Pathologic Downstaging Research Articles

Disitamab vedotin in combination with immune checkpoint inhibitors for locally and locally advanced bladder urothelial carcinoma: a two-center's real-world study.

Objective: Our study aims to assess the effectiveness and safety profile of Disitamab Vedotin (DV, RC48-ADC), an innovative humanized anti-HER2 antibody conjugated with tubulin-disrupting antimitotic drug monomethyl auristatin E (MMAE) via a cleavable peptide linker. This treatment combined immune checkpoint inhibitors as part of the bladder sparing approach for selected patients suffering from locally and locally advanced bladder urothelial carcinoma. Patients and methods: We conducted a two-center, real-world study involving locally advanced urothelial carcinoma (UC) patients. Patients were classified based on HER2 expression (IHC 3+/2+/1+) or lack of HER2 expression (IHC 0). The primary endpoint was the objective response rate (ORR), assessed by the investigator following the criteria of RECIST V1.1. Secondary endpoints encompassed the pathological complete response rate (pCR), pathological partial response rate (pPR), and pathological stable disease (pSD), along with recurrence-free survival (RFS), the pathological downstaging rate, and the safety profile of the treatment. Results: In this study, nine patients were enrolled, with a median follow-up duration of 12.0months. The overall confirmed ORR was 88.9%, Five patients achieved a complete response (CR), and three patients achieved a partial response (PR). The radiological complete response (rCR) aligned perfectly with pCR. The median radiological progression-free survival (rPFS) spanned 12.0months (range from 8.0 to 17.0months). One patient diagnosed with disease progression (PD) underwent a radical cystectomy. The pathological stage evolved from T2N0M0 to T3aN2M0, followed by adjuvant chemotherapy with a gemcitabine-cisplatin (GC) combination radiotherapy. At the 9-month follow-up, neither recurrence nor metastasis was observed. The rate and intensity of complications were manageable among these patients, with no evidence of grade 4 and 5 adverse events. Conclusion: The combination of DV and PD-1 demonstrated considerable activity in the objective response rate (ORR) in patients with HER2 IHC 0/1+/2+/3+ muscle-invasive bladder cancer (MIBC), along with the longest reported median radiological progression-free survival (rPFS) to date. With an extended duration of treatment, the safety profile of DV plus PD-1 was also confirmed to be manageable.

Safety and efficacy of preoperative chemotherapy for muscle-invasive bladder cancer in elderly patients.

This study aimed at describing the feasibility and oncological outcomes of standard cisplatin-based neoadjuvant chemotherapy (C-NAC) for muscle-invasive bladder cancer (MIBC) in patients aged ≥ 75 and assess the impact of baseline geriatric parameters. This retrospective study included patients with stage cT2-4NanyM0 MIBC aged 75 and older treated with ≥ 1 cycle of C-NAC from 2011 to 2021 at a high-volume academic center. Primary outcome was overall survival (OS). Secondary outcomes were chemotherapy feasibility (administration of ≥ 4 cycles), safety, and pathological downstaging. Fifty-six patients were included. Median age was 79 (range 75-90). C-NAC regimen was ddMVAC in 41 patients and GC in 15. Seventy-three percent of patients received ≥ 4 cycles of C-NAC. Grade ≥ 3 toxicity was observed in 55% of patients. The febrile neutropenia rate was 7%. Thirty patients underwent cystectomy, and 13 underwent chemoradiotherapy. Three-year OS was 63%. Geriatric parameters polypharmacy, undernutrition, and age-adjusted Charlson comorbidity index ≥ 8 predicted worse OS. Standard-of-care C-NAC and local treatments are feasible in selected elderly MIBC patients, with efficacy and safety findings similar to that observed in pivotal trials with younger patients. The prognostic impact of geriatric parameters underlines the need for specialized evaluation before treatment initiation.

Neoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study

Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.

Oncological outcomes of visibly complete transurethral resection prior to neoadjuvant chemotherapy for bladder cancer.

To evaluate the potential oncologic benefit of a visibly complete transurethral resection of a bladder tumor (TURBT) prior to neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). We identified patients who received NAC and RC between 2011-2021. Records were reviewed to assess TURBT completeness. The primary outcome was pathologic downstaging (<ypT2N0), with complete pathologic response (ypT0N0) and survival as secondary endpoints. Logistic regression and Cox proportional hazards models were utilized. We identified 153 patients, including 116 (76%) with a complete TURBT. Sixty-four (42%) achieved <ypT2N0 and 43 (28%) achieved ypT0N0. When comparing those with and without a complete TURBT, there was no significant difference in the proportion with <ypT2N0 (43% vs 38%, P=0.57) or ypT0N0 (28% vs 27%, P=0.87). After median follow-up of 3.6 years (IQR 1.5-5.1), 86 patients died, 37 died from bladder cancer, and 61 had recurrence. We did not observe a statistically significant association of complete TURBT with cancer-specific or recurrence-free survival (p≥0.20), although the hazard of death from any cause was significantly higher among those with incomplete TURBT even after adjusting for ECOG and pathologic T stage, HR 1.77 (95% CI 1.04-3.00, P=.034). A visibly complete TURBT was not associated with pathologic downstaging, cancer-specific or recurrence-free survival following NAC and RC. These data do not support the need for repeat TURBT to achieve a visibly complete resection if NAC and RC are planned.

Performance of pre- and post-pembrolizumab vesical imaging–reporting and data system (VI-RADS) to predict the pathological response and efficacy outcomes in muscle-invasive urothelial bladder cancer (MIBC): Full data analysis from the PURE-01 trial.

65 Background: The VI-RADS is a standardized reporting system that uses multiparametric magnetic resonance imaging (mpMRI) parameters to differentiate non muscle-invasive bladder cancer (NMIBC) from MIBC. Limited data on clinical response assessment to neoadjuvant therapy are currently available. In this study, we aimed to analyze the performance of VI-RADS to predict the pT0 or pT≤1 response post-neoadjuvant immunotherapy in MIBC. Methods: In PURE-01 study (NCT02736266) patients (pts) were staged with mpMRI before and after treatment (3 cycles of Pembrolizumab) prior to radical cystectomy (RC). Logistic regression models analyzed pre- and post-pembro VI-RADS, with clinical and tumor-related variables, against ypT≤1N0 (primary endpoint) and ypT0N0 (secondary endpoint). VI-RADS scores were dichotomized between 0-3 (0 = no evidence of disease) and 4-5 (5 = extension to extravescical fat). Event-free survival (EFS) and overall survival (OS) analyses based on VI-RADS were performed. Comprehensive genomic profiling and transcriptome-wide expression profiling data were matched with VI-RADS scores. Model performance was also tested in the ongoing NureCombo (nivolumab+nab-paclitaxel; NCT04876313) and SURE-01 (sacituzumab govitecan; NCT05226117) neoadjuvant studies. Results: In total, 110 patients treated with neoadjuvant pembrolizumab between 02/2017 and 07/2020 had centrally reviewed scans (N=220 mpMRI). Pre-pembrolizumab, 21 patients (19.1%) had no measurable disease (VI-RADS=0), 34 (30.9%) had a VI-RADS 1-3 score, and 55 (50%) had a VI-RADS 4-5 score. Both pre-pembrolizumab and post-pembrolizumab VI-RADS 0-3 scores were the only significant covariates that predicted the ypT≤1N0 endpoint on multivariable analyses (MVA): the strongest effect was seen with post-pembrolizumab VI-RADS 0-3 predicting the ypT≤1N0 response (odds ratio [OR]: 23.4, 95%CI: 7-95.3, p&lt;0.0001). The area-under-the-curve (AUC) of this model was 0.90. Post-pembrolizumab VI-RADS 0-3 also predicted longer EFS (p&lt;0.001) and OS (p=0.044). The scores of several gene signatures from baseline tumors differed between pre-pembrolizumab VI-RADS 0-3 and 4-5 categories. RAF1 mutations were enriched in pre-pembrolizumab VI-RADS 0-3 group (p=0.045). Conclusions: VI-RADS scores post-pembrolizumab revealed a robust association with pathological downstaging and survival. VI-RADS scores were also characterized by distinct biomarker features. These results indicate that VI-RADS is emerging as an important tool to design next-generation trials in MIBC. Clinical trial information: NCT02736266 .

Outcomes of Consolidative Nephrectomy following Primary Immunotherapy in Advanced Renal Cell Carcinoma: A Multicenter Analysis

BackgroundTo evaluate effect and outcomes of combination primary immunotherapy (IO) and nephrectomy for advanced renal cell carcinoma (RCC). MethodsWe conducted a multicenter, retrospective analysis of patients with advanced/metastatic RCC who received IO followed by nephrectomy. Primary outcome was Bifecta (negative surgical margins and no 30-day surgical complications). Secondary outcomes included progression-free survival (PFS) following surgery, reduction in tumor/thrombus size, RENAL score, and clinical/pathologic downstaging. Cox regression multivariable analysis was conducted for predictors of Bifecta and PFS. Kaplan-Meier analysis assessed PFS, comparing Bifecta and non-Bifecta groups. ResultsA total of 56 patients were analyzed (median age 63 years; median follow-up 22.5 months). A total of 40 (71.4%) patients were intermediate IMDC risk. Patients were treated with immunotherapy for median duration of 8.1 months. Immunotherapy resulted in reductions in tumor size (P < .001), thrombus size (P = .02), and RENAL score (P < .001); 38 (67.9%) patients were clinically downstaged on imaging (P < .001) and 25 (44.6%) patients were pathologically downstaged following surgery (P < .001). Bifecta was achieved in 38 (67.9%) patients. Predictors for bifecta achievement included decreasing tumor size (HR 1.08, P = .043) and pathological downstaging (HR 2.13, P = .047). Bifecta (HR 5.65, P = .009), pathologic downstaging (HR 5.15, P = .02), and increasing reduction in tumor size (HR 1.2, P = .007) were associated with improved PFS. Bifecta patients demonstrated improved 2-year PFS (84% vs. 71%, P = .019). ConclusionsPrimary immunotherapy reduced tumor/thrombus size and complexity. Pathologically downstaged patients were more likely to achieve bifecta, and these patients displayed improved 2-year PFS. Our study supports further inquiry in the use of CRN following primary immunotherapy for advanced renal cancer.

Downstaging and Survival Associated with Neoadjuvant Immunotherapy Before Radical Cystectomy for Muscle-invasive Bladder Cancer

BackgroundNeoadjuvant cisplatin-containing chemotherapy before radical cystectomy is the standard of care for patients with localized muscle-invasive bladder cancer (MIBC). However, a large proportion of patients are ineligible for cisplatin. Single-arm phase 2 neoadjuvant immunotherapy trials have reported promising tumor response rates, but interpretation is limited owing to lack of a comparator arm. ObjectiveTo compare rates of pathologic downstaging and overall survival between patients receiving neoadjuvant immunotherapy (NAI), neoadjuvant chemotherapy (NAC), or no neoadjuvant therapy (NNAT). Design, setting, and participantsWe identified 18 483 patients in the National Cancer Data Base who were diagnosed with clinically localized MIBC and underwent radical cystectomy from 2014 to 2019. Outcome measurements and statistical analysisNearest-neighbor propensity-score caliper matching was used to create three demographically similar and equally sized cohorts stratified by NAT receipt. Logistic regression was used to examine the association of treatment received with pathologic downstaging to pT0N0 and pT < 2N0. Cox proportional-hazards regression was used to assess the association of treatment received with overall survival (OS). Results and limitationsPropensity score matching yielded three equally sized cohorts without significant differences in baseline characteristics (n = 840). The NAI group had a higher rate of pathologic downstaging to pT0N0 than the NNAT group and a similar rate to the NAC group (NNAT 6.7% vs NAC 26.4%, odds ratio 5.0, 95% confidence interval [CI] 2.9–8.3; NAI 22.5%, odds ratio 4.0, 95% CI 2.4–7.1). The NAI group had better OS than the NNAT group and similar OS to the NAC group (NAC: hazard ratio 0.62, 95% CI 0.42–0.92; NAI: hazard ratio 0.68, 95% CI 0.46–0.97, with NNAT as the reference). The primary limitation is selection bias from confounding by clinical indication. ConclusionsNAI is a promising alternative to NAC for patients with clinically localized MIBC, as evidenced by similar pathologic downstaging rates and OS benefits in comparison to no NAT. Phase 3 trials should be conducted to test the noninferiority of NAI to NAC. Patient summaryWe compared outcomes for patients with muscle-invasive bladder cancer according to whether they received chemotherapy, immunotherapy, or no medical therapy before surgical removal of their bladder. We found that preoperative immunotherapy improved patient survival and regression of the cancer stage in comparison to no medical therapy, similar to the outcomes seen with preoperative chemotherapy. Randomized clinical trials are needed to confirm these findings.

A phase 2 study of neoadjuvant chemotherapy plus durvalumab in resectable locally advanced head and neck squamous cell carcinoma.

Patients with locally advanced head and neck squamous cell cancer (HNSCC) are treated with surgery followed by adjuvant (chemo) radiotherapy or definitive chemoradiation, but recurrence rates are high. Immune checkpoint blockade improves survival in patients with recurrent/metastatic HNSCC; however, the role of chemo-immunotherapy in the curative setting is not established. This phase 2, single-arm, multicenter study evaluated neoadjuvant chemo-immunotherapy with carboplatin, nab-paclitaxel, and durvalumab in patients with resectable locally advanced HNSCC. The primary end point was a hypothesized pathologic complete response rate of 50%. After chemo-immunotherapy and surgical resection, patients received study-defined, pathologic risk adapted adjuvant therapy consisting of either durvalumab alone (low risk), involved field radiation plus weekly cisplatin and durvalumab (intermediate risk), or standard chemoradiation plus durvalumab (high risk). Between December 2017 and November 2021, 39 subjects were enrolled at three centers. Oral cavity was the most common primary site (69%). A total of 35 of 39 subjects underwent planned surgical resection; one subject had a delay in surgery due to treatment-related toxicity. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. Post treatment imaging demonstrated an objective response rate of 57%. Pathologic complete response and major pathologic response were achieved in 29% and 49% of subjects who underwent planned surgery, respectively. The 1-year progression-free survival was 83.8% (95% confidence interval, 67.4%-92.4%). Neoadjuvant carboplatin, nab-paclitaxel, and durvalumab before surgical resection of HNSCC were safe and feasible. Although the primary end point was not met, encouraging rates of pathologic complete response and clinical to pathologic downstaging were observed.

Clinical and morphological response to neoadjuvant chemotherapy followed by chemoradiotherapy in a patient with locally advanced gastric cancer: a case report

Background. Gastric cancer is one of the most common cancers with the highest incidence and mortality rates worldwide. Gastrectomy/distal subtotal resection with D2 lymphadenectomy and perioperative chemotherapy with FLOT is the standard treatment for locally advanced gastric cancer. Currently, the role of chemoradiation therapy in the treatment of gastric cancer has not been well determined. From 2019 to 2021, a prospective phase 2 clinical trial was undertaken at A. Tsyb Medical Radiological Research Centre (MRRC) to evaluate the safety and efficacy of neoadjuvant therapy: induction chemotherapy with FLOT (2 cycles) and chemoradiotherapy (total dose of 46 Gy with the concurrent chemotherapy with capecitabine and oxaliplatin) followed by surgery. The aim of the study was to demonstrate the effectiveness of neoadjuvant therapy for locally advanced gastric cancer with a favorable pathological response, downstaging and more than 2.5-year disease-free survival. Case description. A 48 year-old male patient was admitted to the MRRC with complain of epigastric pains for 2 months. Gastroscopic biopsy revealed gastric cancer. The comprehensive examination revealed proximal gastric cancer involving the abdominal segment of the esophagus (cT3N3aM0, stage III). The patient was invited to participate in the clinical trial. The patient accepted to participate voluntarily and signed an informed consent. He received 2 cycles of FLOT chemotherapy followed by chemoradiotherapy and surgery (gastrectomy with resection of the abdominal segment of the esophagus and D2 lymph node dissection). Histological examination of the surgical specimen revealed grade 1b pathological response (Becker criteria). Histological examination of lymph nodes revealed pathological complete response. The patient is alive after 33 months of gollow-up without the evidence of disease progression. Conclusion. Neoadjuvant induction chemotherapy followed by chemoradiotherapy resulted in a favorable pathological response, downstaging and 2.5-year disease-free survival.

Pathological Outcomes of Patients With Advanced Renal Cell Carcinoma Who Receive Nephrectomy Following Immunotherapy.

Even though cytoreductive nephrectomy (CN) was once the standard of care for patients with advanced renal cell carcinoma (RCC), its role in treatment has not been well analyzed or defined in the era of immunotherapy (IO). This study analyzed pathological outcomes in patients with advanced or metastatic RCC who received IO prior to CN. This was a multi-institutional, retrospective study of patients with advanced or metastatic RCC. Patients were required to receive IO monotherapy or combination therapy prior to radical or partial CN. The primary endpoint assessed surgical pathologic outcomes, including American Joint Committee on Cancer (AJCC) staging and frequency of downstaging, at the time of surgery. Pathologic outcomes were correlated to clinical variables using a Wald-chi squared test from Cox regression in a multi-variable analysis. Secondary outcomes included objective response rate (ORR) defined by response evaluation criteria in solid tumors (RECIST) version 1.1 and progression-free survival (PFS), which were estimated using the Kaplan-Meier method with reported 95% CIs. Fifty-two patients from 9 sites were included. Most patients were male (65%), 81% had clear cell histology, 11% had sarcomatoid differentiation. Overall, 44% of patients experienced pathologic downstaging, and 13% had a complete pathologic response. The ORR immediately prior to nephrectomy was stable disease in 29% of patients, partial response in 63%, progressive disease in 4%, and 4% unknown. Median follow-up for the entire cohort was 25.3 months and median PFS was 3.5 years (95% CI, 2.1-4.9). IO-based interventions prior to CN in patients with advanced or metastatic RCC demonstrates efficacy, with a small fraction of patients showing a complete response. Additional prospective studies are warranted to investigate the role of CN in the modern IO-era.

Efficacy of Degarelix in the Neoadjuvant Setting in Managing Locally Advanced Prostate Cancer.

Background Prostate cancer holds a substantial presence in the global cancer landscape, and a considerable proportion of diagnoses occur at late stages, particularly in India. Management of locally advanced prostate cancer necessitates a multimodal treatment strategy. A critical part of this strategy is neoadjuvant androgen deprivation therapy, typically administered via luteinizing hormone-releasing hormone (LHRH) analogs. This study explores the potential of an alternative approach: neoadjuvant therapy with degarelix, an LHRH antagonist, and its impact on perioperative and postoperative outcomes in patients undergoing radical prostatectomy for locally advanced or high-risk prostate cancer. Methodology We conducted a retrospective, non-randomized clinical study at Apollo Hospitals in Chennai, India. Patients diagnosed with locally advanced or high-risk prostate cancer who underwent radical prostatectomy were included. Participants were patients treated with neoadjuvant degarelix and subsequent radical prostatectomy between March 2020 and June 2022. We excluded patients receiving radical radiotherapy, those switching from LHRH agonists to antagonists, and those contraindicated for androgen deprivation therapy due to existing comorbidities. For comparison, we selected a group from the institutional database who received conventional treatment (i.e., without neoadjuvant therapy). Results The study compared two groups, each with 32 patients. The groups had no significant difference in total operative duration and console times. The postoperative pathological assessment showed significantly lower margin positivity rates and notable pathological downstaging in the group receiving neoadjuvant degarelix compared to the control group. The incidence of node positivity, prostate-specific antigen levels at three months postoperative, and number of pads used per day at one month did not differ significantly between the two groups. Conclusions Our study suggests that neoadjuvant degarelix could notably enhance patient outcomes in locally advanced prostate cancer management. The benefits include improved symptom control, significant reductions in margin positivity rates, and facilitated surgical procedures. Neoadjuvant degarelix therapy could potentially enhance the feasibility of the surgical intervention in locally advanced prostate cancer management, thus suggesting a promising pathway for improved patient care.

Neoadjuvant cemiplimab with platinum-doublet chemotherapy and cetuximab to de-escalate surgery and omit adjuvant radiation in locoregionally advanced head &amp; neck squamous cell carcinoma (HNSCC).

6019 Background: Locoregionally advanced (LA) HNSCC treated with surgery can carry significant functional morbidity, further intensified by adjuvant (adj) radiation (RT) often with concurrent chemotherapy. Although the pathologic response rate of anti-PD1 therapy is modest, combination approaches may provide enhanced clinical benefit. This pilot study evaluates whether the combination of neoadjuvant cemiplimab + platinum-doublet chemotherapy + cetuximab is safe, feasible, and effective in pathologic down-staging to reduce the extent of surgery and justify omission of adj RT. Methods: 10 patients (pts) with resectable LA HNSCC who would warrant adj RT per clinical stage were enrolled. Neoadjuvant treatment consisted of cetuximab loading dose with cemiplimab followed by 3 cycles of chemotherapy (cisplatin or carboplatin + docetaxel) with cetuximab and cemiplimab prior to definitive surgical resection. Standard of care adj RT+/- chemotherapy was administered based on pathologic staging. Pts with ypT0-2N0 tumors without adverse features or ypT0-1N1 tumors with minimal residual disease ( &lt; 10% viable tumor) were offered 6 months of adj cemiplimab in lieu of RT. Primary endpoint was safety (defined by dose limiting toxicity (DLT) related to the addition of cemiplimab to this combination regimen). Secondary endpoints included feasibility (defined as no surgical delay &gt; 20 weeks from start of neoadjuvant therapy due to treatment toxicity) and pathologic down-staging allowing for omission of adj RT. Results: 10 pts completed treatment with no DLTs and surgical delays. 8/10 (80%) pts were clinically staged as T3/T4 and 5/10 (50%) were N2b/c (AJCC 7th Ed). Pathologic down-staging was observed in 9/10 (90%) pts after neoadjuvant therapy. 60% had a major pathologic response and 40% had a complete pathologic response. 6/8 pts and 7/10 pts who would have required a mandibulectomy and free flap, respectively, did not require it following neoadjuvant treatment. Of the 5/10 (50%) pts who were eligible for omission of adj RT, 4 did not undergo RT and 3 received adj cemiplimab. All pts remain disease-free at a median follow-up of 16 months. The most common adverse events (AEs) of any grade (G) were rash (80%), nausea (70%), fatigue (50%), and diarrhea (50%). 2/10 (20%) pts experienced a G3 or G4 immune-related AE attributed to the addition of cemiplimab. One pt developed G3 transaminase elevation prior to surgery and 1 pt experienced G3 myasthenia gravis and G4 myocarditis (resolved) outside the DLT window. Conclusions: Neoadjuvant cemiplimab with platinum-doublet chemotherapy and cetuximab has an acceptable toxicity profile, is feasible in pts with LA HNSCC, and led to notable pathologic down-staging allowing for reduction in extent of surgery and omission of adj RT. Further evaluation of this regimen is clearly warranted. Clinical trial information: NCT04722523 .

Phase Ib study of neoadjuvant concurrent chemoradiation plus durvalumab followed by surgery and adjuvant durvalumab for resectable stage III NSCLC.

8556 Background: The use of neoadjuvant and adjuvant immunotherapy in resectable non-small cell lung cancer (NSCLC) has become a standard of care. However, the integration of immunotherapy into a trimodality treatment regimen has not been widely explored. We hypothesized that adding durvalumab to neoadjuvant concurrent chemoradiation and surgery would not increase treatment-related adverse events (TRAE) during neoadjuvant period. Methods: This was a prospective, single center, single-arm, open-label phase Ib study. Patients with resectable, stage III N2 NSCLC received concurrent chemoradiation [weekly paclitaxel (45mg/m2)/carboplatin (AUC 2.0) for 5 weeks with radiotherapy 45Gy] and durvalumab 1,500mg Q4W for 2 cycles followed by surgical resection and adjuvant durvalumab for 1 year. The primary endpoint was the frequency of patients who experience grade 3 or more TRAE during neoadjuvant therapy based on CTCAE 4.03. Results: Of 30 patients (median age 65.5 years; 67% male), 56.7% had squamous histology and 60.0% had stage IIIA. Any grade AEs and TRAEs (neoadjuvant/adjuvant) were reported in 83.3%/76.7% and 70.0%/63.3% of patients, respectively. Grade 3 or more AEs and TRAEs (neoadjuvant/adjuvant) were reported in 10.0/3.3% and 10.0%/0.0%, respectively. Grade 3 or more TRAE reported during neoadjuvant treatment were neutropenia, anemia, and nausea, one each; no Grade 5 AEs occurred. Surgical resection was not performed in three patients: two due to treatment-related adverse events (AEs) and one due to patient refusal. Among 27 patients who received complete resection, the pathologic complete response (pCR) rate and major pathologic response (MPR) rate were 40.7% (95% CI, 22.4 – 61.2) and 74.1% (95% CI, 53.7 – 88.9), respectively. Excluding four patients with EGFR, ALK, KRAS G12C, or MET ex14skipping mutations, the pCR rate was 47.8% (95% CI, 26.8 – 69.4) and MPR rate was 87.0% (95% CI, 66.4 – 97.2). Overall, pathologic downstaging was achieved in 70.4% (95% CI, 49.8 – 86.2). Objective response rate according to RECIST v1.1 was 50.0% (95% CI, 31.3 – 68.7). One patient delayed the schedule for surgical resection due to radiation pneumonitis (G2), unrelated to the drug administered. Otherwise, there were no peri-operative mortality or morbidity. All patients who underwent surgery, except one whose disease progressed immediately after resection, received at least one dose of adjuvant durvalumab; 61.5% completed 1-year treatment, 11.5% were continuing treatment, 11.5% discontinued due to AE, and 11.5% discontinued due to disease progression at the time of data cutoff. Grade 3 or more TRAE reported during adjuvant treatment were radiation pneumonitis and proteinuria, one each. Conclusions: This study confirms the manageable safety profile of adding durvalumab to neoadjuvant concurrent chemoradiation for treatment of resectable stage III NSCLC. Clinical trial information: NCT03694236 .

Tislelizumab in combination with gemcitabine plus cisplatin as neoadjuvant therapy for lymph node‐positive bladder cancer.

e16599 Background: Although multiple single-arm clinical trials have shown promising pathologic complete response (pCR) rates with neoadjuvant ICIs combined with gemcitabine plus cisplatin in MIBC, lymph node‐positive bladder cancer is generally excluded. Our specific aim was to compare the efficacy and prognosis of neoadjuvant tislelizumab combined with gemcitabine plus cisplatin in patients with lymph node‐positive bladder cancer. Methods: In this single arm phase II study, eligible patients had cT2-T4a N+ M0 MIBC, cisplatin-eligible, and to be planned radical cystectomy (RC). Patients received tislelizumab 200 mg in day D8, cisplatin 70 mg/m2 D2, and gemcitabine 1000 mg/m2 D1 and D8 every 21 days for 3 or 4 cycles. RC was performed within 6 weeks after last dose treatment. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included pathologic downstaging ( &lt; ypT2), EFS, OS and safety. Results: By Jan 2023, 17 eligible pts (2cT2, 10 cT3, 5 cT4) were enrolled. 14 pts have completed neoadjuvant therapy, with median age of 67 (60-81) years, among whom 10 pts underwent RC and two declined RC. According to RECIST 1.1, 6 pts achieved a clinical complete response (cCR)(6/14,42.8%). Pathological results revealed 5 pCR (ypT0N0, 50%), 3 ypT1N0, and 2 ypT2/T3N0. A complete nodal response (pN0) occurred in 10 (100%) pts post- tislelizumab +chemotherapy and 8 ( &lt; ypT2N0,80%) pts achieved pathologic downstaging. Most common neoadjuvant therapy related AEs of any grade were hematologic toxicities (11/14,78.5%), nausea (9/14,64.2%), vomiting (8/14,57.1%), decreased appetite (6/14,42.8%), fatigue (4/14,28.5%), pruritus (3/14,21.4%) and ALT/AST increased (4/14,28.5%). Grade ≥3 neoadjuvant therapy related AEs were neutropenia (n = 3), thrombocytopenia (n = 2), anemia (n = 2). One patient discontinued GC plus tislelizumab due to AEs. Conclusions: Patients with clinically lymph node‐positive bladder cancer have significant pN0 after neoadjuvant therapy. Neoadjuvant tislelizumab plus gemcitabine/cisplatin was feasible and provided meaningful pathologic responses in lymph node‐positive bladder cancer. Clinical trial information: NCT04570410 .

Study EV-103: Neoadjuvant treatment with enfortumab vedotin monotherapy in cisplatin-ineligible patients (pts) with muscle invasive bladder cancer (MIBC): Updated results for Cohort H.

4595 Background: Cisplatin-ineligible pts with MIBC have no established neoadjuvant treatment options known to prolong survival before undergoing radical cystectomy and pelvic lymph node dissection (RC+PLND), Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer. In a phase 3 study, EV showed improved overall survival vs standard chemotherapy and a tolerable safety profile in pts with advanced urothelial cancer previously treated with a platinum agent and a PD-1/L1 inhibitor (Powles NEJM 2021). In Cohort H of the EV-103 phase 1b/2 study, preliminary results, including pathological complete response (pCR) and pathological downstaging (pDS) rates, showed antitumor activity in cisplatin-ineligible pts with MIBC who received neoadjuvant EV treatment (Petrylak ASCO GU 2022). Here we report updated results, including event-free survival (EFS) and subsequent cancer-related therapy. Methods: Cohort H of the EV-103 phase 1b/2 study (NCT03288545) enrolled cisplatin-ineligible pts with MIBC (T2-T4aN0M0) and ECOG PS ≤2 who were eligible for RC+PLND. Pts received neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 every 21 days for 3 cycles before undergoing RC+PLND. The primary endpoint was pCR rate (ypT0 and N0) by central pathology review. Key secondary endpoints included pDS rate (ypT0, ypTis, ypTa, ypT1, and N0), EFS based on investigator assessment, and safety. Results: 22 pts (median age 74.5 yr, range 56-81) were enrolled and treated; 17 pts (77.3%) remain on study. Pts had stage cT2 (68.2%), cT3 (27.3%), or cT4 (4.5%) disease. 68.2% of pts had transitional cell carcinoma only; 31.8% had a mixed histology. 86.4% of pts completed all 3 cycles of EV treatment; the median duration of EV treatment was 2.1 months (range 0.7-2.3). The pCR rate was 36.4% (95% CI, 17.2, 59.3) and the pDS rate was 50.0% (95% CI, 28.2, 71.8). Median EFS has not been reached. The EFS rate at 12 months was 76.4% (95% CI, 52.2, 89.4). All pts underwent surgery with no delays due to EV-related TEAEs. The most common EV-related TEAEs were fatigue (45.5%), dysgeusia (36.4%), and alopecia (31.8%); 18.2% of pts had grade ≥3 EV-related TEAEs. 68.2% of pts had surgery-related TEAEs and 31.8% pts had grade ≥3 surgery-related TEAEs. The most common surgery-related TEAEs were procedural pain (18.2%), anaemia (13.6%), and constipation (13.6%). 3 pts died due to AEs unrelated to EV treatment; in 2 pts the AEs occurred &gt;30 days after RC+PLND. 36.4% of pts received subsequent cancer-related therapy. Conclusions: Neoadjuvant EV monotherapy treatment showed promising results for antitumor activity and EFS with a manageable safety profile in cisplatin-ineligible pts with MIBC. These results support ongoing phase 2 and 3 programs in MIBC evaluating EV alone or combined with pembrolizumab (EV-103 Cohort L, KN-905, KN-B15). Clinical trial information: NCT03288545 .

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

4585 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). At predefined interim analysis, the study has met the first stage aim. Here reported the results of the predefined final analysis. Methods: This 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) (pDS), 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: At the data cut off time of 14th Dec 2022, 63 pts (38 cT2, 19 cT3, and 6 cT4a) have completed neoadjuvant therapy, with median age of 64 (48-75) years. The median relative dose intensity of tislelizumab, cisplatin and gemcitabine were 92.3%, 85.7% and 85.6%, respectively. At this time, 55 pts underwent RC and completed 30 days post-surgery follow-up. The median time from last dose to RC was 4.4 (range: 0.6-13.3) weeks. Eight pts refused RC. Among 55 efficacy evaluable pts, 27 (49.1% [90% CI, 37.4-60.9]) pts achieved pCR, while 41 (74.5% [95% CI, 61.0-85.3]) pDS. Pts with cT2 achieved 55.6% (20/36) pCR and 86.1% (31/36) pDS. Among 14 non-responders, 3 of them (1 cT2, 2 cT3) achieved pT0, but with pathologic N1. Clavien-Dindo grade ≥3 postoperative complications occurred in 7.9% pts. Most common neoadjuvant therapy related AEs of any grade were hematologic toxicities (88.9%), nausea (77.8%), and vomiting (50.8%). Grade ≥3 neoadjuvant therapy related AEs occurred in 60.3% pts, which were hematologic toxicities (58.7%) in most. The frequently occurring immune-related AEs (irAEs) (&gt;5%) included dizziness (14.3%), fatigue (12.7%), ASL/ALT increased (7.9%), rash (7.9%), pruritus (7.9%), and GGT increased (6.3%). Grade ≥3 irAEs occurred in 2 pts (pneumonia, n=1; cardiomyopathy, n=1). Conclusions: The study met its primary endpoint. Neoadjuvant tislelizumab combined with gemcitabine and cisplatin showed promising anti-tumor activity with high pCR and well tolerance in MIBC pts. Clinical trial information: ChiCTR2000037670 .

Biology and performance of pre- and post-pembrolizumab (pembro) vesical imaging–reporting and data system (VI-RADS) to predict the pathological response in muscle-invasive urothelial bladder cancer (MIBC): Full data analysis from a clinical trials pipeline.

4591 Background: The VI-RADS is a standardized reporting system that uses multiparametric magnetic resonance imaging (mpMRI) parameters to predict the probability of MIBC. It has been also used in studies using standard neoadjuvant chemotherapy. No studies have analyzed the performance of VI-RADS to predict the pT0 or pT≤1 response post-immunotherapy (IO) in MIBC. Methods: In PURE-01 study patients (pts) were staged with mpMRI before and after treatment (3 cycles of pembro) prior to radical cystectomy (RC). All mpMRI scans were centrally reviewed. Logistic regression models analyzed pre- and post-pembro VI-RADS against pT≤1 (primary endpoint) and pT0 (secondary endpoint). VI-RADS scores were dichotomized between 0-3 (0=no evidence of disease) and 4-5. Covariates included cT-stage, age, gender, PD-L1 combined positive score (CPS) and tumor mutational burden (TMB). Model performance was also tested in the ongoing NureCombo (nivolumab+nab-paclitaxel; NCT04876313) and SURE-01 (sacituzumab govitecan; NCT05226117) studies. Transcriptome-wide expression profiling was matched with VI-RADS scores. Results: In PURE-01, 115 pts had centrally-reviewed MRI scans (N=230 mpMRI), treated between 02/17 and 08/18. In total, 32 (27.8%) had pure/predominant non-urothelial carcinoma (UC) histology, 54 (47%) had a cT3-4N0 MIBC. Pre-pembro: 21 pts (18.3%) had no measurable disease (VI-RADS=0), 37 (32.2%) a VI-RADS 1-3 score, and 57 (49.5%) had a VI-RADS 4-5 score. 20 pts (17.4%) had a downstage from VI-RADS 4-5 to VIRADS 0-3 post-pembro. Pre-pembro VIRADS 4-5 were associated with higher angiogenesis and epithelial-mesenchymal transition (EMT) activity vs VI-RADS 0-3 (p=0.011 and 0.033). Both pre-pembro and post-pembro VI-RADS 0-3 scores were the only significant covariates against pT≤1 endpoint on multivariable analyses (MVA): the strongest effect was seen with post-pembro VI-RADS 0-3 against pT≤1 response (OR: 23.4, 95%CI: 7-95.3, p&lt;0.0001). The AUC of this model was 0.90. Model-based decisions were supported in the range of threshold probabilities of 10-80%. Post-pembro VI-RADS 4-5 were characterized by higher stromal signature scores vs VI-RADS 0-3. When post-therapy VI-RADS were tested in evaluable pts from the combined NureCombo+SURE-01 cohort (N=17pts, 34 mpMRI): 90% of post-VI-RADS 0-3 revealed a pT≤1 stage at radical cystectomy. Conclusions: VI-RADS scores mirrored distinct biological features in MIBC, recapitulating tissue biomarkers of IO response. VI-RADS scores post-IO revealed a strong association with pathological downstaging and represented a robust feature based on which selecting pts for bladder-sparing strategies. Results seemed to be also applicable to other novel neoadjuvant therapies beyond IO monotherapy. Clinical trial information: NCT02736266 .

A phase II study of toripalimab combined with gemcitabine-cisplatin as neoadjuvant therapy for patients with muscle-invasive bladder cancer (MIBC).

e16602 Background: Cisplatin-based neoadjuvant chemotherapy is the standard of care in MIBC with improved pathologic response (PaR) and overall survival (OS) compared to radical cystectomy (RC) alone. The efficacy of PD-1 inhibitor in combination with chemotherapy as a new neoadjuvant treatment option for MIBC still needs further confirmation. This study evaluated the efficacy and safety of toripalimab (an anti-PD-1 monoclonal antibody) combined with gemcitabine-cisplatin (GC) as neoadjuvant therapy for patients with MIBC. Methods: Eligible pts with MIBC (cT2-T4a, N≤1, M0) who were candidates for RC were enrolled. Toripalimab (240mg, d1) combined with GC (gemcitabine 1000mg/m2 d1,d8 plus cisplatin 35mg/m2 d1,d2) every 21 days, up to 4 cycles. RC was performed within 6 weeks after the last dose treatment. The primary endpoint was PaR (≤ pT1,N0). Secondary endpoints were PFS at 2 years and safety. Results: Between Apr 2021 and Jun 2022, 16 pts (4 pts cT2, 11 pts cT3, 1 pts cT4) were enrolled and received 4 cycles of neoadjuvant therapy, with median age of 63.5 and 75% male. 14 of the 16 pts underwent RC and two declined RC. Among 14 evaluable pts, PaR ≤pT1N0 was achieved in 12 pts (85.71%, 4 were pT0, 8 were pT1/a/is). Survival data are not yet mature. The most common adverse events (AEs) of any grade were anemia (14/16; 87.5%) and nausea/vomiting (11/16; 68.75%). One had Grade≥3 AEs (hemorrhagic shock) while on study that was unrelated to GC or toripalimab. Five pts experienced grade 1-2 immune related AEs, including thyroiditis (3/16, 18.75%) and rash (2/16,12.5%). Conclusions: Neoadjuvant toripalimab combined with GC showed promising safety and efficacy in MIBC with significant pathologic downstaging rates. Clinical trial information: NCT04861584 .

ANTICIPATE phase I: Oral APL-1202 in combination with tislelizumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC).

e16607 Background: APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Single-agent neoadjuvant programmed death 1 (PD-1) antibodies achieve pathological complete responses in a subset of patients with MIBC. APL-1202 and PD-1 antibody combination therapy demonstrates synergistic effects in several model systems of cancer, including bladder cancer. We hypothesized that APL-1202, in combination with tislelizumab, a humanized IgG4 anti-PD-1 antibody, may be an effective neoadjuvant therapy in MIBC. Methods: ANTICIPATE Phase I was a dose escalation study to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of APL-1202. Eligible patients had newly diagnosed MIBC, were cisplatin-ineligible or refused cisplatin-based neoadjuvant chemotherapy, and were planned for radical cystectomy (RC). A standard 3+3 dose-escalation design was employed. On day 1 of each cycle, a single dose of 200 mg tislelizumab was administered intravenously. APL-1202 was administered orally 3 times daily and with the dose escalated in 3 successive cohorts (375 mg, 750 mg, and 1,125 mg). Intra-patient dose escalation was not allowed. Blood samples were collected for pharmacokinetics and other translational studies. Results: Nine patients have been enrolled in phase I: 3 patients each at 375 mg, 750 mg, and 1125 mg of APL-1202. All patients had predominant urothelial cancer with cT2 (6/9) and cT3 (3/9); PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) Assay and 1/9 (11.1%) patients was positive. No dose-limiting toxicities were observed at either 375 mg, 750 mg, or 1125 mg daily dose of APL-1202. Treatment-related adverse events (TRAE) were observed in 6 patients. All AEs were grade 1, except 1 grade 2 T wave abnormality on ECG and 1 grade 3 liver dysfunction. No grade 4 or 5 related AEs were observed. The patient with grade 3 liver dysfunction recovered to baseline within 2 weeks and underwent RC. Pathologic downstaging to &lt; pT2 was observed in 5/8 (62.5%) and 1/8 (12.5%) with pT0 in 8 evaluable patients; 1 patient refused RC. Conclusions: APL-1202 plus tislelizumab was well tolerated. The RP2D of APL-1202 was identified as 1125 mg daily dose. Early efficacy signals were observed including pathologic downstaging to &lt; pT2 (5/8, 62.5%) and pT0 (1/8, 12.5%). Phase 2 trial was ongoing. (NCT04813107). Clinical trial information: NCT04813107 .

KEYNOTE-905/EV-303: A phase 3 study to evaluate the efficacy and safety of perioperative pembrolizumab or pembrolizumab plus enfortumab vedotin (EV) for muscle-invasive bladder cancer (MIBC).

TPS4601 Background: Standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy + pelvic lymph node dissection (RC + PLND), but many patients with MIBC are ineligible for cisplatin-based chemotherapy. In the phase 1b/2 KEYNOTE-869/EV-103 study, combination therapy with the PD-1 inhibitor pembrolizumab and the Nectin-4–directed antibody-drug conjugate EV showed promising antitumor activity in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma. KEYNOTE-905/EV-303 (NCT03924895) is a multicenter, randomized, open-label, phase 3 study to evaluate efficacy and safety of perioperative pembrolizumab alone or combined with EV versus RC + PLND alone in patients with MIBC who are ineligible for or decline cisplatin-based treatment. Methods: Patients with treatment-naive MIBC (T2-T4aN0M0 or T1-T4aN1M0) and predominantly (≥50%) urothelial histology who are cisplatin ineligible or decline cisplatin-based treatment and have an ECOG PS score of 0-2 are eligible. Cisplatin ineligibility will be defined as meeting ≥1 of the following criteria: impaired renal function with calculated creatinine clearance 30-59 mL/min; ECOG PS 2; grade ≥2 audiometric hearing loss per CTCAE v4.0; or NYHA class III heart failure. Patients will receive neoadjuvant pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for ≤3 cycles followed by RC + PLND and adjuvant pembrolizumab 200 mg IV Q3W for ≤14 cycles (arm A); RC + PLND followed by observation (adjuvant nivolumab permitted based on clinical indication and regulatory approval [arm B]); or neoadjuvant EV 1.25 mg/kg + pembrolizumab 200 mg IV Q3W for ≤3 cycles followed by RC + PLND and adjuvant EV + pembrolizumab for ≤6 cycles and adjuvant pembrolizumab 200 mg IV Q3W for ≤8 cycles (arm C). In the neoadjuvant and adjuvant phases of arm C, pembrolizumab will be administered on day 1 and EV will be administered on days 1 and 8 of each cycle. Enrollment is complete for arm A; patients will continue to be randomly assigned 1:1 to arm B or arm C. Stratification factors are tumor stage (T2N0 vs T3/T4aN0 vs T1-T4aN1), geographic region (United States vs Europe vs most of world), and cisplatin eligibility (cisplatin ineligible or cisplatin eligible but declines treatment). The primary end point is event-free survival between arm B and arm C. Secondary end points are event-free survival (arm A vs arm B) pathologic complete response, overall survival, disease-free survival, pathologic downstaging rates, and safety. Enrollment is planned for 308 patients, and recruitment is ongoing in Africa, Asia, Australia, Europe, North America, and South America. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO-GU Annual Meeting. All rights reserved. Clinical trial information: NCT03924895 .