Complete Clinical Response Research Articles

ESORES-Trial: Surgery as needed versus surgery on principle in patients with postneoadjuvant clinical complete tumor response of esophageal cancer.

TPS4185 Background: A substantial fraction of patients with esophageal cancer (EC) shows post-neoadjuvant pathological complete response (pCR). Principal esophagectomy after neoadjuvant treatment is the standard of care for all patients. Active surveillance (AS) and surgery as needed may be a treatment alternative for patients with clinical complete response (cCR). Methods: ESORES is a multicenter randomized controlled parallel-group non-inferiority trial. Patients are randomized either to surgery on principle and subsequent follow-up (Arm B) or clinical response evaluation (CRE) and surgery as needed (Arm A). CRE consists of esophagogastroscopy with deep biopsies (EGD), endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) of suspicious lymph nodes, and F18-FDG-PET CT. In case of residual tumor (non-CR) after CRE, treatment is surgery. Patients with cCR will proceed with AS and surgery only if local regrowth occurs. AS comprises EGD, EUS-FNA and CT-Thorax/Abdomen at 3/6/9/12/18/24 months and yearly thereafter. A sample size of 670 patients is needed to demonstrate non-inferiority of Arm A vs. Arm B with regard to overall survival (OS) at a one-sided significance level of 5%, choosing a hazard ratio of 1.325 as non-inferiority margin which corresponds to a difference in 3-year OS rates of 8%. Superiority with regard to quality of life will be evaluated hierarchically only after non-inferiority with respect to OS has been shown. Key inclusion criteria: histologically verified EC, TNM stage ycT0-3 ycN0 ycM0, completion of neoadjuvant chemotherapy (nCT) or chemoradiation (nCRT) (irrespective of specific protocol), no visible lymphatic or distant metastasis in routine postneoadjuvant CT. Key exclusion criteria: postneoadjuvant dysphagia and/or esophageal obstruction, tumors of the cervical esophagus, tumors with direct proximity to the membranous part of the central airways (if regrowth is suspected to evoke locally irresectable ryT4b-stage), TNM stage cT4/ycT4 and/or cM1/ycM1, tumor progression during/after nCT/nCRT, and nCRT with >50 Gy radiation dose. Primary endpoints (hierarchically tested): 1) OS, 2) EORTC QLQ C30 global quality of life subscale. Secondary endpoints: Efficacy: long term tumor control, disease free survival, distant metastasis/local recurrence/regional recurrence; quality of life: EORTC QLQ C30, QLQ OES18, fear of progression: FoP-Q-12, surgery-free survival time in Arm A, patients’ satisfaction: EORTC OUT-PATSAT7; economic impact: days and costs of hospitalization; Safety: Interventional Safety: 3-Year-Comprehensive Complication Index, Oncological Safety (diagnostic accuracy of CRE, resection status (R0/R1/R2), irresectable regrowth during AS). Enrollment of patients started on January 30th, 2024. Clinical trial information: DRKS00032613 .

Long term outcome of patients with rectal cancer with complete clinical response or near complete clinical response after neoadjuvant therapy: A multicenter registry study by Chinese Watch and Wait Database.

e15597 Background: To report the long-term outcomes of Chinese rectal cancer patients after Watch and Wait (W&W) following neoadjuvant therapy(NAT). Methods: Collecting real-world multicenter retrospective data, including the Chinese W&W Database group (CWWD) and data from centers that initiated this work earlier in China. Patients with a follow-up time of no less than 2 years were included. Analyzing and reporting on their oncological outcomes and comparing differences between cCR and near-cCR groups. Results: The study included 318 rectal cancer patients from 8 institutions who received NAT and underwent W&W. Among them, 291 initially achieved cCR, and 27 had near-cCR. The median follow-up time was 48.4 months (10.2-110.3 months). The 5-year OS and CSS were 92.4% (95% CI 86.8-95.7%) and 96.6% (95% CI 92.2-98.5%), respectively. The 5-year OP-DFS(organ preservation adapted DFS) was 86.6% (95% CI 81.0-90.7%), and the 5-year OPR was 85.3% (95% CI 80.3-89.1%). The overall 5-year local regrowth rate and distant metastasis rate were 18.5% (95% CI 14.9-20.8%) and 8.2% (95% CI 5.4-12.5%), respectively. The 5-year local regrowth rate in the near-cCR group was higher than in the cCR group (41.6% vs. 16.4%, p<0.01), with a lower OPR rate (69.2 vs. 88.0%, p<0.001). However, there were no significant differences in OS, CSS, and OP-DFS between the two groups. 91% of local regrowths occurred within the intestinal lumen, 7.2% (4/56) occurred simultaneously in the intestinal lumen and mesentery, and 1.8% (1/56) occurred only in the mesentery. 82.1% of local regrowths occurred within 2 years, 91.0% occurred within 3 years, with a median regrowth time of 11.7 months (2.5-66.6 months). Among cases with local regrowth beyond 2 years, 30% (3/10) had mesenteric regrowth. The salvage success rate after local regrowth (conversion to disease-free status after salvage surgery) was 82.1% (46/56). 60.8% of distant metastases occurred within 2 years, 73.9% occurred within 3 years. Common sites included lung metastasis (65.2%), liver metastasis (34.8%), and bone metastasis (30.4%), with 26% involving multiple organs. 83.3% (5/6) of liver metastases occurred within 2 years, while lung and bone metastases spread out over 5 years follow-up. Among patients with local regrowth, 16.0% (9/56) developed distant metastases. The salvage success rates for local regrowth and distant metastasis were 82.1% (46/56) and 12.5% (3/23), respectively. Conclusions: Rectal cancer patients who achieve cCR or near-cCR after NAT and undergo W&W have favorable oncological outcomes and a high rate of organ preservation. Local regrowth and distant metastasis during W&W follow certain patterns, with a relatively high salvage rate for local regrowth. It emphasizes the importance of close follow-up and timely intervention during the W&W process.

Real life comparison between doxorubicin and cyclophosphamide (AC) dose-dense (dd) and conventional dose AC in patients with triple negative breast cancer (TNBC) under neoadjuvant treatment.

e12662 Background: High-risk early triple-negative breast cancer (TNBC) is frequently associated with early recurrence and high mortality. Studies suggest a sustained clinical benefit in patients with TNBC who have a pathological complete response (PCR) after neoadjuvant chemotherapy (NACT). The dose-dense (dd) regimen demonstrated improved survival regardless of hormone receptor expression or HER2 status. The doxorubicin and cyclophosphamide (AC) regimen can be performed in (dd), therefore it must include granulocyte growth factors, which may increase costs and toxicities. The object of the study was to evaluate their clinical characteristics and treatment, patients with TNBC, stage I-III who received ACdd in neoadjuvant treatment versus patients who received AC dose conventional (dc). Methods: We performed a retrospective observational cohort study of patients with early TNBC, stage I-III who received neoadjuvant treatment with chemotherapy based on doxorubicin, cyclophosphamide, paclitaxel and carboplatin associated with pembrolizumab. Results: All 82 patients were women 57.3% received ACdd, 30.4% received AC dc. In group ACdd 59.5% had intercurrence related with chemotherapy, in which 17.8% were neutropenic fever and 21.4% had developed different types of infections (ex: diarrhea, pneumonia and others). In these 2 groups all of them had received antibiotic. About 50% of the patients had developed intercurrence because of treatment toxicity and just 3.5% had disease progression. The other group that we evaluated is composed by patients who ACdc, dose Regarding to these group 48% developed any intercurrence during the neoadjuvant treatment, in which 8.3% had neutropenic fever and 25% had different types of infections. All of them earned antibiotic. About clinical and pathological response, the group that earned ACdd 61.7% got complete clinical response and 8.5% had a disease progression during the treatment. In the other arm 68% got complete clinical response and 4% had a progression. Conclusions: AC dd was more prevalent in our series, despite the additional use of granulocyte growth factor, there were more complications in this group and it did not demonstrate better results than those who received conventional dose AC.

Rethinking rectal cancer management through COVID: Real word evidence in a public hospital in the south of Brazil.

e15620 Background: Treatment of locally advanced rectal cancer is based on a combination of radiotherapy and chemotherapy, either as adjuvant, neoadjuvant or total strategies. Short course radiotherapy followed by neoadjuvant chemotherapy, as described in the RAPIDO trial, was chosen by our Oncology, Radiotherapy and Coloproctological tumor board at Hospital de Clínicas de Porto Alegre during the COVID19 pandemic as a measure to reduce hospital visits and thus the possibility of transmission and infection by the SARS-COV-2 virus. Methods: We performed an observational analysis, including all patients treated with short course radiotherapy for locally advanced rectal cancer, at the Hospital de Clínicas de Porto Alegre in the period between January 2020 and March 2023. Metastatic patients were included, either treated with curative or palliative intent. Demographic characteristics, clinical staging, timing of chemotherapy, radiotherapy and surgery were analyzed. Clinical response was evaluated through sigmoidoscopy and clinical rectal exam. Patients with complete clinical response were offered the watch and wait strategy or surgery, after careful discussion of the possible benefits and risks. Results: Ninety-six patients were submitted to short course radiotherapy in the period described. Seven (7) patients were excluded; 89 patients were included in the final analysis. Fifty-five percent were male; mean age was 62 ±12.5 years; 52.8% were ECOG 1 at the diagnosis. Median CEA value at diagnosis was 7 ng/mL (CI 95%:4.4 - 9.8). Sixty-four percent were stage III, 31.4% stage IV, 3.3% stage II. Ninety-eight percent completed the programmed radiotherapy treatment. Only two patients received less than 25Gy. Forty-nine percent of patients completed the whole planned chemotherapy treatment; 15.7% were treated with palliative intent chemotherapy and 5.6% couldn’t receive chemotherapy for other reasons. Clinical response data were available in 62 patients: the main reason for unavailable clinical response was metastatic disease. Disease control was achieved in 98.4% of the cases, with only 1 patient having progressive disease during treatment (1.6%). The overall clinical response rate was 72.6%, 25.8% had stable disease and 24.2% complete clinical response. Fifteen of the 16 patients that presented with complete clinical response opted into a watch and wait strategy, achieving a 1-year disease free survival of 86.6%. Conclusions: Adopting the RAPIDO approach had a positive outcome in our advanced rectal cancer population. Short course radiotherapy followed by chemotherapy achieved excellent rates of disease control. Almost 25% of the non-metastatic patients undergoing RAPIDO treatment achieved complete clinical response opting into a watch and wait program.

Gemcitabine and cisplatin chemotherapy plus penpulimab combined with or without anlotinib as neoadjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: A prospective, phase II clinical trial.

e18038 Background: Patients with locoregionally advanced nasopharyngeal carcinoma (LANPC) still have a risk of disease relapse after receiving the standard treatment of neoadjuvant chemotherapy followed by concurrent chemoradiotherapy (CCRT). Nowadays, PD-1 inhibitors have been widely used in recurrent or metastatic NPC, but the efficacy in LANPC requires further investigation. Besides, the synergistic antitumor effects between immune checkpoint inhibitors and anti-angiogenesis agents have been well established. In this phase II trial, we compared the efficacy and safety of gemcitabine and cisplatin (GP) + penpulimab (PD-1 inhibitor) combined with or without anlotinib (VEGFR-targeted TKI) as neoadjuvant therapy (NAT) for LANPC to establish the optimal regimen. Methods: Patients with LANPC (stage III–IVa, AJCC 8th Staging System, excluding T3–4N0 and T3N1 with only retropharyngeal lymph node +) were enrolled. In the first stage, patients were randomly assigned 1:1 to receive 3 cycles of GP + penpulimab (200 mg, day 1, Q3W) combined with or without anlotinib (10 mg, days 1 to 14, Q3W) for 3 cycles. All patients were followed by CCRT and penpulimab maintenance treatment. The primary endpoint in the first stage was the clinical complete response (CR) rate after NAT based on endoscopy and imaging examinations. A pick-the-winner statistical design was applied and the regimen with a higher CR rate ( > 2.5%) was the winner. In the second stage, patients were continuingly enrolled and treated with the winner regimen; the primary endpoint was 3-year progression-free survival. Results: In the first stage, 60 patients were enrolled between August 2022 and April 2023 (30 patients in each arm). After NAT, 27 patients (45.0%) had CR, with 11 patients (36.7%; 95% CI, 18.4% to 55.0%) in the GP + penpulimab arm and 18 patients (60.0%; 95% CI, 41.4% to 78.6%) in the GP + penpulimab + anlotinib arm (winner regimen). In the second stage, 45 patients were enrolled between June 2023 and October 2023 and treated with GP + penpulimab + anlotinib. Among all 75 patients receiving the winner regimen, the CR rate was 53.3% (95% CI, 41.8% to 64.9%) after NAT. Acute adverse events (AEs) during NAT and CCRT were analyzed. In the first stage, grade 3-4 acute AEs were reported in 22 (73.3%) patients in the GP + penpulimab arm and 26 (86.7%) patients in the GP + penpulimab + anlotinib arm. The most common grades 3-4 acute AEs in the GP + penpulimab arm and GP + penpulimab + anlotinib arm were neutropenia (40% vs 46.7%), leukopenia (40% vs 30%) and mucositis (33.3% vs 36.7%). Among all 75 patients receiving additional anlotinib, the incidence of grade 3-4 acute toxicities was 85.3%. Conclusions: GP + penpulimab + anlotinib regimen showed encouraging efficacy as NAT for LANPC. This finding requires validation in longer follow-up and larger phase III clinical trials. Clinical trial information: NCT05193617 .

De-escalation of breast cancer surgery using vacuum-assisted biopsy (VAB): Interim results.

e12590 Background: Currently, there is a point of view according to which, in patients diagnosed with breast cancer (BC), surgical intervention when achieving a complete pathological response (pCR) after neoadjuvant systemic therapy (NST) is diagnostic, not therapeutic, and does not affect long-term treatment outcomes. Vacuum-assisted biopsy (VAB) of the tumor bed in breast cancer has shown promising results as a minimally invasive method for diagnosing pCR. This work presents a prospective analysis of treatment of patients with triple-negative and HER2-positive breast cancer who achieved pCR after NST and who underwent VAB alone without subsequent breast surgery. Methods: Women aged 18 years old and older with unicentric (cT1-2N0-1M0) triple-negative or HER2-positive breast cancer were included. Primary lesions were marked with a single clip before NST. In cases with nodal involvement (cN1) the affected lymph nodes were also clipped. Patients with TNBC received 4 cycles of AC q21d followed by 12 cycles of weekly paclitaxel and carboplatin AUC 2.0. HER2+ patients received dual anti-HER2 blockade with chemotherapy (TCHP or AC-DHP regimen). Breast US, mammography and mammolymphoscintigraphy were used at baseline and at response evaluation. Patients with complete clinical response after NST underwent VAB with 7G needle and US-guidance simultaneously with the sentinel lymph node biopsy and/or targeted axillary dissection. In case if no invasive or in situ residual tumor cells were detected (ypT0N0), no further breast surgery was performed and patients underwent subsequent radiation therapy. Primary endpoint was 2-year ipsilateral breast tumour recurrence-free survival [IBTR-FS]. Secondary endpoints included 2-year disease-free survival (DFS) and complication rates. The study is registered on сlinicaltrials.gov, NCT04293796. Results: 35 patients with a mean age of 48.3 (31–67) years were included in the trial. Examination of VAB samples showed that 11 (31.4%) patients had a residual tumor, and in 24 (68.6%) patients no tumor cells were detected (ypT0N0). This 24 patients were included in the analysis. Median follow-up was 26 months. Median survival was not reached for any endpoint. 2-year IBTR-FS was 91.7% in the VAB group. 2-year DFS was 83.3% in the VAB group. We registered 4 events: in 2 patients biopsy-proven de novo breast cancer occurred in contralateral breast, in 1 patient recurrence occurred in the postoperative zone and in 1 patient recurrence occurred in another quadrant of the ipsilateral breast. Conclusions: Additional observation and large randomized prospective studies are needed to determine the safety of VAB use. Clinical trial information: NCT04293796 .

A pilot study of early PET and biomarker dynamics in patients with stage 2 and 3 triple negative breast cancer treated with neoadjuvant response-adapted chemotherapy with pembrolizumab (NeoADAPT).

TPS624 Background: In patients with triple negative breast cancer (TNBC) the addition of pembrolizumab to neoadjuvant chemotherapy has improved pathologic complete response rates (pCR) and 5-year event free survival (EFS). Patients with TNBC who achieve a pCR have a significantly lower risk of recurrence compared to those with residual disease (RD). However, pCR can only be assessed at the time of surgery after completion of 6 months of intensive chemo-immunotherapy, associated with up to 77% high-grade treatment-related toxicity. Identifying pCR early on is imperative in developing optimized and individualized treatments, however, there are no predictive biomarkers. Studies in HER2-positive breast cancer have shown that early fluorodeoxyglucose positron emission tomography (FDG-PET) changes soon after initiation of neoadjuvant treatment can help predict the pathological outcomes at the time of surgery and also the risk of recurrence. Emerging data also support that clearance of circulating tumor DNA (ctDNA) during neoadjuvant treatment may be associated with higher rates of pCR. We thus designed a study to determine the association of early FDG-PET changes and ctDNA clearance with pCR in early-stage TNBC. Methods: NeoADAPT is a phase 2, open label, single center clinical trial including adult patients with previously untreated clinical stage 2 or 3 TNBC. Participants will receive 4 cycles of neoadjuvant paclitaxel/carboplatin with pembrolizumab (TC/pembro), per standard-of-care (SOC). An FDG-PET will be performed at baseline and after 1 cycle. A breast MRI will be performed at baseline and after completion of 4 cycles of treatment. Patients with a complete clinical response (cCR) will proceed to surgery and will forgo more neoadjuvant treatment. Patients with clinical RD on MRI will complete SOC neoadjuvant therapy with 4 cycles of doxorubicin/cyclophosphamide (AC) with pembro prior to surgery. If RD is identified after surgery, adjuvant therapy will be determined by the treating oncologist, which may include pembro with AC (if not given prior), capecitabine, etc. The primary objective is to evaluate if lack of decrease in maximum FDG-PET standard uptake value of lean body mass (SULmax) by less than 40% after 1 cycle of neoadjuvant treatment correlates with RD at the time of surgery (i.e. determining the negative predictive value of FDG-PET). Additional key endpoints include ctDNA clearance, evaluation of pCR and cCR rates in the treatment population and EFS. Distributions of percent reduction in SULmax will be compared between pCR and no-pCR groups using the Wilcoxon rank sum test. Receiver operating characteristic (ROC) curve analysis will be performed to estimate the ability of FDG-PET SULmax reduction and cCR by MRI in predicting pCR at surgery. Clinical trial information: NCT06245889 .

Contact x-ray brachytherapy for the treatment of rectal cancer: A systematic review and meta-analysis.

e15628 Background: Rectal cancer is a highly prevalent disease, particularly among the elderly and frail populations. While surgical resection has traditionally been the primary management approach, it carries inherent risks, including operative mortality, morbidity, and poor long-term functional outcomes. These risks are particularly pronounced in older, co-morbid individuals. Evidence presented in the 2023 phase III OPERA randomised trial suggests that Contact X-ray Brachytherapy (CXB) is a viable organ-preserving alternative to radical surgery. We conducted a systematic review and meta-analysis to assess the clinical effectiveness of CXB in the treatment of rectal cancer. Methods: This systematic review was prospectively registered (CRD42021284969) and reported in accordance with PRISMA guidelines. PubMed, EMBASE, SCOPUS and Cochrane CENTRAL Libraries were interrogated using the search terms “Rectal cancer”, “Contact Brachytherapy”, and synonym terms. Literature search and data extraction were conducted by two reviewers, with recourse to a senior author for resolution of conflicts. Clinical complete response (cCR) was the primary outcome. Secondary outcomes include local regrowth, regional recurrence, salvage surgery rates, long-term disease control post-salvage surgery and survival outcomes. Proportional meta-analyses were conducted and presented as forest plots with summary proportions and 95% confidence intervals. The Higgins I2 statistic was used to assess for heterogeneity. The random effects model was employed in studies reporting substantial heterogeneity (I2> 50%). Results: The literature search identified 973 studies, of which 48 studies encompassing 5,447 patients were included in the meta-analysis. Pooled estimates of outcomes were as follows: cCR rate = 80% (95% CI 76-88%), local regrowth = 15% (95% CI 12-18%), regional failure rate = 3% (95% CI 2-4%), salvage surgery rate = 14% (95% CI 11-18%), long-term disease control post-salvage surgery rate = 88% (95% CI 78-96%) and organ preservation 82% (95% CI 75-88%). A subgroup analysis was conducted and stratified by concomitant therapy (CXB alone, CXB & EBRT, CXB & EBCRT). CXB, in conjunction with EBCRT, leads to a statistically significant reduction in both local regrowth and regional failure. The local regrowth rates were 16% (95% CI 11-21%), 17% (95% CI 11-23%), and 10% (95% CI 8-13%) respectively, with a p-value of 0.05. The regional failure rates were 4% (95% CI 2-8%), 4% (95% CI 2-5%), and 1% (95% CI 0-2%), p = 0.02. Conclusions: CXB, combined with EBCRT, in the appropriately selected patient can achieve long-term disease control whilst avoiding major surgery. Salvage surgery is a viable option for patients who experience disease regrowth, with excellent long-term disease control. CXB may be considered a safe alternative to surgery in the appropriately selected patient.

Neoadjuvant immunotherapy (PD-1) combined with chemotherapy for locally advanced thoracic esophageal carcinoma (EC): A single-arm, open-label, phase II study.

4075 Background: This study aimed to evaluate the efficacy and safety of PD-1 combined with chemotherapy as neoadjuvant therapy in patients with locally advanced EC and sought to explore biomarkers related to treatment prognosis and efficacy prediction for screening patients who would benefit most from this therapy. Methods: In this phase 2 study, patients (pts) with histopathologically confirmed ESCC, diagnosed as clinical stage cT1-3N1-3M0 and ECOG PS 0-1 were enrolled to receive two cycles of neoadjuvant chemoimmunotherapy with PD-1 blockade (Pembrolizumab/Tislelizumab on d1) plus nab-paclitaxel (260mg/m2 in total on d1 and d8) and cisplatin (60mg/m2 in total on d1-3) of each 21-day cycle, followed by esophagectomy. Biopsied pretreatment tumor tissues along with surgical tumor specimens were collected for RNA sequencing. The primary endpoint was complete pathologic response (pCR) rate. The secondary endpoints were overall response rate (ORR), event-free survival (EFS), overall survival (OS) and safety. Biomarkers associated with clinical prognosis were assessed as exploratory objectives. Results: From Jan 11, 2021 to, Apr 25 2022, 56 pts were enrolled and 42 pts received neoadjuvant therapy and operation. Among them, 66.7% (28/42) had clinical complete response, 50% (21/42) had partial response, and ORR was 78.6% (33/42). 42 pts underwent surgical resection, achieving a 100% (42/42) R0 resection rate and a pCR rate of 33.3% (14/42), tumor regression grade (TRG, Mandard system) 1, 2 and 3 were 14.3% (6/42), 14.3% (6/42) and 71.4% (30/42) respectively. With a median follow-up of 24.4 months (range 14.3-33.4), 12(28.6%) patients had disease recurrence. Within 24 months, 14.3% (2/14) pts who achieved pCR experienced recurrence. 2-year EFS rate was 54.8% (95%CI,43.4, 66.3% ), 2-year OS rate was 81.5% (95%CI,69.4, 90.2% ). Overall, grade ≥3 AEs included leukopenia (11.9% [5/42]), thrombocytopenia (4.8% [2/42]), and no deaths were due to TRAEs. With 34 patients of RNA sequenced, we divided the patients into two groups based on whether they had recurred within 24 months as favorable prognosis and poor prognosis respectively, to analyze gene expression in different treatment effect. The poor outcome patients had significant molecular differences were seen in PI3K−Akt pathway gene expression, markers of immune activation, and genes involved in ECM−receptor interaction and focal adhesion in baseline samples, and the pathway enriched by differential genes expression in samples after treatment validated this result. Conclusions: Combining PD-1 blockade with nab-paclitaxel and cisplatin is feasible and effective in patients with locally advanced resectable ESCC, and might be a promising approach for neoadjuvant treatment. Clinical trial information: NCT05028231 .

A phase 2 study of de-escalation in resectable, locally advanced cutaneous squamous cell carcinoma (cSCC) with the use of neoadjuvant pembrolizumab: De-Squamate.

9514 Background: Neoadjuvant anti-Programmed Death therapy has shown a 64% complete or major pathological response rate in patients (pts) with resected stage II-IV(M0) cSCC. The De-Squamate study (NCT05025813) evaluated the feasibility of a risk adapted surgical de-escalation approach guided by clinical, radiological and pathological response in resectable cSCC pts of all sites receiving neoadjuvant pembrolizumab. Methods: This multi-centre, open-labelled, non-randomised, single-arm phase 2 study evaluated the response of neoadjuvant Pembrolizumab for 4 cycles administered IV 200mg Q3W in immunocompetent pts with Stage II-IV (M0) resectable cSCC. Pts underwent CT/MRI and 18F-FDG-PET imaging at baseline and following completion of neoadjuvant pembrolizumab. In those with a complete metabolic response, mapping biopsies of target site(s) were performed and if negative for residual SCC (clinical complete response [CCR]), surgery and post operative radiation therapy (PORT) were omitted. Patients with clinical or radiological residual disease/ positive mapping biopsy underwent surgical resection. PORT was de-escalated if there was a pathological complete response (PCR - no residual tumour cells) or major pathological response (MPR - less than or equal to 10% viable tumour cells). Pts proceeded to 13 cycles of maintenance Pembrolizumab. The primary endpoint was the combined rate of PCR, MPR and CCR following neoadjuvant Pembrolizumab and secondary endpoint includes treatment de-escalation and safety. Results: All 27 patients were enrolled and received a minimum of 2 cycles of neoadjuvant Pembrolizumab. The primary endpoint was observed in 17 patients (63%, 95% CI: 42-80), comprised of PCR (15%), MPR (0%) and CCR (48%). De-escalation of both surgery and PORT was achieved in 48% and a further 15% avoided PORT alone. With a minimum follow up of 6 months, no pts with PCR/MPR/CCR recurred. Investigator assessed treatment-related adverse events ≥ grade 3 was seen in 2 patients (7%). Conclusions: Pembrolizumab led to a high rate of PCR and CCR in resectable cSCC. The de-squamate study design effectively selected pts for surgical and PORT de-escalation and demonstrated a sustained response in this cohort. Clinical trial information: NCT05025813 .

Short-course radiotherapy (SCRT) followed by fruquintinib plus adebrelimab and CAPOX in the total neoadjuvant therapy of locally advanced rectal cancer (LARC): A multicenter, single-arm, open-label, phase II study.

TPS3643 Background: For LARC patients (pts), long-course concurrent chemoradiotherapy or SCRT followed by chemotherapy is recommended by the NCCN guidelines (Version 1.2024) as neoadjuvant therapy. Compared with chemoradiotherapy, the addition of immune checkpoint inhibitors (ICIs) or anti-angiogenic drugs could further improve complete response (CR) rate in the neoadjuvant treatment of LARC. Fruquintinib, a highly selective small-molecule inhibitor of VEGFR-1, -2, and -3, has gained FDA approval for pts with metastatic colorectal cancer previously treated. For pts with LARC at high risk of recurrence, the CR rate of SCRT followed by chemotherapy was 29%. There is an urgent need for new therapeutical options to improve the CR rate in these pts. This study introduces an innovative approach, combining SCRT, chemotherapy, Fruquintinib, and ICIs as a total neoadjuvant therapy for high-risk LARC pts. Methods: This is a multicenter, single-arm, open-label, phase II study (NCT06234007) investigating the efficacy and safety of SCRT sequential fruquintinib, combined with adebrelimab (an anti-PD-L1 monoclonal antibody) and CAPOX in pts with LARC. Eligible participants were 18 years or older, with an ECOG PS of 0–1, and a biopsy-proven, newly diagnosed, primary, LARC, classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for surgery. Total neoadjuvant therapy included SCRT (5 × 5 Gy over 5 days, 1-week rest) followed by six cycles of fruquintinib (4mg, qd, po, q3w. For the initial 6 pts in the safety run-in period, dosage was adjusted based on dose-limited toxicities in the 1st cycle) combined with adebrelimab (1200mg, iv, d1, q3w) and CAPOX (q3w). Subsequently, pts who did not reach clinical CR underwent total mesorectal excision, others received the “Watch and Wait” policy or surgery. Primary endpoint was CR rate (including clinical CR & pathologic CR). Secondary endpoints included 3-year event free survival rate, overall survival, R0 resection rate and adverse events (AEs). Exploratory endpoints aimed to evaluate the correlation between potential biomarkers and efficacy. Using PASS 15 software (version 15.0.5.0), in the Tests for One Proportion analysis, with a two-sided α of 5% and to guarantee the power over 80%. The null hypothesis of CR rate was 29%, and the alternative hypothesis was 51%, accounting for a 10% drop-out rate, resulting in a sample size of 39 pts. With the 6 pts in the safety run-in period, a total of 45 pts would be enrolled in the study. Until Feb 1, 2024, 7 of planned 45 pts have been enrolled. Clinical trial information: NCT06234007 .

Neoadjuvant dual checkpoint inhibition followed by immune-chemoradiation in patients with resectable gastric adenocarcinoma.

4067 Background: Localized gastric cancer is a potentially curable condition and long-term outcomes depend on YP staging. Currently, preferred adjunctive therapy depends on geographic location. Preliminary data from NCT01928394 have shown promising clinical activity of immunotherapy (IO) agents nivolumab (nivo) +/- ipilimumab (ipi) in the metastatic setting. We conducted a single-arm study using IO + chemotherapy followed by immune-chemoradiation prior to surgery, followed by adjuvant IO, in patients with localized gastric adenocarcinoma. Our primary objective was to determine safety and toxicity with this approach. Secondary objectives included efficacy by YP staging and R0 resection rate. Methods: Patients with localized gastric adenocarcinoma were enrolled into NCT03776487 (n=30). Participants received the following: (1) biweekly chemotherapy with 4 doses of 5-Fluorouracil (5-FU)/Oxaliplatin, (2) nivo 240mg q2weeks (x3) and ipi 1mg/kg q6weeks (x1), (3) immune-chemoradiation (biweekly nivo + 5FU Mon-Fri concurrently with a total of 45 Gy given in 25 fractions), and (4) surgical resection. Those with residual disease received adjuvant nivolumab monthly for 6 doses. Correlative studies are planned. To assess preliminary efficacy, the clinical and pathologic complete response rates (pCR) were estimated along with the corresponding exact 95% confidence interval. Adverse events and toxicities were summarized using descriptive statistics. Results: Median follow-up was 27.4 months at the time of data cutoff. Of 30 enrolled, 23 patients completed surgery and seven did not due to progression of disease(n=5) and worsening co-morbidities(n=2). The side effect profile was similar to prior IO studies, with no grade 5 events observed. Three patients (10%) experienced grade 4 events (acute kidney injury, myocarditis, and neutropenia). The most frequent grade 3 toxicity was nausea and vomiting (10%). From the 23 participants that underwent resection, 22 had pathologic data at the time of analysis, with 9 achieving ypT0ypN0 (40.9%, 95% CI: 20.7%, 63.7%). There was an 86% R0 resection rate. Conclusions: Our results are encouraging and support further development of this strategy for localized gastric adenocarcinomas. The regimen is safe and potentially generalizable. Clinical trial information: NCT03776487 .

Transanal endoscopic microsurgery vs. radical surgery for mid-low rectal cancer in patients with clinical complete or near-complete response after neoadjuvant chemoradiotherapy.

e15616 Background: Following neoadjuvant chemoradiotherapy (nCRT), total mesorectal excision surgery used to be the standard therapy for locally advanced rectal cancer (LARC). However, the radical surgery is associated with high complication rates and impairs patients' quality of life, especially for non-sphincter preservation procedures. For the past two decades, nCRT followed by organ preservation strategies like watch-and-wait (W&W) or local resection offers an alternative for patients being clinically evaluated with complete response or near complete response, however the oncological outcomes of these approaches require further exploration. Methods: We prospectively collected data on 80 patients with T3-4N0M0 or TanyN+M0 mid-low rectal cancer who achieved cCR or near-cCR after nCRT from May 2017 to September 2021 at 5 tertiary centers in China. Patients were divided into the TEM group (group A) or the radical surgery group (group B). Clinicopathological features, operative outcomes, oncological and functional results were analyzed. Results: A total of 76 cases were analyzed, with 38 in each group. Baseline characteristics were comparable between the two groups. Postoperative histology revealed 22 ypT0Nx(57.9%), 5 ypT1Nx(13.2%), 10 ypT2Nx (26.3%), 1 ypT3Nx(2.6%) in group A, and 18 ypT0N0 (47.4%), 5 ypT1N0 (13.2%), 11 ypT2-3N0 (28.9%), 1 ypT0N1 (2.6%), 3 ypT2-3N1 (7.9%) in group B. After a median follow-up of 61 months, 2 patients (5.26%) in group A experienced local recurrence, while none in group B. 8 patients (21.05%) in group A developed distant metastases compared to 5 (13.16%) in group B. There was no statistically significant difference between two groups in 5-year disease-free survival(P = 0.320), or 5-year overall survival (P = 0.425). Patients in group A had significantly faster postoperative recovery and a superior quality of life evaluated by the Wexner and LARS scores compared to group B. Conclusions: For cCR and near-cCR LARC patients after nCRT, organ preservation with TEM may serve as a staging method to evaluate local tumor persisrence. And it provides an alternative therapy for carefully selected patients who have needs to preserve sphincteric function or can’t tolerate radical resection, without significantly compensate long-term oncological outcomes. This strategy could relatively safely enable sphincteric function preservation for these patients with faster postoperative recovery and better quality of life. Clinical trial information: NCT03042000 .

Cost-effectiveness of short-course radiotherapy versus long-course chemoradiation in organ preservation for locally advanced rectal cancer.

11089 Background: Short-course radiation therapy (SCRT) has previously been found to be cost-effective compared to long-course chemoradiation (LCRT) for patients with locally advanced rectal cancer undergoing operative management. However, non-operative management protocols have recently become a standard treatment option for patients diagnosed with locally advanced rectal cancer achieving a complete clinical response after total neoadjuvant therapy (TNT) as surgery has significant impacts on quality of life. Recent data suggests higher rates of local regrowth and a correspondingly lower rate of organ preservation with SCRT-TNT compared to LCRT-TNT. With this study, we evaluated the cost-effectiveness of SCRT versus LCRT in the setting of non-operative management for locally advanced rectal cancer. Methods: We built a microsimulation model to simulate 5-year outcomes for 1 million hypothetical patients aged 65 years with locally advanced rectal cancer treated with TNT including either SCRT or LCRT. Patients achieving a complete clinical response with TNT opted for a non-operative management approach, undergoing surgery only with subsequent local progression. Patients not achieving a complete clinical response went directly to surgery. The model incorporated costs, quality of life (measured by health utility), and probabilities of disease progression and death. We extracted probabilities of disease progression and death and health utilities from published literature. We assessed costs from the healthcare payer perspective. We measured cost-effectiveness with incremental cost-effectiveness ratio (ICER), with ICERs under $100,000 per quality-adjusted life-year (QALY) considered cost-effective. One way and probabilistic sensitivity analyses were used to test model uncertainty. Results: We found that compared to SCRT, LCRT increased overall cost by $10,457 and improved effectiveness by 0.16 QALYs resulting in an ICER of $67,200/QALY. The model was most sensitive to assumptions about risks of local recurrence in the non-operative setting, the health utility of non-operative management, and the costs of LCRT and SCRT. The model was not sensitive to assumptions about costs of diagnostic evaluation (i.e. flexible sigmoidoscopy) and probability of distant recurrence. Probabilistic sensitivity analysis demonstrated that LCRT was cost-effective in 91% of iterations. Conclusions: Long-course chemoradiation could represent a cost-effective strategy compared with short-course radiotherapy in the non-operative management of patients with locally advanced rectal cancer. The ongoing ACO/ARO/AIO-18.1 trial testing the hypothesis that LCRT-TNT will increase organ preservation rates relative to SCRT-TNT will help confirm these findings.

Pathologic examination of specimen after vacuum-assisted biopsy (VAB) in patients with breast cancer after neoadjuvant systemic therapy (NST).

e12589 Background: VAB of the tumor bed in the breast has shown promising results as a minimally invasive method for determining pathologic complete response (pCR). A significant disadvantage of VAB is the fragmentation of the obtained material and the lack of methods for determining generally accepted predictive and prognostic factors such as RCB index in case if residual tumor is detected. Here we present a description of the accumulated experience of histological examination of specimens obtained using VAB in patients with breast cancer after NST. Methods: A single-center, prospective, non-randomized study included patients with unifocal breast cancer (cT1–2N0–1M0). Patients who achieved a complete clinical response (cCR) underwent VAB. VAB specimen intraoperatively was divided into «inner contour» (first 6-12 samples) and «outer contour» (latter 6-12 samples). Patients without signs of residual tumor (pCR, ypT0N0) did not undergo further surgical intervention. In case if residual tumor cells (RTC) were detected, standard breast surgery was performed. To assess an extent of tumor response to NST instead of RCB we used Miller-Payne system which has correlation with RCB. Results: 35 patients with a mean age of 48.3 (31–67) years were included in the analysis. Examination of VAB samples showed that 11 (31.4%) patients had a residual tumor, and in 24 (68.6%) patients no tumor cells were detected (ypT0N0). According to the Miller-Payne system, 28 patients had a complete pathological response, which corresponds to Miller-Payne = 5 and pathological stage ypT0/ypTis (24 patients ypT0N0, 3 patients ypTisN0 and 1 patient ypT0N1). In 7 patients with residual invasive tumor, the tumor response according to the Miller-Payne scale corresponded to grades 3 and 4. There was a statistically significant correlation between presence of RTC in the «outer contour» of VAB and presence of RTC in the postoperative histology after standard surgery (Х2 p=0.01, Fisher exact test p=0.048). In case when RTC were found in the «inner contour» no correlation with the presence of RTC in the postoperative histology after standard surgery was observed (Х2 p=0.292, Fisher exact test p=1.0). Radiologic-pathologic discordance was 25% for mammolymphoscintigraphy, 35.5% for US and 39.4% for mammography. In case if 3 of 3 studies after NST described cCR radiologic-pathologic discordance was 16.7%, in case if 2 of 3 studies described cCR it was 22.2% and in case if only 1 of 3 studies described cCR it was 27.3%. Conclusions: The method used to evaluate histological material allows us to obtain predictive and prognostic information necessary to clarify further treatment tactics in accordance with modern standards. It is necessary to conduct large-scale studies in this area to answer the question if this method can be used in routine clinical practice. Clinical trial information: NCT04293796 .

Neoadjuvant chemoradiotherapy (nCRT) combined with sequential tislelizumab for resectable esophageal squamous cell carcinoma (ESCC): Preliminary results of a single-arm, open-label phase Ib trial (CRIS).

e16116 Background: Neoajuvant chemoradiation is the standard treatment for resectable locally advanced esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitors (ICIs) have shown a survival benefit for advanced ESCC and showed promising efficacy in neoadjuvant treatment for several cancers. This study aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy (nCRT) combined with sequential tislelizumab followed by surgery for resectable ESCC. Methods: This is a single-arm, phase Ib study. Eligibility criteria include histologically confirmed ESCC and clinical T3-4aN0M0 or T2-4aN+M0 (AJCC/UICC 8th). Patients received neoadjuvant radiotherapy (41.4Gy in 23 fractions) with concurrent chemotherapy (paclitaxel, 50 mg/m2, carboplatin area under the curve of 2mg/mL/min, QW*5). Then followed by two cycles of tislelizumab (200mg, Q3W). The primary endpoint was the pathological complete response (pCR) rate and safety. Results: From Feb 2022 to Jan 2024, 35 patients had been enrolled, of whom the median age was (65.5 (95%CI, 59-67), including 31 (88.6%) males. 12 patients were still undergoing chemoradiotherapy and 2 patients did not receive immunotherapy due to pneumonia and myocarditis after chemoradiotherapy. 16 patients completed all 2 cycles tislelizumab preoperatively and 5 patients completed 1 cycle tislelizumab because of AEs. Two patients refused surgery after achieved complete clinical response under radiology and were still alive, the other 19 patients underwent resection. The R0 resection rate was 94.7% (18/19). The pCR rate was 63.2% (12/19) and the MPR rate was 78.9% (15/19). During neoadjuvant treatment, 8 patients had a grade 3 or worse adverse event including leukopenia (33.3%, 7/21, Grade 3), esophagitis (4.8%, 1/21, Grade 3) and anemia (4.8%, 1/20, Grade 4). One patient developed grade 4 postoperative complication (5.3%, 1/19, pneumonia) and died within 90 days of surgery due to COVID-19. Grade 1-2 postoperative complications occurred in 21.1% (4/19) patients, including anastomotic fistula (21.1%, 4/19), chylothorax (5.3%, 1/19) and pneumonia (10.5%, 2/19). Conclusions: Preliminary results showed that neoadjuvant chemoradiotherapy (nCRT) combined with sequential tislelizumab showed promising outcomes and well tolerated for resectable ESCC patients. Further larger prospective studies are needed to confirm such findings.

NETOS: A personalized approach of neoadjuvant therapy, including INCB099280 monotherapy and bladder preservation, for muscle-invasive urothelial bladder carcinoma (MIBC) with ctDNA monitoring.

TPS4624 Background: MIBC is a systemic disease as >40% of patients (pts) ultimately develop recurrence after radical cystectomy (RC). For pts who cannot receive or refuse cisplatin-based chemotherapy there is no standard-of-care neoadjuvant therapy. Single-agent pembrolizumab, given neoadjuvantly in patients with T2-4N0M0 MIBC, was effective in PURE-01 trial. A proportion of these pts refused RC and were cured with pembro and redo transurethral resection of the bladder tumor (reTURBT; Bandini et al. PMID: 32979511). There are increasing concerns by the pts related to the need to undergo RC whenever they achieve a clinical complete response (cCR) with TURBT and systemic therapy. INCB099280 is a potent, orally bioavailable, selective, small molecule that targets PD-L1 that is being developed for the treatment of advanced malignant diseases. A phase 1, dose-escalation and expansion study is ongoing in pts with select advanced solid tumors (NCT04242199); safety and preliminary efficacy results have been reported (Prenen et al. ESMO-IO 2023). Our hypothesis is that INCB099280 can be offered in biomarker-selected pts as a maintenance therapy instead of any additional treatment, provided that a cCR after the induction phase is obtained. Methods: Pts should have a predominant urothelial carcinoma (UC) histology, have a clinical stage T2-T4N0M0 MIBC, be ineligible for or refuse to receive cisplatin-based chemotherapy. The study will also select pts with a circulating tumor DNA (ctDNA)-positive test (Signatera ctDNA assay) and will be staged with pelvic MRI. Pts will receive 12 weeks of INCB099280 at the dose of 400 mg twice daily (BID), continuously. Restaging will be planned with ctDNA, imaging and reTURBT. Pts who will achieve a cCR (i.e., no evidence of residual disease at the histological examination, clearance of ctDNA and the evidence of no residual detectable disease at cross-sectional imaging, evaluated locally) will receive additional INCB099280 400 mg BID for a maintenance period of 12 months. Pts with evidence of high grade or infiltrating residual disease will be discontinued from the study. Those with a Ta/T1-low grade disease will be managed according to physician’s preference: they may be eligible to continue within the study protocol and receive maintenance INCB099280 400 mg BID for a total period of 12 months. The primary endpoint is the proportion of cCR and the study is planned according to A'Hern one-stage binomial design, with H0 ≤5% and H1 ≥20%, 5% one-sided Alpha, 80% power and 10% drop-out rate. The overall sample size Will be of 30 pts. Secondary endpoints will include safety (CTCAE v.5.0), event-free survival, bladder-intact overall survival (OS) and OS (EUCT number: 2024-511029-73-00). Clinical trial information: 2024-511029-73-00.

Preliminary efficacy and safety of total neoadjuvant therapy combined with PD-L1 blockade in pMMR/MSS locally advanced rectal cancer (ESTIMATE): A prospective, single-arm, phase II trial.

e15602 Background: Patients with locally advanced rectal cancer (LARC) experience benefits from total neoadjuvant therapy (TNT). This study aims to explore the efficacy and safety of combining TNT with immunotherapy for pMMR/MSS LARC patients. Methods: ESTIMATE is a prospective, single-center, phase II study (ChiCTR2400079718) enrolling pMMR/MSS LARC patients with tumors located 10cm away from the anal margin. Treatment involved induction chemotherapy with immunotherapy ([mFOLFOX6, days 1-2 + Envafolimab 200mg, ih, day 1]; q2w; 2 cycles), long-course concurrent chemoradiotherapy (LCRT) with immunotherapy ([IMRT, 50Gy/25f, 2Gy + Cape 825mg/m2, bid]; 5w + Envafolimab 200mg, ih, day 1; q2w; 3 cycles), consolidation chemotherapy with immunotherapy ([mFOLFOX6 + Envafolimab; 2 cycles), and then total mesorectal excision (TME) 3 weeks later or watch and wait (W&W). The primary endpoint is the pathological complete response (pCR) rate. Results: Until Nov. 16th, 2023, 35 patients were enrolled, with 28 completing the TNT regimen. The efficacy analysis revealed that out of 28 patients, 12 (42.9%) achieved clinical complete response (cCR), with 7 individuals choosing the W&W strategy. 21 patients underwent TME, yielding 8 with a tumor regression grade (TRG) of 0, 7 with TRG of 1, and 6 with TRG of 2. The rates of pCR, major pathological response (MPR), and complete response (CR) were 38.1% (8/21), 71.4% (15/21), and 53.6% (15/28), respectively. 25 (89.3%) patients experienced treatment-related adverse events (AEs) of any grade. Non-hematological AEs included decreased appetite, fatigue, nausea, and vomiting, while hematological AEs mainly comprised thrombocytopenia, anemia, and leukopenia or neutrophilia. Grade III AEs were primarily leukopenia or neutrophilia (2/28, 7.1%). Additionally, circulating tumor DNA (ctDNA) levels were measured in 7 patients who chose the W&W strategy after achieving cCR. Of these, 6 tested negative for minimal residual disease (MRD), while 1 had a positive MRD result (ctDNA: 0.56 MTM/ml). As of Jan. 26th, 2024, with a median follow-up of 5 months (range: 3-6), no recurrence was observed in any of the patients. Conclusions: The TNT approach, integrating LCRT with mFOLFOX6 and PD-L1 blockade, demonstrated a favorable CR rate and acceptable tolerability, offering a potential avenue for organ preservation in low rectal cancer patients with pMMR/MSS. Long-term benefits need validation through further follow-up. Clinical trial information: ChiCTR2400079718. [Table: see text]

The NEO-RT trial: A phase 3 randomized trial of neoadjuvant chemotherapy, excision and observation versus chemoradiotherapy for early rectal cancer, CCTG CO.32.

TPS3646 Background: There is significant interest in organ-sparing management of rectal cancer. Data from the National Cancer Database suggest that in 2020 only 20% of US patients with stage I rectal cancer are managed non-operatively. The phase II CCTG CO.28/NEO trial previously reported high rates of tumor downstaging, organ preservation and excellent rectal function among patients with T1-T3abN0 rectal adenocarcinoma treated with 3 months of FOLFOX/CAPOX followed by Transanal Endoscopic Surgery (TES). The phase III CO.32/NEO-RT trial (NCT06205485) will compare two organ sparing strategies for patients with stage I rectal cancer. Methods: Eligible patients with clinical stage T1/2 N0 adenocarcinoma with preserved mismatch repair (MMR) will be randomized 1:1 to ARM A, 3 months of FOLFOX or CAPOX versus ARM B, chemoradiation (54 Gy) followed by tumor restaging within 16 weeks of start of therapy. Patients with histological high grade, mucinous or deficient MMR and those that can be treated with tumor excision alone are excluded. The primary endpoint is tumor downstaging to clinical Complete Response (cCR) by pelvic MRI, endoscopy and digital rectal exam. Subsequent TES is recommended for all patients with tumor response and may be done within 24 weeks of treatment begin, followed by 5 years (y) of observation with serial MRI (q6m x 2y then annually) and endoscopy (q4m x 2y, then q6m during year 3, then annually). The co-primary endpoint is Quality Of Life (QOL) measured by the Low Anterior Resection Score (LARS). In a non-inferiority comparison between treatment arms, if the cCR is assumed to be 45% in ARM B and if there is no true difference between ARMS A and B, then 250 patients are required to be 80% sure that the upper limit of a one-sided 90% confidence interval will exclude a difference in favor of chemoradiation of more than 14%. Results: The approved CCTG CO.32 trial is expected to open February, 2024 at Canadian CCTG and US Alliance, ECOG-ACRIN, NRG, and SWOG NCTN sites with an estimated accrual duration of 4 years. Conclusions: The results of this study will have a major impact on the treatment of patients with stage I rectal cancer. Both arms offer the potential of organ preservation and results will inform whether induction chemotherapy is non-inferior to ChemoRT and compare patient QOL and functional outcomes. Clinical trial information: NCT06205485 .

Adjuvant or rescue disitamab vedotin (RC48-ADC) for high-risk non-muscle invasive bladder cancer with HER2 overexpression: A phase II multi-center study.

TPS4625 Background: Non-muscle invasive bladder cancer (NMIBC) comprises approximately three-quarters of newly diagnosed cases of bladder cancer. Based on the risk of disease progression, NMIBC is categorized into low, intermediate, and high risk, with high-risk NMIBC patients facing a 5-year disease progression rate of up to 40%. The current standard treatment for high-risk NMIBC involves transurethral resection of the bladder tumor (TURBT) combined with intravesical Bacillus Calmette-Guérin (BCG) instillation as adjuvant therapy. In cases of BCG instillation treatment failure, the standard approach is radical cystectomy. Multiple studies have reported HER2 positivity in 20-44% of NMIBC cases, and HER2 overexpression (immunohistochemistry ≥2+) is closely linked to the progression and adverse prognosis of bladder cancer. Consequently, HER2 may serve as a novel therapeutic target for bladder cancer. Disitamab Vedotin (DV; RC48-ADC) is an antibody-drug conjugate (ADC) comprising a fully humanized HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. Results from a Phase II clinical trial (NCT03507166) suggest that Disitamab Vedotin exhibits favorable efficacy and safety in HER2-positive metastatic urothelial carcinoma patients who have previously failed chemotherapy. This clinical trial aims to investigate the efficacy and safety of RC48-ADC as adjuvant or rescue therapy for high-risk NMIBC with HER2 overexpression and to explore molecular biomarkers predicting the efficacy of RC48-ADC. Methods: This multicenter, Phase II clinical trial will enroll two cohorts: Cohort A, consisting of 52 patients undergoing first-line adjuvant therapy, and Cohort B, with 25 patients receiving rescue therapy after BCG instillation failure, both exhibiting HER2 overexpression in high-risk NMIBC. Following the Simon two-stage optimal design, the first stage will involve enrolling 19 patients in Cohort A and 12 patients in Cohort B. After safety and baseline assessments, both cohorts will undergo six cycles of treatment with RC48-ADC (120 mg intravenous infusion every two weeks), totaling 12 weeks of treatment. Primary endpoints include safety, 12-month recurrence-free rate (Cohort A), and 3-month clinical complete response rate (Cohort B). Secondary endpoints encompass the 6-month recurrence-free rate (Cohort A), duration of response (Cohort B), recurrence-free survival, progression-free survival, overall survival, and quality of life (assessed through eEuroQoL EQ-5D and FACT-BI). Additionally, exploratory endpoints will investigate the relationship between biomarkers in tumor tissues, blood, and urine, and treatment efficacy. Clinical trial information: NCT05996952 .