Three-Year Safety,Tolerability, and Health-Related Quality of Life Outcomes of Adjuvant Osimertinib in Patients With Resected Stage IB to IIIA EGFR-Mutated NSCLC: Updated Analysis From the Phase 3 ADAURA Trial

IntroductionIn ADAURA, adjuvant osimertinib significantly improved disease-free survival versus placebo in resected stage IB to IIIA EGFR-mutated NSCLC. We report in-depth analyses of three-year safety, tolerability, and health-related quality of life (HRQoL) from ADAURA.MethodsPatients were randomized 1:1 to osimertinib 80 mg or placebo once daily for up to 3 years. Safety assessments were performed at baseline, week 2, week 4, week 12, and every 12 weeks until treatment completion or discontinuation, and 28 days after treatment was stopped. The SF-36 survey measured HRQoL at baseline, week 12, week 24, and every 24 weeks until recurrence, treatment completion or discontinuation. Data cutoff: April 11, 2022.ResultsSafety and HRQoL analysis sets: osimertinib, n = 337 and n = 339; placebo, n = 343 each. Median (range) total exposure duration was longer with osimertinib versus placebo: 35.8 (0–38) versus 25.1 (0–39) months. Most adverse events (AEs) were first reported within 12 months of starting treatment (osimertinib 97%, placebo 86%). AEs leading to dose reduction, interruption or discontinuation were reported in 12%, 27% and 13% respectively of patients with osimertinib; 1%, 13% and 3% with placebo. Stomatitis and diarrhea were the most common AEs leading to osimertinib dose reduction or interruption; interstitial lung disease was the most common leading to osimertinib discontinuation (per protocol). There were no differences in time to deterioration for SF-36 physical, mental component summaries between osimertinib and placebo.ConclusionsNo new safety signals were reported and HRQoL was maintained with 3 years of adjuvant osimertinib treatment. Combined with significant efficacy benefit, these data further support adjuvant osimertinib in stage IB to IIIA EGFR-mutated NSCLC.     

Osimertinib Plus Durvalumab in Patients With EGFR-Mutated,Advanced NSCLC: A Phase 1b,Open-Label,Multicenter Trial

IntroductionEGFR tyrosine kinase inhibitors (TKIs) are recommended for EGFR-mutated NSCLC treatment. EGFR activation up-regulates programmed death-ligand 1 expression and other immunosuppressive factors in NSCLC, causing immune microenvironment remodeling. Osimertinib (an EGFR TKI) plus durvalumab (programmed death-ligand 1 blockade) was evaluated in the TATTON study (NCT02143466).MethodsThis open-label, phase 1b study enrolled patients with advanced EGFR-mutated NSCLC. In part A, patients who had progressed on a previous EGFR TKI received osimertinib (80 mg once daily) plus durvalumab 3 or 10 mg/kg every 2 weeks. In part B, patients received first-line osimertinib plus durvalumab 10 mg/kg every 2 weeks. However, part B enrollment was terminated early owing to an increased incidence of interstitial lung disease (ILD)-related adverse events (AEs). Safety (primary objective) and preliminary anti-tumor activity determined by objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival were evaluated.ResultsBefore enrollment termination, 23 and 11 patients received treatment across parts A and B, respectively. The most common AEs across parts A and B were as follows: diarrhea (50%), nausea (41%), and decreased appetite (35%). A total of 12 patients (35%) reported ILD-related AEs (lung disorder, ILD or pneumonitis). In part A, ORR was 43% (95% confidence interval [CI]: 23–66); median DOR was 20.4 months. In part B, ORR was 82% (95% CI: 48–98), median DOR was 7.1 months, and median progression-free survival was 9.0 months (95% CI: 3.5–12.3).ConclusionsThis study highlighted a potential risk of ILD-related AEs when combining osimertinib with durvalumab. Further research looking to combine EGFR TKIs with immune checkpoint inhibitors should be approached with caution.     

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

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

Adjuvant Systemic Therapy in Patients With Early-Stage NSCLC Treated With Stereotactic Body Radiation Therapy

Introduction

Stereotactic body radiation therapy (SBRT) is commonly used to treat nonsurgical patients with early-stage NSCLC. There are no prospective data on the role of adjuvant chemotherapy in this setting.

Sarcopenia in Resected NSCLC: Effect on Postoperative Outcomes

Introduction

Skeletal muscle depletion, referred to as sarcopenia, has recently been identified as a risk factor for poor outcomes in various malignancies. However, the prognostic significance of sarcopenia in patients with NSCLC after surgery has not been adequately determined. This study investigated the impact of sarcopenia in patients undergoing pulmonary resection for lung cancer.

Durvalumab for Stage III EGFR-Mutated NSCLC After Definitive Chemoradiotherapy

IntroductionIn 2018, durvalumab was approved by the U.S. Food and Drug Administration as consolidation immunotherapy for patients with stage III NSCLC after definitive chemoradiotherapy (CRT). However, whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown.MethodsWe conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab.ResultsAmong 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab owing to progression and five owing to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and eight completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKIs). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank p = 0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 mo) compared with CRT and durvalumab or CRT alone (log-rank p = 0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib.ConclusionsIn this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction or consolidation EGFR TKIs further investigated as definitive treatment.     

乳腺癌术后辅助化疗的进展

辅助化疗是乳腺癌综合治疗中的重要组成部分,也是预防远处转移的主要手段。本文对近年来乳腺癌术后辅助化疗进展的相关文献进行了回顾,在内科治疗方面,规范化、个体化是乳腺癌辅助治疗的方向。     

Osimertinib Improves Overall Survival in Patients With EGFR-Mutated NSCLC With Leptomeningeal Metastases Regardless of T790M Mutational Status

IntroductionOsimertinib, a third-generation EGFR tyrosine kinase inhibitor, efficiently penetrates the blood-brain barrier. This study explored whether treatment with osimertinib leads to improved overall survival (OS) for patients with EGFR-mutated NSCLC with leptomeningeal metastases (LM) compared with those not treated with osimertinib.MethodsFrom October 2008 to October 2019, patients with EGFR-mutated NSCLC and cytologically confirmed LM were retrospectively analyzed for OS according to osimertinib treatment and T790M mutational status. The OS was defined as the time from the diagnosis of LM to death.ResultsFor the 351 patients with LM included in the analysis, the median OS (mOS) was 8.1 months (95% confidence interval [CI]: 7.2–9.0). T790M mutation was detected in 88 of 197 patients tested, and a total of 110 patients were treated with osimertinib after LM. No difference in mOS according to T790M mutational status (10.1 mo [95% CI: 4.31–15.82] versus 9.0 [95% CI: 6.81–11.21], p = 0.936) was found. Nevertheless, patients treated with osimertinib had a superior OS of 17.0 months (95% CI: 15.13–18.94) compared with those not treated with osimertinib who had a mOS of 5.5 months (95% CI: 4.34–6.63), regardless of T790M mutational status (hazard ratio: 0.36 [95% CI: 0.28–0.47], p < 0.001). This was also considerably longer even than the mOS of 8.7 months (95% CI: 7.01–10.39) of those who were never treated with osimertinib but had first- or second-generation EGFR tyrosine kinase inhibitors.ConclusionsOsimertinib is a promising treatment option for EGFR-mutated NSCLC with LM regardless of T790M mutational status.     

洛铂联合长春瑞滨对NSCLC术后辅助化疗疗效及安全性研究

目的 探讨非小细胞肺癌术后患者联用洛铂(LBP)与长春瑞滨(NVB)的有效性和安全性.方法 对60例非小细胞肺癌患者采用长春瑞滨联合洛铂方案治疗,21天为1个治疗周期,治疗两个周期以上.结果 60例患者中53例可进行疗效评价,完全缓解、部分缓解、无变化和进展的例数分别为18例、21例、11例和2例.总治疗有效率和疾病控制率分别为37.7％和75.5％.主要不良反应为可逆性的骨髓抑制和胃肠道反应,治疗过程中未出现肝肾毒性作用.结论 洛铂联合长春瑞滨作为NSCLC患者术后的辅助化疗疗效尚可,不良反应在耐受范围,可对患者生活质量提升有一定的效果.     

ADAURA: Phase III,Double-blind,Randomized Study of Osimertinib Versus Placebo in EGFR Mutation-positive Early-stage NSCLC After Complete Surgical Resection

Introduction

Currently, the role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as adjuvant therapy for early-stage non–small-cell lung cancer after complete surgical tumor resection remains under investigation. We present the rationale and study design for the ADAURA (ClinicalTrials.gov identifier, NCT02511106) trial, a multicenter, double-blind, randomized, placebo-controlled study.

Programmed Cell Death Ligand 1 Expression in Untreated EGFR Mutated Advanced NSCLC and Response to Osimertinib Versus Comparator in FLAURA

IntroductionEGFR mutated (EGFRm) NSCLC tumors occasionally express programmed cell death ligand 1 (PD-L1), although frequency and clinical relevance are not fully characterized. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following treatment with osimertinib or comparator EGFR tyrosine kinase inhibitors in the FLAURA trial (phase III, NCT02296125).MethodsOf 231 tissue blocks available from the screened population (including EGFRm-positive and -negative samples), 197 had sufficient tissue for PD-L1 testing using the SP263 (Ventana, Tucson, Arizona) immunohistochemical assay. Tumor cell (TC) staining thresholds of PD-L1 TC greater than or equal to 1%, TC greater than or equal to 25%, and TC greater than or equal to 50% were applied. Progression-free survival (PFS) was investigator-assessed, per Response Evaluation Criteria in Solid Tumor, version 1.1, according to PD-L1 expressors (TC ≥ 1%) or negatives (TC < 1%) in randomized patients.ResultsPD-L1 staining was successful in 193 of 197 patient formalin-fixed paraffin-embedded blocks; of these, 128 of 193 were EGFRm-positive and 106 of 128 patients were randomized to treatment (osimertinib: 54; comparator: 52). At the PD-L1 TC greater than or equal to 25% threshold, 8% (10 of 128) of EGFRm-positive tumors expressed PD-L1 versus 35% (23 of 65) of EGFRm-negative tumors. With the TC greater than or equal to 1% threshold, 51% (65 of 128) versus 68% (44 of 65) were mutation-positive and –negative, respectively, and with the TC greater than or equal to 50% threshold, 5% (7 of 128) versus 28% (18 of 65), were mutation-positive and -negative, respectively. For PD-L1 expressors (TC ≥ 1%), median PFS was 18.4 months with osimertinib and 6.9 months with comparator (hazard ratio = 0.30; 95% confidence interval: 0.15–0.60). For PD-L1–negative patients (TC < 1%), median PFS was 18.9 months with osimertinib and 10.9 months with comparator (hazard ratio = 0.37; 95% confidence interval: 0.17–0.74).ConclusionsClinical benefit with osimertinib was unaffected by PD-L1 expression status.     

Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M–Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report

Introduction

Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti–programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) investigated osimertinib plus durvalumab versus osimertinib monotherapy in patients with EGFR-TKI sensitizing and EGFR T790M mutation–positive advanced NSCLC and disease progression after EGFR-TKI therapy.

ⅠB期非小细胞肺癌完全切除术后辅助治疗方式的研究进展

原发性肺癌是肿瘤相关死亡率较高的恶性肿瘤之一，非小细胞肺癌约占原发性肺癌的85%。近年来，由于医疗技术水平的提升和健康体检的普及，早期非小细胞肺癌检出率逐渐提高。早期NSCLC的治疗方式主要是手术切除和辅助治疗，但ⅠB期患者在肿瘤完全切除术后的辅助治疗及随访管理存在诸多争议。这篇综述聚焦于ⅠB期NSCLC患者完全切除后辅助化疗、靶向及免疫治疗选择的关键问题，同时探讨了筛选早期NSCLC高危患者的生物标志物及预后因子。     

A Cisplatin and Vinorelbine (NP) Regimen as a Postoperative Adjuvant Chemotherapy for Completely Resected Breast Cancers in China: Final Results of a Phase II Clinical Trial

Objective: To evaluate the efficacy and toxicity of cisplatin and vinorelbine (NP) for postoperative adjuvantchemotherapy of completely resected breast cancers. Methods: Between September 1994 and April 2005, 91Chinese breast cancer patients, with pathologically-confirmed adenocarcinoma in Jiangsu Cancer Hospitaland Research Institute, were enrolled. They received postoperative vinorelbine at 25mg/m2 on days 1 and 8,and cisplatin 25mg/m2 on days 1 to 3, this regimen being repeated every 3 weeks. Results: Median age was 49years (range, 25-69 years). A ccording to the TNM stage system, stage Ⅰ, Ⅱ, ⅢA patients accounted for 7.7%,58.2% and 34.1%, respectively. The median number of chemotherapy cycles was 4.5 (range, 1-8), over half ofthe patients receiving 4 to 6 NP cycles. After a median follow-up of 48 months, 11 deaths and 29 relapses weredocumented. Median disease-free survival was 45 months, with disease-free and overall survival at 5 years being76% and 88.7%, respectively. All patients could be evaluated with regard to toxicity, 17 (18.7%) developing gradeⅢ neutropenia during treatment, but all recovering after recombinant human granulocyte colony stimulatingfactor (G-CSF) injection, 3 suffering thrombocytopenia (3.3%), 5 anemia (5.5%) and 5 nausea/vomiting (5.5%).No treatment related deaths occurred. Conclusions: NP is an effective and feasible treatment for completelyresected breast cancer cases at the doses tested. A randomized clinical trial is now needed to compare NP withother conventional regimens.     

Osimertinib versus Standard of Care EGFR TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC: FLAURA Asian Subset

Introduction

Here we report efficacy and safety data of an Asian subset of the phase III FLAURA trial (NCT02296125), which compares osimertinib with standard of care (SoC) EGFR tyrosine kinase inhibitors (TKIs) in patients with previously untreated advanced NSCLC with tumors harboring exon 19 deletion (Ex19del)/L858R EGFR TKI–sensitizing mutations.

Genotyping of Cerebrospinal Fluid Associated With Osimertinib Response and Resistance for Leptomeningeal Metastases in EGFR-Mutated NSCLC

IntroductionPatients with NSCLC with leptomeningeal metastases (LM) presented dismal prognosis. Cerebrospinal fluid (CSF) is suggested as a medium of liquid biopsy of LM. However, the clinical implications of CSF genotyping on treatment outcomes remained elusive.MethodsPatients with EGFR-mutated advanced NSCLC with LM were included: cohort 1, patients with LM who were treated with osimertinib with CSF and plasma genotyping performed before the first dosing of osimertinib (baseline, n = 45); cohort 2, CSF genotyping on progression on osimertinib and development of LM (the progression event on osimertinib is the diagnosis of LM, n = 35). Circulating tumor DNA in CSF underwent next-generation sequencing.ResultsSensitivity of CSF genotyping for EGFR-sensitizing mutations was 93.3% (42 of 45) and 97.1% (34 of 35) in cohorts 1 and 2, respectively. In cohort 1, patients with EGFR exon 19 deletion had higher median intracranial progression free survival (iPFS) than those with EGFR exon 21 L858R mutation (11.9 versus 2.8 mo; p = 0.02). Median iPFS was significantly longer in patients with T790M-positive CSF genotyping (15.6 mo) than T790M-negative CSF (7.0 mo, p = 0.04). Concurrent CDK4 (2.8 versus 11.6 mo, p = 0.002) and CDKN2A (2.5 versus 9.6 mo, p = 0.04) mutation with EGFR-sensitizing mutations indicated lower median iPFS. Patients with T790M-negative CSF, EGFR exon 21 L858R mutation, concurrent FGF3 alteration, and over first-line osimertinib had shortened iPFS. In cohort 2, possible EGFR-related and EGFR-independent resistance mechanisms were found including C797S mutation, MET dysregulation, and TP53 plus RB1 co-occurrence. Patients with loss of T790M in CSF had a shorter median iPFS (7.4 mo) compared with those with reserved T790M (13.6 mo, p = 0.01).ConclusionsGenotyping of CSF indicated heterogeneous response to osimertinib and revealed the genetic characteristic of LM on osimertinib failure in patients with EGFR-mutated NSCLC diagnosed with LM.