The Efficacy of TACE Combined With Lenvatinib Plus Sintilimab in Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study

ObjectiveTo assess the efficacy and safety of transarterial Chemoembolization (TACE) combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma (HCC).Patients and MethodsThe data of patients with unresectable HCC administered a combination therapy with TACE and lenvatinib plus sintilimab were retrospectively assessed. Patients received lenvatinib orally once daily 2 weeks before TACE, followed by sintilimab administration at 200 mg intravenously on day 1 of a 21-day therapeutic cycle after TACE. The primary endpoints were objective response rate (ORR) and duration of response (DOR) by the modified RECIST criteria.ResultsMedian duration of follow-up was 12.5 months (95%CI 9.1 to 14.8 months). ORR was 46.7% (28/60). Median DOR in confirmed responders was 10.0 months (95%CI 9.0-11.0 months). Median progression-free survival (PFS) was 13.3 months (95%CI 11.9-14.7 months). Median overall survival (OS) was 23.6 months (95%CI 22.2-25.0 months).ConclusionsTACE combined with lenvatinib plus sintilimab is a promising therapeutic regimen in unresectable hepatocellular carcinoma.

RECIST 1.1, mRECIST 1.1: RADIOLOGICAL ASSESSMENT OF TUMOR RESPONSE TO CHEMOTHERAPY (literature review)

Определение изменений опухолевого роста является важной характеристикой клинической оценки терапии рака - как уменьшение размеров опухоли (объективный ответ), так и прогрессирование заболевания являются полезными конечными точками клинических исследований. Критерии RECIST были впервые опубликованы в 2000 г. и с тех пор начали применяться в мировой онкологической практике для оценки эффективности лечения. В 2009 году критерии RECIST 1.0 были пересмотрены и дополнены новыми данными RECIST 1.1 (2009 г.). Учитывая применение химиотаргетной терапии и особенности ответа на нее опухоли, предложены SACT критерии, модифицированные критерии RECIST (mRECIST) как способ адаптации критериев RECIST. Современные знания критериев оценки лечения солидных опухолей поможет лучевым диагностам правильно интерпретировать результаты исследований. В работе представлен обзор научных исследований по критериям оценки опухолевого ответа на лечение по данным радиологических исследований. Determining of tumor changes is an important characteristic of the clinical evaluation of cancer therapy - both tumor shrinkage (objective response) and disease progression are useful endpoints of clinical trials. The RECIST criteria were first published in 2000 and since then have been used in the global oncological practice to assess the effectiveness of treatment. In 2009, the RECIST 1.0 criteria were revised and supplemented with new data from RECIST 1.1 (2009). Taking into account the use of target chemotherapy and the peculiarities of the tumor response to it, the SACT criteria and modified RECIST criteria (mRECIST) are proposed as a way to adapt the RECIST criteria. Modern knowledge of the criteria for ASSESSMENT OF TUMOR RESPONSE will help radiologyst to correctly interpret the research results. The paper provides an overview of scientific studies on the criteria for evaluating tumor response to treatment based on radiological studies.

418 Phase 1b/2 KEYNOTE-365 cohort I: platinum-containing chemotherapy alone or in combination with pembrolizumab for treatment-emergent neuroendocrine prostate carcinoma

BackgroundTreatment-emergent neuroendocrine prostate carcinoma (t-NE) can occur de novo or after diagnosis of prostate adenocarcinoma. Treatment often includes platinum-containing chemotherapy because of t-NE’s histologic similarity to small cell lung cancer. The PD-1 inhibitor pembrolizumab has shown promising efficacy and acceptable safety when combined with olaparib, docetaxel, or enzalutamide for treatment of metastatic castration-resistant prostate cancer (mCRPC) in the multicohort phase 1b/2 KEYNOTE-365 study (NCT02861573). Cohort I will be used to compare platinum-containing chemotherapy alone with chemotherapy + pembrolizumab as treatment for t-NE.MethodsPatients who have t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review); experienced progression within 6 months of starting a next-generation hormonal agent (NHA) for mCRPC or hormone-sensitive prostate cancer and experienced progression within 6 cycles of docetaxel treatment for mCRPC; and have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 are eligible. Prior therapy with ≤2 NHAs and 1 other chemotherapy for mCRPC is permitted. Patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg IV on day 1 of each cycle every 3 weeks + carboplatin AUC of 5 IV on day 1 + etoposide 100 mg/m2 IV on days 1, 2, and 3 of each 21-day cycle for 4 cycles (arm 1) or the same chemotherapy regimen without pembrolizumab (arm 2); in each arm 40–100 patients will be enrolled. Pembrolizumab treatment will continue up to 2 years until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be stratified by ECOG performance status score (0 or 1). Computed tomography or magnetic resonance imaging will be performed every 9 weeks through week 54 and every 12 weeks thereafter. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are time to PSA progression; ORR and radiographic progression-free survival (PFS) per PCWG3-modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 by BICR and PCWG3-modified RECIST v1.1 by BICR; and overall survival. End points will be summarized for each arm without formal hypothesis testing.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT02861573Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

425 Pembrolizumab + vibostolimab in patients with adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC) or treatment-emergent neuroendocrine mCRPC: phase 1b/2 KEYNOTE-365 cohorts G/H

BackgroundFrontline treatment for patients with adenocarcinoma mCRPC includes docetaxel, radium 223, or the next-generation hormonal agents (NHAs) abiraterone or enzalutamide. For patients with disease progression on these therapies, approximately 20% will develop treatment-emergent neuroendocrine mCRPC (t-NE) after diagnosis of prostate adenocarcinoma. The PD-1 inhibitor pembrolizumab showed antitumor activity when combined with olaparib in cohort A of the phase 1b/2 KEYNOTE-365 trial, and the TIGIT inhibitor vibostolimab showed antitumor activity in preclinical models. Combining PD-1 and TIGIT inhibition may have enhanced benefit in adenocarcinoma mCRPC or t-NE.MethodsKEYNOTE-365 is a nonrandomized, open-label, multicohort study (NCT02861573) to assess several pembrolizumab combination therapies in patient populations with adenocarcinoma mCRPC or t-NE. In each of cohorts G and H, 40–100 adults with Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1 who received docetaxel for mCRPC will be enrolled. Prior therapy with ≤2 NHAs and 1 other chemotherapy for adenocarcinoma mCRPC is permitted. Patients in cohort G must have adenocarcinoma of the prostate without small cell histology at study entry. Patients in cohort H must have t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review) that progressed within 6 months of starting an NHA for mCRPC or hormone-sensitive prostate cancer and progressed within 6 cycles of docetaxel for mCRPC. All patients will receive MK-7684A, a coformulation of pembrolizumab 200 mg and vibostolimab 200 mg intravenously every 3 weeks until disease progression, consent withdrawal, or other discontinuation event. Adverse events will be monitored through 30 days after discontinuation (90 days if serious) and graded per CTCAE v4.0. Computed tomography or magnetic resonance imaging will be performed at screening, every 9 weeks through week 54, and every 12 weeks thereafter. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are time to PSA progression, ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and overall survival.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT02861573Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

Pilot Study to Evaluate Serum Soluble Mesothelin-Related Peptide (SMRP) as Marker for Clinical Monitoring of Pleural Mesothelioma (PM): Correlation with Modified RECIST Score

A soluble mesothelin-related peptide (SMRP) is the only FDA-approved biomarker for diagnosis of pleural mesothelioma (PM) and the most used for monitoring treatment. Radiological assessment of PM, based on modified RECIST (mRECIST) criteria, is challenging. This pilot study was designed to evaluate whether SMRP levels correlated over time with mRECIST score. Serial serum samples from PM patients were collected and SMRP levels were measured and compared with the mRECIST score obtained through centralized CT scans by blinded review. The within-patient SMRP-mRECIST relationship over time was estimated through a normal random-effects regression approach applied to the log-transformed mRECIST score. Overall, 58 PM patients were included (46 males and 12 females) with a median age at diagnosis of 67 years (min–max = 48–79), 44 (76%) with epithelioid and 14 (24%) with non-epithelioid histology. The total number of SMRP measurements and CT scans considered for analysis was 183. There was a statistically significant correlation between SMRP and mRECIST score in the 2 cohorts considered both separately and jointly. These results, although exploratory, suggest that SMRP measurement might be considered as an adjunct to monitor PM patients in order to delay CT scans time interval, thus warranting further investigation.

Role of CT and modified Response Evaluation Criteria in Solid Tumors (RECIST criteria) in response evaluation of malignant pleural mesothelioma

Background Malignant pleural mesothelioma is a rare and aggressive tumor that the growth pattern of it poses unique difficulties in measurement and response assessment . however, robust and reproducible assessment of response is critically important in the conduct, interpretation, and reporting of clinical trials. Objectives The aim of this study is to assess the value of CT and modified RECIST criteria in follow up patients of malignant pleural mesothelioma patient during treatment with chemotherapy . Patients and methods We evaluated 20 malignant pleural mesothelioma patients undergoing to chemotherapy . Tumor thickness is measures perpendicular to the chest wall or mediastinum in two positions at three separate levels on thoracic CT scans. The sum of the six measurements defined a pleural unidimensional measure. A reduction of at least 30% on two occasions 6 weeks apart defined a partial response; an increase of 20% over the nadir measurement known as progressive disease. Patients who fulfilled the criteria for neither PR nor PD called CD .The validity of the modified criteria was gauged by clinical evaluation . Results In our study, CT and modified RECIST criteria were used as the method of choice in response evaluation of malignant pleural mesothelioma .Our study showed as follow up results of each group and comparison between clinical evaluation and modified RECIST criteria show over all accuracy 73.3% with P value = 0.03 and this results confirm accuracy of CT with modified RECIST criteria as good predictor of disease outcome . Conclusion These Modified RECIST criteria for tumor response correlate with clinical evaluation and can be used to measure outcome in pleural mesothelioma.

Early Experience of Atezolizumab Plus Bevacizumab Therapy in Japanese Patients With Unresectable Hepatocellular Carcinoma in Real-world Practice

Background: We aimed to investigate the efficacy and safety of atezolizumab plus bevacizumab therapy in patients with unresectable hepatocellular carcinoma (u-HCC) based on whether they had previously received systemic therapy, as well as the association of atezolizumab plus bevacizumab with early alpha-fetoprotein (AFP) response in real-world practice. Methods: A total of 52 patients with u-HCC were treated with atezolizumab plus bevacizumab between October 2020 and April 2021. The Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST were used to evaluate radiological responses. Results: The patients received atezolizumab plus bevacizumab as 1st-line (n = 23), 2nd-line (n = 16), 3rd-line (n = 6), 4th-line (n = 3), 5th-line (n = 3), or 6th-line (n = 1) therapy. The objective response rate and disease control rate in all patients were 18.4% and 63.2%, respectively. Sixteen patients experienced no adverse events (AEs), whereas 4 patients discontinued therapy due to AEs. The median time to progression (TTP) was significantly longer among patients receiving atezolizumab plus bevacizumab as 1st-line therapy than in patients receiving atezolizumab plus bevacizumab as later-line therapy (P = 0.02). Patients with an AFP response (reduction ≥20% from baseline) at 6 weeks had a significantly longer TTP than those without an AFP response (P = 0.02). Conclusion: Patients who received atezolizumab plus bevacizumab as 1st-line therapy had better clinical outcome than those who received atezolizumab plus bevacizumab in later lines. The AFP response at 6 weeks could be a predictor of disease progression.

Comparison of Methods for Analyzing Radiological Response of Colorectal Cancer Liver Metastasis After Neoadjuvant Chemotherapeutic Treatment

Background: We analyzed different methods used to assess the radiological responses of patients undergoing neoadjuvant chemotherapy and metastasectomy treatment for liver metastases associated with colorectal cancer (CRC) by comparing the response evaluation criteria in solid tumors (RECIST) 1.1, the modified RECIST, and the criteria of the European Association for the Study of the Liver (EASL) methods and the histological response obtained after metastasectomy. Objectives: We aimed to determine the optimal radiological method to assess the response of colorectal liver metastases to neoadjuvant chemotherapy. Materials and Methods: We conducted a retrospective study of CRC patients treated for liver metastases who had received neoadjuvant chemotherapy in our hospital between January 2000 and December 2017. We analyzed the agreement between the methods for analyzing the radiological response using the quadratic weighted kappa coefficient (κ). We studied the overall survival and analyzed factors related to survival using the Kaplan-Meier method. We performed multivariate analysis to study the prognostic factors of survival. We analyzed the relationship between the radiological and histological responses using Goodman and Kruskal's gamma (γ). Results: A significant agreement was observed between the modified RECIST and EASL methods (κ = 0.841, P < 0.001). Cox regression multivariate analysis indicated the RECIST 1.1 criteria as an independent prognostic factor (P = 0.03). The γ value showed a significant relationship between the three radiological response methods and histological response. Conclusion: In our study, we showed that using RECIST 1.1 criteria is the ideal radiological analysis method for studying CRC liver metastases treated with neoadjuvant chemotherapy when compared to other methods that are based on functional imaging markers.

Efficacy and safety of selective internal radiation therapy with yttrium-90 for the treatment of unresectable hepatocellular carcinoma

Background This retrospective analysis was undertaken to evaluate the efficiency of SIRT with Y-90 microspheres and determined prognostic factors affecting patients with unresectable HCC. Methods A total of 97 patients diagnosed with unresectable HCC who underwent SIRT with Y-90 microspheres. Patient survival was assessed using the Kaplan–Meier method, and prognostic factors affecting survival were assessed using log-rank tests and Cox proportional hazards regression. Results Among the 97 patients (90 males, mean age 60.4 ± 12.3 years) who underwent SIRT, the median clinical follow-up was 16.4 (1.8–62) months. The median overall survival (OS) was 23.9 ± 2.4 months. Tumor response according to the Modified RECIST in patients followed up beyond 6 months included a complete response (CR) to treatment in 12 patients (18.8%), partial response (PR) in 23 (35.8%), stable disease (SD) in 8 (12.5%), and progressive disease (PD) in 21 (32.8%). Factors associated with longer OS included age > 65 years, BCLC stage B, tumor size < 5 cm, tumor burden < 25%, and tumor response (CR/PR). In multivariate analysis, unilobar disease and objective tumor response (CR/PR) were predictors of longer OS. Conclusion SIRT was an effective treatment for unresectable HCC. Unilobar disease before SIRT and tumor response (CR/PR) were positive prognostic factors.

Initial Experience of Atezolizumab Plus Bevacizumab for Advanced Hepatocellular Carcinoma in Clinical Practice

Background/Aim: The aim of this study was to investigate the outcomes of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC), including those with disease refractory to lenvatinib, in clinical practice. Patients and Methods: Of 34 patients treated with atezolizumab plus bevacizumab, a total of 23, including 16 with lenvatinib failure, were enrolled in this retrospective study. The adverse events, changes in liver function and antitumor responses at 6 weeks after starting therapy were evaluated. Results: The incidence of grade 3 adverse events was low, at 13.0%. Albumin–bilirubin scores did not worsen at 3 and 6 weeks compared to baseline. The objective response rate and disease control rate at 6 weeks were 17.4% and 78.3% according to Response Evaluation Criteria in Solid Tumors (RECIST), and 30.4% and 78.3% according to modified RECIST, respectively. Conclusion: Our results suggest that atezolizumab plus bevacizumab might have potential therapeutic safety and efficacy in patients with advanced HCC, including those with disease refractory to lenvatinib. Further studies are needed to confirm the outcomes of atezolizumab plus bevacizumab after lenvatinib failure.