Neoadjuvant Therapy In Patients Research Articles

EP02.04-005 Phase II NAUTIKA1 Study of Targeted Therapies in Stage II-III NSCLC: Preliminary Data of Neoadjuvant Alectinib for ALK+ NSCLC

Targeted therapies for patients with NSCLC with molecular alterations, including alectinib (a preferred first-line treatment for patients with advanced anaplastic lymphoma kinase [ALK+] NSCLC), are being explored in the adjuvant setting in clinical trials. However, the role of targeted treatments as neoadjuvant therapy for patients with resectable NSCLC remains unclear. NAUTIKA1 (NCT04302025) is an ongoing, phase II umbrella trial investigating the efficacy and safety of targeted therapies as neo(adjuvant) treatment in patients with resectable NSCLC with molecular alterations, including ALK, ROS1, NTRK, BRAF V600, and RET.

949TiP Neoadjuvant durvalumab in non-surgical early stage/locally advanced non-small cell lung cancer (NSCLC) followed by radical RT/CRT (IDEAR) study concept of a phase II investigator initiated clinical trial

Targeting the PD1/PD-L1 pathway has demonstrated activity in patients with advanced malignancies. Treatment with anti-PD1/PD-L1 blockade in advanced and locally advanced NSCLC, is already standard of care. The positive outcomes of durvalumab following CRT emphasized the potential of immunotherapy integration in multimodality treatment strategies and in earlier phases of the disease, leading to the first immune checkpoint inhibitor approval in non-metastatic setting in NSCLC. This study proposes to evaluate the safety and efficacy of an anti-PD-L1 (durvalumab) agent as neoadjuvant therapy in patients with localized NSCLC who are planned to undergo radical RT or CRT. Main inclusion criteria: ≥ 18 y/o; histologically documented NSCLC; clinical Stage IIIA NSCLC eligible for RT or clinical stage IB (≥ 4 cm)-IIIA NSCLC that are not considered for surgical treatment by the clinical team or by patient choice who, however, are eligible for radical RT or CRT; ≥ 1 measurable lesion by RECIST v1.1. This is a Phase Ib/II, single-center, open-label, single-arm study, expected to expand to other center within the country. Durvalumab will be administered as neoadjuvant therapy before standard of care RT/CRT to 30 patients with untreated NSCLC not amenable for surgery but planned to undergo radical RT or CRT. The primary endpoint is the rate of patients without Dose-Limiting Toxicity (DLT). The study will be conducted in two parts; the first, DLT will be evaluated on a total of 18 patients over 3 cohorts; the second, an expansion cohort of 12 patients will be enrolled to further evaluate the safety, efficacy and feasibility of neoadjuvant durvalumab followed by standard of care RT/CRT. A single IV infusion of durvalumab 1500 mg will be administered at Visit 1. RT/RCT will be initiated between 4-5 weeks after. Standard RT/CRT and adjuvant treatment will be offered according to clinical practice. After completion of RT/RCT patients will be treated according to standard of care. A biomarker sub-study will be performed. Tumor and immune cells phenotype, somatic genetic alterations evaluation of tumor sample and ctDNA will be assessed. NCT05267392. IPO-Porto and AstraZeneca.

IMMUNOEXPRESSION OF DEK AND PHOSPHO-P38 PROTEINS IN RECTAL CANCER BEFORE CHEMORADIATION THERAPY.

Colorectal cancer is the third cause of cancer worldwide and a quarter of them are in the rectum. DEK oncogene is involved in several nuclear processes and can accelerate tumorigenesis. This study aims to evaluate the immunoexpression of DEK and Phospho-P38 proteins before neoadjuvant therapy in patients with rectum adenocarcinoma and correlate it with a clinical response and survival. Patients with adenocarcinoma of the middle and low rectum who underwent chemotherapy and radiotherapy followed by surgical tumor resection were included. The expression and quantification were studied by immunohistochemistry in the tumor biopsy tissues using a HScore system. Score ≥4 were considered positive and those with <4 negative. 22 patients were included with a mean age of 63.55 years (SD: ±13.49). The clinical-stage before treatment was T3 on 72.7%, T4 on 18.2%, 31.8% were N1, 50% N0 and all M0. After chemo and radiotherapy, 54.6% were T3; 22.7% were classified as T2; 9.1% as T1, and 13.6% were T0. Among the tumors, 22.7% were positive for DEK and 63.6% positive for Phospho-P38. There was a positive correlation between DEK protein before treatment and pTNM stage (P=0.011). Phospho-P38 protein showed no correlation with these parameters. Patients with a negative HScore had a mean survival of 141.33 months (95%CI: 112.41-170.25) and those with a positive HSscore had a mean survival of 25.10 months (95%CI: 17.36-32.84; P<0.001). A higher expression of DEK was observed in advanced stages. Patients who presented DEK expression <4 had a higher survival, being a factor of worst prognosis.

1220P Efficacy and safety of camrelizumab combined with FLOT versus FLOT alone as neoadjuvant therapy in patients with resectable locally advanced gastric and gastroesophageal junction adenocarcinoma who received D2 radical gastrectomy

1220P Efficacy and safety of camrelizumab combined with FLOT versus FLOT alone as neoadjuvant therapy in patients with resectable locally advanced gastric and gastroesophageal junction adenocarcinoma who received D2 radical gastrectomy

CT perfusion as a potential biomarker for pancreatic ductal adenocarcinoma during routine staging and restaging.

To evaluate the significance of CT perfusion parameters predicting response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma (PDAC). Seventy patients with PDAC prospectively had CT perfusion acquisition incorporated into baseline multiphase staging CT. Twenty-eight who were naïve to therapy were retained for further investigation. Perfusion was performed 5-42.5s after contrast, followed by parenchymal and portal venous phases. Blood flow (BF), blood volume (BV), and permeability surface area product (PS) were calculated using deconvolution algorithms. Patients were categorized as responders or non-responders per RECIST 1.1. Perfusion variables with AUC ≥ 0.70 in differentiating responders from non-responders were retained. Logistic regression was used to assess associations between baseline perfusion variables and response. 18 of 28 patients showed favorable response to therapy. Baseline heterogeneity variables in tumor max ROI were higher in non-responders than responders [median BF coefficient of variation (CV) 0.91 vs. 0.51 respectively, odds ratio (OR) 6.8 per one standard deviation (1-SD) increase, P = 0.047; median PS CV 1.6 vs. 0.68, OR 3.9 per 1-SD increase, P = 0.047; and median BV CV 0.75 vs. 0.54, OR = 4.0 per 1-SD increase, P = 0.047]. Baseline BV mean in tumor center was lower in non-responders than responders (median BV mean: 0.74 vs. 2.9ml/100g respectively, OR 0.28 per 1-SD increase, P = 0.047). For patients with PDAC receiving neoadjuvant therapy, lower and more heterogeneous perfusion parameters correlated with an unfavorable response to therapy. Such quantitative information can be acquired utilizing a comprehensive protocol interleaving perfusion CT acquisition with standard of care multiphase CT scans using a single contrast injection, which could be used to identify surgical candidates and predict outcome.

An exploratory study on the checkout rate of circulating tumor cells and the prediction of efficacy of neoadjuvant therapy and prognosis in patients with HER-2-positive early breast cancer.

BackgroundNeoadjuvant therapy is a standard treatment for patients with large, nonmetastatic breast cancer and may allow breast-conserving surgery after tumor downsizing while decreasing the risk of subsequent relapse. Dynamic changes of circulation tumor cells (CTCs) have a role in predicting treatment efficacy of breast cancer. However, the relationship between CTC enumeration before neoadjuvant therapy and pathologic complete response rate is still uncertain.MethodsThe study was exploratory. A total of 50 breast cancer patients were enrolled in a phase II clinical study of neoadjuvant therapy for HER-2-positive early breast cancer. They were enrolled for blood draws before and after neoadjuvant therapy. We used two methods (CellSearch and TUMORFISH) to detect CTCs. We compared the sensitivity of the two systems and investigated the correlation of the enumeration on baseline CTCs with the diagnosis, prognosis, and efficacy of neoadjuvant therapy of the patients with HER-2-positive early breast cancer. We also explored the dynamic change of CTCs after neoadjuvant therapy.ResultsThe sensitivity of TUMORFISHER (27/50) method was significantly higher than that of the CellSearch system (15/50, p=0.008). The CTC numbers detected by the two detection systems were not significantly correlated with lymph node status, clinical stage, ki-67 level and hormone receptor status. Patients with ≥1 CTC before neoadjuvant therapy measured by the TUMORFISHER system had a significant high pCR rate (74.1% vs. 39.1%, p = 0.013); whereas, there was no predictive effect on pCR by CellSearch system (73.3% vs. 51.4%, p = 0.15). Patients with a decrease in CTCs enumeration after neoadjuvant therapy were more likely to achieve pCR than those with no change or increase in CTCs enumeration (87.5% vs 50.0%, p = 0.015) by the TUMORFISHER method. Unfortunately, there was no predictive value of CTCs enumeration for EFS before and after neoadjuvant therapy by two methods.ConclusionsOur study demonstrates that the new CTCs detection method TUMORFISHER system has a higher checkout rate in early breast cancer than the CellSearch system, and shows the opportunity of CTC enumeration as a novel assistant biomarker to predict the response of neoadjuvant therapy in patients with HER-2-positive early breast cancer.

Efficacy and safety of camrelizumab in combination with neoadjuvant chemotherapy for ESCC and its impact on esophagectomy.

BackgroundEsophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer in China. The use of neoadjuvant immunotherapy for the treatment of ESCC is gradually increasing. Camrelizumab is one such immune checkpoint inhibitor (ICI) used for treatment. In this retrospective study, we explored the efficacy, safety, and short-term perioperative prognosis of camrelizumab in combination with neoadjuvant chemotherapy for ESCC.Materials and MethodsA total of 254 Chinese patients with ESCC were enrolled in the study; 48 received camrelizumab in combination with neoadjuvant chemotherapy (C-NC group), and 206 received neoadjuvant chemotherapy (NC group). All patients underwent surgery after the completion of 2 cycles of neoadjuvant therapy.ResultsTwenty patients (20/48, 41.7%) in the C-NC group and 22 patients (22/206, 10.7%) in the NC group achieved a pathologic complete response (pCR) (p<0.001). Twenty-nine patients (29/48, 60.4%) in the C-NC group and 56 patients (56/206, 27.2%) in the NC group achieved major pathologic remission (MPR) (p<0.001). There was a lower incidence of myelosuppression during neoadjuvant therapy in patients in the C-NC group (33/48, 68.8%) than in the NC group (174/206, 84.5%, p=0.012). The total incidence of adverse reactions during neoadjuvant therapy was also lower in the C-NC group (37/48, 77.1%) than in the NC group (189/206, 91.7%, p=0.003). Patients in the C-NC group had more lymph nodes cleared during surgery than those in the NC group (34 vs.30, p<0.001). The logistic model showed that the treatment regimen, age, and presence of lymph node metastasis were influential factors for achieving a pCR in these patients (p<0.001). Regarding other adverse events and surgery-related data, there were no significant differences observed between the two groups.ConclusionCamrelizumab in combination with neoadjuvant chemotherapy is an efficacious neoadjuvant regimen with an acceptable safety profile and does not increase the difficulty of surgery or the incidence of complications. A pCR is more likely to be achieved in patients treated with camrelizumab in combination with neoadjuvant chemotherapy, in younger patients, or in those without lymph node metastases.

Understanding the association between clinical staging accuracy, treatment response, and survival among gastric cancer patients through Bayesian analysis.

Neoadjuvant therapy (NAT) improves survival among patients with locally advanced gastric cancer (GC), but it remains unclear whether its benefit is contingent on treatment response. This is a national cohort study of stage Ib-III GC patients in the National Cancer Data Base (2006-2015) treated with upfront resection or NAT followed by surgery. Bayesian analysis was used for NAT patients to ascertain staging concordance and to account for down-staging. We used multivariable Cox regression to evaluate the association between staging concordance, treatment, response to NAT, and survival. The cohort included 13 340 patients treated at 1124 hospitals. Staging concordance ranged from 86.1% for cT3-4N+to 34.7% for cT2N0 patients. Relative to accurately staged patients treated with upfront surgery, NAT was associated with a decreased risk of death if there was disease down-staging among those with cT1-2N+(hazard ratio[HR]: 0.43 [0.30-0.61]), cT3-4N0 (HR: 0.69 [0.54-0.88]), and cT3-4N+(HR: 0.51 [0.48-0.58]) tumors, and in the absence of down-staging among cT3-4N+ patients (HR: 0.83 [0.74-0.92]). Conversely, NAT without down-staging increased the risk of death among those with intermediate-stage disease. NAT is associated with improved survival for GC, but it seems to be contingent on treatment response among patients with intermediate-stage disease.

Clinical Understaging, Treatment Response, and Survival Among Esophageal Adenocarcinoma Patients

IntroductionSelecting appropriate management for patients with esophageal adenocarcinoma (EA) is predicated on accurate clinical staging information. Inaccurate information could lead to inappropriate treatment and suboptimal survival. We investigated the relationship between staging accuracy, treatment, and survival. MethodsThis was a national cohort study of EA patients in the National Cancer Data Base (2006-2015) treated with upfront resection or neoadjuvant therapy (NAT). Clinical and pathological staging information was used to ascertain staging concordance for each patient. For NAT patients, Bayesian analysis was used to account for potential downstaging. We evaluated the association between staging concordance, receipt of NAT, and survival through hierarchical logistic regression and multivariable Cox regression. ResultsAmong 7635 EA patients treated at 877 hospitals, 3038 had upfront resection and 4597 NAT followed by surgery. Relative to accurately staged patients, understaging was associated with a lower likelihood (odds ratio [OR] 0.04 95% confidence interval [CI] 0.02-0.05) while overstaging was associated with a greater likelihood of receiving NAT (OR 1.98 [1.53-2.56]). Relative to upfront surgery, treatment of cT1N0 patients with NAT was associated with a higher risk of death (HR 3.08 [2.36-4.02]). For accurately or overstaged cT3-T4 patients, NAT was associated with a lower risk of death whether downstaging occurred (ypN0 disease—HR 0.67 [0.49-0.92]; N+ disease—HR 0.55 [0.45-0.66]) or not (ypN + disease—HR 0.78 [95% CI 0.65-0.93]). ConclusionsClinical understaging is associated with receipt of NAT which in turn may have a stage-specific impact on patients’ survival regardless of treatment response. Guidelines should account for the possibility of inaccurate clinical staging.

Current status of neoadjuvant therapy for locally advanced rectal cancer in Wuhan Union Hospital Cancer Center

BackgroundTo analyze and explore the evolution and short-term efficacy of neoadjuvant therapy for patients with mid and low LARC in Wuhan Union Hospital Cancer Center.MethodsPatients diagnosed with rectal cancer from January 2015 to December 2021 were collected. The treatment patterns, short-term efficacy and treatment-related adverse events (AEs) of mid and low LARC patients who received neoadjuvant therapy were analyzed. The Chi-square test was used to compare the differences between groups.ResultsA total of 980 patients with mid and low LARC were enrolled, over time, the proportion of patients receiving neoadjuvant therapy gradually increased, and the treatment mode of direct surgery after diagnosis was gradually watered down. More than 80% of the patients implemented radiotherapy-based neoadjuvant therapy, and the proportion of patients receiving SCRT sequential systemic therapy gradually exceeded that of LCRT combined chemotherapy after 2020. Of all patients who completed radiotherapy and underwent surgery, 170 patients received long-course chemoradiotherapy (LCRT) combined with chemotherapy (Group C) and 98 patients received short-course radiotherapy (SCRT) combined with systemic therapy (chemotherapy with or without immunotherapy) (Group D). The pathological complete response (pCR) rate in Group D was significantly higher than that in Group C (38.8% vs. 19.4%, P = 0.001). The pCR rate in the SCRT plus immunotherapy group was better than that in the group without immunotherapy (49.2% vs. 21.6%, P = 0.007). 82.3% of the patients receiving immunotherapy were treated with SCRT sequential 2-cycle CapOX plus Camrelizumab treatment, and the pCR was as high as 52.9%. Immunotherapy did not increase the incidence of Grade 3–4 AEs.ConclusionsNeoadjuvant therapy based on radiotherapy is becoming used in patients with mid and low LARC. SCRT sequential systemic therapy is increasingly widely used in LARC patients in our center. Compared with the traditional LCRT or SCRT sequential chemotherapy, SCRT sequential chemotherapy plus immunotherapy has a remarkable pCR rate and manageable toxicity. Looking forward this new treatment mode will bring lasting survival benefits to patients.

Abstract 6110: Immune cell infiltrative characteristics reveals the superior efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in a real-world cohort of resectable non-small cell lung cancer

Abstract We aimed to analyze the efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in the real-world settings, and to further explore tumor immune microenviroment (TIME), as well as its influence on response of neoadjuvant therapy in patients with NSCLC. Fifty-three patients with neoadjuvant therapy (immunochemotherapy, n=22; chemotherapy alone, n=31), resectable stage I~III, age≥18 years, and ECOG performance status 0-1 were recruited in the study. Fluorescent multiplex immunohistochemistry was performed by the automated quantitative pathology imaging system with tumor samples obtained in radical surgery. The major pathologic response (MPR) rate was significantly higher in patients with neoadjuvant immunochemotherapy than chemotherapy alone (p=.025; OR=4.222, 95% CI: 1.292~13.800). Patients received immunochemotherapy had higher pathologic complete response (pCR) rate than those with chemotherapy (p=.168; OR=3.150, 95% CI: 0.792~12.535). Compared with chemo alone, the tumor to stroma ratio of CD68+CD163- density was significantly elevated in patients subjected to immunochemotherapy (p=.0399). When patients were stratified by the pathologic response to neoadjuvant immunochemotherapy, the CD56dim in stroma significantly increased in patients achieved pCR than non-pCR (p=.038). The density of CD3+CD4+ cells (stroma, p=.039; total, p=.027) and CD20+ (total, p=.027) immune cells was significantly higher in patients achieved MPR than non-MPR. In patients administered with neoadjuvant chemotherapy alone, the expression level of PD-1 (p=.036), the density of FoxP3+ (stroma, p=.025; total, p=.013) and CD3+CD4+FoxP3+ (total, p=.042) cells significantly reduced in patients reached pCR. The density of CD20+ cells in stroma (p=.034) and the number of tertiary lymphoid structures (TLS; p=.006) were significantly higher in patients reached MPR. In conclusion, the therapeutic efficacy was improved by neoadjuvant immunochemotherapy in patients with NSCLC, which may be associated with the TIME remodeling, especially the migration of M1 macrophage from stroma to tumor islet. Clusters of NK, Th, Treg and B, PD-1, and TLS also play important role in response to neoadjuvant therapy. This work was supported by National Natural Science Foundation of China (NO. 62076254) Citation Format: Wenhan Cai, Miao Jing, Jiaxin Wen, Yajun Gu, Xiaochen Zhao, Zhiqiang Xue. Immune cell infiltrative characteristics reveals the superior efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in a real-world cohort of resectable non-small cell lung cancer [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 6110.

Interim results from a multicenter clinical study of tislelizumab combined with gemcitabine and cisplatin as neoadjuvant therapy for patients with cT2-T4aN0M0 MIBC.

4580 Background: To evaluate the efficacy and safety of tislelizumab combined with gemcitabine and cisplatin as neoadjuvant therapy for patients (pts) with clinical T2-T4aN0M0 (cT2-T4aN0M0) muscle-invasive bladder urothelial cancer (MIBC). Methods: This multicenter, open-label, single arm phase II study enrolled pts tolerated with the cisplatin therapy. Eligible pts received tislelizumab 200 mg in day 1 (D1), cisplatin 70 mg/m2 D2, and gemcitabine 1000 mg/m2 D1 and D8 every 21 days for four cycles. Radical cystectomy (RC) was performed within 6 weeks after last dose treatment. The primary end point was pathologic complete response (pCR, pT0N0M0). Secondary end points were pathologic downstaging (≤pT1N0M0), EFS, OS and safety. Simon two-stage design was used. If &gt; 5 pts achieved pCR in the first stage (n = 22), study would proceed to the second stage and enroll 33 additional pts. If &gt; 18 of 55 pts achieved pCR, we would deem the study to have met the primary endpoint. Results: We reported the results in the first stage. By Oct 2021, 23 eligible pts were enrolled. Eighteen pts have completed neoadjuvant therapy, with median age of 62 (48-72) years and 8 (44.4%) pts of PD-L1 positive, among whom 17 pts underwent RC and one declined RC. At the data cut off time of 14th Jan 2022, among 17 evaluable pts (12 cT2, 3 cT3, and 2 cT4a), 10 (58.8% [95% CI, 32.9-81.6]) pts achieved pCR and 13 (76.5% [95% CI, 50.1-93.2]) achieved pathologic downstaging. No significant differences were found in pCR (62.5% vs. 55.6%) and downstaging (75.0% vs. 77.8%) rates between pts with PD-L1 positive versus PD-L1 negative. Eighteen pts completed 71/72 cycles of tislelizumab, 68/72 cycles of cisplatin and 135/144 cycles of gemcitabine therapy. The rate of dose reduction (all due to AEs) of cisplatin and gemcitabine therapy was 25.0% (17/68 cycles) and 23.7% (32/135 cycles), respectively. The relative dose intensity of tislelizumab, cisplatin and gemcitabine were 93.6%, 84.5% and 85.9%, respectively. Most common neoadjuvant therapy related AEs of any grade were hematologic toxicities (94.4%), nausea (72.2%), vomiting (61.1%), decreased appetite (55.6%), fatigue (27.8%), pruritus (22.2%) and ALT/AST increased (22.2%). Grade ≥3 neoadjuvant therapy related AEs were neutropenia (n = 6), thrombocytopenia (n = 4), anemia (n = 2) and lymphocyte count decreased (n = 1). Eight pts experienced grade 1-2 immune related AEs, including pruritus (n = 4), rash (n = 2), ALT/AST increased (n = 4), GGT increased (n = 2), CPK increased (n = 1), hyperthyroidism (n = 1), hypothyroidism (n = 1). Conclusions: Neoadjuvant tislelizumab combined with gemcitabine and cisplatin showed promising anti-tumor activity with high pCR and well tolerance in MIBC pts. The target of first stage has been achieved, and enrollment is ongoing. At the data cut off 14th Jan 2022, 34 pts have been enrolled. Clinical trial information: ChiCTR2000037670.

ANTICIPATE: A phase I/II, open-label, multicenter study to evaluate the safety and efficacy of oral APL-1202 in combination with tislelizumab compared to tislelizumab alone as neoadjuvant therapy (NAC) in patients with muscle invasive bladder cancer (MIBC).

TPS4613 Background: Standard treatment for muscle invasive bladder cancer (MIBC) is radical cystectomy (RC) and administration of NAC in patients who are eligible to receive cisplatin. Approximately 50% of patients are ineligible to receive cisplatin as a result of pre-existing contraindications, and some refuse to receive any chemotherapy due to concerns of toxicities. Immune checkpoint inhibitors (ICIs) have been shown to be highly active in metastatic urothelial cancer. APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Synergistic effects of APL-1202 and ICIs have been shown in model systems of bladder cancer. It is hypothesized that APL-1202 in combination with tislelizumab, a humanized IgG4 anti-PD-1 MAb, may be an effective neoadjuvant therapy in MIBC. This trial will evaluate the safety, efficacy, and pharmacodynamic effects of APL-1202 in combination with tislelizumab as neoadjuvant therapy for patients with MIBC who are cisplatin ineligible or refuse cisplatin-based chemotherapy. Methods: ANTICIPATE is an open-label, multi-center clinical trial enrolling 79 patients in two phases: Phase Ⅰ and Phase Ⅱ. Phase I is a dose escalation study to determine MTD (maximum tolerated dose) and/or RP2D. Phase II is an expanded proof-of-concept study to evaluate the safety and efficacy of APL-1202 in combination with tislelizumab compared to tislelizumab alone as neoadjuvant therapy for MIBC as measured by pathological complete response (pCR). Phase Ⅰ and Phase Ⅱ both are divided into 3 periods: screening period of 4 weeks, neoadjuvant therapy comprising 3 cycles (each 21 days) prior to radical cystectomy; and a follow-up period of up to 90 days after surgery. The phase Ⅰ will determine the RP2D of APL-1202 in combination with tislelizumab as neoadjuvant therapy for MIBC. Eligible patients have newly diagnosed MIBC and are cisplatin ineligible or refuse cisplatin-based NAC and are planned for RC. In phase Ⅰ, a standard 3+3 dose-escalation design will be used. On day 1 of each cycle, a single dose of 200 mg tislelizumab will be administered intravenously. The daily dose APL-1202 will be escalated in successive cohorts (375 mg à 750 mg à 1,125 mg). The DLT observation window for any dose level will be treatment cycle 1. There will be no intra-patient dose escalation. In phase II patients will be randomly assigned to group 1 (APL-1202 + tislelizumab) or group 2 (tislelizumab only), stratified by PD-L1 expression. The IND has been approved by FDA and NMPA, and the study execution is under preparation both in US and China. Clinical trial information: NCT04813107.

Gut microbiota composition and outcomes following neoadjuvant therapy in patients with localized pancreatic cancer: A prospective biomarker study.

4143 Background: The prognostic role of the gut microbiome, which modulates cancer development and therapeutic response, is unknown in patients with pancreatic ductal adenocarcinoma (PDAC). With increasing utilization of neoadjuvant therapy (NAT) prior to pancreatic cancer surgery, identification of patient-specific biologic signatures associated with NAT response a priori could help inform PDAC precision medicine. Thus, we assessed the influence of the baseline gut microbiome on clinical outcomes in patients with PDAC receiving NAT. Methods: Stool samples were collected at diagnosis from 42 consenting patients with localized PDAC intending to undergo NAT and surgical resection between 2018 and 2020. 16S rRNA sequencing was completed on pre-NAT stool and resected tumor samples. Microbiota alpha diversity and log transformed taxonomic classifications were utilized in multiple regression analyses to predict oncologic outcomes. Results: Five patients progressed during NAT and eight of the 37 operated patients were deemed NAT responders, demonstrating pathologic near complete or partial response (CAP 0-2), T1N0 AJCC 8th staging, and ≥ 80% CA 19-9 reduction. Compared to the gut, the tumor microbiota demonstrated remarkably reduced Shannon diversity (2.4±0.5 vs 1.5±0.4, p&lt; 0.0001) and distinct taxa (75.2±19.7 vs 8.0±4.5, p&lt; 0.0001) and, accordingly, was not associated with clinical outcomes. Overall, several taxa, including Bacteroides and Akkermansia, were enriched in the gut relative to the tumor ( p&lt; 0.001). The gut microbiota of NAT non-responders had an increased proportion of the gemcitabine metabolizing Enterobacteriaceae (additive log ratio (ALR) -3.4±2.0 vs -8.7±0.8, p= 0.0004). NAT responders, by contrast, had an increased proportion of the adaptive immune cell activating Akkermansia (ALR -0.9±1.2 vs -6.2±3.3, p= 0.0004). The incidence of jaundice or biliary stent placement was associated with relative increases in Enterobacteriaceae (+3.3 ALR, p&lt; 0.01 and +4.9 ALR, p&lt; 0.0001) and decreases in Akkermansia (-3.2 ALR, p= 0.02 and -2.4 ALR, p= 0.057), without altering total gut microbiota diversity. Age, sex, BMI, comorbidities, receipt of pre-NAT antibiotics, diagnostic EUS tumor size, resectability, and pre-NAT CA 19-9 were not predictive of NAT response or survival in a univariate regression model. However, inclusion of gut microbiota data improved the ability of the model to predict NAT response ( p= 0.016, adjusted R2 0.76) and survival ( p= 0.001, adjusted R2 0.89), with Enterobacteriaceae (FDR p= 0.012) and Akkermansia (FDR p= 0.015) being significant negative and positive predictors of NAT response, respectively. Conclusions: The baseline gut microbiota could be leveraged as a biomarker of NAT response and prognosis in patients with pancreatic cancer and warrants further investigation.

Efficacy and safety of sintilimab plus XELOX as neoadjuvant therapy in patients with locally advanced gastric cancer: A single-arm open-label phase II trial.

e16091 Background: Neoadjuvant chemotherapies have been widely recommended by clinical guidelines for patients with locally advanced gastric cancer. However, the evidence of combining neoadjuvant chemotherapy with anti-programmed death 1 (anti-PD-1) antibody therapy for patients with locally advanced gastric cancer is inadequate. Thus, we conducted a single-arm phase II trial to evaluate the efficacy and safety of anti-PD-1 antibody sintilimab and XELOX regimen (capecitabine plus oxaliplatin) in patients with locally advanced gastric adenocarcinoma. Methods: Patients with locally advanced(cT3-4 N+ M0, CY0,P0) were enrolled and received four preoperative cycles of XELOX (oxaliplatin 130mg/m2, IV, d1 with capecitabine 1000mg/m2, bid, d1-d14, q21d) and sintilimab (200mg, IV, q21d). Surgery was performed within 3-4 weeks after completion preoperative therapy. After surgery, patients received four cycles of XELOX. The primary endpoint was the pathological complete response (pCR) rate and the secondary endpoints were major pathologic response (MPR) rate, R0 resection rate, safety, disease-free survival (DFS) and overall survival (OS). This clinical trial is registered at ChiCTR.gov.cn: ChiCTR2000030414. Results: From March 2020 to July 2021, 30 patients were enrolled, with median age 62 years (range30-72), males 18, cT3/T4: 8/22, cN1/2/3: 10/14/6, intestinal diffuse type (Lauren classification):17/13, ECOG PS 0/1/2: 19/8/3. There were 19(63.3%) patients with PD-L1 CPS≥1. All patients were available for preoperative response evaluation, the objective response (ORR) rate was 70.0% (95% CI, 50.6%-85.3%) and the disease control (DCR) rate was 100% (95% CI, 88.4%-100%). All (100%) achieved R0 resection. 10 patients (33.3%) achieved pCR (TRG 0) and 19 patients (63.3%) had MPR (TRG 0-1). Common treatment-related adverse events (TRAEs) were anemia (36.7%), leukopenia (36.7%), neutropenia (30.0%), diarrhea (26.6%), ALT increase (23.3%), AST increase (13.3%), thrombocytopenia (10.0%), vomiting (10.0%). The potential immune-related adverse events (irAEs) were dermatitis (6.7%), hypothyroidism (3.3%), pneumonia (10.0%). Most of the TRAEs and potential irAEs were grade 1 or 2. Grade3 TRAEs and irAEs included ALT increase (3.3%), AST increase (3.3%), dermatitis (3.3%). There were no severe complications and death related to the operation. The median postoperative hospital stay was 8 days (range6-23 days). Conclusions: Sintilimab plus XELOX as neoadjuvant therapy showed an encouraging pCR rate, MPR rate and manageable safety. This combination regimen might provide a new option for patients with locally advanced gastric cancer. Clinical trial information: ChiCTR2000030414.

Efficacy and safety of camrelizumab combined with FLOT versus FLOT alone as neoadjuvant therapy in patients with resectable locally advanced gastric and gastroesophageal junction adenocarcinoma who received D2 radical gastrectomy: Data update.

e16044 Background: Docetaxel-based neoadjuvant chemotherapy has been suggested to be beneficial in patients with locally advanced gastric and gastro-oesophageal junction cancer (GC/GEJC). And immunotherapy also show promising treatment efficacy for advanced GC/GEJC. Here we compared the safety and efficacy of camrelizumab combined with chemotherapy versus chemotherapy alone as the neoadjuvant therapy for patients with resectable locally advanced GC/GEJC. Methods: Eligible patients diagnosed as resectable locally advanced GC/GEJC were randomized to receive neoadjuvant treatment, in arm A, the patients received FLOT alone, in arm B, the patients received FLOT combined with camrelizumab(camrelizumab 200mg intravenously every 3 weeks). Eligible patients underwent gastrectomy with D2 lymph node dissection. The primary end point of this trial was pCR rate and R0 resection rate, and the secondary end points were ORR,PFS, OS and safety profile. Results: From January 15 2020 to January 15 2022, 61 patients were recruited (28 patients in arm A and 33 patients in arm B). 51 patients had completed planned neoadjuvant treatment for 4 cycles (25 pts in the arm A, 26 ptsin the arm B). Four patients in the arm A were failure to complete surgical treatment. This analysis was based on the 47 pts. In the arm A, the median age was 63 years (45-74 years) and a total of 16 males and 4 females, ECOG PS 0 (n = 3), ECOG PS 1 (n = 18). In the arm B, the median age was 63 years (28-72 years) and a total of 20 males and 6 females, ECOG PS 0 (n = 5), ECOG PS 1 (n = 21). The R0 resection rate was high in arm B compared with arm A (26/26,100% vs. 19/21, 90.5%). The same results are also reflected in pCR:arm B compared with arm A (3/26,11.5% vs. 1/21, 4.8%). Tumour regression grade were as follows:TRG0 [arm A 5% (1/21), arm B 15% (4/26)], TRG1 [arm A 10% (2/21), arm B 4% (1/26)], TRG2 [arm A 33% (7/21), arm B 54% (14/26)], TRG3 [arm A 52% (11/21), arm B 27% (7/26)].There was a greater proportion of postoperative stage ypN0 in arm B [arm A 24% (5/21); arm B 46% (12/26)]. Postoperative pathologic staging was as follows: ypT0 [arm A 5% (1/21); armB 15% (4/26)].ypT1 [arm A 14% (3/21); armB 8% (2/26)]. ypT2 [armA 0% (0/21); armB 27% (7/21)]. ypT3 [arm A 57% (12/21); arm B 38% (10/26)]. ypT4 [armA 24% (5/21); armB 12% (3/26)]. Neither serious intraoperative complications nor immune-related adverse events were observed during perioperation. Treatment-related AEs neutropenia and leukopenia were manageable and there was no treatment-related death. Conclusions: Camrelizumab combined with FLOT showed promising efficacy as neoadjuvant treatment for patients with locally advanced gastric or GEJ adenocarcinoma, with low complications and acceptable toxicity. Clinical trial information: ChiCTR2000030610.

A phase II clinical trial of neoadjuvant sasanlimab and stereotactic body radiation therapy as an in situ vaccine for cisplatin-ineligible muscle invasive bladder cancer (RAD VACCINE MIBC).

TPS4611 Background: The utilization of neoadjuvant immune checkpoint inhibitor (ICI) therapy, including anti-PD1/L1 agents, prior to radical cystectomy (RC), is an emerging paradigm in muscle invasive bladder cancer (MIBC). Pathologic complete responses (pCR) have been observed in 25-40% of patients with neoadjuvant PD1/L1 inhibitor monotherapy for cisplatin-ineligible MIBC. In situ vaccination using stereotactic body radiation therapy (SBRT) may augment T-cell responses to tumor-specific antigens through immunogenic cell death. Sasanlimab (PF-06801591) is a humanized IgG monoclonal antibody that targets PD-1 selectively, for which there are both Phase 1 data and ongoing Phase 3 trials in early-stage urothelial carcinoma. There exists a strong rationale to evaluate a novel strategy of combination neoadjuvant ICI therapy with SBRT as an in situ vaccine to improve loco-regional control and decrease the risk of distant recurrence in cisplatin-ineligible patients with MIBC. Methods: This is a prospective, investigator-initiated, single-arm, single-institution, phase II trial that evaluates neoadjuvant sasanlimab in combination with SBRT as neoadjuvant therapy for patients with MIBC before RC. Eligibility requires patients to be cisplatin-ineligible (one of the following: ECOG-PS=2, creatinine clearance &lt;60 ml/min, or comorbidities such as hearing loss or neuropathy) or those who refuse cisplatin-based chemotherapy. Sasanlimab (300 mg) will be administered subcutaneously on Day 1 of each 28-day cycle for a total of 2 cycles, in combination with SBRT to the primary tumor at a dose of 24Gy given in 3 fractions, starting on Day 1 of Cycle 2 with a 48-hour interval between fractions. The combination treatment will be assessed by using a Simon’s 2-Stage design, which the first 10 patients are enrolled as a safety lead-in to evaluate the safety and feasibility. Futility analysis will be performed after a total of 18 patients. The primary endpoint is pCR rate after neoadjuvant sasanlimab/SBRT, followed by RC. If pCR is observed in 4 or fewer patients, further enrollment of patients may be stopped with the conclusion that pT0 cannot be 40% or greater. Otherwise, an additional 15 patients will be accrued in stage II, resulting in a total of 33 patients. Secondary endpoints include adverse events, surgical complication rates, health related quality-of-life, overall survival, and recurrence free survival. Exploratory endpoints include analysis of and association with pCR of the tumor/germline genetic signatures, circulating tumor DNA, tumor PD-L1 expression, blood cytometry time-of-flight analysis to identify immune response. Enrollment opened on February 15, 2022. Clinical trial information: NCT05241340.

HDAC inhibitor Tucidinostat plus exemestane as neoadjuvant therapy in patients with hormone receptor positive, HER2 negative breast cancer.

e12623 Background: Tucidinostat (formerly known as chidamide) is an oral subtype-selective histone deacetylase (HDAC) inhibitor with demonstrated efficacy and safety in combination with exemestane in postmenopausal patients with advanced, hormone receptor-positive breast cancer. The aim of this study was to evaluate the efficacy of tucidinostat combined with exemestane as neoadjuvant strategy in hormone receptor-positive early breast cancer patients. Methods: The study (ChiCTR2100046678) is a single-center, prospective, open-labeled, single-arm phase II study. Patients with HR-positive, HER2-negative, and node-positive, stage II–III breast cancer were enrolled at Tianjin Medical University Cancer Institute and Hospital. Eligible patients received 30 mg oral tucidinostat twice weekly in combination with 25 mg oral exemestane daily for up to a total of 24 weeks. The primary endpoint was to determine percent of pts who achieve a PEPI score of 0. The secondary endpoints were to analyze the the pathological complete remission (pCR) rate, complete cell cycle arrest (CCCA, defined as Ki67&lt;2.7%), objective response rate (ORR), disease control rate (DCR) and event free survival (EFS), and overall survival (OS) as well as the safety and tolerability. Results: Patient enrollment initiated in Jan. 2021 and ended in Nov. 2021. Of the 20 pts enrolled, 20 were treated and radiologically evaluable for response. The ORR was 40% with CR 5% (n=1) and PR 35% (n=7). The DCR was 100%. Four patients were still on wait lists for surgery. Of the 16 pts with surgery, one case achieved pCR. The follow-up remains ongoing and updated results will be presented thereafter. Most adverse events (AEs) were grade 1 or 2. Grade 3 AEs included neutropenia (11.8%), thrombocytopenia (5.9%) and lung infection (5.9%), respectively. Conclusions: The combination of Tucidinostat and exemestane was well tolerated with encouraging clinical responses in early hormone receptor positive, HER2 negative breast cancer. Further investigation is warranted. Clinical trial information: ChiCTR2100046678.

Anti-EGFR antibody plus anti-PD-1 antibody and chemotherapy as a neoadjuvant regimen for patients with locally-advanced penile squamous cell carcinoma: A prospective, single-arm, single-center, phase II clinical trial.

5037 Background: Advanced penile squamous cell carcinoma (PSCC) is a rare disease with a poor prognosis. We performed a monocentric, Simon’s two-stage phase II study to evaluate the efficacy and safety of PD-1 blockade plus anti-EGFR target therapy and chemotherapy as neoadjuvant therapy in patients with locally advanced PSCC. We previously reported promising results in the first stage. The enrollment of the second stage had been completed by January 2022, herein we reported the updated results. Methods: Patients with chemotherapy-naive, locally-advanced PSCC (cT4 or cTxN3M0) were enrolled. The neoadjuvant regimen consists of anti–PD-1 antibody toripalimab, anti–EGFR antibody nimotuzumab, and chemotherapy (albumin-bound paclitaxel plus cisplatin and ifosfamide). Curative surgery was performed following a maximum of four cycles of treatment. The primary endpoint is the pathological complete response (pCR) rate. Secondary endpoints include overall response rate (ORR), relapse-free survival (RFS), overall survival (OS), and treatment-related adverse events (TRAEs). Results: A total of 29 patients were enrolled in two stages, with a median age of 57 (range 31-71) years. Till January 2022, 21 patients had completed the neoadjuvant treatment, 17 (81%) achieved an objective response, (CR 5, PR 12), 2 had SD, and 2 showed PD. Among 18 patients who underwent radical surgery, 11 showed no residual tumor on histopathology, with a pCR rate of 61.1% (11/18). The median follow-up time was 10.6 months. Two patients with PD died from disease, and 2 patients who experienced disease relapsed after radical surgery, in which 1 with SD, and 1 with PR. No relapse was observed among patients with pCR. The survival data are still immature. No unexpected toxicities and treatment-related death were recorded. Five out of 21 (23.8%) patients experienced grade 3 or 4 TRAEs. Grade 3 neutropenia occurred in 3 (14.3%) patients with 10 used G-CSF prophylaxis. No febrile neutropenia occurred. Other grades 3 toxicities included 1 case of peripheral sensory neuropathy and 1 anemia. The most common grade 1/2 TRAEs were alopecia (100%), decreased appetite (85.7%), nausea (71.4%), peripheral sensory neuropathy (66.7%), anemia (66.7%), neutropenia (33.3%), and infusion-related reactions (28.6%). The most common immune-related adverse events (IRAEs) were grade 1/2 hypothyroidism (19.0%), and grade 1 hyperthyroidism (4.8%). No severe IRAEs including pneumonitis, colitis, and myocarditis were observed. Conclusions: The triple combination is a provoking safe and efficacious neoadjuvant regimen for patients with advanced PSCC. Clinical trial information: NCT04475016.

Pyrotinib combined with EC-TH neoadjuvant therapy for patients with HER2-positive breast cancer: A multicenter, randomized, phase II, open-label trial.

e12604 Background: Neoadjuvant therapy plays an important role in improving the clinical efficacy for patients with stage II-III epidermal growth factor receptor 2 (HER2)-positive breast cancer. Pyrotinib, a new irreversible tyrosine kinase inhibitor (TKI), combined with capecitabine have demonstrated a promising anti-tumour activity in metastatic breast cancer. Here, we conducted a multicenter, randomized, phase II, open-label trial aiming exploring the outcomes of adding pyrotinib to EC-TH neoadjuvant therapy. Methods: Patients aged 18–65 years old with invasive carcinoma, cT1-4N0-3M0 stage, HER2-positive breast cancer were enrolled. Cases were randomly assigned into neoadjuvant therapy with four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (or Paclitaxel for Injection, albumin bound) and trastuzumab (EC-TH), or pyrotinib (400mg day 1-21) combined with EC-TH. Results: 56 patients had completed 8 cycles of neoadjuvant therapy (40 in the treatment group and 16 in the controlled group). 20 patients underwent radical surgery after neoadjuvant therapy. Compared with EC-TH along (37.5%, 3/8), the addition of pyrotinib to EC-TH neoadjuvant chemotherapy (py+EC-TH) significantly increased the pathological complete response (pCR)rate (75%, 9/12) in patients with HER2-positive breast cancer. The objective response rate (ORR) was 87.5% (7/8) vs 100% (12/12) . The most common adverse effects (AEs) in the treatment group was diarrhoea with grade 3 occurred in 3 cases (7.5% 3/40), which most limited in the first treatment cycle. No grade 3 diarrhoea was observed in controlled group. Other AEs including leukopenia occurred similarly in both groups and no cardiovascular dysfunction was observed. Conclusions: Pyrotinib added to EC-TH neoadjuvant therapy significantly increased the pCR rate, suggesting an applicable strategy for HER2-positive breast cancer. Clinical trial information: NCT04290793.