422 Safety and efficacy of neoadjuvant intravesical oncolytic MV-NIS in patients with urothelial carcinoma

BackgroundBladder cancer is a leading cause of cancer death in the United States.1 The histology in > 90% of cases is urothelial carcinoma (UC). Tumors may present either as non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Current standard of care for patients with high risk NMIBC includes transurethral resection of bladder tumor (TURBT) followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG).2 Meanwhile, patients with BCG unresponsive NMIBC or MIBC are recommended to undergo radical cystectomy (RC), which adversely impacts quality of life and is associated with significant morbidity.3 MV-NIS is an investigational oncolytic measles virus with an excellent clinical safety profile.4 This ongoing phase I clinical study is designed to test the safety, efficacy and identify the recommended phase 2 dose (RP2D) of intravesical MV-NIS in patients with NMIBC or MIBC who are scheduled for RC and not eligible for neoadjuvant chemotherapy.MethodsBladder UC patients were evaluated for eligibility and provided informed consent prior to enrolling. To date 8 patients have been enrolled: 4 to the single dose safety cohort, and 4 to the multi-dose expansion cohort. Patients were administered intravesical ~1x109 TCID50 MV-NIS once at least 1 week prior to RC (safety cohort), or twice at 4 and 2 weeks prior to RC (expansion cohort). Patients were closely monitored during the 2-hour instillation period. Tumor specimens from the pre-treatment TURBT and post-treatment RC were analyzed to determine pre- and post-treatment pathological stage and evaluate tumor killing and immune cell infiltrate.ResultsIntravesical MV-NIS treatment was well tolerated in all patients. Only a single Adverse Event (AE) attributable to MV-NIS treatment (Grade 1 hematuria). AEs Grade>2 were related to post-surgical complications. Tumor pathology findings are summarized in table 1. Tumor downstaging was observed in 4 of 8 patients. Among 4 patients in the expansion cohort, 2 had no residual disease (pT0). Central assessment of RC tissues showed significant inflammatory infiltrate in all treated bladder specimens. Detailed analyses are ongoing to characterize MV infection and immune infiltrate in bladder tissueAbstract 422 Table 1Pre-treatment (TURBT) and post- treatment (RC) pathologyConclusionsThe higher-than-expected rate of tumor downstaging and pT0 pathology, paired with the significant immune infiltrate observed in post-treatment bladder tissue, provide compelling evidence that intravesical MV-NIS has clinical activity against UC. These results support the use of two doses of ~1x109 TCID50 as the RP2D in future clinical studies for BCG unresponsive NMIBC or MIBC patients. MV-NIS induced inflammation may act synergistically with checkpoint blockade therapies.Trial RegistrationNCT03171493ReferencesSiegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69(1):7–34.Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 2015;15(1):25–41.Zakaria AS, Santos F, Dragomir A, Tanguay S, Kassouf W, Aprikian AG. Postoperative mortality and complications after radical cystectomy for bladder cancer in Quebec: A population-based analysis during the years 2000–2009. Can Urol Assoc J 2014;8(7–8):259–267.Galanis E, Atherton PJ, Maurer MJ, Knutson KL, Dowdy SC, Cliby WA, Haluska P Jr, Long HJ, Oberg A, Aderca I, Block MS, Bakkum-Gamez J, Federspiel MJ, Russell SJ, Kalli KR, Keeney G, Peng KW, Hartmann LC. Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer. Cancer Res 2015;75(1):22–30.Ethics ApprovalApproval was received from the Institutional Review boards (IRBs) at all clinical sites including Mayo Clinic (#17–004167); Ochsner Health (#2020 060); and University of Miami (#20200174). All study participants are required to review and sign an IRB approved informed consent before taking part in the clinical trial.

Neoadjuvant Therapy of Metformin is Associated with Good Tumor Response After Preoperative Concurrent Chemoradiotherapy for Rectal Cancer

Metformin is associated with good tumor response in preoperative concurrent chemoradiotherapy (CCRT) for rectal cancer. This study aims to demonstrate that the timing of metformin is related to the tumor response on preoperative CCRT for rectal cancer. From January 2010 to December 2017, 232 patients who underwent curative resection after preoperative CCRT were reviewed. Patients were divided into groups with or without diabetes or metformin. The timing of metformin administration was divided based on before and after initiation of chemoradiotherapy. Multivariate logistic regression analysis was used to identify predictors for tumor response. Tumor downstaging (p = 0.02) and good response rates of tumor regression grade (TRG) (p = 0.008) were significantly higher in the group administered metformin before CCRT than other groups. In the multivariate analysis, metformin administration before CCRT was a significant factor in predicting tumor downstaging (odds ratio [OR] 10.31, 95% confidence interval [CI]: 1.76 - 102.08, p = 0.02) and good TRG (OR 12.55, 95% CI: 2.38 - 80.24, p = 0.004). In patients with rectal cancer who underwent preoperative CCRT, neoadjuvant therapy of metformin before CCRT was significantly associated with good tumor response and tumor downstaging.

The Key Role of Staging Definitions for Assessment of Downstaging for Hepatocellular Carcinoma

The success of liver transplant (LT) for hepatocellular carcinoma (HCC) is dependent on accurate tumor staging using validated imaging criteria, and adherence to acceptable criteria based on tumor size and number. Other factors including α-fetoprotein (AFP) and response to local regional therapy (LRT) have now played a larger role in candidate selection. Tumor downstaging is defined as reduction in the size of viable tumors using LRT to meet acceptable criteria for LT, and serves as a selection tool for a subgroup of HCC with more favorable biology. The application of tumor downstaging requires a structured approach involving three key components in tumor staging—initial tumor stage and eligibility criteria, tumor viability assessment following LRT, and target tumor stage prior to LT—and incorporation of AFP into staging and treatment response assessments. In this review, we provide in-depth discussions of the key role of these staging definitions in ensuring successful outcome.

Long-lasting remission in a metastatic hepatocellular carcinoma patient after combined regorafenib therapy and surgery

Aims: The therapeutic scenario of systemic treatments for hepatocellular carcinoma (HCC) is rapidly changing. There is much interest in the possibility of combining new therapies with surgery, but clinical data is lacking. We aimed to provide an example of such integration. Patients & methods: We report a patient with metastatic HCC who received regorafenib in the setting of the RESORCE trial. Results: A brilliant response led to a tumor downstaging and a subsequent adrenal metastasectomy with radical intent. Conclusions: New agents will change the therapeutic perspectives in advanced HCC and lead to a higher rate of objective responses, with possibilities of associating systemic therapy and surgery. Thus, the management of HCC will require more and more of an integrated, multidisciplinary and personalized approach.

Consolidation chemotherapy may improve pathological complete response for locally advanced rectal cancer after neoadjuvant chemoradiotherapy: a retrospective study

Background Patients with locally advanced rectal cancer (LARC) have an improved prognosis if achieved a pathological complete response (pCR) on account of neoadjuvant chemoradiation therapy (nCRT). However, the proportion of patients achieving pCR is only 8–24%. The purpose of this study was to explore whether the addition of consolidation chemotherapy to nCRT could improve pCR rate in patients with LARC. Materials and Methods The subjects were 144 individuals with clinical stage II (T3–4, N0) or III (any T, N1–2) LARC who had received neoadjuvant CRT followed by total mesorectal excision (TME). Eighty-three patients in the consolidation chemotherapy group received two cycles XELOX between CRT and TME, while 61 patients in the standard treatment group without consolidation chemotherapy. The pCR (ypT0N0), tumor downstaging (ypT0-2N0) after TME and adverse events (AEs) during and post treatment were compared between the treatment groups using multivariable logistic regression analysis. To adjust the unbalanced variables for the primary endpoint, logistic regression analysis and stratified analysis were performed. Results The consolidation chemotherapy group improved pCR rate (19.3% vs 4.9%, p = 0.01) and tumor downstaging rate (45.8% vs 24.6%, p = 0.009) compared to the standard treatment group. After adjustment for clinical tumor stage, clinical nodal stage and time interval to surgery, patients with consolidation chemotherapy were more likely to reach pCR (adjusted odds ratio 4.91, 95% CI [1.01–23.79], p = 0.048). AEs during and post treatment in the two groups were 54.1% vs 49.3% (p = 0.57), respectively. In addition, the incidence of any grade 1–2 AEs in the two groups was 93.4% vs 95.1% (p = 0.93), while the incidence of grade 3 AEs was 1.6% versus 2.4% (p = 0.74), respectively. No grade 4 AEs occurred in two groups. Conclusions The addition of neoadjuvant consolidation chemotherapy after CRT significantly increased the pCR rate and did not increase the AEs during and post treatment and in patients with LARC.