Major Pathologic Response Research Articles

Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial.

Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3. In the NICHE-3 study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg) before surgery. Pathologic response was observed in 57 of 59 (97%; 95% confidence interval (CI): 88-100%) patients, meeting the primary endpoint. Responses included 54 (92%; 95% CI: 81-97%) major pathologic responses (≤10% residual viable tumor) and 40 (68%; 95% CI: 54-79%) pathologic complete responses. With a median follow-up of 8 months (range, 2-19), one patient had recurrence of disease. The treatment displayed an acceptable safety profile, with all-grade and grade 3-4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). In conclusion, our results show that neoadjuvant nivolumab/relatlimab induces high rates of pathologic responses and that further investigation of this treatment in larger studies is warranted. These data add to the body of evidence in support of neoadjuvant immunotherapy regimens in dMMR CC. ClinicalTrials.gov identifier: NCT03026140 .

Identifying patients who benefit more from perioperative immunotherapy combinations for resectable non-small cell lung cancer based on clinical and molecular characteristics: a meta-analysis of randomized clinical trials.

This study aims to identify patient subgroups who benefit more from perioperative immunotherapy combined with chemotherapy (IO-CT) based on clinical and molecular characteristics in resectable non-small cell lung cancer (NSCLC). Randomized controlled trials (RCTs) on perioperative IO-CT were searched. Beneficial differences of IO-CT regimens across different patient subgroups were assessed by pooling trial-specific ratios in event-free survival (EFS), overall survival (OS), pathological complete response (pCR), and major pathological response (MPR). Six studies (n = 3003) involving five IO-CT regimens were included. Compared to CT alone, all IO-CT regimens significantly improved EFS, OS, MPR, and pCR, but increased toxicity. Toripa-chemo showed the best EFS and nivo-chemo showed the best OS. Patients with PD-L1 ≥ 1% had more EFS benefits compared to those with PD-L1 < 1% (HR [hazard ratio]: 1.55, 95% CI 1.17-2.04). Squamous NSCLC patients had significantly more pCR and MPR benefits than non-squamous NSCLC patients (pCR: OR [odds ratio] 0.68, 95% CI 0.49-0.95; MPR: OR 0.61, 95% CI 0.45-0.82). Former smokers had significantly higher pCR benefits than non-smokers (OR: 2.18; 95% CI 1.21-3.92). Additionally, OS benefit was significantly higher in patients < 65years compared to those ≥ 65years (HR ratio: 0.59, 95% CI 0.36-0.95). For MPR, males benefited significantly more from IO-CT compared to females (OR: 1.69, 95% CI 1.18-2.42). Perioperative IO-CT is more effective but more toxic than CT alone in resectable NSCLC. Patients with PD-L1 ≥ 1%, squamous NSCLC, a history of smoking, age < 65years and male gender may experience greater benefits from perioperative IO-CT.

Impact of proton pump inhibitors on pathologic response rates following fluoropyrimidine-based neoadjuvant chemotherapy in pancreatic cancer patients.

Proton pump inhibitors (PPIs) negatively impact fluoropyrimidine-based chemotherapy efficacy in colorectal cancer. This study assessed PPI impact on major pathologic response (mPR) rates of pancreatic adenocarcinoma (PDAC) patients receiving fluoropyrimidine-based chemotherapy. An institutional retrospective review of resected PDAC patients receiving neoadjuvant fluoropyrimidine-based chemotherapy (98% FOLFIRINOX) from 2011 to 2021 was conducted. Outcomes were stratified by use or nonuse of PPIs within 6 months of neoadjuvant chemotherapy initiation. Primary outcome was mPR defined as complete or near complete response. Among 540 patients included, the median age was 64 (IQR: 60-70) years, 297 (55%) were male, and 202 (37%) were PPI users. 170 (31%) patients had mPR with similar rates among PPI users and nonusers (29% vs. 33%, p = 0.38). No difference in mPR was seen between PPI users and nonusers receiving chemoradiation (35% vs. 36%, p = 0.89) or ≥8 cycles of NAC (33% vs. 36%, p = 0.55). Median OS for PPI users was 30.9 versus 31.7 months for nonusers (p = 0.62). On multivariable analysis, PPI therapy was not associated with decreased survival. PPI usage did not significantly influence mPR or OS following neoadjuvant fluoropyrimidine-based chemotherapy in resected PDAC patients. Further analysis of all patients, not just those who underwent resection, is required.

The utility of 18F-FDG PET/CT for predicting the pathological response and prognosis to neoadjuvant immunochemotherapy in resectable non-small-cell lung cancer

ObjectiveTo evaluate the potential utility of 18F-FDG PET/CT to assess response to neoadjuvant immunochemotherapy in patients with resectable NSCLC, and the ability to screen patients who may benefit from neoadjuvant immunochemotherapy.MethodsFifty one resectable NSCLC (stage IA–IIIB) patients were analyzed, who received two-three cycles neoadjuvant immunochemotherapy.18F-FDG PET/CT was carried out at baseline(scan-1) and prior to radical resection(scan-2). SULmax, SULpeak, MTV, TLG, T/N ratio, ΔSULmax%,ΔSULpeak%, ΔMTV%, ΔTLG%,ΔT/N ratio% were calculated. 18F-FDG PET/CT responses were classified using PERCIST. We then compared the RECIST 1.1 and PERCIST criteria for response assessment.With surgical pathology of primary lesions as the gold standard, the correlation between metabolic parameters of 18F-FDG PET/CT and major pathologic response (MPR) was analyzed. All metabolic parameters were compared to treatment response and correlated to PFS and OS.ResultsIn total of fifty one patients, MPR was achieved in 25(49%, 25/51) patients after neoadjuvant therapy. The metabolic parameters of Scan-1 were not correlated with MPR.The degree of pathological regression was negatively correlated with SULmax, SULpeak, MTV, TLG, T/N ratio of scan-2, and the percentage changes of the ΔSULmax%, ΔSULpeak%, ΔMTV%,ΔTLG%,ΔT/N ratio% after neoadjuvant therapy (p < 0.05). According to PERCIST, 36 patients (70.6%, 36/51) showed PMR, 12 patients(23.5%, 12/51) had stable metabolic disease(SMD), and 3 patients(5.9%, 3/51) had progressive metabolic disease (PMD). ROC indicated that all of scan-2 metabolic parameters and the percentage changes of metabolic parameters had ability to predict MPR and non-MPR, SULmax and T/N ratio of scan-2 had the best differentiation ability.The accuracy of RECIST 1.1 and PERCIST criteria were no statistical significance(p = 0.91). On univariate analysis, ΔMTV% has the highest correlation with PFS.ConclusionsMetabolic response by 18F-FDG PET/CT can predict MPR to neoadjuvant immunochemotherapy in resectable NSCLC. ΔMTV% was significantly correlated with PFS.

Neoadjuvant Osimertinib for the Treatment of Stage I-IIIA Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: A Phase II Multicenter Study.

To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC). This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling. A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%). Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

Histological Assessment and Interobserver Agreement in Major Pathologic Response for Non-Small Cell Lung Cancer with Neoadjuvant Therapy.

Major pathologic response (MPR), defined as ≤10% of residual viable tumor (VT), is a prognostic factor in non-small cell lung cancer (NSCLC) after neoadjuvant therapy. This study evaluated interobserver reproducibility in assessing MPR, compared area-weighted and unweighted VT (%) calculation, and determined optimal VT (%) cutoffs across histologic subtypes for survival prediction. This retrospective study included 108 patients with NSCLC who underwent surgical resection after neoadjuvant chemotherapy or chemoradiation at Seoul National University Bundang Hospital between 2009-2018. Three observers with varying expertise independently assessed tumor bed and VT (%) based on digital whole-slide images. Reproducibility in tumor bed delineation was reduced in squamous cell carcinoma (SqCC) with smaller tumor bed, although overall concordance was high (Dice coefficient, 0.96; IoU score, 0.92). Excellent agreement was achieved for VT (%) (ICC=0.959) and MPR using 10% cutoff (Fleiss' kappa=0.911). Shifting between area-weighted and unweighted VT (%) showed only one case differing in MPR status out of 81 cases. The optimal cutoff was 10% for both adenocarcinoma (ADC) and SqCC. MPR+ was observed in 18 patients (17%), with SqCC showing higher MPR+ rates (p=0.044), lower VT (%) (p<0.001), and better event-free survival (p=0.015) than ADC. MPR+ significantly improved overall survival (p=0.023), event-free survival (p=0.001), and lung cancer-specific survival (p=0.012). While MPR assessment demonstrated robust reproducibility with minimal impact from the tumor bed, attention is warranted when evaluating smaller tumor beds in SqCC. A 10% cutoff reliably predicted survival across histologic subtypes with higher interobserver reproducibility.

Secretome and immune cell attraction analysis of head and neck cancers

Immune checkpoint inhibitors are approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) but the response rate is only 13–18%. For an effective antitumor immune response, trafficking of immune cells to the tumor microenvironment (TME) is essential. We aimed to better understand immune cell migration as well as the involved chemokines in HNSCC. A transwell assay was used to study immune cell migration toward TME-conditioned medium. While T cell migration was not observed, conventional dendritic cell (cDC) migration was induced by TME-conditioned media. cDC migration correlated with various proteins in the TME secretome. CCL8, CXCL5, CCL13 and CCL7 were tested in validation experiments and addition of these chemokines induced cDC migration. Using single cell RNA-sequencing, we observed expression of CCL8, CXCL5, CCL13 and CCL7 in cancer-associated fibroblasts (CAFs). Depleting fibroblasts led to reduced cDC migration. Thus CAFs, while often seen as suppressors of antitumor immunity, play a role in attracting cDCs toward the head and neck cancer TME, which might be crucial for effective antitumor immunity and response to therapies. Indeed, we found RNA expression signatures of the indicated chemokines, cDC and CAF subpopulations, to be significantly higher in baseline tumor specimen of patients with a major pathological response to pre-surgical anti-PD-1 treatment compared to non-responding patients.

The short-term efficacy of neoadjuvant SOX versus SOX plus immune checkpoint inhibitor following laparoscopic gastrectomy for locally advanced gastric cancer: a multicenter retrospective cohort study in China

BackgroundThis study aims to evaluate the short-term efficacy for locally advanced gastric cancer (LAGC) who accepted laparoscopic gastrectomy (LG) after neoadjuvant SOX versus SOX plus immune checkpoint inhibitors (ICIs).MethodsLAGC patients who accepted LG after neoadjuvant SOX (SOX-LG, n = 169) and SOX plus ICIs (SOX + ICIs-LG, n = 140) in three medical centers between Jan 2020 and Mar 2024 were analyzed. We compared the tumor regression, treatment-related adverse events (TRAEs), perioperative safety between two groups, and explored the risk factors of postoperative complications (POCs) for LG after neoadjuvant therapy.ResultsThe baseline characteristics were comparable between two groups (P > 0.05). SOX + ICIs-LG group acquired a higher proportion of objective response (63.6% vs. 46.7%, P = 0.003), major pathological response (43.6% vs. 31.4%, P = 0.001), and pathological complete response (17.9% vs. 9.5%, P = 0.030). There were no significant differences in the TRAEs rates, operation time, R0 resection, retrieved lymph nodes, postoperative first flatus, and hospitalized days, overall and severe POCs between two groups (P > 0.05). Patients in the SOX-ICIs-LG group had lower estimated blood loss (EBL) compared with SOX-LG (P = 0.001). Multivariate analysis showed that more EBL (P = 0.003) and prognostic nutritional index (PNI) < 40 (P = 0.005) were independent risk factors of POCs for LG after neoadjuvant therapy.ConclusionNeoadjuvant SOX plus ICIs brings better tumor regression and similar TRAEs compared with SOX alone for LAGC. SOX + ICIs-LG is safe and feasible to conduct with less EBL. Surgeons should focus on the perioperative management to control POCs for patients with PNI < 40 and more EBL.

Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study

Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.

413. LYMPH NODE MAJOR PATHOLOGIC RESPONSE IS A POTENTIAL PROGNOSTIC FACTOR AFTER NEOADJUVANT CHEMORADIOTHERAPY IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Esophageal cancer ranks tenth in incidence and is the sixth most common cause of cancer-related deaths. Neoadjuvant chemoradiotherapy before and after surgery has been shown to improve ESCC patients' survival compared with surgery alone. However, the outcomes of nCRT are heterogeneous, and clinical or pathological methods that can predict nCRT responses have been extensively studied. There are currently no standard grading methods that assess the treatment response in lymph nodes after nCRT. We aimed to assess the clinicopathological relevance and determine the prognostic significance of lymph node major pathologic response (MPR) after nCRT in ESCC patients. Methods Patients who received nCRT for ESCC followed by surgery were retrospectively reviewed and classified into different lymph node stage (LNS) according to their pathological regression: LNS0 (no tumor cells in lymph node before nCRT); LNS1 (residual tumor cells in lymph node after nCRT≤50%; major pathologic response); LNS2 (residual tumor cells in lymph node after nCRT&amp;gt;50%; not major pathologic response). Results In total, 187patients, comprising 91,49 and 47 patients with LNS stage of 0(no tumor cells in lymph node before nCRT),1(major pathologic response), or 2(not major pathologic response), respectively, were included. The result showed that the higher LNS stage was strongly associated with decreased overall survival (P&amp;lt;0.001) and disease-free survival (P&amp;lt;0.001), and increased recurrence risks (P=0.002). The cox regression showed MPR was significantly an independent prognostic factor of OS and DFS. Among 96 patients with clinically positive LNs,54patients (56.3%) showed discordance between the PT and LN pathological regression grades. Conclusions Residual tumor cells in lymph node after nCRT≤50% could be defined as lymph node major complete response. The Lymph node MPR can be an independent prognostic indicator of ESCC patients who received nCRT plus curative surgery.

Impact of Duration of Adjuvant Therapy on Patients with Initially Unresectable Hepatocellular Carcinoma After Conversion Surgery: A Propensity Score Matching Study.

This study aimed to assess the effect of adjuvant therapy with different durations in patients with initially unresectable hepatocellular carcinoma (uHCC) after conversion surgery. This study included 85 patients with initially uHCC who received conversion surgery between May 2019 and November 2022. They were divided into the long duration group (n = 57) and short duration group (n = 28) based on postoperative medication duration. Recurrence-free survival (RFS) and overall survival (OS) were analyzed and compared between the cohorts. No significant difference in RFS or OS was found between the two groups [RFS: hazard ratio (HR) = 0.486; 95% confidence interval (CI), 0.229-1.034, P = 0.061; OS: HR = 0.377; 95% CI, 0.119-1.196, P = 0.098]. Patients without major pathologic response (MPR) in the long duration group had better RFS and OS results compared to those in the short duration group (RFS: HR = 0.242; 95% CI, 0.092-0.634, P = 0.004; OS: HR = 0.264; 95% CI, 0.079-0.882, P = 0.031). No significant difference was detected in RFS or OS between the two groups in patients with MPR (RFS: HR = 1.250; 95% CI, 0.373-4.183, P = 0.718; OS: HR = 7.389; 95% CI, 0.147-372.4, P = 0.317). After propensity score matching, 25 pairs of patients were selected and the results remained consistent. At least 6 months of adjuvant therapy may be beneficial for patients without MPR after conversion surgery. However, in patients with MPR, the effect of adjuvant therapy remains unclear. Further studies are needed to confirm the optimal duration of adjuvant therapy.

Single-arm trial of neoadjuvant ipilimumab plus nivolumab with chemoradiotherapy in patients with resectable and borderline resectable lung cancer: the INCREASE study

BackgroundIn non-small cell lung cancer (NSCLC), chemoradiotherapy (CRT) yields pathological complete response (pCR) rates of approximately 30%. We investigated using ipilimumab plus nivolumab (IPI-NIVO) with neoadjuvant CRT in resectable, and...

Single-cell RNA sequencing reveals microenvironmental infiltration in non-small cell lung cancer with different responses to immunotherapy.

Immunotherapy represents a groundbreaking and monumental achievement in the field of cancer therapy, marking a significant advancement in fighting against this devastating disease. Lung cancer has showed consistent clinical improvements in response to immunotherapy treatments, yet, it is undeniable that challenges such as limited response rates acquire resistance, and the unclear fundamental mechanisms were inevitable problems. The cellular composition was defined and distinguished through single-cell RNA sequencing (scRNA-seq) analysis of MPR (major pathologic response) and NMPR (non-major pathologic response) samples in GSE207422, including four primary MPR samples and eight primary NMPR samples. We found obvious difference in CD8+ T cell population between MPR and NMPR samples, with high expression of TYMS, RRM2, and BIRC5 in NPMR samples. Meanwhile, the proportion of macrophages and tumor epithelial cells infiltration increased in the NMPR samples. We discovered biomarkers (ACTN4, ATF3, BRD2, CDKN1A, and CHMP4B) in epithelial cells which were potentially represented worse outcomes. By exploring the difference of tumor microenvironment (TME) in samples with different corresponding degrees of neoadjuvant immunotherapy, this research introduces a number of novel biomarkers for predicting the response of treatment and a theoretical basis for overcoming immunotherapy resistance.

384. NEOADJUVANT ANLOTINIB COMBINED WITH PENPULIMAB FOR RESECTABLE LOCALLY ADVANCED ESOPHAGEAL SQUAMOUS CELL CARCINOMA (ESCC): A PROSPECTIVE, SINGLE-ARM, PHASE II TRIAL

Abstract Background Neoadjuvant chemoradiation therapy followed by radical surgery has been extensively recommended for locally advanced esophageal squamous cell carcinoma (ESCC). However, toxicities and challenges to the subsequent surgery limit its wide clinical application. Immune checkpoint inhibitors combined with antiangiogenesis have synergistic effects and have shown good therapeutic effects in previous studies, as well as fewer side effects. Here, we tested a novel combination of anlotinib (an antiangiogeneic kinase inhibitor) and penpulimab (an anti-PD-1 antibody), without the use of radio- or chemo-therapy, for the neoadjuvant therapy of locally advanced ESCC. Methods In this prospective, single-arm, phase II clinical trial (ChiCTR2200064848), patients with resectable locally advanced ESCC (clinical stage III-IVa) were recruited. The study was designed using a two-stage minimax approach. The planned sample size was 40 patients would provide 80% power at a one-sided alpha error of 5%, threshold pathological complete response (pCR) of 16% and expected pCR of 30%. Here, the first-stage data was included. Notably, 85% (22/25) enrolled patients had medical contraindications (including cardiopulmonary diseases or other underlying medical conditions, along with poor nutritional status and so on). Patients received neoadjuvant therapy with anlotinib (8 mg, po, D1-14, Q3W) combined with penpulimab (200 mg, ivgtt, Q3W) for 2 cycles. Six to eight weeks later, patients underwent radical surgery after exclusion of contraindications. The primary endpoint was pathologic complete response (pCR) rate. Secondary endpoints included tumor regression grade (TRG), R0 resection rate, objective response rate (ORR) and safety profile. Results From Jan 2023 to Sep 2023, 25 patients (19 males and 6 females) were enrolled with a median age of 67 years (range: 50-74). All patients were available for efficacy assessment and 16 were evaluable for the primary end point. The rest of the patients are waiting for surgery. As of 15 Sep, 2023, 19 patients underwent esophagectomy and R0 resection rate was 87.5%. The pCR rate was 18.8% (3/16) and 31.3% of patients had a major pathologic response (MPR). The ORR and DCR were 48.0% and 96.0%, respectively. 84.0% of patients experienced grade 1-2 treatment-related adverse events (TRAEs), 3 (12.0%) patients experienced grade 3 TRAEs (2 elevated blood pressure and 1 elevation of liver enzymes). The safety profile revealed that the most common TRAEs (≥10%) included hypertension (28.0%), hand-foot syndrome (20%), fatigue (20%), abdominal pain (12%), toothache (12%). Conclusions The preliminary results of this study show promising safety and efficacy of anlotinib combined with penpulimab as neoadjuvant for patients with ESCC, especially for patients not suitable for neoadjuvant chemoradiation or chemotherapy. More ESCC patients would be recruited in the future.

448. PREOPERATIVE PEMBROLIZUMAB COMBINED WITH CHEMOTHERAPY FOR THORACIC ESCC WITH CERVICAL LYMPH NODE METASTASIS (PICC-1): A PROSPECTIVE, PHASE 2 STUDY

Abstract Background Thoracic esophageal squamous cell carcinoma patients with cervical lymph node metastasis have poor prognosis and less effective of first-line therapy. The PICC-1 study aimed to assess efficacy and safety of the pembrolizumab combined with chemotherapy for patients with cervical lymph node metastasis. Methods Preoperative therapy includes pembrolizumab, nab-paclitaxel and cisplatin every three weeks for 2 cycles. The surgery was performed 3-6 weeks after the completion of the preoperative neoadjuvant therapy. Three weeks after surgery, two periods of maintenance therapy were continued with pembrolizumab combined with chemotherapy. Then maintenance treatment was continued with pembrolizumab for a full year. The primary endpoint was the pathologic complete response (pCR) rate. The secondary endpoints included the R0 resection rate, the major pathological response (MPR), recurrence-free survival (RFS), overall survival (OS) and perioperative complications. Results As of December 31, 2023, 22 patients who met the criteria were enrolled. All 22 patients suffered from treatment-related AEs of any grade during the neoadjuvant treatment period. The majority of AEs were lymphopenia (72.7%), anemia (59.1%), neurotoxicity (77.3%), nausea/vomiting (77.3%) and leukopenia (40.9%). In 8 of the 22 patients (36.4%), grade III or higher AEs were observed. All the patients underwent thoraco-laparoscopic esophagectomy without intraoperative conversion to open surgery. R0 resection was achieved in 90.9% of patients (20/22). pCR and mPR were observed in 31.8% (7/22) and 13.6% (3/22) of the resected patients, respectively. No patient died postoperatively. Conclusions Esophagectomy after neoadjuvant immunochemotherapy is a promising radical treatment for thoracic esophageal squamous cell carcinoma patients with cervical lymph node metastasis. R0 resection was achieved in 90.9% of patients, and pCR was observed in 31.8% (7/22) of resected patients.

A Phase II Study of Neoadjuvant Opnurasib KRAS G12C Inhibitor in Patients With Surgically Resectable Non-Small Cell Lung Cancer (CCTG IND.242A): A Substudy of the IND.242 Platform Master Protocol

Molecularly targeted agents are increasingly being studied in the treatment of early-stage non-small cell lung cancer (NSCLC) to try and improve cure. However, phase 3 data on neoadjuvant therapy have largely been conducted in a biomarker agnostic manner with inconsistent exclusion of EGFR and ALK alterations. Our objective was to develop IND.242 as a large-scale neoadjuvant platform trial to introduce novel agents into the preoperative window for molecularly-defined NSCLC patient populations. Given that KRAS G12C mutations are common in the overall NSCLC patient population, ranging from 9.4% to 13% of cases across different cohorts, and may be associated to worse prognosis, the initial IND.242A Substudy was designed to test neoadjuvant JDQ443 (opnurasib), a selective KRAS G12C inhibitor. This current trial report describes the multicenter, Canadian Cancer Trials Group (CCTG)-led IND.242 neoadjuvant phase 2 platform master protocol and its first Substudy (IND.242A) of neoadjuvant opnurasib KRAS G12C inhibitor for patients with surgically resectable NSCLC (AJCC 8th edition stage IA2 to IIIA). In IND.242A, a maximum of 27 patients will be accrued in participating Canadian sites. The primary objective is the rate of major pathological response (MPR) following neoadjuvant opnurasib. Secondary objectives include safety and tolerability of the treatment regimen, objective response rate (ORR) by RECIST 1.1 for the neoadjuvant treatment period, pathological complete response (pCR) rate, event-free survival (EFS) at 2 years, and surgical outcomes. Exploratory objectives are to explore patient related outcomes (PROs) and identify potential predictive biomarkers of response and mechanisms of resistance on tissue and peripheral blood samples.

Spatial proteomic profiling elucidates immune determinants of neoadjuvant chemo-immunotherapy in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) presents significant clinical and therapeutic challenges due to its aggressive nature and generally poor prognosis. We initiated a Phase II clinical trial (ChiCTR1900027160) to assess the efficacy of a pioneering neoadjuvant chemo-immunotherapy regimen comprising programmed death-1 (PD-1) blockade (Toripalimab), nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the oral fluoropyrimidine derivative S-1, in patients with locally advanced ESCC. This study uniquely integrates clinical outcomes with advanced spatial proteomic profiling using Imaging Mass Cytometry (IMC) to elucidate the dynamics within the tumor microenvironment (TME), focusing on the mechanistic interplay of resistance and response. Sixty patients participated, receiving the combination therapy prior to surgical resection. Our findings demonstrated a major pathological response (MPR) in 62% of patients and a pathological complete response (pCR) in 29%. The IMC analysis provided a detailed regional assessment, revealing that the spatial arrangement of immune cells, particularly CD8+ T cells and B cells within tertiary lymphoid structures (TLS), and S100A9+ inflammatory macrophages in fibrotic regions are predictive of therapeutic outcomes. Employing machine learning approaches, such as support vector machine (SVM) and random forest (RF) analysis, we identified critical spatial features linked to drug resistance and developed predictive models for drug response, achieving an area under the curve (AUC) of 97%. These insights underscore the vital role of integrating spatial proteomics into clinical trials to dissect TME dynamics thoroughly, paving the way for personalized and precise cancer treatment strategies in ESCC. This holistic approach not only enhances our understanding of the mechanistic basis behind drug resistance but also sets a robust foundation for optimizing therapeutic interventions in ESCC.

575. PATHOLOGIC RESPONSE AND RESIDUAL LYMPH NODE PATTERNS IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA PATIENTS UNDERGOING NEOADJUVANT IMMUNOCHEMOTHERAPY COMPARED TO NEOADJUVANT CHEMORADIOTHERAPY

Abstract Background Concurrent chemoradiotherapy is the cornerstone treatment for locally advanced esophageal cancer. Immunochemotherapy, established as the standard treatment for advanced esophageal cancer, concurrently exhibits excellent short-term efficacy in the neoadjuvant stage. Combining concurrent chemoradiotherapy with immunochemotherapy may enhance control over primary tumor and metastatic lymph nodes, potentially improving patients’ outcomes and survival. Therefore, comparing the pros and cons of these two treatment modalities in controlling primary lesions and lymph node metastasis is crucial for guiding clinical treatment. Methods Our study enrolled a total of 137 patients with esophageal squamous cell carcinoma (ESCC) who underwent neoadjuvant immunochemotherapy (NICT) and 151 ESCC patients who underwent neoadjuvant chemoradiotherapy (NCRT) between January 2019 and March 2022. We documented baseline patient characteristics, including clinical TNM stage, tumor location, and clinical metastatic lymph nodes, as well as pathologic outcomes such as pathological stage, pathologic complete response (pCR), tumor regression grade (TRG), and pathological metastatic lymph nodes. To balance baseline patient characteristics, we employed inverse probability of treatment weighting (IPTW) to adjust for confounding in different neoadjuvant treatment groups. Results After balancing baseline characteristics, there was no statistically significant difference in pathologic outcomes, including pCR rate, major pathologic response rate, TRG, yp-TNM stage, and R0 resection rate between NCRT and NICT. However, patients with clinical N2-3 stage (OR 2.66; 95% CI 1.05 to 6.79) or lower thoracic esophageal tumors (OR 2.31; 95% CI 1.05 to 5.04) had a higher chance of achieving pCR after NICT compared to NCRT. For patients undergoing NICT, the ypN0 rates for clinically N0 patients were 100.0% (5/5), while only 65.0% (13/20) of clinical N0 patients achieved ypN0 in the NCRT group. Even after adjusting for differences in clinical stage, tumor location, and baseline lymph node metastasis rates in various locations, the NICT group still demonstrated a lower rate of abdominal lymph node metastasis during surgery (p=0.030). Conclusion In comparison to concurrent chemoradiotherapy, immunochemotherapy exhibits comparable overall disease control for primary lesions and lymph node metastasis. Notably, patients with clinical N2-3 and lower thoracic esophageal cancer may derive greater benefits from NICT. The potential of immunochemotherapy in enhancing the effectiveness of chemoradiotherapy is evident in its ability to improve the control of occult metastatic lymph nodes and reduce abdominal lymph node metastasis.

Neoadjuvant camrelizumab followed by concurrent camrelizumab plus chemotherapy for locally advanced esophageal squamous cell carcinoma: a single-arm, phase II study.

Neoadjuvant therapy combining camrelizumab with chemotherapy has emerged as a promising approach for treating locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal strategy for integrating immunotherapy with chemotherapy remains to be fully defined. This single-arm phase II study aimed to evaluate the efficacy and safety of neoadjuvant therapy with camrelizumab induction followed by camrelizumab plus chemotherapy in locally advanced ESCC. Patients with clinical stage cT2-4N0M0 or cTxN1-3M0 ESCC were enrolled in the study. Patients received one dose of camrelizumab (200 mg) followed by docetaxel (75 mg/m2) and nedaplatin (75 mg/m2) plus camrelizumab (200 mg) every 3 weeks for two cycles, and then underwent surgery within 3-4 weeks. The primary endpoint was the major pathological response (MPR) rate. The secondary endpoints included the pathological complete response (pCR) rate, R0 resection rate, downstaging rate, disease-free survival (DFS), overall survival (OS), and safety. In total, 55 patients were enrolled in the study between 16 April 2020 and 30 October 2021. Of these 55 patients, 53 (96.4%) completed neoadjuvant therapy, and 48 (87.3%) underwent surgery. The MPR rate was 77.1% [37/48, 95% confidence interval (CI): 62.7-88.0%]. The pCR (ypT0N0) rate was 39.6% (19/48, 95% CI: 25.8-54.7%). All the patients had R0 resections. Primary tumor downstaging occurred in 44 (91.7%) patients, and nodal downstaging occurred in 19 (39.6%) patients. The 2-year DFS rate was 68.9% (95% CI: 53.0-80.4%), and the 2-year OS rate was 74.7% (95% CI: 60.2-84.6%). Grade ≥3 treatment-related adverse events (TRAEs) were observed in 7 (12.7%) patients. In conclusion, neoadjuvant camrelizumab followed by camrelizumab plus chemotherapy showed promising efficacy in treating locally advanced ESCC and had a manageable safety profile.

Tislelizumab synergizes with surgery to augment the survival benefit in stage II-III non-small cell lung cancer

ObjectivesThis retrospective study evaluated the individual benefits of tislelizumab and surgery, as well as their synergistic effect on progression-free survival (PFS) and overall survival (OS) of stage II-III non-small cell lung cancer (NSCLC) patients.MethodsFrom September 2019 to June 2022, all participants with potentially resectable NSCLC who received chemotherapy (C) or tislelizumab plus chemotherapy (T) were included in the study. Participants were categorized into four groups based on surgery or not (S or NS) and the utilization of tislelizumab (T or C). Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan–Meier method and log-rank test, as well as Cox proportional hazards models.ResultsCompared to C, T was associated with significantly higher objective response rate (64.54% vs. 34.78%, p = 0.003), higher pathological complete response rate (40.00% vs. 14.06%, p = 0.007), and higher major pathological response rate (60.00% vs. 20.31%, p < 0.001). The T + S group exhibited a proportionately higher reduction in the risk of disease progression or death compared to the sum of the T + NS group and C + S group. Regardless of C or T, surgery was associated with improved OS (p < 0.01). Without surgery, T did not show significant improvement in PFS or OS. However, with surgery, T significantly improved both PFS and OS (ps < 0.01).ConclusionTislelizumab with subsequent surgery synergistically improves the survival benefits in patients with NSCLC.