Stage IB-IIIA Non-small Cell Lung Research Articles

IMpower010: Final disease-free survival (DFS) and second overall survival (OS) interim results after ≥5 years of follow up of a phase III study of adjuvant atezolizumab vs best supportive care in resected stage IB-IIIA non-small cell lung cancer (NSCLC).

LBA8035 Background: IMpower010 (NCT02486718) met its primary endpoint of significant DFS improvement with atezo vs BSC after adj chemotherapy in resected NSCLC in the PD-L1 TC ≥1% and all-randomized stage II-IIIA populations, leading to worldwide approval of adj atezo for PD-L1 TC ≥1% or PD-L1 TC ≥50% stage II-IIIA NSCLC. At OS IA1, a trend favoring atezo was seen in the PD-L1 TC ≥1% stage II-IIIA population. Here we report findings from the DFS FA and OS IA2. Methods: The IMpower010 study design has been previously described (Felip et al, Lancet 2021). The primary DFS and secondary OS endpoints were tested hierarchically: DFS in the PD-L1 TC ≥1% (SP263) stage II-IIIA, then in the all-randomized stage II-IIIA, and then in the intent-to-treat (ITT; stage IB-IIIA) populations, followed by OS in the ITT population. Secondary endpoints included 3- and 5-y DFS and DFS in the PD-L1 TC ≥50% (SP263) stage II-IIIA population. OS in the ITT population could only be formally tested if the significance boundary for DFS in that population was crossed. Results: At the DFS FA and OS IA2 (clinical cutoff date: Jan 26, 2024), with a minimum follow-up of 60 mo, DFS and OS for the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations were consistent with previously observed benefit; the difference in median (m) DFS between arms in the PD-L1 TC ≥1% population was 31.2 mo (Table). In the ITT population, the significance boundary for DFS was not crossed and OS was similar between arms, although data were immature. The safety profile of atezo was consistent with prior analyses. Conclusions: These results provide the first cancer immunotherapy data with ≥5 y of follow-up from a Phase III study in resectable NSCLC. Although the statistical boundary for the ITT population was not crossed, DFS benefit with adj atezo continues to translate into a positive OS trend vs BSC in the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations. These results further support the use of adj atezo in PD-L1–selected populations. Clinical trial information: NCT02486718 . [Table: see text]

Molecular residual disease (MRD) analysis from the ADAURA trial of adjuvant (adj) osimertinib in patients (pts) with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC).

8005 Background: Osimertinib (osi) is a third-generation, central nervous system-active EGFR-TKI, that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. Adj osi (3 years [yrs]) is recommended for resected EGFRm stage IB–IIIA NSCLC, based on significant improvements in disease-free survival (DFS) and overall survival (OS) in the Phase III ADAURA study (NCT02511106). A trend towards an increased DFS event rate beyond 3 yrs suggests some pts may benefit from longer adj osi treatment (tx). We explored if plasma ctDNA-based, tumor-informed MRD could predict disease recurrence. Methods: Eligible pts (≥18 yrs [≥20 in Japan/Taiwan], WHO PS 0/1 with completely resected EGFRm [Ex19del/L858R] stage IB, II or IIIA [AJCC 7th edition] NSCLC) were randomized 1:1 to osi 80 mg once daily or placebo (pbo) until disease recurrence, tx completion (up to 3 yrs), or a discontinuation criterion was met. Personalized MRD panels (RaDaR, NeoGenomics) were used, comprised of ≤50 tumor-specific variants, based on whole exome sequencing of resected tumor tissue (variants identified in germline DNA removed). Plasma sample collection: baseline (BL; at randomization surgery and adj Ctx, if received), on tx (every 12 weeks [wks]), tx discontinuation, and post-tx completion (wk 12, wk 24, then every 24 wks until 5 yrs). Plasma samples were analyzed for detection of ctDNA (MRD+). Molecular recurrence or DFS (MRD/DFS) was defined as time from randomization to post-BL MRD+, disease recurrence, or death and was compared across arms. DFS was investigator-assessed. Results: Of 682 pts randomized, 245 (36%) had samples required to produce MRD panels, which were evaluable for 220 (32%) pts across both arms. In the osi vs pbo arms, 5/112 (4%) vs 13/108 (12%) pts were MRD+ at BL; 4/5 pts became MRD– during osi tx vs 0/13 pts on pbo. On tx, MRD detection had clinical sensitivity of 65% (62 MRD+/96 DFS+), specificity of 95% (118 MRD–/124 DFS–) and preceded a DFS event by a median (95% CI) of 4.7 (2.2, 5.6) months (mos) across both arms. Median follow-up time from randomization was 44.2 (95% CI 42.4, 49.1) and 19.1 (95% CI 11.1, 28.3) mos for osi and pbo arms, respectively. Overall, 86% (95% CI 78, 92) vs 36% (95% CI 27, 45) pts in the osi vs pbo arms were MRD/DFS event free at 36 mos (HR: 0.23; 95% CI 0.15, 0.36). MRD/DFS events in the osi arm were detected at any time post-BL in 28 (25%) pts, of whom 19/28 (68%) had events post-adj osi. Most (11/19 [58%]) MRD/DFS events detected occurred within 12 mos of osi tx completion. Conclusions: MRD+ preceded DFS events in most pts with a median lead time of 4.7 mos across both arms. MRD– was maintained for most pts during adj osi tx with the majority of MRD/DFS events occurring after osi tx completion. MRD detection could potentially identify a subset of pts likely to benefit from longer adj osi. Clinical trial information: NCT02511106 .

Yes to adjuvant osimertinib therapy in EGFR-mutated stage IB–IIIA non-small cell lung cancer post resection, but for how long? (ADAURA/NCT02511106)

Yes to adjuvant osimertinib therapy in EGFR-mutated stage IB–IIIA non-small cell lung cancer post resection, but for how long? (ADAURA/NCT02511106)

Abstract 5840: Identifying drug tolerant persister to neoadjuvant osimertinib in resectable non-small cell lung cancer harbouring EGFR mutations (NORA) via single-cell RNA sequencing

Abstract Introduction: Adjuvant osimertinib is the standard of care for resected, stage IB-IIIA non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutation. Yet, the role of neoadjuvant osimertinib is not clear. In the NORA trial (NCT04816838), we aimed to identify the drug tolerant persister (DTP) after neoadjuvant osimertinib for surgically resectable, EGFR-mutated stage IA-IIIA NSCLC. Methods: Patients harboring EGFR Exon 19 deletion or L858R at clinical stage IA-IIIA were given 80 mg of neoadjuvant osimertinib daily for two 28-day cycles followed by surgical resection and adjuvant osimertinib for 3 years. The key exploratory endpoint was to characterize the DTP via single-cell RNA sequencing (scRNA-seq) with pre and post-osimertinib samples. Results: We performed scRNA-seq on twenty-five patients enrolled at Yonsei Cancer Center from June 2021 to March 2022. Patients with stage IA (n=8, 32%), IB (n=7, 28%), IIA (n=4, 16%), IIB (n=4, 16%), and IIIA (n=2, 8%) were included. For EGFR mutation, exon 19 del and L858R accounted for 10 (40%) patients and 15 (60%) patients, respectively. The ORR (all partial response) was 44% (n=11), major pathologic response (MPR) rate was 24% (n=6), and pathologic complete response rate was 0%. ScRNA-seq revealed a total of 252,339 cells (60 clusters) annotated as epithelial cells (10 clusters), fibroblasts (7 clusters), immune cells (17 clusters), myeloid (15 clusters), endothelial cells (11 clusters) that showed distinct enrichment in post-osimertinib samples, non-MPR, and L858R subset. We found that a distint epithelial subset, namely EP8-AGER, identified as alveolar type 1 (AT1) cells was enriched in the non-MPR subset showing activation of Wnt, Hippo, and YAP/TAZ pathway. Pseudotemporal ordering of this cluster showed activation of signaling pathway for COL4A2/COL4A3 related to structural consistuent of extracellular matrix, and RTKN2 associated with NF-κB. In the fibroblast subset, the proportion of FB6-CD74 associated with chemokine activity and NF-κB was higher in the non-MPR and L858R group. In the myeloid subset, CD8-C1-GZMK identified as CD8+ T cells with activation/effector and cytotoxic signatures was also enriched in the post-osimertinib samples. Among macrophages, 3 clusters (annotated as SELENOP+, SPP1+, PLXDC2+) showed enrichment of cholesterol metabolism with activation of apolipoprotein E that promotes conversion of proinflammatory macrophages into anti-inflammatory phenotypes. Lastly, the proportion of EC9-LYZ, annotated as scavenging endothelial cells was higher in the non-MPR and L858R group. Conclusion: Neoadjuvant osimertinib resulted in the cellular reprogramming in the tumor microenvironment, notably AT1 epithelial cell which may lead to a loop between cancer cells and fibroblasts for the generation of DTP cells. Citation Format: Jii Bum (Joy) Lee, Su-Jin Choi, Young Joon Park, Kyoung-Ho Park, Seung Hyun Yong, Hyo Sup Shim, Byung Jo Park, Chang Young Lee, Min Hee Hong, Byoung Chul Cho, Sun Min Lim. Identifying drug tolerant persister to neoadjuvant osimertinib in resectable non-small cell lung cancer harbouring EGFR mutations (NORA) via single-cell RNA sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5840.

EGFR-mutation testing, treatment patterns and clinical outcomes in patients with stage IB–IIIA non-small cell lung cancer in Norway–a nationwide cohort study

IntroductionTesting for mutations of epidermal growth factor receptor (EGFR) is crucial to identify non-small cell lung cancer (NSCLC) patients eligible for treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs); This study aims to describe EGFR-mutation testing, treatment patterns, and overall survival (OS) in localized NSCLC patients. Materials and MethodsPatients with localized (Stage IB–IIIA) NSCLC registered in the Norwegian Cancer Registry during 2010–2017 were followed from diagnosis until emigration, death, or end of study in 2018. The cohort was linked to data from the Norwegian Patient Registry, the Prescription Database, and the Cause of Death Registry. ResultsOf 2367 patients identified with localized NSCLC, 52 % were females and median age at diagnosis was 69 years. Most (66 %) were treated with surgery, while 16 % received curatively-intended radiotherapy (RT). EGFR-mutation testing increased significantly from 58 to 84 % during the study period. Testing frequencies varied across regions and comorbidity levels. Nine-percent of tested patients were EGFR-mutation positive (EGFRm+), of whom 27 % were treated with EGFR-TKIs. There was no correlation between initial treatment with either surgery or RT and EGFR-TKI use. The 3-year OS did not vary considerably by EGFR-mutation testing, but EGFRm+ patients had a higher 3-year OS (78.8 %) than wild-type EGFR (EGFRwt) patients (65.9 %). DiscussionAlthough EGFR-mutation testing is increasingly being implemented in the early-stage setting in line with national recommendations, some patients are still not being tested for molecular markers as part of their diagnostic workup–a prerequisite for providing equal access to effective targeted treatments, such as EGFR-TKIs, to eligible patients.

Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC).

LBA3 Background: Osimertinib is a third-generation, central nervous system (CNS) active EGFR-TKI, that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. In the primary analysis from the Phase III ADAURA study (NCT02511106), adjuvant osimertinib demonstrated a clinically meaningful, statistically significant, and practice-changing disease-free survival (DFS) benefit vs placebo in patients with completely resected EGFRm (ex19del/L858R) NSCLC ± adjuvant chemotherapy. In an updated DFS analysis, with 2 years additional follow-up, DFS and CNS DFS benefit with adjuvant osimertinib were sustained (stage II–IIIA DFS hazard ratio [HR] 0.23; 95% confidence interval [CI] 0.18, 0.30; stage IB–IIIA DFS HR 0.27; 95% CI 0.21, 0.34; stage II–IIIA CNS DFS HR 0.24; 95% CI 0.14, 0.42), with a tolerable safety profile observed over the extended treatment duration. Here, we report the planned final overall survival (OS) analysis from ADAURA. Methods: Eligible patients (aged ≥18 years [≥20 in Japan and Taiwan], WHO PS 0/1 with completely resected EGFRm (ex19del/L858R) stage IB, II or IIIA [AJCC/UICC 7th edition] NSCLC; adjuvant chemotherapy allowed) were randomized 1:1 to osimertinib 80 mg once daily or placebo until disease recurrence, treatment completion (3 years), or a discontinuation criterion was met. The primary endpoint was investigator-assessed DFS in stage II–IIIA. Key secondary endpoints: DFS in stage IB–IIIA, OS and safety. Data cut-off: January 27, 2023. Results: Globally, 682 patients were randomized; osimertinib n=339, placebo n=343. Adjuvant osimertinib significantly improved OS vs placebo. In patients with stage II–IIIA disease, OS HR was 0.49 (95% CI 0.33, 0.73; p=0.0004; 100/470 events, 21% maturity); 5-year OS rate was 85% with osimertinib vs 73% with placebo. Median follow-up for OS in stage II–IIIA was 59.9 months (osimertinib) and 56.2 months (placebo). In the overall population (stage IB–IIIA), OS HR was 0.49 (95% CI 0.34, 0.70; p<0.0001; 124/682 events, 18% maturity); 5-year OS rate was 88% with osimertinib vs 78% with placebo, with a median follow-up for OS of 60.4 months (osimertinib) and 59.4 months (placebo). Median OS was not reached in either population or treatment group. Conclusions: Adjuvant osimertinib demonstrated an unprecedented, highly statistically significant and clinically meaningful OS benefit in patients with EGFRm stage IB–IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy. ADAURA is the first global Phase III study to demonstrate a statistically significant DFS and OS benefit with targeted treatment for patients with EGFRm stage IB–IIIA NSCLC. Clinical trial information: NCT02511106 .

Prevalence of EGFR and PDL1 testing in a population-based lung cancer surgical resection cohort from 2018-2022.

e20585 Background: Most long-term survivors of lung cancer had surgery for early stage disease, but long-term survival rates are about 50%. In 2020 and 2021 the ADAURA and IMpower010 trials established adjuvant Osimertinib and Atezolizumab therapy for stage IB-IIIA non-small cell lung cancer. Eligibility for these treatments depends on specific biomarkers. We evaluated biomarker testing patterns and prevalence in a population based surgical resection cohort. Methods: In the prospective observational Mid-South Quality of Surgical Resection cohort, we evaluated EGFR and PDL1 testing from 2018-2022, spanning time before (2018-2020) and after (2021-2022) FDA approval of adjuvant Osimertinib and Atezolizumab therapy. We estimated the prevalence of EGFR mutations and PDL1 expression ( > 0%) using the binomial distribution with exact 95% confidence intervals (CI). We compared demographic characteristics using Wilcoxon and Fishers Exact tests. Results: From 2018-2022, 1687 patients had surgical resection across 12 institutions (1045 from 2018-2020; 642 from 2021-2022). They were 21% black and 77% white, 49% male and 51% female, with a median age of 69 years. From 2018-2020 11% had EGFR testing, compared to 38% in 2021-2022 (p < 0.0001). There were no differences in testing by age (p = 0.79), sex (p = 0.99), race (p = 0.69), or insurance type (p = 0.45). In 132 ADAURA eligible individuals (stage IB-IIIA, non-squamous, R0, > 4cm tumor), EGFR was tested in 13% in 2018-2020 and 56% in 2021-2022 (p < 0.0001) with no differences by demographic factors (all p > 0.20). 15% (53 of 360) of EGFR tests were next-generation sequencing, increasing from 4% in 2018-2020 to 20% in 2021-2022 (p < 0.0001). The prevalence of EGFR mutations was 8.1% (95% CI: 5.5% to 11.4%) overall; 9% in males vs. 7% in females (p = 0.57); 12% in black persons vs. 7% in white persons (p = 0.40). From 2018-2020 8% of patients received PDL1 testing, compared to 20% in 2021-2022 (p < 0.0001). There were no differences in testing by age (p = 0.47), sex (p = 0.41), and race (p = 0.51), but a trend for insurance type (p = 0.07). In 791 Impower010 eligible patients (Stage IB-IIIA, R0), PDL1 was tested in 8% in 2018-2020 and 23% in 2021-2022 (p < 0.0001) with no significant differences by demographic factors (all p > 0.10). Among all 207 PDL1 tests, PDL1 was > 0% in 143, for a prevalence of 69% (95% CI: 62% to 75%). It was 69% in males, 70% in females (p = 0.88); 68% in black persons, 69% in white persons (p = 0.99). Testing differed significantly by institution for both EGFR and PDL1 testing (p < 0.001). When EGFR was not evaluated, PDL1 was evaluated 2% of the time but when EGFR was evaluated, PDL1 was evaluated 51% of the time. Conclusions: With the advent of biomarker-directed adjuvant therapy, EGFR and PDL1 testing are rising but testing levels are sub-optimal. Institutional factors influence testing.

Adjuvant therapies in stages I-III epidermal growth factor receptor-mutated lung cancer: current and future perspectives.

Surgical resection followed by adjuvant cisplatin-based chemotherapy is the recommended treatment for patients with completely resected stage IB-IIIA non-small cell lung cancer (NSCLC). Even with the best management, recurrence is common and increases with disease stage (stage I: 26-45%; stage II: 42-62%; stage III: 70-77%). For patients with metastatic lung cancer and tumours that harbour epidermal growth factor receptor (EGFR) mutations, EGFR-tyrosine kinase inhibitors (TKIs) have improved survival. Their effectiveness in advanced stages of NSCLC raises the possibility that these agents may improve outcomes for patients with resectable EGFR-mutated lung cancer. In the ADAURA study, adjuvant osimertinib provided a significant improvement in disease-free survival (DFS) and reduced central nervous system (CNS) disease recurrence in patients with resected stage IB-IIIA EGFR-mutated NSCLC, with or without prior adjuvant chemotherapy. To reap the maximum benefits of EGFR-TKIs for patients with lung cancer, the early and rapid identification of EGFR mutations [and other oncogenic drivers, such as programmed cell death-ligand 1 (PD-L1), with matched targeted therapies] in diagnostic pathologic specimens has become essential. To ensure patients receive the most appropriate treatment, routine, comprehensive histological, immunohistochemical, and molecular analyses (with multiplex next generation sequencing) should be undertaken at the time of diagnosis. The potential for personalised treatments to cure more patients with early-stage lung cancer can only be realised if all therapies are considered when the care plan is formulated, by the multi-specialty experts managing patients. In this review, we discuss the progress and prospects for adjuvant treatments as part of a comprehensive plan of care for patients with resected stages I-III EGFR-mutated lung cancer, and explore how the field could go beyond DFS and overall survival to make cure a more frequent outcome of treatment in patients with resected EGFR-mutated lung cancer.

OA01.09 Adjuvant Osimertinib in Resected EGFR-Mutated Stage IB–IIIA Non-Small Cell Lung Cancer: Updated ADAURA Results

OA01.09 Adjuvant Osimertinib in Resected EGFR-Mutated Stage IB–IIIA Non-Small Cell Lung Cancer: Updated ADAURA Results

Economic Burden of Recurrence in Completely Resected Stage IB-IIIA Non-Small Cell Lung Cancer: A Retrospective Study Using Nationwide Claims Data of South Korea.

Although many patients with early stage non-small cell lung cancer (NSCLC) experience recurrence despite complete resection, few studies have reported on the corresponding economic burden. This study aimed to understand the economic impact of recurrence by measuring healthcare costs and resource utilization in patients with recurrent stage IB-IIIA NSCLC. Using Health Insurance Review and Assessment claims data from South Korea, we included patients who underwent complete resection for stage IB-IIIA NSCLC during the index period (January 1, 2012, to October 31, 2018). Patients who experienced recurrence were matched with those who did not using 1:1 propensity score (PS) matching. The mean healthcare costs and resource utilization were analyzed from the date of complete resection to the last claims for cancer treatment. A generalized linear model (GLM) was used to estimate the impact of covariates on healthcare costs. A difference-in-difference (DID) analysis was conducted to analyze the healthcare costs between the two groups before and after recurrence. Patients with recurrence incurred higher healthcare costs, particularly in outpatient settings. The cost of targeted therapy and immune checkpoint inhibitors primarily contributed to cost differences, and medication costs increased over time after complete resection. Patients with recurrence were also hospitalized more frequently (9.3 vs. 5.0, p < 0.0001) for a longer period (74days vs. 42days, p < 0.0001) than those without recurrence. GLM analysis showed that the total cost was 2.31-fold higher in patients with recurrence (95% confidence interval: 2.19-2.44). The DID analysis showed significantly increased total costs in patients with recurrence (β = 26,269, p < 0.0001), which was mostly attributed to medication costs (β = 17,951, p < 0.0001). Recurrence of completely resected NSCLC leads to a substantial increase in healthcare costs and resource utilization. The results of this study show the economic burden of recurrence, which may help future economic analyses and resource allocation.

296P Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): Updated results from ADAURA

Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitising and EGFR T790M resistance mutations. It has efficacy in EGFRm NSCLC, including in central nervous system (CNS) metastases. In the Phase III ADAURA (NCT02511106) primary analysis adjuvant osimertinib showed a significant and clinically meaningful disease-free survival (DFS) benefit vs placebo (PBO) in pts with completely resected EGFRm (ex19del/L858R) NSCLC, ± adjuvant chemotherapy (CT): stage IIꟷIIIA DFS HR, 0.17; 99.06% CI, 0.11, 0.26; p<0.0001; stage IBꟷIIIA DFS HR, 0.20; 99.12% CI 0.14, 0.30; p<0.0001.

LBA4 CANOPY-N: A phase II study of canakinumab (CAN) or pembrolizumab (PEM), alone or in combination, as neoadjuvant therapy in patients (pts) with resectable stage Ib–IIIa non-small cell lung cancer (NSCLC)

CAN is a monoclonal antibody that inhibits proinflammatory IL-1β–driven pathways that may play a role in tumor growth in early-stage NSCLC. Preclinical data suggest targeting IL-1β could decrease inflammation and immunosuppression in the tumor microenvironment (TME).

LBA5 Long-term tolerability of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC) from ADAURA

Osimertinib (osi) is a 3rd-gen CNS active EGFR-TKI for EGFRm NSCLC. In the Ph III ADAURA (NCT02511106) primary analysis adjuvant osi showed a significant DFS benefit vs placebo (PBO) in resected EGFRm NSCLC, with a low frequency of osi dose modifications/discontinuations and no new safety signals observed. We report exploratory analyses of long-term safety data from ADAURA.

LBA47 Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): Updated results from ADAURA

Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitising and EGFR T790M resistance mutations. It has efficacy in EGFRm NSCLC, including in central nervous system (CNS) metastases. In the Phase III ADAURA (NCT02511106) primary analysis adjuvant osimertinib showed a significant and clinically meaningful disease-free survival (DFS) benefit vs placebo (PBO) in pts with completely resected EGFRm (ex19del/L858R) NSCLC, ± adjuvant chemotherapy (CT): stage IIꟷIIIA DFS HR, 0.17; 99.06% CI, 0.11, 0.26; p<0.0001; stage IBꟷIIIA DFS HR, 0.20; 99.12% CI 0.14, 0.30; p<0.0001. We report updated exploratory analyses of DFS and recurrence patterns after 2 yrs added follow up. Eligible pts (aged ≥18 yrs [≥20 in Japan/Taiwan], WHO PS 0/1, completely resected EGFRm stage IBꟷIIIA [AJCC 7th edition] NSCLC; adjuvant CT allowed) were randomised 1:1 to osimertinib 80 mg once daily or PBO for up to 3 yrs. Primary endpoint: investigator-assessed DFS in stage IIꟷIIIA. Secondary endpoints: DFS in stage IBꟷIIIA, overall survival and safety. Patterns of recurrence and CNS DFS were pre-specified exploratory endpoints. Data cut-off: 11 April 2022. Globally, 682 pts were randomised; osimertinib n=339, PBO n=343. In this updated analysis, in pts with stage IIꟷIIIA disease DFS HR was 0.23 (95% CI 0.18, 0.30; 242/470 events; 51% maturity); 3-yr DFS rate was 84% with osimertinib vs 34% with PBO. In the overall population (stage IBꟷIIIA) DFS HR was 0.27 (95% CI 0.21, 0.34; 305/682 events); 3-yr DFS rate was 85% with osimertinib vs 44% with PBO. In the osimertinib arm, fewer pts experienced local/regional and distant recurrence vs PBO. CNS DFS HR was 0.24 (95% CI 0.14, 0.42; 63/470 events) in stage IIꟷIIIA. The long-term safety profile remains consistent with the known profile of osimertinib. With 2 yrs further follow-up, a continued DFS benefit was sustained with osimertinib vs PBO, consistent with the primary analysis. These mature data reinforce adjuvant osimertinib as standard of care for pts with EGFRm stage IB–‍IIIA NSCLC after complete tumour resection and adjuvant CT, when indicated.

Physician referral patterns and use of adjuvant therapy among stage IB-IIIA non-small cell lung cancer (NSCLC) patients (2010-2017).

e20509 Background: As the treatment landscape for early-stage NSCLC continues to evolve with the recent approvals of targeted and immunotherapy agents in the adjuvant setting, it is important to understand physician referral patterns and predictors of adjuvant therapy (AT). This study examined physician referral patterns at key treatment phases and assessed predictors of receiving AT in stages IB-IIIA NSCLC patients. Methods: A retrospective study using the linked SEER-Medicare database (01/01/2010-12/31/2017) included patients newly diagnosed with stages IB-IIIA NSCLC who received surgical resection. Specialties were identified by linking NSCLC claims to the AMA Physician Masterfile. AT was defined as the use of systemic chemotherapy or radiation therapy within 4 months of surgery. Multivariable logistic regression was conducted to assess predictors of receiving AT. Results: A total of 7,108 patients met the study criteria (53% IB; 9% IIA; 19% IIB; 20% IIIA). Primary care physicians (PCP) (71%), surgical oncologists (29%), and medical oncologists (36%) were the most frequently visited first specialists during pre-diagnosis, diagnosis to surgery, and post-surgery phases, respectively. The median time from diagnosis to surgery was 44 days. After surgery, 74% patients visited a medical oncologist (62% IB; 87% IIA; 83% IIB; 88% IIIA). About 41% received AT (21% IB; 64% IIA; 56% IIB; 69% IIIA). Of those, the median time from surgery to adjuvant therapy was 46 days. In the adjusted analysis, later stage at diagnosis and shorter referral time to medical oncologist had the highest odds of receiving AT (Table). Conclusions: The strongest predictors of receiving adjuvant therapy were time to medical oncologist post-surgery and stage at diagnosis. Future studies in the era of targeted therapies can use these results as a benchmark to optimize management and outcomes as well as assess changes in referral patterns in IB-IIIA NSCLC patients.[Table: see text]

Clinical-Molecular Prospective Cohort Study in Non-Small Cell Lung Cancer (PROMOLE study): A Comprehensive Approach to Identify New Predictive Markers of Pharmacological Response

Lung cancers account for over 90% of thoracic malignancies and the rapid development of specific cytotoxic drugs and molecular therapies requires a detailed identification of the different histologies, gene drivers or immune microenvironment biomarkers. Nevertheless, the heterogeneous clonal evolution, the emergency of drug-induced resistance and the limited occurrence of genetic alterations claim the need of a deep integration of the tumor's and the patient's biological features.The aim of the present study is to generate a tecnological platform for precision medicine in order to set predictive personalized algorithms for patient diagnosis and therapy.All resectable patients having histologically confirmed stage IB-IIIA non-small cell lung cancer will be enrolled for tissue sampling. A large biobank of lung cancer samples and the corresponding healthy tissues and biological components (ie, blood, stools, etc.) with complete clinical, pathological and molecular information will be collected. The platform will include: a) digital patient data collection; b) whole NGS molecular analyses (exome, transcriptome, methylome) for tumor characterization; c) exploitation and collection of organoids from tissue patients; d) Surface Amplified Raman Spectroscopy; e) microfluidic-based technological drug screening; f) preclinical in vivo models based on patient-derived xenografts; g) generation of specific predictive algorithms taking into account all collected multiparameters.The project will lay the basis of a knowledge hub and qualified technology aimed not only at answering the medical and scientific community's questions, but also meant to be useful to individual patients by predicting the response to adjuvant and second-line drugs in case of relapse of the disease.

Deconstructing ADAURA. It is Not Yet Time to Forgo Platinum-based Adjuvant Chemotherapy in Resected Early Stage (IB-IIIA) EGFR-mutant NSCLC.

Recently, the ADAURA study demonstrated statistically significant improved disease-free survival (DFS) with adjuvant osimertinib in patients with resected stage IB-IIIA non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. A consistent improvement in disease-free survival (DFS) was shown, regardless of whether or not patients received adjuvant chemotherapy. Given benefit seen with and without adjuvant chemotherapy, some clinicians may be tempted to forgo chemotherapy and only offer osimertinib post surgical resection. Would this approach be appropriate? Here we carefully dissect data from the ADAURA trial and review how this may fit into the existing evidence on the treatment of early stage NSCLC by discussing five themes, the study design of ADAURA, attempts on adjuvant tyrosine kinase inhibitors, prior studies to support adjuvant chemotherapy, how adjuvant chemotherapy was administered in ADAURA and consideration of toxicities.

Clinical outcome of Brazilian patients with non-small cell lung cancer in early stage harboring rare mutations in epidermal growth factor receptor.

The common epidermal growth factor receptor (EGFR) mutations, such as the L858R point mutation in exon 21 and the in-frame deletional mutation in exon 19, have been definitively associated with response to EGFR-tyrosine kinase inhibitors (EGFR-TKI). However, the clinical outcome and response to treatment for many other rarer mutations are still unclear. In this study, we report the results of Brazilian patients in stage IB-IIIA non-small cell lung cancer (NSCLC) following complete resection with minimal residual disease and EGFR mutations treated with adjuvant chemotherapy and/or EGFR-TKIs. The frequency of EGFR mutations was investigated in 70 cases of early stage NSCLC. Mutations in exons 18 and 20, uncommon mutations in exons 19 and 21, as well as in exons 3, 7, 14, 16, 22, 27, and 28, and/or the presence of different mutations in a single tumor (complex mutations) are considered rare. EGFR mutations were detected in 23 tumors (32.9%). Fourteen cases carried rare mutations and were treated with platinum-based chemotherapy and two cases were treated with erlotinib. The clinical outcome is described case by case with references to the literature. Notably, we found two rare EGFR mutations and one of them with an unknown response to chemotherapy and/or EGFR-TKIs. We have provided complementary information concerning the clinical outcome and treatment of patients with early stage NSCLC for several rare EGFR mutations not previously or only rarely reported. Description of cases harboring rare mutations can support the decision-making process in this subset of patients.

Neoadjuvant camrelizumab, nab-paclitaxel, and carboplatin in patients with stage IB-IIIA non-small cell lung cancer (NANE-LC): a study protocol of prospective, single-arm, multicenter, phase II study.

BackgroundPrevious studies have shown that neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy in patients with stage IB–IIIA non-small cell lung cancer (NSCLC) significantly improved the major pathological response (MPR) and the pathological complete response (pCR) rates. However, high-level evidence-based medical data confirming this effect are still lacking. In addition, there is an urgent need to develop an appropriate strategy to predict the benefit for patients receiving ICIs. In this study, we describe an ongoing study on the effect of neoadjuvant therapy with camrelizumab, nab-paclitaxel, and carboplatin on stage IB–IIIA NSCLC patients. The aim of this study is to establish a multiomics artificial intelligence system for predicting neoadjuvant therapy efficacy and assisting decision-making.MethodsThis prospective, single-arm, multicenter, phase II trial will enroll a total of 40 patients who will undergo surgery after three cycles of neoadjuvant therapy with camrelizumab, nab-paclitaxel, and carboplatin. The MPR rate is the primary endpoint, while the rates of pCR, complete resection, objective response, disease-free survival (DFS), adverse events (AEs), and quality of life (QOL) are secondary endpoints. Exploratory endpoints will serve to establish a multiomics artificial intelligence system for neoadjuvant therapy effect prediction and decision-making assistance based on radiomics, metabolism, genetic, and clinic-pathological characteristics and to explore the mechanisms of drug resistance.DiscussionThe efficacy of ICIs is influenced by many factors, including patient’s driver genes and smoking status. Thus, further subgroup analysis is needed. This study will indicate if our new multiomics artificial intelligence system constitutes a valid strategy for neoadjuvant therapy effect prediction and decision-making assistance in the context of neoadjuvant camrelizumab, nab-paclitaxel, and carboplatin treatment for patients with stage IB–IIIA NSCLC.Trial RegistrationThis trial has been registered at ClinicalTrials.gov (identification number: NCT04541251).

The result of adjuvant Vinorelbine plus Cisplatin in completely resected stage IB-IIIA non-small cell lung cancer at Hanoi Medical Unoversity Hospital

Background: Assess clinical, subclinical characteristics of stage IB-IIIA non - small cell lung cancer patients (NSCLC). Evaluating the result of adjuvant vinorelbine plus cisplatin in completely resected stage IB - IIIA NSCLC. Methods: Descriptive study of 70 patients completely resected stage IB - IIIA non - small cell lung cancer were received adjuvant vinorelbine plus cisplatin chemotherapy at Hanoi Medical University Hospital from 01/2016 to 6/2020. Results: The mean age of 56.94 years old, male: female ratio was 2.9:1. 23 (32.8%) patients had postoperative stage IB disease, 24 (34.3%) had stage IIA disease, 13 (18.6%) had stage IIB disease and 10 (14.3%) had stage IIIA disease. The major histological type was adenocarcinoma (78.6%). Median disease free survival was 29.10 ± 1.63 months, and 3 - year survival was 41%. Chemotherapy caused hematologic side effects in 66.67% of patients including neutropenia in 61.4% and grade 3/4 neutropenia in 28.1%. Non - hematologic toxic effects of chemotherapy were reported at low rates and almost mild (grade 1/2). Conclusions: The vinorelbine - cisplatin regimen is an effective regimen in the adjuvant treatment of non - small cell lung cancer, the study showed that the results in disease - free survival and overall survival were comparable to those of other studies in the world. The most common side effect was neutropenia, the other side effects were reported at low rate and usually mild.