Analyses of Intermediate-Stage Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization prior to Designing Clinical Trials.

BACKGROUND: Intermediate-stage hepatocellular carcinoma (HCC) has a high frequency of recurrence and progression to advanced stage after transarterial chemoembolization (TACE), particularly in patients with high tumor burden. Promising new results from immune checkpoint inhibitors (ICIs) and ICI-based therapies are expected to replace TACE, especially in HCC patients with high tumor burden. AIMS: The present study aimed to evaluate the effectiveness of TACE with a view to design clinical trials comparing TACE and ICIs. METHODS: We retrospectively identified intermediate-stage HCC patients undergoing TACE from our database and subdivided patients into low- and high-burden groups based on three subclassification models using the diameter of the maximum tumor and the number of tumors. Clinical outcomes were compared between low- and high-burden intermediate-stage HCC. RESULTS: Of 1,161 newly diagnosed HCC patients, 316 were diagnosed with intermediate-stage disease and underwent TACE. The median overall survival from high-burden intermediate-stage disease was not significantly different by clinical course, reaching high tumor burden in all subclassification models. The prognosis of high-burden patients after initial TACE was poor compared with low-burden patients for two models (except for the up-to-seven criteria). In all three models, high-burden patients showed a poor durable response rate (DRR) both ≥3 months and ≥6 months and poor prognosis after TACE. Moreover, patients with confirmed durable response ≥3 months and ≥6 months showed better survival outcomes for high-burden intermediate-stage HCC. CONCLUSIONS: Our results demonstrate the basis for selecting a population that would not benefit from TACE and setting DRR ≥3 months or ≥6 months as alternative endpoints when designing clinical trials comparing TACE and ICIs.

Meta-analytical methods for estimating outcomes from overall response rate in patients with relapsed/refractory diffuse large B-cell lymphoma.

Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is highly heterogeneous and current trials are investigating new approaches to improve outcomes. Limited data on response endpoints can confound estimation of a treatment effect when designing studies of novel agents in this setting, which can hinder study sample size calculations, especially if a net estimate is required for a 'physician's choice' comparator arm. Here we estimate complete response rate (CRR), overall response rate (ORR), and extrapolate durable response rates (DRR; CR/partial response lasting ≥16 weeks) for such a comparator arm from published ORRs in DLBCL. CRR, ORR, and DRR (if reported) were obtained from published clinical trials for approved single-agent therapies in patients with relapsed/refractory aggressive non-Hodgkin lymphoma after ≥2 prior therapies. Meta-analyses were performed to estimate CRR, ORR, and DRR based on ORR data reported from these studies. Published data from studies of eight monotherapies were included. Meta-analyses using fixed and random effects models showed a pooled estimate for a CRR of 12% (95% confidence interval [CI]: 9-15) and 11% (95% CI: 8-15), respectively, an ORR of 30% (95% CI: 25-35) and 30% (95% CI: 24-36), respectively, and a DRR of 14% (95% CI: 11-18; same for fixed and random effects models). Bayesian meta-analysis estimated a pooled DRR of 14% (95% credible interval: 11-19). CRR estimates for a physician's choice comparator arm in patients with relapsed/refractory DLBCL were 11-12%; DRR estimates were 14% regardless of methodology. Lack of consistency in reported data and choice of endpoints can be addressed using meta-analytic approaches.

Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials.

BACKGROUND: Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting ≥6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival. METHODS: We evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation). RESULTS: Four hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9 months (HR = 0.07; P = 0.0003), 12 months (HR = 0.05, P < 0.0001), and 18 months (HR = 0.11; P = 0.0002) that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI (HR = 0.33; P = 0.0007) and a higher TOI improvement rate (58.1% versus 30.0%; P = 0.025). CONCLUSIONS: Achieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00769704 ( https://clinicaltrials.gov/ct2/show/NCT00769704 ) October 7, 2008.

Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the Phase III OPTiM trial.

OBJECTIVES: Talimogene laherparepvec is the first oncolytic immunotherapy to receive approval in Europe, the USA and Australia. In the randomized, open-label Phase III OPTiM trial (NCT00769704), talimogene laherparepvec significantly improved durable response rate (DRR) versus granulocyte-macrophage colony-stimulating factor (GM-CSF) in 436 patients with unresectable stage IIIB-IVM1c melanoma. The median overall survival (OS) was longer versus GM-CSF in patients with earlier-stage melanoma (IIIB-IVM1a). Here, we report a detailed subgroup analysis of the OPTiM study in patients with IIIB-IVM1a disease. PATIENTS AND METHODS: The patients were randomized (2:1 ratio) to intralesional talimogene laherparepvec or subcutaneous GM-CSF and were evaluated for DRR, overall response rate (ORR), OS, safety, benefit-risk and numbers needed to treat. Descriptive statistics were used for subgroup comparisons. RESULTS: Among 249 evaluated patients with stage IIIB-IVM1a melanoma, DRR was higher with talimogene laherparepvec compared with GM-CSF (25.2% versus 1.2%; P<0.0001). ORR was also higher in the talimogene laherparepvec arm (40.5% versus 2.3%; P<0.0001), and 27 patients in the talimogene laherparepvec arm had a complete response, compared with none in GM-CSF-treated patients. The incidence rates of exposure-adjusted adverse events (AE) and serious AEs were similar with both treatments. CONCLUSION: The subgroup of patients with stage IIIB, IIIC and IVM1a melanoma (57.1% of the OPTiM intent-to-treat population) derived greater benefit in DRR and ORR from talimogene laherparepvec compared with GM-CSF. Talimogene laherparepvec was well tolerated.