Stage IB-IIIA Non-small Cell Lung Cancer Research Articles

EP08.02-123 First Line Osimertinib in Lung Cancer Patients with Postoperative Recurrence

Although osimertinib was recently approved by the FDA as adjuvant therapy for non-small cell lung cancer (NSCLC) patients with EGFR exon 19 deletion or exon 21 L858R mutation based on positive PFS results from the ADAURA trial (Osimertinib versus placebo in patients with stage IB-IIIA NSCLC, following complete tumor resection with or without adjuvant chemotherapy, NCT02511106), it remains controversial whether all eligible patients should receive osimertinib as adjuvant therapy following tumor resection.

Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy

BackgroundNeoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus...

Abstract 5114: Ultra-sensitive detection of minimal residual disease (MRD) through whole genome sequencing (WGS) using an AI-based error suppression model in resected early-stage non-small cell lung cancer (NSCLC)

Abstract Background: Early detection of recurrence and monitoring of MRD post-surgery is critical for clinical decision-making to tailor adjuvant therapy. In early-stage NSCLC, circulating tumor DNA (ctDNA) detection is especially challenging, requiring highly sensitive and specific assays. Therefore, we used a WGS approach (MRDetect) for ultra-sensitive ctDNA detection in NSCLC patients (pts) undergoing curative surgery. Methods: We conducted a pilot study to evaluate the MRDetect approach in serial plasma samples (including pre-surgery, post-surgery and follow-up [f/u] timepoints) from resected stage IB-IIIA NSCLC pts. Pts underwent routine surveillance by computed tomography scans. ctDNA was extracted from ~1mL plasma. MRDetect uses WGS by a tumor-informed approach (sequencing coverage 40x for tumor, 20x for plasma DNA) combined with AI-based error suppression models (trained and calibrated with a non-cancer cohort, n=17) to increase the signal to noise ratio for precise ctDNA detection, and improve the accuracy of readouts especially for low tumor burden scenarios. The assay reports the detection and quantification of ctDNA burden in blood with a prognostic value for risk of recurrence. The ability of the assay to predict recurrence from a single sample, taken at the clinical landmark point (median 1.6 mths post-surgery, range 0.1-6.5) was evaluated. Results: Overall, 52 NSCLC pts were enrolled (n=88 plasma samples) with median clinical f/u of 32.6 mths (range 3.1-98.6). There were 43 pts with post-surgery landmark samples, with median age 62 years, 70% were male, 79% were adenocarcinoma and 49% were EGFR mutated. 26% were stage IB and 37% each were stage II and III. There were 15/18 (sensitivity 83%) pts with confirmed radiological recurrence in which MRDetect was positive, including 6/7 (86%) EGFR mutated pts. The median RFS in MRDetect positive pts was 15.2 mths (range 3.7-33.4). Among 25 pts with no recurrence (median f/u 25.6 mths), MRDetect reported 4 pts to be MRD positive (specificity 84%). These results were consistent between EGFR mutated (sensitivity 86%, specificity 86%) and wildtype pts (sensitivity 82%, specificity 82%). For longitudinal samples (n=17 pts), negative ctDNA was associated with absence of recurrence in 14/15 pts (specificity 93%). At the AACR meeting, results from a planned larger validation study will be presented. Conclusion: Using a robust WGS implemented AI-based computational platform (MRDetect), we demonstrate high sensitivity and specificity detection of MRD in both EGFR mutated and wildtype NSCLC. With an increasing number of therapeutic options in the adjuvant setting for NSCLC, an ultra-sensitive MRD assay has the potential to facilitate personalized clinical decision-making for tailoring both the need and choice of adjuvant therapies. Citation Format: Aaron C. Tan, Stephanie P. Saw, Gillianne G. Lai, Kevin L. Chua, Angela Takano, Boon-Hean Ong, Tina P. Koh, Amit Jain, Wan Ling Tan, Quan Sing Ng, Ravindran Kanesvaran, Tanujaa Rajasekaran, Sunil Deochand, Dillon Maloney, Danielle Afterman, Tomer Lauterman, Noah Friedman, Imane Bourzgui, Nidhi Ramaraj, Zohar Donenhirsh, Ronel Veksler, Jonathan Rosenfeld, Ravi Kandasamy, Iman Tavassoly, Boris Oklander, Asaf Zviran, Wan-Teck Lim, Eng-Huat Tan, Anders J. Skanderup, Mei-Kim Ang, Daniel S. Tan. Ultra-sensitive detection of minimal residual disease (MRD) through whole genome sequencing (WGS) using an AI-based error suppression model in resected early-stage 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 5114.

LIBRETTO-001 cohort 7: A single-arm, phase 2 study of neoadjuvant selpercatinib in patients with resectable stage IB-IIIA RET fusion-positive NSCLC.

TPS8594 Background: Despite definitive surgery and perioperative chemotherapy, many patients with locoregional non-small cell lung cancer (NSCLC) continue to experience recurrent disease and limited survival. Although targeted therapies are standard treatment for metastatic NSCLC with genomic alterations, their use in the early-stage setting is still being characterized. Initial studies examining targeted therapy in neoadjuvant setting for early-stage epidermal growth factor receptor positive NSCLC has shown promise. Selpercatinib is a highly selective, potent, and central nervous system active rearranged during transfection (RET) inhibitor with demonstrated robust and sustained antitumor activity and manageable toxicity in patients with RET fusion-positive advanced NSCLC. Cohort 7 of the Phase 2, open-label, single arm LIBRETTO-001 study evaluates efficacy and safety of neoadjuvant selpercatinib in patients with resectable stage IB-IIIA RET fusion-positive NSCLC (NCT03157128). Methods: Key eligibility criteria include age ≥18 years; histologically confirmed stage IB–IIIA NSCLC (AJCC, version 8); presence of RET fusion in tumor (by PCR or NGS) or blood (by NGS) (pre-treatment biopsy confirmed); resectable and operable tumor; measurable disease (RECIST 1.1); and ECOG performance status 0-1. Key exclusion criteria include presence of other known oncogenic drivers; and concurrent investigational anticancer therapy. Eligible patients will undergo full staging including radiographic tumor measurements using CT, PET, and brain MRI at baseline and after two 28-day cycles of neoadjuvant selpercatinib, followed by surgery. Dosing regimen is 160 mg twice daily. Resected tumor specimens will be sent to an Independent Pathology Review Committee (IPRC) for evaluation. Patients may then be treated with stage-appropriate adjuvant therapy/surveillance, based on the treating physician’s decision, followed by selpercatinib until disease recurrence, unacceptable toxicity, withdrawal, or death, for a maximum treatment duration of 3 years. The primary endpoint is to determine the rate of major pathologic response (MPR) by IPRC, defined as ≤ 10% residual viable tumor cells in the surgically resected specimen. Efficacy based on the MPR will be assessed using the Simon's 2-stage design. In Stage I, 9 patients will be enrolled; if ≤1 patient achieves an MPR, the study will be stopped. Otherwise, at least 10 additional patients will be enrolled, with a total of 19 patients undergoing surgery. The rate of pathologic complete response (pCR) by IPRC, disease-free survival, and overall survival will be assessed as secondary endpoints. pCR rate will be determined at the time of surgery, indicating no remaining viable tumor cells. Safety of peri-operative treatment will be assessed, including 30- and 90-day post-operative readmission and mortality rates. Clinical trial information: NCT03157128.

Assessing the predictive value of ctDNA on relapse in patients with resected stage IB-IIIA NSCLC treated with adjuvant chemotherapy plus concomitant atezolizumab followed by atezolizumab: BTCRC LUN 19-396.

TPS8592 Background: A standard of care treatment for most patients with stage II and III non-small cell lung cancer (NSCLC) and a PD-L1 > 1% is surgery followed by adjuvant (adj) histology-specific chemotherapy followed by 1 year of atezolizumab. The benefit of adding atezolizumab concomitantly to chemotherapy in the adj setting has not been reported. In addition, the optimal duration of adjuvant therapy is undefined. Emerging data have demonstrated the potential for ctDNA to predict clinical recurrence in patients with surgically resected lung, breast, and colon cancer. The current study explores the predictive value of ctDNA for early relapse in patients treated with adj chemotherapy plus atezolizumab. Methods: The LUN19-396 is a phase II biomarker study that enrolls pts with resected NSCLC stage IB (tumors ≥ 4cm), IIA, IIB, and select IIIA (T3N1-2, T4N0-2). The ctDNA will be assessed within 60 days post-surgery and then every 3 months up to 12 months. All pts will receive treatment with 4 cycles of Cisplatin 60-75mg/m2 + Docetaxel 60-75mg/m2 + Atezolizumab 1200mg IV on day 1 q 3w (for patients with squamous cell cancer) or Cisplatin 60-75mg/m2 + Pemetrexed 500mg/m2 + Atezolizumab 1200mg on day 1 IV q 3w (for patients with non-squamous cell), followed by up to 13 additional cycles of Atezolizumab 1200mg IV every 3w. This trial will enroll a total of 100 pts to achieve more than 80% power. The primary objective is to estimate the percentage of pts with detectable ctDNA after surgery who have clearance of ctDNA at designated time points during adjuvant therapy. The key secondary objective is to estimate the 1-year disease-free survival in pts with undetectable ctDNA after 4 cycles of adj chemotherapy plus atezolizumab who had detectable ctDNA after surgery. This trial has enrolled 17 pts as of February 8, 2022. Clinical trial information: NCT04367311.

Two cycles versus three cycles of neoadjuvant sintilimab plus platinum-doublet chemotherapy in patients with resectable non-small-cell lung cancer (neoSCORE): A randomized, single center, two-arm phase II trial.

8500 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) plus chemotherapy have a promising efficacy in resectable non-small-cell lung cancer (NSCLC), yet the period of neoadjuvant immunochemotherapy is undetermined. This phase II study compared the efficacy and safety of two cycles with three cycles of neoadjuvant sintilimab plus chemotherapy in resectable stage IB-IIIA NSCLC. Methods: This randomized, open-label phase II trial recruited patients aged 18 or older with histologically confirmed, treatment-naïve, American Joint Committee on Cancer-defined stage IB-IIIA, resectable NSCLC. Eligible patients were randomly assigned to two or three cycles of neoadjuvant treatment with intravenous sintilimab (200 mg) plus carboplatin (area under curve 5) and nab-paclitaxel (260mg/m2, for squamous) or pemetrexed (500mg/m2, for non-squamous) on day 1 of three-week cycle. After surgical resection, patients received totally four doses of perioperative immunochemotherapy, followed by one-year sintilimab maintenance under patient decision. Randomisation was stratified by tumor PD-L1 expression (≥1% vs < 1%). The primary endpoint was MPR rate. Secondary endpoints included complete pathology response (pCR) rate, objective response rate (ORR), 2-year disease-free survival (DFS) rate, 2-year overall survival (OS) rate and safety. This trial is registered with ClinicalTrials.gov, number: NCT04459611. Results: From 6/2020 to 9/2021, 60 patients were enrolled and received neoadjuvant treatment. The patient characteristics of both arms were well balanced. Among 55 patients with successful R0 resection, we observed a higher MPR rate (41.4%, 12/29) in three-cycle group compared with two-cycle group (26.9%, 7/26) (p = 0.260), meanwhile, pCR rate achieved 24.1% (7/29) and 19.2% (5/26) respectively (p = 0.660). Patients of squamous subtype generally achieved a statistically higher MPR rate (51.6%, 16/31) compared with the non-squamous subtype (12.5%, 3/24) (p = 0.002). In squamous subgroup, three cycles neoadjuvant treatment induced a MPR rate of 60% compared with 43.8% after two cycles treatment (p = 0.366).In the meantime, the MPR rate was 21.4% versus 0% in non-squamous subgroup, respectively (p = 0.239). The ORR showed no statistical difference between three-cycle group (55.2%, 16/29) and two-cycle (50%, 13/26) (p = 0.701). Patients were well-tolerated in both groups and 5% (3/60) experienced grade 3 immune related adverse events. Conclusions: It is the first randomized study comparing different treatment periods of immuno-chemotherapy in the neoadjuvant setting. Three cycles neoadjuvant treatment achieved a numerically higher MPR rate compared with two cycles. Patients with squamous lung cancer obtained a better MPR rate compared with non-squamous subtype. Clinical trial information: NCT04459611.

Management of Patients With Resectable and Metastatic Non–Small Cell Lung Cancer

For patients with resectable non–small cell lung cancer (NSCLC) as well as those with metastatic disease, there have been significant recent advances in therapies. In patients with resectable disease, new evidence supports use of neoadjuvant nivolumab + chemotherapy for eligible patients with resectable stage II–IIIA NSCLC. Separate data lead to the recommendation for adjuvant atezolizumab (after adjuvant chemotherapy) for eligible patients with completely resected stage II–IIIA NSCLC and PD-L1 expression ≥1%. Adjuvant osimertinib (± adjuvant chemotherapy) is an alternative for eligible patients with completely resected stage IB–IIIA NSCLC and EGFR mutations (exon 19 del or L858R). For patients with metastatic NSCLC, molecular testing is recommended for EGFR and BRAF mutations; MET exon skipping 14 alterations; ALK, ROS1, RET, and NTRK1/2/3 gene arrangements; and KRAS G12C mutations. First-line targeted therapies are available for many of these targets and, in the second-line setting, there are new targeted agents for KRAS G12C mutations and EGFR exon 20 insertions.

89P Treatment patterns, overall survival (OS), and disease-free survival (DFS) in early stage non-small cell lung cancer (NSCLC) following complete resection

To understand adjuvant therapy use and clinical burden in patients (pts) with completely resected stage IB-IIIA NSCLC, this study described adjuvant therapy treatment pattern, OS, and DFS following surgery in the early-stage NSCLC population.

Deconstructing ADAURA: It is Time to Forgo Adjuvant Platinum-Based Chemotherapy in Resected IB-IIIA EGFR+ NSCLC (Except with RB Alterations?) When Adopting Adjuvant Osimertinib.

Adjuvant cisplatin-based chemotherapy is considered the standard of care for resected stage IB (tumor ≥ 4m)–IIIA non-small cell lung cancer (NSCLC). The ADAURA trial is a randomized placebo-controlled Phase III trial that demonstrated statistically significant improved disease-free survival (DFS) with the use of 3-years of adjuvant osimertinib in resected stage IB–IIIA NSCLC harboring epidermal growth factor receptor (EGFR) del 19 or L858R mutations. Subgroup analysis revealed that the DFS improvement with adjuvant osimertinib is independent of adjuvant chemotherapy in the primary analysis. A recent follow-up report suggested that adjuvant cisplatin-based chemotherapy provided no additional 2-year DFS improvement on top of adjuvant osimertinib regardless of stage (IB, II, or IIIA) and minimal numerical DFS benefit in stage II or IIIA resected EGFR+ NSCLC for those patients who did not receive adjuvant osimertinib. Here, we argue that if clinicians adopt the use of 3 years of adjuvant osimertinib in resected early-stage EGFR+ NSCLC, there is no role for adjuvant platinum-based chemotherapy. The use of adjuvant chemotherapy was balanced between the osimertinib and the placebo arms by stage even though adjuvant chemotherapy was not one of the three stratification factors (del 19 vs L858R; Stage IA vs II vs III; Asians versus non-Asian) in ADAURA. There may be a potential role of adjuvant cisplatin/vinorelbine in a small subgroup of EGFR+ NSCLC patients whose tumor harbors retinoblastoma (RB) gene alterations but requires further investigation.

ADAURA: The Splash of Osimertinib in Adjuvant EGFR-Mutant Non-small Cell Lung Cancer.

The introduction of tyrosine kinase inhibitors (TKI) for the treatment of metastatic non-small cell lung cancer (NSCLC) harbouring sensitizing epidermal growth factor receptor (EGFR) gene mutations revolutionized the diagnostic and treatment algorithm of this subset of patients almost two decades ago. Since then, a number of trials have evaluated the role of TKI therapy in early-stage disease, with encouraging disease-free survival (DFS) results but lack of a survival advantage. ADAURA, a phase III trial evaluating 3 years of adjuvant osimertinib versus placebo in patients harbouring EGFR mutations with completely resected stage IB–IIIA NSCLC, recently reported a profound DFS benefit (hazard ratio 0.21), favourable quality of life and reduction in the risk of brain metastases. These results led to osimertinib’s fast track approval by the US Food and Drug Administration, with this drug thus becoming the first EGFR-TKI approved for the treatment of early-stage disease. However, the key endpoint of overall survival remains immature and questions around indication (i.e. stage, need for adjuvant chemotherapy), optimal treatment duration, biomarkers of response and cost-effectiveness remain to be answered. In this article, we critically appraise the findings of ADAURA and discuss future challenges.

Circulating tumor DNA predicts neoadjuvant immunotherapy efficacy and recurrence-free survival in surgical non-small cell lung cancer patients.

BackgroundThere is currently a lack of effective biomarkers to evaluate efficacy of neoadjuvant therapy (NAT) for resectable non-small cell lung cancer (NSCLC) patients. Circulating tumor DNA (ctDNA) has been investigated as a non-invasive tool for the assessment of tumor burden and minimal residual disease (MRD). The utility of ctDNA profiling in reflecting NAT efficacy, however, has not been confirmed. This study explored the association of ctDNA change with treatment response to NAT and recurrence-free survival (RFS) after surgery.MethodsEligible patients with stage IB–IIIA NSCLC were retrospectively included if they had received neoadjuvant immunotherapy combined with chemotherapy (IO+Chemo), dual immunotherapy (IO+IO), or chemotherapy alone (Chemo). We conducted ctDNA profiling before and after NAT, after surgery, and during follow-ups using an ultra-deep lung cancer-specific MRD (LC-MRD) sequencing panel.ResultsA total of 22 patients who received NAT followed by surgery between August 2018 and July 2019 were included in this study. The major pathological response (MPR) rates were 58.33% (7/12) in the IO+Chemo group, 25.00% (1/4) in the IO+IO group, and 16.67% (1/6) in the Chemo group. The ctDNA dynamics during NAT were highly concordant with pathologic response, demonstrating 100% sensitivity and 83.33% specificity, for an overall accuracy of 91.67%. Pre-surgery detectable ctDNA (after NAT) trended to correlate with inferior RFS [hazard ratio (HR), 7.41; 95% confidence interval (CI): 0.91–60.22, log-rank P=0.03]. At 3-8 days after surgery, ctDNA was detectable in 31.8% of patients and was an independent risk factor for recurrence (HR, 5.37; 95% CI: 1.27–22.67; log-rank P=0.01). The presence of ctDNA at 3 months after surgery showed 83% sensitivity and 90% specificity for predicting relapse (C-index, 0.79; 95% CI: 0.62–0.95). During disease monitoring after surgery, molecular recurrence by means of ctDNA preceded radiographic relapse, with a median time of 6.83 months.ConclusionsThis study investigated the potential of ctDNA in evaluating NAT efficacy in NSCLC, implying the high concordance between ctDNA and pathological response. We also set out the prognostic value of perioperative ctDNA in predicting recurrence.

A Support Vector Machine Based on Liquid Immune Profiling Predicts Major Pathological Response to Chemotherapy Plus Anti-PD-1/PD-L1 as a Neoadjuvant Treatment for Patients With Resectable Non-Small Cell Lung Cancer.

The biomarkers for the pathological response of neoadjuvant chemotherapy plus anti-programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) (CAPD) are unclear in non-small cell lung cancer (NSCLC). Two hundred and eleven patients with stage Ib-IIIa NSCLC undergoing CAPD prior to surgical resection were enrolled, and 11 immune cell subsets in peripheral blood were prospectively analyzed using multicolor flow cytometry. Immune cell subtypes were selected by recursive feature elimination and least absolute shrinkage and selection operator methods. The support vector machine (SVM) was used to build a model. Multivariate analysis for major pathological response (MPR) was also performed. Finally, five immune cell subtypes were identified and an SVM based on liquid immune profiling (LIP-SVM) was developed. The LIP-SVM model achieved high accuracies in discovery and validation sets (AUC = 0.886, 95% CI: 0.823–0.949, P < 0.001; AUC = 0.874, 95% CI: 0.791–0.958, P < 0.001, respectively). Multivariate analysis revealed that age, radiological response, and LIP-SVM were independent factors for MPR in the two sets (each P < 0.05). The integration of LIP-SVM, clinical factors, and radiological response showed significantly high accuracies for predicting MPR in discovery and validation sets (AUC = 0.951, 95% CI: 0.916–0.986, P < 0.001; AUC = 0.943, 95% CI: 0.912–0.993, P < 0.001, respectively). Based on immune cell profiling of peripheral blood, our study developed a predictive model for the MPR of patients with NSCLC undergoing CAPD treatment that can potentially guide clinical therapy.

Abstract LBA035: Canakinumab or Pembrolizumab as Monotherapy or in Combination as Neoadjuvant Therapy in Patients With Resectable Non-Small Cell Lung Cancer: CANOPY-N Trial

Abstract Background: Complete surgical resection is the standard treatment for patients with stage I-IIIA non-small cell lung cancer (NSCLC). Five-year survival rates in this population range from 19% to 50%, with most patients dying from distant recurrence. As neoadjuvant/adjuvant chemotherapy yields a modest 5% absolute overall survival benefit for these patients with NSCLC, new treatment options are needed. Preliminary data with PD-1 or PD-L1 inhibitors as neoadjuvant therapy have shown major pathologic responses (MPRs) or pathologic complete responses in patients with resectable NSCLC. In the CANTOS study, reduced incidence of NSCLC and decreased lung cancer–related mortality were observed in a dose-dependent manner in patients with atherosclerosis who received canakinumab (interleukin 1β inhibitor) versus those who received placebo. In preclinical NSCLC humanized models, treatment with canakinumab ± anti–PD-1 inhibitor has shown promising activity, and a synergistic effect was observed with this combination, which may enhance the efficacy of PD-1 inhibition by modulating pro-tumor inflammation in the tumor microenvironment. In this context, the CANOPY-N study was designed to evaluate the effect of canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant treatment for patients with resectable NSCLC. Methods: CANOPY-N (NCT03968419) is a Phase II, randomized, open-label study evaluating the effect of canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant treatment in patients with resectable NSCLC. Patients with histologically confirmed stage IB-IIIA NSCLC (excluding N2 and T4 tumors), no prior systemic therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and eligibility for surgery with a planned resection in approximately 4-6 weeks after first dose of study treatment are eligible to participate. An archival (if obtained up to 6 months before first day of treatment) or new biopsy is required. Approximately 110 patients will be randomized in a 2:2:1 ratio (stratified by histology [squamous/nonsquamous]) to receive a total of 2 doses (200 mg every 3 weeks) of canakinumab alone (n=44) or in combination with pembrolizumab (n=44) or pembrolizumab alone (n=22), with safety follow-up up to 130 days from last study-drug dose. The primary endpoint is MPR rate (≤10% of residual viable tumor cells at time of surgery), and secondary endpoints include overall response rate per RECIST 1.1, MPR rate based on local assessment, surgical feasibility rates, safety, incidence of antidrug antibodies, pharmacokinetic parameters, and assessment of the relationship between blood- or tissue-based biomarkers and MPR. As of May 27, 2021, there are 44 active study locations. Citation Format: Jay M. Lee, Jean-Louis Pujol, Pilar Garrido, Edward S. Kim, Masahiro Tsuboi, Rafael Caparica Bitton, Jiawei Duan, Cecile Blin, Alexander Savchenko, Tony Mok. Canakinumab or Pembrolizumab as Monotherapy or in Combination as Neoadjuvant Therapy in Patients With Resectable Non-Small Cell Lung Cancer: CANOPY-N Trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA035.

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).

FP01.03 Prevalence, Treatment Patterns and Long-Term Clinical Outcomes of Patients with EGFR Positive Resected Stage IB-IIIA NSCLC

The phase III ADAURA trial showed a significant disease-free survival (DFS) benefit for adjuvant osimertinib versus placebo in resected stage IB-IIIA EGFR mutated non-small cell lung cancer (NSCLC). The aim of this analysis was to estimate EGFR mutation prevalence, treatment patterns and long-term outcomes in early stage (IB-IIIA) resected NSCLC patients in a real-world setting.

Prospective Clinical Study of Postoperative Individualized Adjuvant Chemotherapy for Patients with Non-Small-Cell Lung Cancer Based on mRNA Expression of the Molecular Markers RRM1, TUBB3, and ERCC1

Objective To investigate the clinical significance of the mRNA expression of RRM1, TUBB3, and ERCC1 in non-small-cell lung cancer (NSCLC) tissues for the selection of adjuvant/postoperative chemotherapy regimens. Methods Patients diagnosed with stage Ib-IIIa NSCLC were enrolled and randomly divided into a control group (undetected group) and an experimental group (detected group) after radical operation. The control group randomly received chemotherapy with gemcitabine plus cisplatin or paclitaxel plus cisplatin. The mRNA expression of RRM1, TUBB3, and ERCC1 was detected in the experimental group before chemotherapy, and based on the detected expression, the chemotherapy regimen of cisplatin plus gemcitabine or cisplatin plus paclitaxel was chosen. The disease-free survival (DFS) of the control group and experimental group was compared. Results Pathological type, stage, gene expression detection, and treatment method were not significantly correlated with DFS (P > 0.05). In the subgroups treated with gemcitabine, the median DFS was 17 months in the detected group and 10.5 months in the undetected group (hazard ratio = 0.2147, 95% confidence interval: 0.07909–0.5827, P=0.0025). Multivariate regression analysis was performed to analyse whether gene expression detection was independently correlated with DFS in the subgroups treated with gemcitabine (P=0.025). In the detected group, the prognosis of patients with low expression of RRM1 was better than that of patients with high expression of RRM1 after paclitaxel treatment (P=0.0039). Conclusions The selection of chemotherapy regimen based on mRNA expression of the RRM1, TUBB3, and ERCC1 genes may improve selection of candidate patients to receive clinical chemotherapy. However, large-scale prospective clinical studies are needed for in-depth investigation.

Surgical perspective in neoadjuvant chemoimmunotherapy for stage II-III non-small cell lung cancer.

BackgroundThere are many studies on neoadjuvant immunotherapy for locally advanced non‐small cell lung cancer (NSCLC) patients. Expert consensus recommends neoadjuvant immunotherapy for patients with resectable stage IB–IIIA NSCLC. However, there are few clinical studies or cases to verify this.MethodsData were collected from all NSCLC patients who underwent surgical resection after neoadjuvant chemoimmunotherapy admitted to the Affiliated Hospital of Xuzhou Medical University and Xuzhou Central Hospital between September 2020 and April 2021. Data collected included patient information, relevant examination results, intraoperative parameters, postoperative complications, pathological changes, and 90‐day mortality.ResultsIn total, 25 patients achieved R0 resection. Eleven (44%) patients completed surgery by thoracotomy, and three (12%) procedures were changed from minimally invasive procedures due to dense adhesions of hilar lymph nodes, which rendered it difficult to dissect the blood vessels. Thirteen (52%) patients achieved a major pathological response (MPR) with eight (32%) of these patients having a pathological complete response (pCR). Twenty‐two (88%) patients showed radiological regression, and three (12%) patients had stable disease. The median drainage time was 8.50 (3–27) days. Thirteen (52%) postoperative complications were observed, but none were above grade 3.ConclusionsIn this study, neoadjuvant chemoimmunotherapy was found to reduce tumor volume, cause pathological downstaging, and raise the surgical resection rate of patients with locally advanced NSCLC, and achieve a 100% R0 resection rate. There was an acceptable rate of postoperative complications. Thus, neoadjuvant chemoimmunotherapy is safe and practical.

Abstract CT237: Canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant therapy in patients with surgically resected non-small cell lung cancer: CANOPY-N trial

Abstract Background: Complete surgical resection is the standard treatment for patients with stage I-IIIA non-small cell lung cancer (NSCLC). Five-year survival rates range from 19% to 50%, with most patients dying from distant recurrence. Neoadjuvant or adjuvant chemotherapy improves overall survival (OS) by only 5% in patients with NSCLC, and new treatment options are needed. Preliminary data for PD1 or PD-L1 inhibitors as neoadjuvant therapy have shown major pathologic responses (MPRs) or pathologic complete responses (pCRs) in patients with early-stage NSCLC. The CANTOS study demonstrated reduced incidence of NSCLC and decreased lung cancer-related mortality with canakinumab (interleukin 1β inhibitor) versus placebo, in a dose-dependent manner for patients with atherosclerosis. In preclinical NSCLC humanized models, treatment with canakinumab ± anti-PD-1 inhibitor could lead to antitumor activity. Combination of canakinumab and pembrolizumab is expected to enhance the efficacy of PD-1 inhibition by inhibiting dysregulated inflammation in the tumor microenvironment. Based on available evidence, the CANOPY-N study was designed to evaluate the effect of canakinumab and pembrolizumab as monotherapy or in combination as neoadjuvant treatment for patients with resectable NSCLC. Methods: CANOPY-N (NCT03968419) is a Phase II, randomized, open-label study evaluating the effect of canakinumab and pembrolizumab as monotherapy or in combination as neoadjuvant treatment in patients with resectable NSCLC. Patients with histologically confirmed stage IB-IIIA NSCLC (excluding N2 and T4 tumors), no prior systemic therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and eligibility for surgery and with a planned surgical resection in approximately 4-6 weeks (after first dose of study treatment) are eligible to participate. An archival (if obtained up to 6 months before first day of treatment) or new biopsy is required. Approximately 110 patients will be randomized in a 2:2:1 ratio (stratified by histology [squamous/nonsquamous]) to one of the treatment arms to receive a total of 2 doses (200 mg every 3 weeks) of canakinumab alone (n=44) or in combination with pembrolizumab (n=44) or pembrolizumab alone (n=22), with safety follow-up up to 130 days from last study drug dose. The primary endpoint is MPR rate (≤10% of residual viable tumor cells at time of surgery), and secondary endpoints include determination of overall response rate, MPR rate based on local review, surgical feasibility rates, incidence of antidrug antibodies, and pharmacokinetic parameters. As of October 19, 2020, there are 36 active study locations. Citation Format: Jay M. Lee, Tony Mok, Pilar Garrido, Edward S. Kim, Çağatay Arslan, Masahiro Tsuboi, Tuochuan Dong, Cecile Blin, Vanessa Rodrik-Outmezguine, Bijoyesh Mookerjee, Vanessa Passos, Jean-Louis Pujol. Canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant therapy in patients with surgically resected non-small cell lung cancer: CANOPY-N trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT237.

The role of EGFR-TKIs as adjuvant therapy in EGFR mutation-positive early-stage NSCLC: A meta-analysis.

BackgroundThe role of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) is not clear in early‐stage nonsmall‐cell lung cancer (NSCLC) patients. This meta‐analysis aims to compare the efficacy and safety of EGFR‐TKIs as adjuvant therapy with chemotherapy or placebo in NSCLC patients harboring EGFR mutations.Patients and MethodsPubmed, Embase, and Cochrane databases were searched for randomized controlled trials. The hazard ratio (HR) of disease‐free survival (DFS) and overall survival (OS) as well as the risk ratio (RR) of severe adverse events were merged.ResultsSeven articles from five studies from 1843 records, a total of 1227 patients, were included in the analysis. The HR for DFS was 0.38 (95% confidence interval [CI] 0.22–0.63), in favor of EGFR‐TKIs. However, no significant benefit of OS was seen (HR = 0.61, 95% CI 0.31–1.22). Treatment benefit was more pronounced in patients with advanced disease stage and longer duration of medication, EGFR exon 19 deletion mutation, and treatment with third‐generation EGFR‐TKIs. Adjuvant targeted therapy may cause few adverse events compared with chemotherapy (RR = 0.28, 95% CI 0.09–0.94). The possibility of severe adverse events for the first‐generation drugs was significantly lower than for third‐generation drugs.ConclusionIn EGFR mutation‐positive patients with stage IB–IIIA NSCLC, compared with adjuvant chemotherapy or placebo, adjuvant EGFR‐TKIs should effectively improve the patient's DFS, but not effectively improve OS. Disease stage, treatment duration, mutation types, and therapeutic drugs could affect the degree of benefit. Adjuvant EGFR‐TKIs had more favorable tolerability than chemotherapy, especially with the usage of first‐generation drugs.

Expert consensus on neoadjuvant immunotherapy for non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related death worldwide and in China (1). According to the statistics of the National Cancer Center of China, there were 733,300 new cases of non-small cell lung cancer (NSCLC) and approximately 610,200 related deaths in 2015 (2). For patients with early staged disease, surgery is the mainstay of treatment, and it is commonly followed by adjuvant chemotherapy for patients with locally advanced resectable NSCLC. Although complete surgical resection may be curative for NSCLC, 25–70% of patients (with different proportion according to stage) eventually relapse despite complete resection (3). Platinum-based adjuvant chemotherapy has been shown to marginally increase the 5-year survival rate of patients by 4–8% (4-6). Even after treatment with surgery and indicated adjuvant therapies in eligible cases, approximately 20–30% of stage I, 50% of stage II, and 60% of stage IIIA patients still die within 5 years (7). In the past decade, experts have conducted a number of investigations on the perioperative management of resectable NSCLC; however, progress remains slow, and patients still have a high risk of recurrence and death. Neoadjuvant therapy is defined as any therapy delivered prior to definitive local therapy intended to increase the cure rate. It provides several theoretical benefits in managing such patients with NSCLC. In the setting of, neoadjuvant therapy given prior to radical surgery this approach can also have the goals of downstaging, improving the resection rate, and more promptly treating subclinical micro-metastases than adjuvant approaches, delivered after the definitive local therapy. In addition, the compliance with neoadjuvant therapy has been shown to be better than in the adjuvant setting, and the biological effect of the neoadjuvant therapy can be analyzed directly in the resected tumor specimens (8). A meta-analysis on patients with stage IB‒IIIA NSCLC that compared chemotherapy plus subsequent surgery vs. surgery alone showed that the 5-year survival rate was 5% higher after receiving neoadjuvant chemotherapy (NCT) (9). Therefore, the comprehensive NSCLC data suggest that, for resectable NSCLC, NCT improves survival compared with surgery alone but appear to show no significant survival benefit compared with adjuvant chemotherapy (10). In the last 5 years, immune checkpoint inhibitors (ICIs) have profoundly changed the treatment paradigm for patients with advanced NSCLC (11-15). Immunotherapy has provided hope for long-term survival benefits to a minority of patients with metastatic lung cancer. For treatment-naive patients with driver mutation-negative NSCLC, the 5-year survival rate of single agent pembrolizumab was 23.2%; for the previously treated patients with driver mutation-negative NSCLC, the 5-year survival rates of single agent pembrolizumab and nivolumab were 15.5% and 16%, respectively (16,17). Given the profound impact made by immunotherapy drugs for patients with advanced disease, significant attention has been directed in recent years toward investigating the potential role for early-stage NSCLC patients, and whether they, too, can achieve long-term benefits from the inclusion of immunotherapy into their treatment algorithms. Many phase Ib/II clinical trials have reported promising results, and a series of large-scale phase III clinical trials are underway. However, these various investigations have employed different strategies of neoadjuvant immunotherapy, in terms of the specific regimens as well as number of treatment cycles (18). To better guide Chinese thoracic surgeons in the neoadjuvant immunotherapy of NSCLC, well-known thoracic surgeons in China participated in an in-depth discussion on the hot topics and controversial issues of neoadjuvant immunotherapy and formed the Expert consensus on neoadjuvant immunotherapy for non-small-cell lung cancer by incorporating the latest evidence on neoadjuvant immunotherapy.