-2 months. Adverse events were assessed by CTCAE 5.0. Results: In total, 32 NSCLC patients were enrolled between July 2020 and January 2022, and 18 (56.3%) patients received dacomitinib as first-line therapy. Median age was 64 years, and 20 (62.5%) were female. The mutations identified were G719X (n = 24; 75%), followed by L861X (n = 10; 31.3%), and S768I (n = 8; 25%). In the first-line setting, 72.2% of patients (13/18) had a confirmed partial response and 100% (18/18) had disease control, and the median progression-free survival (PFS) and overall survival (OS) were unreached. In the whole cohort, 56.3% of patients (18/32) had a confirmed partial response and 90.6% (29/32) had disease control, and the median PFS was 10.3 months (95% confidence interval, 6.1-14.5) and the median OS was 36.5 months. Except for one case not available for brain re-evaluation, control of the intracranial metastases was observed in 13 patients (13/14, 92.9%). No grade 4-5 adverse events (AEs) occurred, but all patients had grade 1-2 AEs, and 12.5% (4/32) patients required a dosage reduction due to intolerable AEs. Conclusions: Dacomitinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring major uncommon EGFR mutations.

Afatinib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: An Updated Database of 1023 Cases Brief Report.

Introduction: Previously, we developed a database of 693 patients with NSCLC and uncommon EGFR mutations treated with afatinib. Here, we provide an update of >1000 patients, with more data on specific mutations. Methods: Patients were identified from a prospective database developed by Boehringer Ingelheim and via literature review. Mutations were categorized as T790M-positive, exon 20 insertions, major uncommon (G719X, L861Q, S768I) and 'others'. Patients with compound mutations (≥2 EGFR mutations) were analyzed separately. Key endpoints were time to treatment failure (TTF) and objective response rate (ORR). Results: Of 1023 patients included, 587 patients were EGFR TKI-naïve and 425 were EGFR TKI-pretreated. The distribution of mutation categories was: major uncommon (41.4%); exon 20 insertions (22.3%); T790M (20.3%); and 'others' (15.9%); 38.6% had compound mutations. Overall, median TTF (TKI naïve/pretreated) was 10.7 and 4.5 months. ORR was 49.8% and 26.8%, respectively. In TKI-naïve patients, afatinib demonstrated activity against major uncommon mutations (median TTF: 12.6 months; ORR: 59.0%), 'other' mutations (median TTF: 10.7 months; ORR: 63.9%) including strong activity against E709X (11.4 months; 84.6%) and L747X (14.7 months; 80.0%), and compound mutations (11.5 months; 63.9%). Although sample sizes were small, notable activity was observed against specific exon 20 insertions at residues A763, M766, N771, and V769, and against osimertinib resistance mutations (G724S, L718X, C797S). Conclusion: Afatinib should be considered as a first-line treatment option for NSCLC patients with major uncommon, compound, 'other' (including E709X and L747X) and some specific exon 20 insertion mutations. Moderate activity was seen against osimertinib resistance EGFR mutations.

Osimertinib-Centered Therapy Against Uncommon Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer- A Mini Review.

Osimertinib is a third-generation, irreversible mutant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). Osimertinib is currently the first line drug recommended by National Comprehensive Cancer Network (NCCN) guidelines against lung cancer harboring the EGFR TKI-sensitive mutation and acquired EGFR T790M resistance mutation. Osimertinib demonstrated some efficacy in clinical trials and case reports in patients bearing certain uncommon EGFR mutations, but it is not active in patients with other mutations such as C797S. This mini-review presents the mechanisms underlying the variations in patient responses, discusses the use of osimertinib against non-small-cell lung carcinomas with uncommon EGFR mutations, and addresses the future prospects of osimertinib-centered therapy.

Tyrosine Kinase Inhibitor Activity in Patients with NSCLC Harboring Uncommon EGFR Mutations: A Retrospective International Cohort Study (UpSwinG).

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are standard of care for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) with common mutations (Del19 or L858R); however, 7%-23% of NSCLC tumors harbor uncommon EGFR mutations. These mutations are highly heterogeneous, and developments in detection techniques are helping to identify mutations with little or no clinical data. PATIENTS AND METHODS: In this retrospective, global, multi-center study (NCT04179890), existing health records were identified for consecutive EGFR TKI-naïve patients with uncommon EGFR mutations (T790M, ex20ins, major uncommon [G719X, L861Q, or S768I], or "other" mutations; compound mutations) treated with erlotinib, gefitinib, afatinib, or osimertinib in first or second line. Endpoints included time-to-treatment failure (TTF), objective response rate (ORR), and overall survival (OS). RESULTS: Overall, 246 patients (median age: 69.5 years; Asian: 84%) were included from 9 countries. Most patients (92%) received an EGFR TKI as first-line therapy; 54%, 43% and 3% received afatinib, first-generation TKIs, and osimertinib, respectively. Median TTF and OS with EGFR TKIs were 9.9 and 24.4 months; ORR was 43%. In patients treated with first-line chemotherapy (n = 20), median TTF and ORR were 6.6 months and 41%. Outcomes were most favorable in patients with major uncommon or compound mutations. Overall, TTF was 11.3 months with afatinib and 8.8 months with first-generation EGFR TKIs across mutation categories. In most mutation categories, median OS was >2 years. CONCLUSION: In a real-world setting, EGFR TKIs were the preferred treatment option in patients with uncommon EGFR mutations; strongest outcomes were seen in patients with major uncommon and compound mutations.

Clinical outcomes of advanced non-small cell lung cancer patients harboring distinct subtypes of EGFR mutations and receiving first-line tyrosine kinase inhibitors: brain metastasis and de novo T790M matters.

BACKGROUND: The clinical features, survival outcomes and patterns of treatment failure of advanced non-small cell lung cancer (NSCLC) patients harboring distinct subtypes of EGFR mutations and receiving first-line EGFR tyrosine kinases inhibitor (TKIs) are not fully understood. METHODS: Consecutive metastatic EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs from October 2010 to March 2020 were enrolled and classified into two main groups based on the EGFR mutation subtypes: common mutation (L858R or exon 19 deletion), uncommon mutation (other EGFR mutations). RESULTS: Of the 1081 patients included, 74 (6.8%) harbored uncommon mutations. The baseline characteristics were generally balanced between the two groups, except that bone metastasis developed less frequently in patients with uncommon mutations (p = 0.02). No significant difference of survival outcomes was found between the two groups, except that among patients with baseline brain metastasis, the intracranial time to progression was significantly shorter in patients with uncommon mutations. Nine of the 17 patients with de novo T790M mutation received Osimertinib, whose overall survival tended to be longer than the remaining 8 patients without Osimertinib treatment (p = 0.08). The patterns of treatment failure were generally consistent between the two groups, except which patients with uncommon mutations had a higher risk developing progressive disease in the brain. CONCLUSION: First-line EGFR-TKIs seemed to be less effective in controlling and preventing brain metastasis in patients with uncommon EGFR mutations and Osimertinib was associated with promising efficacy in patients with de novo T790M mutation, which warranted further validation.

Uncommon EGFR mutations conducted with osimertinib in patients with NSCLC: a study protocol of phase 2 study (UNICORN/TCOG1901).

Patients with uncommon EGFR-mutated non-small-cell lung cancer (NSCLC) demonstrated lower clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors compared with patients harboring common EGFR-mutated NSCLC. The US FDA has approved afatinib for uncommon EGFR mutation positive NSCLC based on the pooled analysis in the first- or second-line setting. Osimertinib has limited evidence in the small sample sizes of phase 2 studies in any-line settings. The aim of the present single-arm, multicenter, phase 2 study is to evaluate the efficacy of osimertinib for previously untreated NSCLC. The primary end point is to assess the overall response to osimertinib. The secondary end points include disease control rate, progression-free survival, duration of time-to-treatment failure, overall survival and safety. Clinical trial registration: jRCTs071200002.

Lay abstract Tyrosine kinase inhibitor (TKI) medications are targeting EGFR work on the first-line treatment for patients with common EGFR mutation positive non-small-cell lung cancer (EGFR+ NSCLC) that has spread to other parts of the body and has the EGFR+ NSCLC in tumor testing. Uncommon EGFR mutations and compound EGFR mutations have less activity for first-generation EGFR-TKIs; however, second- or third-generation EGFR-TKIs are broader spectrum than first-generation EGFR-TKIs have activities ideally. The authors describe the need for and design a study of osimertinib in patients with uncommon/compound EGFR+ NSCLC.

Experience of Uncommon EGFR Mutation in Lung Scheme Quality Program: Discussing Risks and Opportunities for the Improvement of Laboratory Response.

Background The quality programs can be considered to be a valuable tool for global and individual growth. Each result, obtained by a single laboratory, contributes to define the standardization of the response. In the case of the uncommon epidermal growth factor receptor (EGFR) mutations, the molecular result is sometimes difficult to interpret in terms of biological significance and therapy choosing. The standardization effort in the diagnostic lung setting also consists of active quality program participation. Materials and Methods The quality control analysis, which is defined as a clinical case, was performed by the extraction of DNA from FFPE sections and by RT-PCR on the EGFR (exons 19, 20, 21), BRAF, and KRAS genes. The laboratory performed a validation sequencing of EGFR exon 20 with the help of the Sanger method. Results The laboratory reported positivity for EGFR exon 20 insertions and negative results for BRAF and KRAS. The quality test finished with the redaction of a report containing the recommendation to consider the efficacy of therapy with tyrosine kinase inhibitors (TKI). This specific interpretation has determined poor performance judgment by the quality provider, which explained why most of these mutations are TKI-resistant. Conclusions This experience provides an opportunity to reflect on the critical aspects of this diagnostic setting. The detection of some uncommon EGFR mutations should entail the mutation characterization, especially for the rare exon 20 insertions, of which are not classifiable as "resistant." Moreover, this experience allows reflecting on the quality program design, mandatory actions for the laboratory, and routine activity in the oncologic multidisciplinary team.