Liquid biopsy in clinical outcomes and detection of T790M mutation in metastatic non-small cell lung cancer after progression to EGFR-TKI.

BACKGROUND: Liquid biopsy (LB) is used to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) and has been demonstrated to have prognostic and predictive value. OBJECTIVE: To associate the rates of EGFR and T790M mutations detected by LB during disease progression after first- or second-generation EGFR-TKIs with clinical characteristics and survival outcomes. METHODS: From January 2018 to December 2021, 295 patients with advanced EGFR mutant (EGFRm) NSCLC treated with first- or second-generation EGFR-TKIs were retrospectively analyzed. LB was collected at the time of progression. The frequency of EGFRT790M mutations, overall survival (OS), and the clinical characteristics associated with LB positivity were determined. RESULTS: The prevalence of EGFRT790M mutation detected using LB was 44%. In patients with negative vs. positive LB, the median OS was 45.0 months vs. 25.0 months (p= 0.0001), respectively. Patients with a T790M mutation receiving osimertinib had a median OS of 44 months (95% CI [33.05-54.99]). Clinical characteristics associated with positive LB at progression extra-thoracic involvement, > 3 metastatic sites, and bone metastases. CONCLUSIONS: Our findings showed that LB positivity was associated with worse survival outcomes and specific clinical characteristics. This study also confirmed the feasibility and detection rate of T790M mutation in a Latin American population.

Impact of thoracic tumor radiotherapy on survival in non-small-cell lung cancer with malignant pleural effusion treated with targeted therapy: Propensity score matching study.

BACKGROUND: EGFR-mutant (EGFR-M) and ALK-positive (ALK-P)are common in malignant pleural effusion (MPE) with metastatic non-small-cell lung cancer (NSCLC) (MPE-NSCLC). The impact of thoracic tumor radiotherapy on survival in such patients remains unclear. We aimed to investigate whether thoracic tumor radiotherapy could improve overall survival (OS) in such patients. METHODS: According to whether or not patients accepted thoracic tumor radiotherapy, 148 patients with EGFR-M or ALK-P MPE-NSCLC treated with targeted therapy were classified into two groups: DT group without thoracic tumor radiotherapy and DRT group with thoracic tumor radiotherapy. Propensity score matching (PSM) was performed to balance clinical baseline characteristics. Overall survival was analyzed by Kaplan-Meier, compared by log-rank test, and evaluated using Cox proportional hazards model. RESULTS: Median survival time (MST) was 25 months versus 17 months in the DRT group and DT group. The OS rates at 1, 2, 3, 5 years in the DRT group and DT group were 75.0%, 52.8%, 26.8%, 11.1% and 64.5%, 28.4%, 9.2%, 1.8%, respectively (χ2 = 12.028, p = 0.001). Compared with DT group, the DRT group still had better survival after PSM (p = 0.007). Before and after PSM, factors associated with better OS through multivariable analysis were that thoracic tumor radiotherapy, radiotherapy, N0-2 , and ALK-TKIs. Grades 4-5 radiation toxicities were not observed in patients; 8 (11.6%) and 7 (10.1%) out of the DRT group suffered from Grade 3 radiation esophagitis and radiation pneumonitis, respectively. CONCLUSION: Our results for EGFR-M or ALK-P MPE-NSCLC showed that thoracic tumor radiotherapy may be crucial factor in improving OS with acceptable toxicities. Potential biases should not be neglected: Further randomized controlled trials are necessary to confirm this result.

Design and Rationale for a Phase II, Randomized, Open-Label, Two-Cohort Multicenter Interventional Study of Osimertinib with or Without Savolitinib in De Novo MET Aberrant, EGFR-Mutant Patients with Advanced Non-Small-Cell Lung Cancer: The FLOWERS Trial.

INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are well-known genetic alterations in advanced non-small cell lung cancer (NSCLC) which are associated with remarkable survival benefits from first-line treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, around 30% of patients exhibit primary resistance to EGFR-TKIs therapy. Co-existing MET amplification/over-expression has showed shorter time to progression on EGFR-TKI monotherapy. Osimertinib (TAGRISSO, AZD9291) has been recommended in EGFR-mutant advanced NSCLC patients as first-line treatment. Savolitinib (AZD6094, HMPL-504) is a highly selective MET-TKI which has demonstrated anti-tumor activity in various cancers with MET alterations. METHODS: This FLOWERS study, a phase II, randomized, open-label, 2-cohort multicenter trial aimed to evaluate the efficacy and safety of osimertinib with or without savolitinib as first-line therapy in patients with de novo MET amplified/over-expressed, EGFR-mutant positive, locally advanced or metastatic NSCLC. Approximately 44 patients will be randomized to receive osimertinib (80 mg once daily) monotherapy or osimertinib (80 mg once daily) and savolitinib (300 mg twice daily) combination therapy; patients in osimertinib monotherapy cohort confirmed as MET positive (MET-amplified/over-expressed) after disease progression will have the opportunity to receive the cross-over combination therapy as second-line treatment. Primary endpoint will be objective response rate. Key secondary endpoints will be progression-free survival, duration of response, disease control rate, overall survival, safety and tolerability. CONCLUSION: The results of the study will provide better perspectives on the efficacy and safety of EGFR-TKI plus MET-TKI combination therapy (osimertinib plus savolitinib) in patients with de novo MET-amplified/over-expressed, EGFR-mutant positive, treatment naïve, advanced NSCLC and offer a meaningful guidance in clinical practice (NCT05163249).

Case report: Almonertinib in combination with bevacizumab for leptomeningeal metastases from epidermal growth factor receptor-mutation non-small cell lung cancer: Case series.

Leptomeningeal metastasis (LM) is a lethal complication of advanced non-small cell lung cancer (NSCLC) with rapid deterioration and poor prognosis. It has no standard treatment for epidermal growth factor receptor mutation (EGFRm) NSCLC, and improving the clinical outcomes for patients with LM has become an urgent problem in clinical treatment. Both almonertinib and bevacizumab are capable of crossing the blood-brain barrier with comparable central nervous system effectiveness. To date, the almonertinib treatment in combination with bevacizumab in EGFRm NSCLC with LM has not been studied. We herein present five cases to further evaluate the effectiveness and tolerability of almonertinib in combination with bevacizumab for patients with EGFRm NSCLC and LM. For the first time, we report that almonertinib plus bevacizumab can not only effectively improve the neurological symptoms caused by LM but also prolong the survival time of patients with limited and controllable side effects, which provided a novel therapeutic approach for LM from EGFRm NSCLC.

Study Design and Rationale for the PACE-LUNG Trial: A Multicenter, Single-Arm, Phase II Clinical Trial Evaluating the Efficacy of Additional Chemotherapy for Patients with EGFRm NSCLC with the Continued Presence of Plasma ctDNA EGFRm at Week 3 After Start of Osimertinib First-Line Treatment.

BACKGROUND: Tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR) like the third-generation TKI osimertinib have substantially improved the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. However, there is a subset of patients that do not benefit from these therapies in terms of response rate or progression-free-survival (PFS). It has been shown that persistence of EGFR mutations in circulating tumor DNA (ctDNA) at weeks 3 and 6 after start of osimertinib predicts shorter PFS. These patients may benefit from additional chemotherapy. While combination therapies with older TKI have been demonstrated effective in improving outcome, they are associated with a significant increase in toxicity. PATIENTS AND METHODS: PACE-LUNG is a multicenter, single-arm, investigator initiated, phase II trial conducted with the German national Network Genomic Medicine (nNGM). Patients with stage IIIB or IV NSCLC and exon 19 deletion or p.L858R EGFR mutation not amenable to curative treatment with persisting ctDNA after 3 to 4 weeks of first-line osimertinib monotherapy will receive additional chemotherapy (4 cycles of either cisplatin/pemetrexed or carboplatin/pemetrexed). Afterwards, osimertinib will be continued as standard of care until disease progression or intolerable toxicity. The primary endpoint is PFS. Secondary endpoints include overall survival, response rate, safety, and quality of life. Concomitant translational research will be performed to identify patterns of mutational evolution in ctDNA upon disease progression or ctDNA persistence. Enrollment started in December 2021. DISCUSSION: The PACE-LUNG trial is designed to evaluate the efficacy and safety of a biomarker-driven strategy for therapy escalation in patients at high risk for early treatment failure. This approach aims not only to improve treatment outcomes, but also to limit the anticipated additional toxicity to high-risk patients. TRIAL REGISTRATION NUMBER: 2019-004757-88 (EudraCT).

The value of disease-free survival (DFS) and osimertinib in adjuvant non-small-cell lung cancer (NSCLC): an international Delphi consensus report.

BACKGROUND: Rates of disease recurrence and death following surgery remain high in early-stage non-small-cell lung cancer (NSCLC), despite adjuvant treatment and curative intent. Recently, osimertinib showed overwhelming evidence for disease-free survival (DFS), as demonstrated by an overall reduction in the risk of disease recurrence or death in the adjuvant setting of 80% versus control in the ADAURA study (stage IB-IIIA; hazard ratio 0.20; 99.12% confidence interval 0.14-0.30; P < 0.001). However, due to the early unblinding of ADAURA and lack of mature overall survival data, there is a need to qualitatively confirm consensus on the clinical and patient relevance of DFS. MATERIALS AND METHODS: We conducted a modified Delphi panel study consisting of two rounds of surveys, followed by a consensus meeting. An international panel of experts in the field of NSCLC and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) (n = 13) was asked to rate agreement and comment on a list of pre-defined statements covering key consensus gaps. Statements were eliminated or updated between surveys, depending on the level of agreement. A final list of agreed-upon statements was drafted in the consensus meeting. RESULTS: Consensus was reached on 32 qualitative statements, with topics including unmet needs in early-stage NSCLC, the value of DFS, and the value of osimertinib. Crucially, DFS was agreed to be a clinically and patient-relevant endpoint in adjuvant NSCLC. The relevance of DFS was found to relate to the ability of an adjuvant therapy, such as osimertinib, to keep patients in the clinically valuable curative intent setting, while preventing the burden associated with distant and locoregional recurrence, and progressive disease. CONCLUSIONS: Addressing the need for measures that reflect clinical benefit is essential to continue improving outcomes for NSCLC patients. To that end, this work provides a qualitative framework for clinicians to consider the clinical and patient relevance of DFS in adjuvant NSCLC and the benefit demonstrated in ADAURA thus far.

Osimertinib plus platinum-pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study.

BACKGROUND: The phase III FLAURA2 (NCT04035486) study will evaluate efficacy and safety of first-line osimertinib with platinum-pemetrexed chemotherapy versus osimertinib monotherapy in epidermal growth factor receptor mutation-positive (EGFRm) advanced/metastatic non-small-cell lung cancer (NSCLC). The safety run-in, reported here, assessed the safety and tolerability of osimertinib with chemotherapy prior to the randomized phase III evaluation. PATIENTS AND METHODS: Patients (≥18 years; Japan: ≥20 years) with EGFRm locally advanced/metastatic NSCLC received oral osimertinib 80 mg once daily (QD), with either intravenous (IV) cisplatin 75 mg/m2 or IV carboplatin target area under the curve 5, plus pemetrexed 500 mg/m2 every 3 weeks (Q3W) for four cycles. Maintenance was osimertinib 80 mg QD with pemetrexed 500 mg/m2 Q3W until progression/discontinuation. The primary objective was to evaluate safety and tolerability of the osimertinib-chemotherapy combination. RESULTS: Thirty patients (15 per group) received treatment [Asian, 73%; female, 63%; median age (range) 61 (45-84) years]. Adverse events (AEs) were reported by 27 patients (90%): osimertinib-carboplatin-pemetrexed, 100%; osimertinib-cisplatin-pemetrexed, 80%. Most common AEs were constipation (60%) with osimertinib-carboplatin-pemetrexed and nausea (60%) with osimertinib-cisplatin-pemetrexed. In both groups, 20% of patients reported serious AEs. No specific pattern of AEs leading to dose modifications/discontinuations was observed; one patient discontinued all study treatments including osimertinib due to pneumonitis (study-specific discontinuation criterion). Hematologic toxicities were as expected and manageable. CONCLUSIONS: Osimertinib-chemotherapy combination had a manageable safety and tolerability profile in EGFRm advanced/metastatic NSCLC, supporting further assessment in the FLAURA2 randomized phase.

Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD).

INTRODUCTION: Osimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments. METHODS: Adults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety. CONCLUSIONS: ORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves.

The cost-effectiveness of dacomitinib in first-line treatment of advanced/metastatic epidermal growth factor receptor mutation-positive non-small-cell lung cancer (EGFRm NSCLC) in Sweden.

AIMS: Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) over chemotherapy in EGFR mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC) has been demonstrated in clinical trials, the optimal treatment sequence remains unclear. The objective of our study was to evaluate the cost-effectiveness of dacomitinib in Sweden vs afatinib and osimertinib in first-line treatment of EGFRm NSCLC. MATERIALS AND METHODS: A partitioned survival model was developed with three health states: progression-free, post-progression, and death. Progression-free and overall survival curves were used to inform movements between states. Clinical data were taken from randomized trials, compared via a network meta-analysis (NMA). Utility data were taken from published studies and costs from national Swedish sources. The model used a 15-year time horizon and a Swedish healthcare payer perspective. Sensitivity and scenario analyses were performed. RESULTS: The base-case analysis showed that dacomitinib accrued a total of 2.10 quality-adjusted life-years (QALYs) at a total cost of Swedish krona (SEK) 874,615. The incremental cost-effectiveness ratio (ICER) for dacomitinib vs afatinib was SEK 461,556 per QALY gained. The ICER of osimertinib vs dacomitinib, where the small QALY gains of the former came at a high additional cost, was SEK 11,444,709. Deterministic and probabilistic sensitivity analyses confirmed the robustness of these results; changes to drug and medical resource use costs and overall survival had the greatest impact on ICER estimates. LIMITATIONS: This model is subject to uncertainty associated with extrapolating long-term treatment effects from shorter trial follow-up periods, although this would also be a limitation when using direct comparison or time-dependent hazard ratios. The NMA was limited by the use of indirect comparison, although sensitivity analyses supported the robustness of our findings. CONCLUSIONS: Our model demonstrated that dacomitinib is cost-effective for first-line EGFRm NSCLC treatment in Sweden vs afatinib and osimertinib.

A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

Real-world treatment of over 1600 Japanese patients with EGFR mutation-positive non-small cell lung cancer with daily afatinib.

BACKGROUND: This prospective, post-marketing observational study in Japanese patients aimed to evaluate the safety and effectiveness of daily afatinib use in general practice. METHODS: This non-interventional study (NCT02131259) enrolled treatment-naïve and pre-treated patients with inoperable/recurrent EGFR mutation-positive NSCLC, eligible for afatinib treatment as per the afatinib label in Japan. Patients received afatinib at the approved dose (20, 30, 40, or 50 mg/day; physician decision), and were observed following treatment initiation for 52 weeks or until premature discontinuation. Primary endpoint was the incidence of adverse drug reactions (ADRs). Secondary endpoints included ADRs of special interest, and objective response rate (ORR). Post hoc Cox multivariate analyses were used to assess prognostic factors associated with the incidence of ADRs. RESULTS: 1602 patients, at 374 sites (April 2014-March 2015), were included in the analysis; 307 (19%) were aged ≥ 75 years. The most frequently reported ADRs (all/grade 3-4) were diarrhea (78%/15%), rash/acne (59%/6%), stomatitis (31%/4%), and nail effects (38%/4%). Serious ADRs resulting in death occurred in 18 patients (1%). 762 patients (48%) had ≥ 1 afatinib dose reduction and 366 (23%) discontinued due to ADRs; the most common reason for both was diarrhea (8.2% and 6.7%, respectively). ORR was 40.1%. CONCLUSIONS: Real-world treatment of 1602 Japanese patients with afatinib was associated with a predictable ADR profile. Afatinib showed effectiveness in inoperable/recurrent EGFR mutation-positive NSCLC, especially as first-line treatment. As with other EGFR TKIs, prompt management of adverse events is needed in the Japanese population, to reduce serious events and outcomes, including interstitial lung disease.

Detection of epidermal growth factor receptor gene T790M mutation in cytology samples using the cobas® EGFR mutation test.

OBJECTIVE: Detection of epidermal growth factor receptor (EGFR) gene mutations is essential in deciding therapeutic strategy in non-small cell lung cancer (NSCLC) patients at initial diagnosis. Moreover, in EGFR mutation-positive (EGFRm) NSCLC patients, re-biopsy at disease progression to clarify resistance mechanisms is also important. However, collecting histology samples is often difficult because of inaccessibility and invasiveness. In some cases, only cytology samples can be collected, and studies have reported that cytology samples are appropriate for EGFR gene mutation testing. The cobas® EGFR Mutation Test (Roche Molecular Systems Inc., Branchburg, New Jersey, USA) is approved as a companion diagnostic for osimertinib, a third-generation EGFR-tyrosine kinase inhibitor approved in Japan. However, it is not clear whether the EGFR T790M mutation can be detected in cytology samples using this test. The primary objective of this study was to assess concordance of EGFR T790M gene mutation detection between histology and matched cytology samples using the cobas® EGFR Mutation Test. MATERIALS AND METHODS: We conducted a multicenter, observational study in Japan. Overall, 41 EGFRm NSCLC patients who had both histology and cytology samples collected at the same time at re-biopsy and with the results of EGFR mutation test using histology samples were enrolled. The EGFR mutation status of both sample types was tested using the cobas® EGFR Mutation Test and the concordance rates were calculated. RESULTS: The EGFR T790M mutation detection rate in histology and cytology samples was 42.5% and 37.5%, respectively. The overall percent agreement between the histology and cytology samples was 91.7%. CONCLUSIONS: These data demonstrate that the cobas® EGFR Mutation Test can detect the EGFR T790M mutation in both cytology and histology samples.