Growth Factor Receptor-mutant Non-small Cell Research Articles

Real-World Outcomes of Patients with Advanced Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer in Canada Using Data Extracted by Large Language Model-Based Artificial Intelligence.

Real-world evidence for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) in Canada is limited. This study's objective was to use previously validated DARWENTM artificial intelligence (AI) to extract data from electronic heath records of patients with non-squamous NSCLC at University Health Network (UHN) to describe EGFR mutation prevalence, treatment patterns, and outcomes. Of 2154 patients with NSCLC, 613 had advanced disease. Of these, 136 (22%) had common sensitizing EGFR mutations (cEGFRm; ex19del, L858R), 8 (1%) had exon 20 insertions (ex20ins), and 338 (55%) had EGFR wild type. One-year overall survival (OS) (95% CI) for patients with cEGFRm, ex20ins, and EGFR wild type tumours was 88% (83, 94), 100% (100, 100), and 59% (53, 65), respectively. In total, 38% patients with ex20ins received experimental ex20ins targeting treatment as their first-line therapy. A total of 57 patients (36%) with cEGFRm received osimertinib as their first-line treatment, and 61 (39%) received it as their second-line treatment. One-year OS (95% CI) following the discontinuation of osimertinib was 35% (17, 75) post-first-line and 20% (9, 44) post-second-line. In this real-world AI-generated dataset, survival post-osimertinib was poor in patients with cEGFR mutations. Patients with ex20ins in this cohort had improved outcomes, possibly due to ex20ins targeting treatment, highlighting the need for more effective treatments for patients with advanced EGFRm NSCLC.

Factors associated with prolonged progression-free survival of patients treated with first-line afatinib for advanced epidermal growth factor receptor-mutated non-small cell lung cancer.

This study aimed to investigate the factors associated with prolonged progression-free survival (PFS) (>36 months) of advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations treated with first-line afatinib. We performed a retrospective analysis of data of patients with advanced EGFR-mutated NSCLC receiving first-line afatinib at two tertiary care referral centers, Linkou and Kaohsiung Chang Gung Memorial Hospital, in Taiwan between June 2014 and April 2022. The data of 546 treatment-naïve EGFR-mutated advanced NSCLC patients were analyzed. Median PFS and overall survival were 14.5 months and 27.2 months, respectively. The PFS of 462 patients (84.6%) was less than 36 months and of 84 patients (15.4%) was more than 36 months. The PFS > 36 months group had a significantly higher percentage of patients with uncommon mutations (p = 0.002). The PFS ≤36 months group had significantly higher incidences of bone, liver, and adrenal metastases (all p < 0.05) and a higher rate of multiple distant metastases. Multivariate logistic regression analysis showed that liver metastasis was negatively and independently associated with prolonged PFS (adjusted odds ratio = 0.246 [95% CI: 0.067-0.908], p = 0.035). The median overall survival of the PFS >36 months group was 46.0 months and that of the PFS ≤36 months group was 22.9 months (log-rank test, p < 0.001). We found that EGFR-mutated NSCLC patients receiving first-line afatinib were prone to shorter PFS if they had distant organ metastasis, especially liver metastasis.

Transformation of epidermal growth factor receptor-mutated non-small cell lung cancer into small cell lung cancer—case report

Transformation of epidermal growth factor receptor-mutated non-small cell lung cancer into small cell lung cancer—case report

Treatment preferences among Japanese patients and physicians for epidermal growth factor receptor-mutant non-small cell lung cancer.

Evidence is limited on preferences of Japanese patients and physicians in treatment for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Several oral or intravenous novel agents for EGFR exon 20 insertions are under development. The aim of our study was to investigate which attributes of novel treatments influenced selection of oral or intravenous agents among treated patients and treating physicians in Japan. The study was designed by board-certified oncologists, patient representatives, and analytics specialists. Eligible participants completed an online survey with a discrete choice experiment presenting two treatment profiles described by attributes: mode of administration (oral or intravenous); frequency of administration; overall response rate (ORR); average progression-free survival (PFS); chance of experiencing severe side effects (SEs); mild-moderate gastrointestinal SEs; mild-moderate skin-related SEs; and patient out-of-pocket costs. Fifty-four patients (all self-reported EGFR-mutant) and 74 physicians participated from December 2021 to August 2022. All attributes being equal, there was greater preference for oral administration. However, there was greater preference for intravenous over oral, when ORR and PFS improved by 10% and 1 month, and severe SEs reduced by 10%. Physicians exhibited greater preference for PFS compared to patients (p < 0.01). Ranked order of attribute importance was as follows: (1) PFS; (2) ORR; (3) severe SEs, expressed by patients and physicians alike. Our study revealed Japanese physician and patient preferences in treatment options for EGFR-mutant NSCLC. Compared to the strong preference for a more efficacious drug, the preference of oral versus intravenous revealed a smaller impact.

Front-line therapy for brain metastases and non-brain metastases in advanced epidermal growth factor receptor-mutated non-small cell lung cancer: a network meta-analysis.

The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is recommended as the first-line treatment for EGFR-mutated, advanced NSCLC patients. However, intracranial activity varies in different drugs. Thus, brain metastasis (BM) should be considered when choosing the treatment regimens. We conducted this network meta-analysis to explore the optimal first-line therapeutic schedule for advanced EGFR-mutated NSCLC patients with different BM statuses. Randomized controlled trials focusing on EGFR-TKIs (alone or in combination) in advanced and EGFR-mutant NSCLC patients, who have not received systematic treatment, were systematically searched up to December 2021. We extracted and analyzed progression-free survival (PFS) and overall survival (OS). A network meta-analysis was performed with the Bayesian statistical model to determine the survival outcomes of all included therapy regimens using the R software. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to compare intervention measures, and overall rankings of therapies were estimated under the Bayesian framework. This analysis included 17 RCTs with 5077 patients and 12 therapies, including osimertinib + bevacizumab, aumolertinib, osimertinib, afatinib, dacomitinib, standards of care (SoC, including gefitinib, erlotinib, or icotinib), SoC + apatinib, SoC + bevacizumab, SoC + ramucirumab, SoC + pemetrexed based chemotherapy (PbCT), PbCT, and pemetrexed free chemotherapy (PfCT). For patients with BM, SoC + PbCT improved PFS compared with SoC (HR = 0.40, 95% CI: 0.17-0.95), and osimertinib + bevacizumab was most likely to rank first in PFS, with a cumulative probability of 34.5%, followed by aumolertinib, with a cumulative probability of 28.3%. For patients without BM, osimertinib + bevacizumab, osimertinib, aumolertinib, SoC + PbCT, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, and afatinib showed superior efficacy compared with SoC (HR = 0.43, 95% CI: 0.20-0.90; HR = 0.46, 95% CI: 0.31-0.68; HR = 0.51, 95% CI: 0.34-0.77; HR = 0.50, 95% CI: 0.38-0.66; HR = 0.62, 95% CI: 0.43-0.89; HR = 0.64, 95% CI: 0.44-0.94; HR = 0.61, 95% CI: 0.48-0.76; HR = 0.71, 95% CI: 0.50-1.00), PbCT (HR = 0.29, 95% CI: 0.11-0.74; HR = 0.31, 95% CI: 0.15-0.62; HR = 0.34, 95% CI: 0.17-0.69; HR = 0.34, 95% CI: 0.18-0.64; HR = 0.42, 95% CI: 0.21-0.82; HR = 0.43, 95% CI: 0.22-0.87; HR = 0.41, 95% CI: 0.22-0.74; HR = 0.48, 95% CI: 0.31-0.75), and PfCT (HR = 0.14, 95% CI: 0.06-0.32; HR = 0.15, 95% CI: 0.09-0.26; HR = 0.17, 95% CI: 0.09-0.29; HR = 0.16, 95% CI: 0.10-0.26; HR = 0.21, 95% CI: 0.12-0.35; HR = 0.21, 95% CI: 0.12-0.39; HR = 0.20, 95% CI: 0.12-0.31; HR = 0.23, 95% CI: 0.16-0.34) in terms of PFS. And, SoC + apatinib showed relatively superior PFS when compared with PbCT (HR = 0.44, 95% CI: 0.22-0.92) and PfCT (HR = 0.21, 95% CI: 0.12-0.39), but similar PFS to SoC (HR = 0.65, 95% CI: 0.42-1.03). No statistical differences were observed for PFS in patients without BM between PbCT and SoC (HR = 1.49, 95% CI: 0.84-2.64), but both showed favorable PFS when compared with PfCT (PfCT vs. SoC, HR = 3.09, 95% CI: 2.06-4.55; PbCT vs. PfCT, HR = 0.14, 95% CI: 0.06-0.32). For OS, SoC + PbCT was most likely to rank first in patients with and without BM, with cumulative probabilities of 46.8%, and 37.3%, respectively. Osimertinib + bevacizumab is most likely to rank first in PFS in advanced EGFR-mutated NSCLC patients with or without BM, and SoC + PbCT is most likely to rank first in OS.

Mathematical analysis identifies the optimal treatment strategy for epidermal growth factor receptor-mutated non-small cell lung cancer.

In Asians, more than half of non-small cell lung cancers (NSCLC) are induced by epidermal growth factor receptor (EGFR) mutations. Although patients carrying EGFR driver mutations display a good initial response to EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs), additional mutations provoke drug resistance. Hence, predicting tumor dynamics before treatment initiation and formulating a reasonable treatment schedule is an urgent challenge. To overcome this problem, we constructed a mathematical model based on clinical observations and investigated the optimal schedules for EGFR-TKI therapy. Based on published data on cell growth rates under different drugs, we found that using osimertinib that are efficient for secondary resistant cells as the first-line drug is beneficial in monotherapy, which is consistent with published clinical statistical data. Moreover, we identified the existence of a suitable drug-switching time; that is, changing drugs too early or too late was not helpful. Furthermore, we demonstrate that osimertinib combined with erlotinib or gefitinib as first-line treatment, has the potential for clinical application. Finally, we examined the relationship between the initial ratio of resistant cells and final cell number under different treatment conditions, and summarized it into a therapy suggestion map. By performing parameter sensitivity analysis, we identified the condition where osimertinib-first therapy was recommended as the optimal treatment option. This study for the first time theoretically showed the optimal treatment strategies based on the known information in NSCLC. Our framework can be applied to other types of cancer in the future.

Brain metastasis screening in the molecular age.

The incidence of brain metastases (BM) amongst cancer patients has been increasing due to improvements in therapeutic options and an increase in overall survival. Molecular characterization of tumors has provided insights into the biology and oncogenic drivers of BM and molecular subtype-based screening. Though there are currently some screening and surveillance guidelines for BM, they remain limited. In this comprehensive review, we review and present epidemiological data on BM, their molecular characterization, and current screening guidelines. The molecular subtypes with the highest BM incidence are epithelial growth factor receptor-mutated non-small cell lung cancer (NSCLC), BRCA1, triple-negative (TN), and HER2+ breast cancers, and BRAF-mutated melanoma. Furthermore, BMs are more likely to present asymptomatically at diagnosis in oncogene-addicted NSCLC and BRAF-mutated melanoma. European screening standards recommend more frequent screening for oncogene-addicted NSCLC patients, and clinical trials are investigating screening for BM in hormone receptor+, HER2+, and TN breast cancers. However, more work is needed to determine optimal screening guidelines for other primary cancer molecular subtypes. With the advent of personalized medicine, molecular characterization of tumors has revolutionized the landscape of cancer treatment and prognostication. Incorporating molecular characterization into BM screening guidelines may allow physicians to better identify patients at high risk for BM development and improve patient outcomes.

Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer.

Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated (EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+NSCLC patients. Patients who started treatment with osimertinib for EGFRm+NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11-0.73; p=0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p=0.010). ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. No funding was received for this trial.

Abstract CT066: HERTHENA-Lung02: A randomized Phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR tyrosine kinase inhibitor

Abstract Background: Standard therapies for patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) that has progressed after treatment with third-generation EGFR tyrosine kinase inhibitors (TKIs) offer only limited benefit. Human epidermal growth factor receptor 3 (HER3) is often expressed in primary NSCLC tumors, and HER3 expression is commonly observed in patients with EGFR mutations. HER3-DXd is a novel antibody-drug conjugate composed of a human anti-HER3 monoclonal antibody (patritumab) linked to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. HER3-DXd demonstrated efficacy and safety in a phase 1 study in patients with EGFRm NSCLC that progressed following an EGFR TKI and platinum-based chemotherapy (PBC) (U31402-A-U102; NCT03260491). In previously reported results from dose-escalation/expansion, HER3-DXd 5.6 mg/kg demonstrated a manageable safety profile and promising efficacy (confirmed objective response rate by blinded independent central review [BICR] of 39%, median duration of response of 7.0 months, and median progression-free survival of 8.2 months) in a subset of patients (n=44) with advanced EGFRm NSCLC that progressed after ≥1 line of PBC and a third-generation EGFR TKI. Trial Design: HERTHENA-Lung02 (NCT05338970) is a global, open-label, randomized, phase 3 trial evaluating the efficacy and safety of HER3-DXd vs PBC in patients (≈560) with metastatic or locally advanced nonsquamous NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) who have received 1 or 2 lines of EGFR TKI treatment including a third-generation EGFR TKI and had disease progression following treatment with a third-generation EGFR TKI. Patients are randomized 1:1 to receive either HER3-DXd 5.6 mg/kg every 3 weeks or 4 cycles of PBC containing pemetrexed (can be continued as maintenance) with cisplatin or carboplatin. Patients are stratified by prior third-generation EGFR TKI treatment (osimertinib vs other), line of prior third-generation EGFR TKI use (first vs second line), region (Asia vs rest of world), and presence of stable brain metastases (yes vs no). The primary endpoint is progression-free survival by BICR (per RECIST v1.1). The key secondary endpoint is overall survival. Other secondary endpoints include investigator-assessed progression-free survival, objective response rate, duration of response, clinical benefit rate, disease control rate, time to response (all assessed by investigator and BICR per RECIST 1.1), safety, and patient-reported outcomes. Enrollment began May 2022 and is ongoing, with sites in Asia, Australia, Europe, and North America. Citation Format: Balazs Halmos, Helena A. Yu, Yi-Long Wu, Makoto Nishio, Martin Reck, David Sternberg, Stephen Esker, Tony Mok. HERTHENA-Lung02: A randomized Phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR tyrosine kinase inhibitor [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 CT066.

Neoadjuvant Osimertinib Followed by Sequential Definitive Radiation Therapy and/or Surgery in Stage III Epidermal Growth Factor Receptor–Mutant Non-Small Cell Lung Cancer: An Open-Label, Single-Arm, Phase 2 Study

The treatment for unresectable, locally advanced stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CRT) followed by consolidation durvalumab. This study aimed to evaluate the benefit of neoadjuvant osimertinib as an alternative therapy to this approach with the aim of reducing the radiation field. This investigation was a nonrandomized, open-label, single-arm, phase 2, prospective, proof-of-concept study. Eligible patients were classified as having treatment-naïve, nonoperable, stage III epidermal growth factor receptor-mutant NSCLC. Patients received 80 mg of oral osimertinib daily for 12 weeks before definitive radiation therapy (RT) and/or surgery. The response was assessed at weeks 6 and 12. For responders, sequential definitive RT and/or surgery were planned. Nonresponders were started on standard CRT. After RT ± surgery or CRT, patients were followed for 2 years without adjuvant therapy. The primary endpoint was the objective response rate (ORR), with September 20, 2022, set as the cut-off for data collection. Secondary endpoints were safety and the gross tumor volume (GTV), planned tumor volume (PTV), and the percentage of total lung volume minus GTV exceeding 20 Gy (V20%) before versus after osimertinib. Exploratory analyses included assessments of the presence of plasma circulating tumor-free DNA (ctDNA) before osimertinib treatment, at weeks 6 and 12, at the end of RT, and 6 weeks post-RT. Twenty-four patients were included (19 women; median age, 73 years; range, 51-82 years). Nineteen of 24 had never smoked, 20 of 24 had adenocarcinoma, 16 of 24 had exon 19 deletions, and 8 of 24 had exon 21 mutations. Participants had stage IIIA (10), IIIB (9), or IIIC (5) disease. Three patients were excluded from the analysis (1 dropped out and 2 were still undergoing osimertinib treatment at the cut-off date). The ORR to induction osimertinib was 95.2% (17 partial response, 3 complete response, and 1 progressive disease). After induction osimertinib, 13 of 20 patients were definitively radiated, 3 of 20 underwent surgery, and 5 of 20 were excluded. Four patients were restaged as stage IV (contralateral ground-glass opacities responded to osimertinib), and 1 patient withdrew informed consent. Three patients underwent surgery, one of whom was treated with RT. Two patients achieved pT1aN0, and one achieved pathologic complete response. The median GTV, PTV, and V20% before osimertinib treatment were 47.4 ± 76.9 cm3 (13.5-234.9), 227.0 ± 258.8 cm3 (77.8-929.2), and 27.1 ± 16.4% (6.2-60.3), respectively. The values after osimertinib treatment were 27.5 ± 42.3 cm3 (2.99-137.7; -48 ± 20%; P=.02), 181.9 ±198.4 cm3 (54-718.1; -31 ± 20%; P=.01), and 21.8 ± 11.7% (9.1-44.15; -24 ± 40%; P=.04), respectively. PTV/GTV/V20% reduction was associated with tumor size and central location. The median follow-up time was 28.71 months (range, 0.4-45.1 months), and median disease-free survival was not reached (mean, 30.59; standard error, 3.94; 95% confidence interval, 22.86-38.31). ctDNA was detected in 5 patients; 4 of 5 were positive for ctDNA at baseline and became negative during osimertinib induction but were again positive after osimertinib treatment was terminated. Interestingly, 3 patients who were ctDNA negative at baseline became weakly positive after RT and then were negative at follow-up. No significant adverse events were reported during the osimertinib or radiation phases. Neoadjuvant osimertinib therapy is feasible in patients with stage III lung cancer NSCLC, followed by definitive radiation and/or surgery, with an ORR of 95.2% and an excellent safety profile. Osimertinib induction for 12 weeks before definitive radiation (chemo-free) significantly reduced the radiation field by nearly 50% with a linear association with tumor size. Further studies are needed to test this chemo-free approach for long-term outcomes before practices are changed.

Effect of sensory neuron-derived growth factors on acquired resistance to molecular-targeted therapies for epidermal growth factor receptor-mutated non-small cell lung cancer

Effect of sensory neuron-derived growth factors on acquired resistance to molecular-targeted therapies for epidermal growth factor receptor-mutated non-small cell lung cancer

Image-guided thermal ablation for patients with epidermal growth factor receptor-mutant nonsmall cell lung cancer.

Nonsmall cell lung cancer (NSCLC) is treated by various therapies such as surgical intervention, radiotherapy, chemotherapy, molecular targeted therapy, and immunotherapy. Currently, molecular targeted therapy, including epidermal growth factor receptor (EGFR) inhibitors and Anaplastic Lymphoma Kinase (ALK) and Kirsten Rat Sarcoma viral Oncogene (KRAS) inhibitors, has received much attention and improved the prognosis of NSCLC. Nevertheless, the terminal point of molecular targeted drugs is resistance. Drug resistance has been classified into oligoprogression and extensive progression based on the tumor lesion progression after drug resistance. There is extensive research demonstrating that local therapy (surgical resection, radiotherapy, and thermal ablation) can prolong the survival of patients with drug resistance. This review is intended to determine the efficacy of image-guided thermal ablation in patients with NSCLC with EGFR mutation.

EGFR mutation prevalence, real-world treatment patterns, and outcomes among patients with resected, early-stage, non-small cell lung cancer in Canada

ObjectivesThe ADAURA trial demonstrated the benefit of adjuvant osimertinib among patients with resected, early-stage, epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). To understand the potential population impact, it is critical to deduce the prevalence, management, and outcomes of this patient population in the real-world setting before use of adjuvant osimertinib. Materials and MethodsUsing PALEOS (Pan-cAnadian Lung cancEr Observational Study) data (2012–2019), a retrospective, multi-center, observational cohort study was conducted among patients with early-stage (IB–IIIA) resected NSCLC who had not received neoadjuvant therapy. Study outcomes included EGFRm prevalence, treatment patterns, recurrence outcomes, and overall and disease-free survival (OS/DFS). ResultsAmong patients undergoing reflexive EGFRm testing by a pathologist at time of diagnosis irrespective of disease stage (N = 535), 23 % were EGFRm-positive; 15.9 % had common mutations and 5.6 % had uncommon mutations. Within the EGFRm-positive cohort (N = 156), mean age at diagnosis was 68 years, 65 % of patients were female, and 35 % were of Asian descent. At diagnosis, 48 %, 31 %, and 21 % had stage IB, II, or IIIA disease, respectively; 46 % received adjuvant therapy after resection. Half of patients experienced disease recurrence, typically involving distant sites; central nervous system metastasis varied from 12 % to 15.0 % across disease stages. EGFR tyrosine kinase inhibitors were the most commonly received therapy after first metastatic recurrence. Median OS (DFS) was not reached, 71.2 (22.8) months, and 50.1 (18.0) months among stage IB, II, and IIIA patients. Patients with uncommon EGFRm had a lower probability of survival than those with common EGFRm (2 years: 87 % vs 91 %–94 %; 4 years: 56 % vs 73 %–82 %). ConclusionApproximately-one-quarter of patients with resected, early-stage NSCLC were EGFRm-positive in this study. These patients had high recurrence rates and suboptimal long-term survival after treatment with current therapies. New adjuvant treatments are warranted.

1184P Improving the tolerability of osimertinib by identifying its toxic limit

Osimertinib is the cornerstone in the treatment of epidermal growth factor receptor-mutated non-small cell lung cancer (NSCLC). Nonetheless, ±25% of patients experience severe treatment-related toxicities. Currently, it is impossible to identify patients at risk of severe toxicity beforehand. We hence aimed to study the relationship between osimertinib exposure and severe toxicity, and to identify a safe toxic limit for a preventive dose reduction. In this real-life prospective cohort study, patients with NSCLC treated with osimertinib were followed for severe toxicity (grade ≥3 toxicity, dose reduction or discontinuation, hospital admission, or treatment termination). Blood for pharmacokinetic analyses was withdrawn during every out-patient visit. To quantify individual exposure to osimertinib, a population-pharmacokinetic model was developed. Primary endpoint was the correlation between osimertinib clearance (exposure) and severe toxicity. Secondary endpoint was the exposure-efficacy relationship, defined as progression-free (PFS) and overall survival (OS). In total, 819 samples from 159 patients were included in the analysis. Multivariate competing risk analysis showed osimertinib clearance (c.q. exposure) to be significantly correlated with severe toxicity (hazard ratio (HR) 0.93, 95% CI 0.88 – 0.99). An ROC-curve showed the optimal toxic limit to be 259 ng/mL osimertinib. This target concentration divides the cohort in two groups: the risk of severe toxicity in the >259 ng/mL group is 34% versus 14% in the <259 ng/mL group. A 50% dose reduction in the high-exposure group - i.e. 25.8% of the total cohort - would reduce the risk of severe toxicity by 53%. Correlation of the first plasma trough concentrations in collected in the first two months of treatment revealed a similar difference in severe toxicity (31% versus 17%), when dividing the cohort in two by the toxic limit of 259 ng/mL osimertinib. Osimertinib exposure was not significantly associated with PFS nor OS. Osimertinib exposure is highly correlated with occurrence of severe toxicity. To optimize tolerability, patients above the toxic limit concentration of 259 ng/mL could benefit from a preventive dose reduction, without fear for diminished effectiveness.

Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab.

Simple SummaryDenosumab, a bone-modifying agent, has been approved for the prevention of or reduction in skeletal-related events (SREs) in non-small cell lung cancer (NSCLC) patients with bone metastasis. However, the effect of denosumab on survival of epidermal growth factor receptor (EGFR)-mutated NSCLC patients with bone metastasis has been insufficiently investigated. The present study showed that denosumab treatment was significantly correlated with improved overall survival (OS) in EGFR-mutated NSCLC patients with bone metastasis. In subgroup analyses, denosumab adjuvant therapy prolonged SRE-free survival (SRE-FS) in patients without initial SREs and was correlated with a better OS in patients with initial or pre-existing SREs. This study provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.The impact of an initial skeletal-related event (SRE) and denosumab adjuvant treatment on the survival outcome of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with bone metastasis remains unclear. This retrospective study included 400 metastatic EGFR-mutated NSCLC patients. Among 190 bone metastasis patients, 61 had initial SREs and 73 received denosumab. We analyzed patient characteristics, SRE-free survival (SRE-FS), and overall survival (OS). In metastatic EGFR-mutated NSCLC, bone metastasis was associated with a poorer OS (21.7 vs. 33.0 months; p < 0.001). Bone metastasis patients with initial SREs at diagnosis had an even shorter OS, compared with those without initial SRE (15.4 vs. 23.6 months; p = 0.026). Denosumab reduced SRE incidence (hazard ratio (HR) 0.57 (95% confidence interval (CI) 0.34–0.94; p = 0.027) and was associated with improved OS (26.6 vs. 20.1 months; p = 0.015). A multivariate analysis demonstrated that denosumab treatment was correlated with a lower incidence of SRE (HR 0.61 (95% CI 0.37–0.98); p = 0.042) and better OS (HR 0.60 (95% CI 0.41–0.88); p = 0.008). In subgroup analyses, denosumab prolonged SRE-FS (HR 0.36 (95% CI 0.19–0.79); p = 0.009) in patients without initial SREs and was related to a better OS (25.3 vs. 12.9 months; p = 0.016) in patients with initial or pre-existing SREs. Osteonecrosis of the jaw was diagnosed in two patients (2.74%) receiving denosumab. Our study confirmed the association between initial SREs and a worse outcome and provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.

Audit of Molecular Mechanisms of Primary and Secondary Resistance to Various Generations of Tyrosine Kinase Inhibitors in Known Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Cancer Patients in a Tertiary Centre

AimsPresently, three generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved against oncogene addicted EGFR-mutant non-small cell lung cancer (NSCLC). Patients with actionable EGFR mutations invariably develop resistance. This resistance can be intrinsic (primary) or acquired (secondary). Materials and methodsThis was a retrospective study carried out between January 2016 and April 2021 analysing 486 samples of NSCLC for primary and secondary resistance to first- (erlotinib, gefitinb), second- (afatinib) and/or third-generation (osimertinib) TKIs in EGFR-mutant NSCLCs by next generation sequencing (NGS). Tissue NGS was carried out using the Thermofischer Ion Torrent™ Oncomine™ Focus 52 gene assay; liquid biopsy NGS was carried out using the Oncomine Lung Cell-Free Total Nucleic Acid assay. All cases were previously tested for a single EGFR gene with the Therascreen® EGFR RGQ PCR kit. ResultsThe results were divided into four groups: (i) group 1: primary resistance to first- and/or second-generation TKIs. This group, with 21 cases, showed EGFR exon 20 insertions, dual, complex mutations and variant of unknown significance, de novo MET gene amplification besides other mutations. (ii) Group 2: primary resistance to third-generation TKIs. This group showed two cases, with one showing dual EGFR mutation (L858R and E709A) and EGFR gene amplification. (iii) Group 3: secondary resistance to first- and second-generation TKIs. This group had 27 cases, which were previously reported negative for EGFR T790M by single gene testing. Significant findings were MET gene amplification in four cases, with one also showing MET exon 14 skipping mutation. Three cases showed small cell change and one showed loss of primary mutation. (iv) Group 4: secondary resistance to third-generation TKIs. The latter group was further subgrouped into group 4A: secondary resistance to osimertinib (third-generation TKI) when offered as second-line therapy after first- and second-generation TKIs on detection of T790M mutation. This group had 15 cases. EGFR T790M mutation was lost in 10 (10/15; 67%) cases and was retained in five cases. Patients with T790M loss experienced early resistance (6.9 months versus 12.6 months mean, P = 0.0024) compared with cases that retained T790M. Two cases gained MET amplification as the resistance mechanisms. Other mutations that were found when EGFR T790M was lost were in FGFR3, KRAS, PIK3CA, CTNNB1, BRAF genes. One case had EML4-ALK translocation. Two cases showed driver EGFR deletion 19, retained T790M and C797S mutation in Cis form. Group 4B: secondary resistance to osimertinib (when given as first-line therapy) in EGFR-mutant NSCLC. This group had three cases. The duration of osimertinib treatment ranged from 11 to 17 months. Two patients showed additional C797S mutation along with primary EGFR mutation. ConclusionThis study shows the wide spectrum of primary and secondary EGFR resistance mechanisms to first, second and third generation of TKIs and helps us to identify newer therapeutic targets that could carry forward the initial advantage offered by EGFR TKIs.

Sequential chemotherapy and icotinib as first-line treatment for advanced epidermal growth factor receptor-mutated non-small cell lung cancer.

BACKGROUNDIcotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC).AIMTo evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC.METHODSThis multicenter, open-label, pilot randomized controlled trial enrolled 68 EGFR-mutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy + icotinib groups.RESULTSThe median progression-free survival in the icotinib alone and chemotherapy + icotinib groups was 8.0 mo (95%CI: 3.84-11.63) and 13.4 mo (95%CI: 10.18-16.33), respectively (P = 0.0249). No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen (all P > 0.05).CONCLUSIONA sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.

Overall survival benefits of first-line treatments for Asian patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer harboring L858R mutation: A systematic review and network meta-analysis.

e21064 Background: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and their biologically synergistic combinations with other treatments for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) as first-line treatment for EGFR-mutant NSCLC have recently gained considerable attention, in particular for those with L858R mutation, a known worse subgroup compared to exon 19 deletions. However, their efficacy, in particular, the long-term overall survival (OS) benefit in Asian patients with the L858R mutation remains unclear. Methods: We performed a systematic review and fixed-effects frequentist network meta-analysis by retrieving relevant literature from PubMed/MEDLINE Ovid, Embase, Cochrane Library, CINAHL Databases, trial registries and other sources. P-score was used to rank the treatments. We included published and gray sources of randomized clinical trials comparing two or more treatments in the first line setting for Asian patients with advanced EGFR mutated NSCLC harboring L858R mutation. This study was registered in the Prospective Register of Systematic Reviews (CRD42022295897). Results: Eighteen trials involved 1852 Asian patients and 12 treatments: including EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy, and combination treatments (gefitinib plus apatinib, erlotinib plus ramucizumab, erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy). Asian patients with the L858R mutation had no significant OS benefits from all EGFR TKIs or combination treatments over chemotherapies. Gefitinib plus pemetrexed-based chemotherapy, dacomitinib, osimertinib and erlotinib plus bevacizumab were shown to be consistent in yielding the best progression-free survival benefit, with their corresponding P-scores of 93%, 79%, 77% and 70%. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy, which caused the most adverse events of grade 3 or higher. Conclusions: In Asian patients with advanced NSCLC harboring L858R mutation, EGFR TKIs and combination treatments demonstrated no OS benefit when compared with conventional chemotherapies. Further studies are warranted to investigate the resistance mechanism with TKIs and potential combination strategies in patients with the L858R mutation.

Prognostic significance associated with the number of compound mutations in epidermal growth factor receptor-mutated non-small cell lung cancer.

Prognostic significance associated with the number of compound mutations in epidermal growth factor receptor-mutated non-small cell lung cancer.

Improving the tolerability of osimertinib by identifying its toxic limit.

Background:Osimertinib is the cornerstone in the treatment of epidermal growth factor receptor-mutated non-small cell lung cancer (NSCLC). Nonetheless, ±25% of patients experience severe treatment-related toxicities. Currently, it is impossible to identify patients at risk of severe toxicity beforehand. Therefore, we aimed to study the relationship between osimertinib exposure and severe toxicity and to identify a safe toxic limit for a preventive dose reduction.Methods:In this real-life prospective cohort study, patients with NSCLC treated with osimertinib were followed for severe toxicity (grade ⩾3 toxicity, dose reduction or discontinuation, hospital admission, or treatment termination). Blood for pharmacokinetic analyses was withdrawn during every out-patient visit. Primary endpoint was the correlation between osimertinib clearance (exposure) and severe toxicity. Secondary endpoint was the exposure–efficacy relationship, defined as progression-free survival (PFS) and overall survival (OS).Results:In total, 819 samples from 159 patients were included in the analysis. Multivariate competing risk analysis showed osimertinib clearance (c.q. exposure) to be significantly correlated with severe toxicity (hazard ratio 0.93, 95% CI: 0.88–0.99). An relative operating characteristic curve showed the optimal toxic limit to be 259 ng/mL osimertinib. A 50% dose reduction in the high-exposure group, that is 25.8% of the total cohort, would reduce the risk of severe toxicity by 53%. Osimertinib exposure was not associated with PFS nor OS.Conclusion:Osimertinib exposure is highly correlated with the occurrence of severe toxicity. To optimize tolerability, patients above the toxic limit concentration of 259 ng/mL could benefit from a preventive dose reduction, without fear for diminished effectiveness.