Brief Report: Tyrosine Kinase Inhibitors for Lung Cancers That Inhibit MATE-1 Can Lead to "False" Decreases in Renal Function.

INTRODUCTION: Select tyrosine kinase inhibitors (TKIs) used to treat oncogene-driven lung cancers also inhibit MATE-1. When MATE-1 is blocked, creatinine is retained in the serum. Elevated creatinine levels raise the specter of drug-induced intrarenal insufficiency despite the lack of true renal injury. We conducted a systematic analysis of MATE-1 inhibitor (MATEi)-treated patients to comprehensively characterize this phenomenon. METHODS: Patients with oncogene-driven lung cancer treated with a wide variety of MATEi TKIs (brigatinib, cabozantinib, capmatinib, crizotinib, entrectinib, lorlatinib, pralsetinib, selpercatinib, and tepotinib) were eligible for an analysis of renal dysfunction. Acute kidney injury was classified on the basis of creatinine levels (Kidney Disease: Improving Global Outcomes criteria) as stage 1 (≥1.5× but <2× baseline), stage 2 (≥2× but <3× baseline), or stage 3 (>3× baseline). When available, cystatin C, a marker of kidney function unaffected by MATE-1, was used to evaluate the glomerular filtration rate (GFR). RESULTS: We identified 863 patients receiving MATEi TKIs including crizotinib (39%, n = 333), lorlatinib (17%, n = 144), cabozantinib (10%, n = 87), selpercatinib (10%, n = 82), capmatinib (9%, n = 77), brigatinib (6%, n = 53), entrectinib (5%, n = 45), tepotinib (5%, n = 41), and pralsetinib (0.1%, n = 1). Of the 90 patients (10%) with acute kidney injury, Kidney Disease: Improving Global Outcomes stages 1, 2, and 3 were observed in 72% (n = 65), 21% (n = 19), and 7% (n = 6) of patients, respectively. Concurrently drawn creatinine and cystatin C levels on TKI therapy were available for 17 patients. In most cases (n = 15 of 17), the calculated GFR was higher using cystatin C versus creatinine. The percentage of patients whose GFR was higher using cystatin C versus creatinine by less than 10 mL/min, 10 to 19 mL/min, 20 to 29 mL/min, and more than or equal to 30 mL/min was 27% (n = four of 15), 20% (n = three of 15), 20% (n = three of 15), and 33% (n = five of 15), respectively. Long-term data in three patients that spanned 3 years revealed that GFR was higher using cystatin C versus creatinine in 96% (n = 49 of 51) of all time points. Using a virtual clinical trial GFR cutoff of 40 mL/min, the percentage of eligible patients rose from 41% (n = seven of 17) using creatinine calculations to 71% (n = 12 of 17) using cystatin C calculations. CONCLUSIONS: The calculated GFR in patients with cancer receiving MATEi TKIs was higher in almost all cases when using cystatin C. When serum creatinine level seems elevated in patients receiving MATE-1 inhibitors, we recommend recalculating GFR using cystatin C before searching for other etiologies of kidney injury and reducing or stopping TKI therapy.

Artificial Intelligence-Powered Assessment of Pathologic Response to Neoadjuvant Atezolizumab in Patients With NSCLC: Results From the LCMC3 Study.

INTRODUCTION: Pathologic response (PathR) by histopathologic assessment of resected specimens may be an early clinical end point associated with long-term outcomes with neoadjuvant therapy. Digital pathology may improve the efficiency and precision of PathR assessment. LCMC3 (NCT02927301) evaluated neoadjuvant atezolizumab in patients with resectable NSCLC and reported a 20% major PathR rate. METHODS: We determined PathR in primary tumor resection specimens using guidelines-based visual techniques and developed a convolutional neural network model using the same criteria to digitally measure the percent viable tumor on whole-slide images. Concordance was evaluated between visual determination of percent viable tumor (n = 151) performed by one of the 47 local pathologists and three central pathologists. RESULTS: For concordance among visual determination of percent viable tumor, the interclass correlation coefficient was 0.87 (95% confidence interval [CI]: 0.84-0.90). Agreement for visually assessed 10% or less viable tumor (major PathR [MPR]) in the primary tumor was 92.1% (Fleiss kappa = 0.83). Digitally assessed percent viable tumor (n = 136) correlated with visual assessment (Pearson r = 0.73; digital/visual slope = 0.28). Digitally assessed MPR predicted visually assessed MPR with outstanding discrimination (area under receiver operating characteristic curve, 0.98) and was associated with longer disease-free survival (hazard ratio [HR] = 0.30; 95% CI: 0.09-0.97, p = 0.033) and overall survival (HR = 0.14, 95% CI: 0.02-1.06, p = 0.027) versus no MPR. Digitally assessed PathR strongly correlated with visual measurements. CONCLUSIONS: Artificial intelligence-powered digital pathology exhibits promise in assisting pathologic assessments in neoadjuvant NSCLC clinical trials. The development of artificial intelligence-powered approaches in clinical settings may aid pathologists in clinical operations, including routine PathR assessments, and subsequently support improved patient care and long-term outcomes.

Deep learning of cell spatial organizations identifies clinically relevant insights in tissue images.

Recent advancements in tissue imaging techniques have facilitated the visualization and identification of various cell types within physiological and pathological contexts. Despite the emergence of cell-cell interaction studies, there is a lack of methods for evaluating individual spatial interactions. In this study, we introduce Ceograph, a cell spatial organization-based graph convolutional network designed to analyze cell spatial organization (for example,. the cell spatial distribution, morphology, proximity, and interactions) derived from pathology images. Ceograph identifies key cell spatial organization features by accurately predicting their influence on patient clinical outcomes. In patients with oral potentially malignant disorders, our model highlights reduced structural concordance and increased closeness in epithelial substrata as driving features for an elevated risk of malignant transformation. In lung cancer patients, Ceograph detects elongated tumor nuclei and diminished stroma-stroma closeness as biomarkers for insensitivity to EGFR tyrosine kinase inhibitors. With its potential to predict various clinical outcomes, Ceograph offers a deeper understanding of biological processes and supports the development of personalized therapeutic strategies.

ctDNA-based detection of molecular residual disease in stage I-III non-small cell lung cancer patients treated with definitive radiotherapy.

Background: Sensitive and reliable biomarkers for early detection of recurrence are needed to improve post-definitive radiation risk stratification, disease management, and outcomes for patients with unresectable early-stage or locally advanced non-small cell lung cancer (NSCLC) who are treated with definitive radiation therapy (RT). This prospective, multistate single-center, cohort study investigated the association of circulating tumor DNA (ctDNA) status with recurrence in patients with unresectable stage I-III NSCLC who underwent definitive RT. Methods: A total of 70 serial plasma samples from 17 NSCLC patients were collected before, during, and after treatment. A personalized, tumor-informed ctDNA assay was used to track a set of up to 16 somatic, single nucleotide variants in the associated patient's plasma samples. Results: Pre-treatment ctDNA detection rate was 82% (14/17) and varied based on histology and stage. ctDNA was detected in 35% (6/17) of patients at the first post-RT timepoint (median of 1.66 months following the completion of RT), all of whom subsequently developed clinical progression. At this first post-RT time point, patients with ctDNA-positivity had significantly worse progression-free survival (PFS) [hazard ratio (HR): 24.2, p=0.004], and ctDNA-positivity was the only significant prognostic factor associated with PFS (HR: 13.4, p=0.02) in a multivariate analysis. All patients who developed clinical recurrence had detectable ctDNA with an average lead time over radiographic progression of 5.4 months, and post-RT ctDNA positivity was significantly associated with poor PFS (p<0.0001). Conclusion: Personalized, longitudinal ctDNA monitoring can detect recurrence early in patients with unresectable NSCLC patients undergoing curative radiation and potentially risk-stratify patients who might benefit most from treatment intensification.

International Association for the Study of Lung Cancer Study of Reproducibility in Assessment of Pathologic Response in Resected Lung Cancers After Neoadjuvant Therapy.

INTRODUCTION: Pathologic response has been proposed as an early clinical trial end point of survival after neoadjuvant treatment in clinical trials of NSCLC. The International Association for the Study of Lung Cancer (IASLC) published recommendations for pathologic evaluation of resected lung cancers after neoadjuvant therapy. The aim of this study was to assess pathologic response interobserver reproducibility using IASLC criteria. METHODS: An international panel of 11 pulmonary pathologists reviewed hematoxylin and eosin-stained slides from the lung tumors of resected NSCLC from 84 patients who received neoadjuvant immune checkpoint inhibitors in six clinical trials. Pathologic response was assessed for percent viable tumor, necrosis, and stroma. For each slide, tumor bed area was measured microscopically, and pre-embedded formulas calculated unweighted and weighted major pathologic response (MPR) averages to reflect variable tumor bed proportion. RESULTS: Unanimous agreement among pathologists for MPR was observed in 68 patients (81%), and inter-rater agreement (IRA) was 0.84 (95% confidence interval [CI]: 0.76-0.92) and 0.86 (95% CI: 0.79-0.93) for unweighted and weighted averages, respectively. Overall, unweighted and weighted methods did not reveal significant differences in the classification of MPR. The highest concordance by both methods was observed for cases with more than 95% viable tumor (IRA = 0.98, 95% CI: 0.96-1) and 0% viable tumor (IRA = 0.94, 95% CI: 0.89-0.98). The most common reasons for discrepancies included interpretations of tumor bed, presence of prominent stromal inflammation, distinction between reactive and neoplastic pneumocytes, and assessment of invasive mucinous adenocarcinoma. CONCLUSIONS: Our study revealed excellent reliability in cases with no residual viable tumor and good reliability for MPR with the IASLC recommended less than or equal to 10% cutoff for viable tumor after neoadjuvant therapy.

Outcomes of Combination Platinum-Doublet Chemotherapy and Anti-PD(L)-1 Blockade in KRASG12C-Mutant Non-Small Cell Lung Cancer.

BACKGROUND: Direct KRASG12C inhibitors are approved for patients with non-small cell lung cancers (NSCLC) in the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described. Our goal was to define the clinical outcomes to chemo-immunotherapy in patients with NSCLC with KRASG12C mutations. PATIENTS AND METHODS: Through next-generation sequencing, we identified patients with advanced NSCLC with KRAS mutations treated with chemo-immunotherapy at 2 institutions. The primary objective was to determine outcomes and determinants of response to first-line chemo-immunotherapy among patients with KRASG12C by evaluating objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We assessed the impact of coalterations in STK11/KEAP1 on outcomes. As an exploratory objective, we compared the outcomes to chemo-immunotherapy in KRASG12C versus non-G12C groups. RESULTS: One hundred and thirty eight patients with KRASG12C treated with first-line chemo-immunotherapy were included. ORR was 41% (95% confidence interval (CI), 32-41), median PFS was 6.8 months (95%CI, 5.5-10), and median OS was 15 months (95%CI, 11-28). In a multivariable model for PFS, older age (P = .042), squamous cell histology (P = .008), poor ECOG performance status (PS) (P < .001), and comutations in KEAP1 and STK11 (KEAP1MUT/STK11MUT) (P = .015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P = .004) and KEAP1MUT/STK11MUT (P = .009) were associated with worse OS. Patients with KRASG12C (N = 138) experienced similar outcomes to chemo-immunotherapy compared to patients with non-KRASG12C (N = 185) for both PFS (P = .2) and OS (P = .053). CONCLUSIONS: We define the outcomes to first-line chemo-immunotherapy in patients with KRASG12C, which provides a real-world benchmark for clinical trial design involving patients with KRASG12C mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies.

Efficacy of PD-(L)1 blockade monotherapy compared with PD-(L)1 blockade plus chemotherapy in first-line PD-L1-positive advanced lung adenocarcinomas: a cohort study.

BACKGROUND: Single-agent PD-(L)1 blockade (IO) alone or in combination with chemotherapy (Chemotherapy-IO) is approved first-line therapies in patients with advanced lung adenocarcinomas (LUADs) with PD-L1 expression ≥1%. These regimens have not been compared prospectively. The primary objective was to compare first-line efficacies of single-agent IO to Chemotherapy-IO in patients with advanced LUADs. Secondary objectives were to explore if clinical, pathological, and genomic features were associated with differential response to Chemotherapy-IO versus IO. METHODS: This was a multicenter retrospective cohort study. Inclusion criteria were patients with advanced LUADs with tumor PD-L1 ≥1% treated with first-line Chemotherapy-IO or IO. To compare the first-line efficacies of single-agent IO to Chemotherapy-IO, we conducted inverse probability weighted Cox proportional hazards models using estimated propensity scores. RESULTS: The cohort analyzed included 866 patients. Relative to IO, Chemotherapy-IO was associated with improved objective response rate (ORR) (44% vs 35%, p=0.007) and progression-free survival (PFS) in patients with tumor PD-L1≥1% (HR 0.84, 95% CI 0.72 to 0.97, p=0.021) or PD-L1≥50% (ORR 55% vs 38%, p<0.001; PFS HR 0.68, 95% CI 0.53 to 0.87, p=0.002). Using propensity-adjusted analyses, only never-smokers in the PD-L1≥50% subgroup derived a differential survival benefit from Chemotherapy-IO vs IO (p=0.013). Among patients with very high tumor PD-L1 expression (≥90%), there were no differences in outcome between treatment groups. No genomic factors conferred differential survival benefit to Chemotherapy-IO versus IO. CONCLUSIONS: While the addition of chemotherapy to PD-(L)1 blockade increases the probability of initial response, never-smokers with tumor PD-L1≥50% comprise the only population identified that derived an apparent survival benefit with treatment intensification.

Clinical and Molecular Features of Long-term Response to Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.

PURPOSE: We sought to identify features of patients with advanced non-small cell lung cancer (NSCLC) who achieve long-term response (LTR) to immune checkpoint inhibitors (ICI), and how these might differ from features predictive of short-term response (STR). EXPERIMENTAL DESIGN: We performed a multicenter retrospective analysis of patients with advanced NSCLC treated with ICIs between 2011 and 2022. LTR and STR were defined as response ≥ 24 months and response < 12 months, respectively. Tumor programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), next-generation sequencing (NGS), and whole-exome sequencing (WES) data were analyzed to identify characteristics enriched in patients achieving LTR compared with STR and non-LTR. RESULTS: Among 3,118 patients, 8% achieved LTR and 7% achieved STR, with 5-year overall survival (OS) of 81% and 18% among LTR and STR patients, respectively. High TMB (≥50th percentile) enriched for LTR compared with STR (P = 0.001) and non-LTR (P < 0.001). Whereas PD-L1 ≥ 50% enriched for LTR compared with non-LTR (P < 0.001), PD-L1 ≥ 50% did not enrich for LTR compared with STR (P = 0.181). Nonsquamous histology (P = 0.040) and increasing depth of response [median best overall response (BOR) -65% vs. -46%, P < 0.001] also associated with LTR compared with STR; no individual genomic alterations were uniquely enriched among LTR patients. CONCLUSIONS: Among patients with advanced NSCLC treated with ICIs, distinct features including high TMB, nonsquamous histology, and depth of radiographic improvement distinguish patients poised to achieve LTR compared with initial response followed by progression, whereas high PD-L1 does not.

Neoadjuvant Targeted Therapy in Resectable NSCLC: Current and Future Perspectives.

The standard of care (SoC) for medically operable patients with early-stage (stages I-IIIB) NSCLC is surgery combined with (neo)adjuvant systemic therapy for patients with stages II to IIIB disease and some stage IB or, rarely, chemoradiation (stage III disease with mediastinal lymph node metastases). Despite these treatments, metastatic recurrence is common and associated with poor survival, highlighting the need for systemic therapies that are more effective than the current SoC. After the success of targeted therapy (TT) in patients with advanced NSCLC harboring oncogenic drivers, these agents are being investigated for the perioperative (neoadjuvant and adjuvant) treatment of patients with early-stage NSCLC. Adjuvant osimertinib is the only TT approved for use in the early-stage setting, and there are no approved neoadjuvant TTs. We discuss the importance of comprehensive biomarker testing at diagnosis to identify individuals who may benefit from neoadjuvant targeted treatments and review emerging data from neoadjuvant TT trials. We also address the potential challenges for establishing neoadjuvant TTs as SoC in the early-stage setting, including the identification and validation of early response markers to guide care and accelerate drug development, and discuss safety considerations in the perioperative setting. Initial data indicate that neoadjuvant TTs are effective and well tolerated in patients with EGFR- or ALK-positive early-stage NSCLC. Data from ongoing trials will determine whether neoadjuvant targeted agents will become a new SoC for individuals with oncogene-addicted resectable NSCLC.

Deep Learning of Cell Spatial Organizations Identifies Clinically Relevant Insights in Tissue Images.

Recent advancements in tissue imaging techniques have facilitated the visualization and identification of various cell types within physiological and pathological contexts. Despite the emergence of cell-cell interaction studies, there is a lack of methods for evaluating individual spatial interactions. In this study, we introduce Ceograph, a novel cell spatial organization-based graph convolutional network designed to analyze cell spatial organization (i.e. the cell spatial distribution, morphology, proximity, and interactions) derived from pathology images. Ceograph identifies key cell spatial organization features by accurately predicting their influence on patient clinical outcomes. In patients with oral potentially malignant disorders, our model highlights reduced structural concordance and increased closeness in epithelial substrata as driving features for an elevated risk of malignant transformation. In lung cancer patients, Ceograph detects elongated tumor nuclei and diminished stroma-stroma closeness as biomarkers for insensitivity to EGFR tyrosine kinase inhibitors. With its potential to predict various clinical outcomes, Ceograph offers a deeper understanding of biological processes and supports the development of personalized therapeutic strategies.

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.

Brief Report: Combination of Osimertinib and Dacomitinib to Mitigate Primary and Acquired Resistance in EGFR-Mutant Lung Adenocarcinomas.

PURPOSE: Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance. PATIENTS AND METHODS: We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation. RESULTS: Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%-88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%-58%). CONCLUSIONS: We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.

Features of tumor-microenvironment images predict targeted therapy survival benefit in patients with EGFR-mutant lung cancer.

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFR-sensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine H&E-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation data set, EGFR TKI treatment prolonged survival in the predicted-to-benefit group but not in the predicted-not-to-benefit group. Among patients treated with EGFR TKIs, the predicted-to-benefit group had prolonged survival outcomes compared with the predicted not-to-benefit group. The EGFR TKI survival benefit positively correlated with tumor-tumor interaction image features and negatively correlated with tumor-stroma interaction. Moreover, the tumor-stroma interaction was associated with higher activation of the hepatocyte growth factor/MET-mediated PI3K/AKT signaling pathway and epithelial-mesenchymal transition process, supporting the hypothesis of fibroblast-involved resistance to EGFR TKI treatment.

Clinicopathologic outcomes of preoperative targeted therapy in patients with clinical stage I to III non-small cell lung cancer.

OBJECTIVE: Targeted therapy improves outcomes in patients with advanced-stage non-small cell lung cancer (NSCLC) and in the adjuvant setting, but data on its use before surgery are limited. We sought to investigate the safety and feasibility of preoperative targeted therapy in patients with operable NSCLC. METHODS: We retrospectively reviewed 51 patients with clinical stage I to III NSCLC who received targeted therapy, alone or in combination with chemotherapy, before surgical resection with curative intent, treated from 2004 to 2021. The primary outcome was the safety and feasibility of preoperative targeted therapy; secondary outcomes included objective response rate, major pathologic response (defined as ≤10% viable tumor) rate, recurrence-free survival (RFS), and overall survival. RESULTS: Of the 51 patients included, 46 had an activating epidermal growth factor receptor gene alteration and 5 had an anaplastic lymphoma kinase fusion. Overall, 37 of 46 evaluable patients experienced at least 1 adverse event before surgery; however, only 3 patients experienced a grade 3 or 4 event. The objective response rate was 38% (17/45) for all evaluable patients and 44% (14/32) for patients with clinical stage II or III disease. The major pathologic response rate was 20% (9/44); 2 patients had a complete pathologic response. Median RFS was 3.8 years (95% CI, 2.8 to not reached). Targeted therapy alone was associated with better RFS than combination therapy (P = .009) in patients with clinical stage II or III disease. CONCLUSIONS: Preoperative targeted therapy was well tolerated and associated with good outcomes, with or without induction chemotherapy. In addition, radiographic response and pathologic response were strongly correlated.

Surgical results of the Lung Cancer Mutation Consortium 3 trial: A phase II multicenter single-arm study to investigate the efficacy and safety of atezolizumab as neoadjuvant therapy in patients with stages IB-select IIIB resectable non-small cell lung cancer.

OBJECTIVE: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery. METHODS: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0. RESULTS: From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached. CONCLUSIONS: Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer.

Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung Cancers.

INTRODUCTION: Preferred first-line treatment for patients with metastatic EGFR-mutant lung cancer is osimertinib, yet it is not known whether patient outcomes may be improved by identifying and intervening on molecular markers associated with therapeutic resistance. METHODS: All patients with metastatic EGFR-mutant lung cancer treated with first-line osimertinib at the Memorial Sloan Kettering Cancer Center (n = 327) were identified. Available pretreatment and postprogression tumor samples underwent targeted gene panel sequencing and mutational signature analysis using SigMA algorithm. Progression-free survival (PFS) and overall survival were estimated using the Kaplan-Meier method. RESULTS: Using multivariate analysis, baseline atypical EGFR (median PFS = 5.8 mo, p < 0.001) and concurrent TP53/RB1 alterations (median PFS = 10.5 mo, p = 0.015) were associated with shorter PFS on first-line osimertinib. Of 95 patients with postprogression biopsies, acquired resistance mechanisms were identified in 52% (off-target, n = 24; histologic transformation, n = 14; on-target, n = 12), with MET amplification (n = 9), small cell lung transformation (n = 7), and acquired EGFR amplification (n = 7), the most frequently identified mechanisms. Although there was no difference in postprogression survival on the basis of identified resistance (p = 0.07), patients with subsequent second-line therapy tailored to postprogression biopsy results had improved postprogression survival (hazard ratio = 0.09, p = 0.006). The paired postprogression tumors had higher tumor mutational burden (p = 0.008) and further dominant APOBEC mutational signatures (p = 0.07) compared with the pretreatment samples. CONCLUSIONS: Patients with EGFR-mutant lung cancer treated with first-line osimertinib have improved survival with treatment adaptation on the basis of identified mechanisms of resistance at time of progression using tissue-based genomic analysis. Further survival gains may be achieved using risk-based treatment adaptation of pretreatment genomic alterations.

Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.

Phase I trial of the TNF-α inhibitor certolizumab plus chemotherapy in stage IV lung adenocarcinomas.

We previously identified a chemotherapy-induced paracrine inflammatory loop that paradoxically mitigates the anti-tumor effect of chemotherapy and triggers metastatic propagation in breast and lung cancer models. Therefore, we sought to further validate and translate these findings into patient care by coupling the anti-TNF-α drug certolizumab pegol with standard cisplatin doublet chemotherapy. Here we first validate the anti-metastatic effect of certolizumab in a liver-metastatic Lewis Lung Carcinoma model. We then evaluate the safety, efficacy, and pharmacodynamic effects of certolizumab with cisplatin and pemetrexed in an open label Phase 1 clinical trial (NCT02120807) of eighteen adult patients with stage IV lung adenocarcinomas. The primary outcome is maximum tolerated dose. Secondary outcomes are response rate and progression-free survival (PFS); pharmacodynamic changes in blood and tumor are evaluated as a correlative outcome. There were nine partial responses among 16 patients evaluable (56%, 95% CI 30 to 80%). The median duration of response was 9.0 months (range 5.9 to 42.6 months) and median PFS was 7.1 months (95% CI 6.3 to NR). The standard 400 mg dose of certolizumab, added to cisplatin and pemetrexed, is well-tolerated and, as a correlative endpoint, demonstrates potent pharmacodynamic inhibition of peripheral cytokines associated with the paracrine inflammatory loop.