Resected Early-stage Non-small Cell Lung Cancer Research Articles

CtDNA-Lung-DETECT: ctDNA outcomes for resected early stage non-small cell lung cancers at 12 months.

8018 Background: ctDNA Lung DETECT is a multicentre investigator initiated prospective study at 3 thoracic surgery centres in the Greater Toronto Area assessing ctDNA detection and association with recurrence free survival (RFS) in patients with early stage non-small cell lung cancer (NSCLC) (NCT05254782). Patients who have ctDNA detected perioperatively are offered ctDNA Lung RCT, a randomized trial investigating the benefit of adjuvant chemo-immunotherapy in patients where the standard of care is observation alone after surgery (NCT04966663). Herein, we report on ctDNA outcomes at 12 months for patients with resected early stage NSCLC. Methods: Patients with stage I (T1-2N0) or multifocal T3-4 < 4cm N0 NSCLC planned for resection at University Health Network consented to plasma ctDNA assessment before and after surgery, and at 12 months post-operatively or relapse using the tumor-informed RaDaR® assay, which detects up to 48 tumor-specific variants in plasma with a Limit of Detection (LoD₉₅) of 0.0011% variant allele fraction. Results: From July 2021 to January 2024, 178 patients were enrolled; 115 had sufficient tissue for assessment. Of these, 68/72 patients have 12 month post-resection ctDNA results available (3 withdrew, 1 sample failed). ctDNA was detected pre-operatively in 18 patients; 99% (71/72) had ctDNA clearance post-operatively, and 93% (62/67) remained ctDNA negative at 12 months. Median follow up time was 18.7 months (range 12.0– 28.3); 8/72 (11%) patients (5 stage I, 3 stage II) experienced lung cancer recurrence. Median time to recurrence was 13.9 months (range 6.2- 24.9). Of these, 3 had ctDNA detected on their preoperative and 12-month or recurrence sample, 1 had ctDNA detected at 12 months prior to relapse, 1 had ctDNA detected at 12 months and recurred around the same time, 2 had negative ctDNA samples and 1 missed sample collection preoperatively. The recurrence rate was 16.7% (3/18, 95% exact CI 3.6-41.4%) in patients with ctDNA detected pre-operatively vs. 7.5% (4/53, CI 2.1-18.2%) in those without. New lung cancers were diagnosed in 5/72 (median time to new primary 15.3 months, range 4.9-14.2) and 2/72 patients had new cancers diagnosed (ovarian/liposarcoma). For those with new lung primaries, 1 had ctDNA detected preoperatively but none had ctDNA detected at time of new primary diagnosis. Of 4 patients who have died, 2 were from recurrent lung cancer and 2 from new primaries (lung/sarcoma). Conclusions: This study represents one of the largest prospective cohorts of ctDNA kinetics in patients with resected lung cancer. Of patients with at least 12 months follow up, 8/72 experienced a lung cancer recurrence with a higher rate in those with pre-operative ctDNA detected (16.7% vs 7.5%). Pre-operative ctDNA detection may help identify patients with resected stage I NSCLC that could benefit from treatment intensification, currently under study in ctDNA Lung RCT (NCT04966663). Clinical trial information: NCT05254782 .

Integrated management of stage III in nonsmall cell lung cancer: where do perioperative chemotherapy and immunotherapy fit?

Early-stage nonsmall cell lung cancer (NSCLC) accounts for 30% of the total NSCLC, being the stage III a heterogeneous disease that represents a challenge in the management of these patients. Multidisciplinary approach is essential for an adequate treatment strategy, with surgery being the only curative treatment. Neoadjuvant or adjuvant chemotherapy has been the standard of care for a long period, with modest results. Combination of chemotherapy and immunotherapy has revolutionized the neoadjuvant setting of resectable NSCLC, improving pathologic complete responses and survival outcomes in this scenario. Furthermore, perioperative treatment with immunotherapy has also recently shown promising results in several phase III trials. The landscape of early-stage resectable NSCLC has evolved in recent years, with an improvement in the survival of these patients since the incorporation of immunotherapy in this scenario.

An Updated Review of Management of Resectable Stage III NSCLC in the Era of Neoadjuvant Immunotherapy.

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space.

Abstract 3635: Insulin-like growth factor receptor predicts poor prognosis in early-stage non-small cell lung cancer

Abstract Introduction: Insulin like growth factor receptor (IGF1R) is involved in the proliferation and metastasis of various cancers. However, the clinical significance of IGF1R in non-small cell lung cancer (NSCLC) remains to be unclear. In this study, we retrospectively evaluated the correlation between IGF1R expression and clinicopathological features of NSCLC. Method: A total of 782 specimens of NSCLC patients who underwent surgical resection of primary lung cancer between 2010 and 2019 at Osaka Metropolitan University Hospital was enrolled in this study. Immunohistochemical staining of IGF1R were performed, and the correlation between IGF1R expression and clinicopathological features of NSCLC, especially in recurrence free survival (RFS) and overall survival (OS), was evaluated. We also evaluated an association between IGF1R and programmed death ligand 1 (PD-L1) expression. Results: IGF1R expression was positive in 279 (35.8%) patients. IGF1R-positive group had significantly longer smoking histories (median smoking index, 1,000 vs 600, p <0.01) and a higher proportion of squamous cell carcinomas (35.1% vs 14.1 %, p <0.01). IGF1R-positive group also significantly expressed PD-L1 (24.4% vs 6.4%, p<0.01). IGF1R-positive group had significantly worse RFS (10-year recurrence-free rate; 42.7% vs 53.7%, p <0.01) and OS (10-year survival rate; 54.4% vs 67.3%, p <0.01). RFS and OS were significantly worse in the IGF1R-positive NSCLC patients at stage 0 and stage I (10-year recurrence-free rate; 49.0% vs 62.9%, p <0.01, 10-year survival rate; 57.4% vs 74.2%, p<0.01), but not in stage II (10-year recurrence-free rate; 52.0% vs 43.8%, p=0.68, 10-year survival rate; 63.4% vs 47.5%, p=0.95) and III (10-year recurrence-free rate; 20.7% vs 20.8%, p=0.77, 10-year survival rate; 38.3% vs 54.6%, p=0.18). IGF1R expression was associated with poorer RFS and OS in early-stage NSCLC. Conclusion: IGF1R is a predictor of poor prognosis in resected early-stage NSCLC. Citation Format: Hiroaki nagamine, Masakazu Yashiro, Megumi Mizutani, Akira Sugimoto, Yoshiya Matsumoto, Yoko Tani, Kenji Sawa, Kazuhiro Yamada, Hiroyasu Kaneda, Tetsuya Watanabe, Kazuhisa Asai, Satoshi Suzuki, Tomoya Kawaguchi. Insulin-like growth factor receptor predicts poor prognosis in early-stage non-small cell lung cancer [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 3635.

(Neo)adjuvant approaches in lung cancer—paving the road to a cure

SummaryImmune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of metastatic non-small-cell lung cancer (NSCLC). During the past few years the focus of research has shifted toward examining these therapies in patients with early-stage NSCLC to improve long-term overall survival and cure rates. As recurrence rates are high and the relapse pattern in patients with completely resected early-stage NSCLC is predominantly systemic, high expectations rest on the integration of ICI therapy in their treatment approach. A large number of studies with adjuvant or neo-adjuvant ICI are ongoing. The first data from phase III studies have demonstrated improvements in disease-free survival and pathologic remissions, but overall survival data are mostly immature. Additionally, targeted therapies have also been explored in early-stage NSCLC. The first very promising results are available from EGFR-mutant and ALK-translocated NSCLC and have already changed our clinical practice for some patient subgroups. This review discusses the most recent results of phase III trials in the neoadjuvant, perioperative, and adjuvant setting for ICI and targeted therapies in early-stage resectable NSCLC.

PD-1 expression in tumor infiltrating lymphocytes as a prognostic marker in early-stage non-small cell lung cancer.

Programmed death ligand - 1 (PD-L1) expression is a well-established predictive biomarker for immunotherapy in non-small cell lung cancer (NSCLC). Programmed death - 1 (PD-1) serves as the target protein to PD-L1 and their interaction serves as a crucial pathway for immune evasion. This study aimed to investigate the expression pattern of PD-1 on Tumor-infiltrating lymphocytes (TILs) in early-stage NSCLC, and its potential role as prognostic biomarker. PD-1 was evaluated in 474 surgical resected early-stage NSCLC specimens, using Tissue microarray and immunohistochemical staining. Expression was scored as negative (<1%) or positive. Positive PD-1 expression was further divided into low (<10%) and high (≥10%). None of the patients had received treatment with PD-1/PD-L1 inhibitors. PD-1 expression ≥1% in TILs was observed in 83.5% of cases and was associated with pT stage (p=0.02), grade 3 (p=0.004), and adenocarcinoma subtype (p=0.05). Individuals with high PD-1 expression (≥10%) experienced reduced 10-year overall survival (Log-Rank test = 0.005). In addition, high PD-1 expression emerged as an independent factor associated with reduced survival on multivariate analysis (HR: 1.328 (95% CI: 1.074-1.641). Patients with early-stage NSCLC who exhibited PD-1 expression of ≥10% on TILs had an unfavorable 10-year OS rate. These findings indicate that elevated PD-1 expression on TILs can be associated with immune evasion during the early stages of malignancy evolution in the NSCLC setting and further research is required to further delineate the role of PD-1/PD-L1 pathway on tumor immune senescence. These results underline the potential role of PD-1/PD-L1 inhibitors in the treatment of early-stage NSCLC.

Targeted Therapies in Early-Stage Resectable Non-Small-Cell Lung Cancer: New Kids on the Block.

With increased adoption of next-generation sequencing, tailored therapy on the basis of molecular status is being delivered for patients with early-stage resectable non-small-cell lung cancer (NSCLC). The purpose of this narrative review was to focus on recent developments of targeted therapies in the adjuvant and neoadjuvant/adjuvant setting for early-stage disease. A systematic search of the MEDLINE/PubMed database was performed, focusing on studies published within the past 10 years. Our search queried "early-stage NSCLC (AND) tyrosine kinase inhibitor (TKI; OR) epidermal growth factor receptor (EGFR; OR) anaplastic lymphoma kinase (ALK)" and was limited only to prospective and ongoing studies. Most studies examining the benefit of targeted therapies in early-stage resectable NSCLC have been for EGFR-TKIs in the adjuvant setting. Currently, only one study, the ADAURA trial of adjuvant osimertinib, has demonstrated an overall survival benefit with the use of an EGFR-TKI in the adjuvant setting. Future work to build on the success of the ADAURA trial is focused on determining the optimal duration of targeted therapies and using biomarkers, such as circulating tumor DNA, to risk-stratify patients and guide maintenance targeted therapy duration. The results of several ongoing studies are eagerly awaited regarding the use of targeted therapies in the neoadjuvant/adjuvant setting and for more uncommon or rare mutations such as ALK, ROS proto-oncogene 1, rearranged during transfection, mesenchymal-epithelial transition factor, and B-Raf proto-oncogene V600E. The treatment landscape for early-stage NSCLC harboring actionable mutations is likely to shift dramatically in the upcoming decade.

The prognostic value of the preoperative albumin/globulin and monocyte ratio in resected early-stage non-small cell lung cancer

ObjectiveThis study investigated the prognostic value of the preoperative albumin/globulin to monocyte ratio (AGMR) in patients with resected non-small cell lung cancer (NSCLC). MethodsThe study retrospectively enrolled patients with resected NSCLC from the Department of Thoracic Surgery, China–Japan Union Hospital of Jilin University from January 2016 to December 2017. Baseline demographic and clinicopathological data were collected. The preoperative AGMR was calculated. Propensity score matching (PSM) analysis was applied. The receiver operating characteristic curve was used to determine the optimal AGMR cut-off value. The Kaplan–Meier method was used to calculate the overall survival (OS) and disease-free survival (DFS). The Cox proportional hazards regression model was used to evaluate the prognostic value of the AGMR. ResultsA total of 305 NSCLC patients were included. The optimal AGMR value was 2.80. Before PSM. The high AGMR (>2.80) group had a significantly longer OS (41.34 + 11.32 vs. 32.03 + 17.01 months; P < 0.01) and DFS (39.00 + 14.49 vs. 28.78 + 19.13 months; P < 0.01) compared with the low AGMR (≤2.80) group. Multivariate analyses showed that AGMR (P < 0.01) in addition to sex (P < 0.05), body mass index (P < 0.01), history of respiratory diseases (P < 0.01), lymph node metastasis (P < 0.01), and tumor size (P < 0.01) were associated with OS and DFS. After PSM, AGMR remained as an independent prognostic factor for OS (hazard ratio [HR] 2.572, 95% confidence interval [CI]: 1.470–4.502; P = 0.001) and DFS (HR 2.110, 95% CI: 1.228–3.626; P = 0.007). ConclusionThe preoperative AGMR is a potential prognostic indicator for OS and DFS in resected early-stage NSCLC.

Challenges of neoadjuvant targeted therapy in early stage non-small cell lung cancer—a narrative review

Background and Objective: There has been little advancement in the management of resectable non-small cell lung cancer (NSCLC) regarding neoadjuvant and adjuvant setting for almost two decades. Five-year survival rates for radically resected early stage NSCLC remain disappointing. The objective of this narrative review is to assess the current aspects and challenges of neoadjuvant targeted therapy in oncogene-driven NSCLC patients.

Osimertinib Resistance: Molecular Mechanisms and Emerging Treatment Options.

The development of tyrosine kinase inhibitors (TKIs) targeting the mutant epidermal growth factor receptor (EGFR) protein initiated the success story of targeted therapies in non-small-cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is currently indicated as first-line therapy in patients with NSCLC with sensitizing EGFR mutations, as second-line therapy in patients who present the resistance-associated mutation T790M after treatment with previous EGFR-TKIs, and as adjuvant therapy for patients with early stage resected NSCLC, harboring EGFR mutations. Despite durable responses in patients with advanced NSCLC, resistance to osimertinib, similar to other targeted therapies, inevitably develops. Understanding the mechanisms of resistance, including both EGFR-dependent and -independent molecular pathways, as well as their therapeutic potential, represents an unmet need in thoracic oncology. Interestingly, differential resistance mechanisms develop when osimertinib is administered in a first-line versus second-line setting, indicating the importance of selection pressure and clonal evolution of tumor cells. Standard therapeutic approaches after progression to osimertinib include other targeted therapies, when a targetable genetic alteration is detected, and cytotoxic chemotherapy with or without antiangiogenic and immunotherapeutic agents. Deciphering the when and how to use immunotherapeutic agents in EGFR-positive NSCLC is a current challenge in clinical lung cancer research. Emerging treatment options after progression to osimertinib involve combinations of different therapeutic approaches and novel EGFR-TKI inhibitors. Research should also be focused on the standardization of liquid biopsies in order to facilitate the monitoring of molecular alterations after progression to osimertinib.

Adjuvant immunotherapy in early-stage resectable non-small cell lung cancer: A new milestone.

Currently, chemotherapy is the standard adjuvant treatment for early-stage non-small cell lung cancer (NSCLC). However, adjuvant cisplatin-based chemotherapy after surgery has been shown to improve 5-year survival rates by only 4-5%. Immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC, there is a growing interest in the role of immunotherapy in early-stage NSCLC. Here, we summarize the rationale for adjuvant immunotherapy, including the postoperative immunosuppressive environment and immunological effects of platinum chemotherapy. Many ongoing clinical trials and the related progress in adjuvant immunotherapy in early-stage resectable NSCLC are discussed. Furthermore, we highlight several unresolved challenges, including markers predictive of treatment benefit, the efficacy of treatment for some oncogene-addicted tumors, the optimal combination therapy, the duration of adjuvant immunotherapy, and optimal selection between neoadjuvant and adjuvant immunotherapy. Early findings in some clinical trials are promising, and updated overall survival results will be useful for validating the current role of adjuvant immunotherapy, particularly in the context of perioperative strategy.

Concomitant TP53 mutation in early-stage resected EGFR-mutated non-small cell lung cancer: a narrative approach in a genetically admixed Brazilian cohort.

TP53 mutations are frequent in non-small cell lung cancer (NSCLC) and have been associated with poor outcome. The prognostic and predictive relevance of EGFR/TP53 co-mutations in NSCLC is controversial. We analyzed lung tissue specimens from 70 patients with NSCLC using next-generation sequencing to determine EGFR and TP53 status and the association between these status with baseline patient and tumor characteristics, adjuvant treatments, relapse, and progression-free (PFS) and overall survival (OS) after surgical resection. We found the EGFR mutation in 32.9% of patients (20% classical mutations and 12.9% uncommon mutations). TP53 missense mutations occurred in 25.7% and TP53/EGFR co-mutations occurred in 43.5% of patients. Stage after surgical resection was significantly associated with OS (P=0.028). We identified an association between progression-free survival and poor outcome in patients with distant metastases (P=0.007). We found a marginally significant difference in OS between genders (P=0.057) and between mutant and wild type TP53 (P=0.079). In univariate analysis, distant metastases (P=0.027), pathological stage (IIIA-IIIB vs I-II; P=0.028), and TP53 status (borderline significance between wild type and mutant; P=0.079) influenced OS. In multivariable analysis, a significant model for high risk of death and poor OS (P=0.029) selected patients in stage IIIA-IIIB, with relapse and distant metastases, non-responsive to platin-based chemotherapy and erlotinib, with tumors harboring EGFR uncommon mutations, with TP53 mutant, and with EGFR/TP53 co-mutations. Our study suggested that TP53 mutation tends to confer poor survival and a potentially negative predictive effect associated with a non-response to platinum-based chemotherapy and erlotinib in early-stage resected EGFR-mutated NSCLC.

Treatment Patterns and Outcomes in Resected Early-stage Non-small Cell Lung Cancer: An Analysis of the SEER-Medicare Data

BackgroundAs the non-small cell lung cancer (NSCLC) adjuvant treatment landscape evolves, an evaluation of treatment patterns and outcomes of patients with early-stage, resected NSCLC eligible for adjuvant treatment in routine clinical practice is needed to better understand the unmet needs in this patient population. Materials and MethodsData from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2007-2019) were used to identify patients with newly diagnosed stage IB (tumor size ≥4cm)-IIIA (AJCC 7th edition) NSCLC who received primary surgery (index date). We assessed adjuvant treatment patterns, real-world disease-free survival (rwDFS; time from index date to first recurrence or death) and overall survival (OS; time from index date to death), and loco-regional recurrence pattern and treatment distribution. ResultsAmong 1761 patients with primary surgery, mean age was 73.8 years; 47.9% were male; and 83.9% were white. Approximately 41% of patients received adjuvant chemotherapy; median time from surgery to adjuvant chemotherapy initiation was 48 days, and the most frequently observed adjuvant chemotherapy regimen was carboplatin+paclitaxel (24.5%). In the overall population, median rwDFS was 24.8 months and OS was 76.7 months; 5-year rwDFS and OS rates were 29.3% and 57.5%, respectively. Among 392 patients with loco-regional recurrence, the most frequently observed treatment was curative radiation monotherapy (28.2%). ConclusionDespite clinical guideline recommendations, rate of adjuvant chemotherapy among patients with resected early-stage NSCLC was low in clinical practice. Overall, among patients with early-stage NSCLC treated with conventional primary surgery, poor survival outcomes were observed, highlighting the need for and importance of more effective adjuvant treatments.

Clinical significance of preoperative neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in the prognosis of resected early-stage patients with non-small cell lung cancer: A meta-analysis.

Poor prognosis is linked to peripheral blood levels of preoperative platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) in many advanced cancers. Nevertheless, whether the correlation exists in resected early-stage cases with non-small cell lung cancer (NSCLC) stays controversial. Consequently, we performed a meta-analysis to explore the preoperative NLR and PLR's prognostic significance in early-stage patients with NSCLC undergoing curative surgery. Relevant studies that validated the link between preoperative NLR or PLR and survival results were found via the proceeding databases: PubMed, Embase, Cochrane Library, and Web of Science. The merged 95% confidence interval (CI) and hazard ratio (HR) was employed to validate the link between the NLR or PLR's index and overall survival (OS) and disease-free survival (DFS) in resected NSCLC cases. We used sensitivity and subgroup analyses to assess the studies' heterogeneity. An overall of 21 studies were attributed to the meta-analysis. The findings indicated that great preoperative NLR was considerably correlated with poor DFS (HR=1.58, 95% CI: 1.37-1.82, p < 0.001) and poor OS (HR=1.51, 95% CI: 1.33-1.72, p < 0.001), respectively. Subgroup analyses were in line with the pooled findings. In aspect of PLR, raised PLR was indicative of inferior DFS (HR=1.28, 95% CI: 1.04-1.58, p=0.021) and OS (HR=1.37, 95% CI: 1.18-1.60, p < 0.001). In the subgroup analyses between PLR and DFS, only subgroups with a sample size <300 (HR=1.67, 95% CI: 1.15-2.43, p=0.008) and TNM staging of mixed (I-II) (HR=1.47, 95% CI: 1.04-2.07, p=0.028) showed that the link between high PLR and poor DFS was significant. Preoperative elevated NLR and PLR may act as prognostic biomarkers in resected early-stage NSCLC cases and are therefore valuable for guiding postoperative adjuvant treatment.

Role of ctDNA for the detection of minimal residual disease in resected non-small cell lung cancer: a systematic review.

Operable stage I-III non-small cell lung cancer (NSCLC) has a high risk of recurrence, mainly due to remnant clones of the disease defined as minimal residual disease (MRD). Adjuvant chemotherapy has a limited efficacy in reducing the risk of relapse, and prognostic as well as predictive biomarkers in this context are currently missing. We performed a systematic review to evaluate the state of the art about the role of circulating tumor DNA detection through liquid biopsy for the assessment of MRD in resected early-stage NSCLC patients. Among the 650 studies identified, 13 were eligible and included. Although highly heterogeneous, all the studies demonstrated a poor prognosis in patients with post-operative MRD, with a detection rate ranging from 6% to 45%. MRD detection preceded radiographic/clinical recurrence by a mean of 5.5 months. MRD positive patients were most likely to benefit from adjuvant treatment in terms of recurrence-free survival (RFS). Consistently, adjuvant therapy did not minimize the risk of relapse in the MRD negative group. Liquid biopsy has a relevant role in assessing post-surgical MRD in resected NSCLC. Since currently there are no criteria other than stage and risk factors for the choice of adjuvant treatment in this setting, post-operative assessment of MRD through liquid biopsy might be a promising approach to guide the decision.

A Delphi consensus panel about clinical management of early-stage EGFR-mutated non-small cell lung cancer (NSCLC) in Spain: a Delphi consensus panel study

PurposeThis Delphi panel study assessed the level of consensus between medical oncologists on the clinical management of patients with early-stage EGFR-mutated non-small cell lung cancer (NSCLC).MethodsA modified two-round Delphi approach was used. A scientific committee comprised of medical oncologists developed an online questionnaire. Delphi panel experts rated their level of agreement with each questionnaire statement on a 9-point Likert scale. The questionnaire included 36 statements from 3 domains (clinical management of early-stage NSCLC: 15 statements; role of adjuvant therapy in early-stage NSCLC: 9 statements; and role of adjuvant therapy in early-stage NSCLC with sensitizing EGFR mutation: 12 statements).ResultsIn round 1, consensus was reached for 24/36 statements (66.7%). Nine statements that did not achieve consensus after the first round were evaluated in round 2, and none of them reached consensus. Overall, 84.4% of the panelists agreed that EGFR mutation testing should be done after surgery. Consensus was not achieved on whether the implementation of EGFR mutation testing in resected early-stage NSCLC could limit the use of adjuvant osimertinib. The panelists recognized the rationale for the use of osimertinib in the adjuvant scenario (88%) and 72% agreed that it may change the treatment paradigm in stage IB–IIIA EGFR-mutated NSCLC. Consensus was not reached on the inconvenience of prolonged duration of osimertinib.ConclusionsThis Delphi study provides valuable insights into relevant questions in the management of early-stage EGFR-mutated NSCLC. However, specific issues remain unresolved. The expert consensus emphasizes the role of adjuvant treatment with osimertinib in this scenario.

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.

EP03.01-002 Co-occurring Mutations, Smoking Status and Prognosis of Early-stage Resected NSCLCs with EGFR Mutations

Co-occurring pathological mutations in non-small cell lung cancer (NSCLC) may account for clinical heterogeneity not explained by the single driver mutation model. The prognostic significance of various co-mutations and adjuvant treatment modalities has been explored in early-stage NSCLC, but there has not been a focus on the impact of smoking and EGFR co-mutations in early-stage NSCLC. This study aims to characterize the frequency of co-mutations in EGFR-mutated (EGFRm) early-stage resected NSCLC; to describe relationships between smoking history and co-mutation status; and to determine whether prognosis differs by co-mutation status and smoking status among patients with EGFRm NSCLC.

EP02.03-009 Real-world Disease-Free Survival as a Predictor of Overall Survival in Resected Early-Stage Non-Small Cell Lung Cancer

Intermediate endpoints (e.g., disease-free survival [DFS]) have shown very good correlation with overall survival (OS) in early-stage non-small cell lung cancer (NSCLC) clinical trials. Yet limited studies quantified the clinical and economic burden of disease recurrence in this population in the real-world. This study aims to assess the association between real-world DFS (rwDFS) and OS and estimate the clinical and economic burden associated with recurrence among patients with resected early-stage NSCLC.

Abstract CT112: AI-powered and manual assessment of PD-L1 are comparable in predicting response to neoadjuvant atezolizumab in patients (pts) with resectable non-squamous, non-small cell lung cancer (NSCLC)

Abstract Background: PD-L1 expression evaluated by immunohistochemistry (IHC) is a well-established predictor of anti-PD-L1/PD-1 cancer immunotherapy (CIT). The Phase II LCMC3 (NCT02927301) study evaluated pre-operative treatment (tx) with atezolizumab (anti-PD-L1) in pts with untreated early stage resectable NSCLC, achieving a 20% major pathologic response (MPR) rate (primary efficacy pts, n=143). A digital PD-L1 scoring method was developed to assess PD-L1 expression as a potential predictive marker for MPR in squamous and non-squamous tumor samples from LCMC3. Methods: Manual scoring was used to determine PD-L1 status on pre-tx biopsy samples using the tumor proportion score (TPS) with a positive threshold of TPS≥50 (22C3). Binary results were correlated with MPR and stratified by squamous/non-squamous histology. A digital pathology workflow for automated PD-L1 scoring was developed to yield a precise continuous PD-L1 TPS. Deep convolutional neural networks trained using pathologist annotations were used to detect individual cells within the tumor and tumor microenvironment and quantify their PD-L1 expression. These cell type predictions were used to compute a digital PD-L1 TPS. LCMC3 pts with available digital and manual PD-L1 scores were then used to assess the role of PD-L1 expression in predicting MPR. Results: PD-L1 scores were available for pre-tx biopsies from 108 pts. No significant difference in scores was seen between histological subtypes. At cutoff (Oct 15, 2021), TPS≥50 was seen in 41 (non-squamous, n=26 [39%]; squamous, n=15 [36%]) of 108 pts and was associated with MPR in non-squamous (odds ratio [OR], 28.6; P&amp;lt;0.001; Fisher’s exact test) but not squamous histology (OR, 1.3; P=1.0). Continuous digital PD-L1 scores (range: 0-100) were highly correlated with local manual PD-L1 scores (range: 0-100) for squamous (n=42, Pearson r=0.90, P&amp;lt;0.001) and non-squamous stained histology slides (n=66, Pearson r=0.90, P&amp;lt;0.001). Continuous digital and manual PD-L1 TPS on pre-tx biopsies (n=108) were predictive of MPR (digital: area under the receiver operating curve (AUROC)=0.678, logistic regression [LR] P=0.01; manual: AUROC=0.675, LR P=0.003). Strikingly, when pts were stratified by histology, PD-L1 scores were predictive of MPR from pre-tx biopsies for non-squamous samples (n=66; digital: AUROC=0.821, LR P=0.002; manual: AUROC=0.819, LR P=0.001) but not for squamous samples (n=42; digital: AUROC=0.519, LR P=0.93; manual: AUROC=0.506, LR P=0.90), despite no significant difference in MPR rate between the 2 groups. Conclusions: These findings support using digitally assessed PD-L1 IHC as a centralized and standardized scoring system and suggest that tumor histological subtype could be an important factor in the utility of PD-L1 as a predictive biomarker for neoadjuvant CIT in early stage NSCLC. Citation Format: John Abel, Christopher Rivard, Filip Kos, Guillaume Chhor, Yi Liu, Jennifer Giltnane, Sara Hoffman, Murray Resnick, Cyrus Hedvat, Amaro Taylor-Weiner, Farah Khalil, Alan Nicholas, Gregory A. Fishbein, Lynette M. Sholl, Natasha Rekhtman, Stephanie Hennek, Ilan Wapinski, Ann Johnson, Michael Montalto, Katja Schulze, Bruce E. Johnson, David P. Carbone, Konstantin Shilo, Andrew H. Beck, Sanja Dacic, William D. Travis, Ignacio Wistuba. AI-powered and manual assessment of PD-L1 are comparable in predicting response to neoadjuvant atezolizumab in patients (pts) with resectable non-squamous, non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT112.