Outcomes in biomarker-selected subgroups from the KESTREL study of durvalumab and tremelimumab in recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Selective biomarkers may improve outcomes in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitor therapy. We investigated three independent biomarkers for association with efficacy in the randomized, phase III KESTREL study (NCT02551159) of first-line durvalumab monotherapy or durvalumab plus tremelimumab versus the EXTREME regimen: programmed cell death ligand-1 (PD-L1) immunohistochemistry, blood tumor mutational burden (bTMB) via circulating tumor DNA, and neutrophil-to-lymphocyte ratio (NLR). METHODS: Tumor or blood samples from patients enrolled in the KESTREL study were analyzed for PD-L1, bTMB, and NLR. Associations with overall survival (OS) or objective response rates (ORRs) were evaluated based on prespecified cut-offs for PD-L1 (tumor cell [TC] ≥ 50%/immune cell ≥ 25% or TC ≥ 25%), bTMB (≥ 16 mutations [mut] per megabase [Mb]), and NLR (≤ 7). Ad hoc analyses of exploratory cut-offs were performed. RESULTS: Prespecified or exploratory cut-offs for PD-L1 did not enrich for ORR or OS for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME. In the bTMB ≥ 16 mut/Mb subgroup, OS hazard ratios (95% confidence interval) for durvalumab monotherapy and durvalumab plus tremelimumab versus EXTREME were 0.90 (0.48-1.72) and 0.69 (0.39-1.25), respectively. Complete response rates were 8.6% with durvalumab plus tremelimumab and 4.3% with EXTREME (≥ 16 mut/Mb subgroup). No improvement in OS was observed for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME at prespecified or exploratory NLR cut-offs. CONCLUSIONS: bTMB demonstrated potential utility for selecting patients with R/M HNSCC who benefited from durvalumab with or without tremelimumab versus EXTREME. Trial registration ClinicalTrials.gov identifier NCT02551159.

Tumor Mutational Burden as a Predictor of Survival with Durvalumab and/or Tremelimumab Treatment in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

PURPOSE: Biomarkers that predict response to immune checkpoint inhibitors (ICI) in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are needed. This retrospective study assessed tumor mutational burden (TMB) and outcomes in the phase II HAWK and CONDOR and phase III EAGLE studies of durvalumab with or without tremelimumab in platinum-resistant R/M HNSCC. PATIENTS AND METHODS: Tumor samples from HAWK/CONDOR (N = 153) and blood samples from EAGLE (N = 247) were analyzed for TMB. Associations with survival were evaluated for tissue TMB (tTMB) at cutoffs from 10 to 20 mutations/megabase (mut/Mb) and for blood plasma TMB (bTMB) at cutoffs from 8 to 24 mut/Mb. RESULTS: In HAWK/CONDOR, overall survival (OS) with durvalumab with or without tremelimumab was longer for high versus low tTMB: statistically significant differences were observed with durvalumab plus tremelimumab at tTMB ≥ 10 mut/Mb [HR, 0.52 (95% confidence interval, CI, 0.28-0.98)] and tTMB ≥ 12 mut/Mb [HR, 0.46 (95% CI, 0.24-0.86)]. In EAGLE, a significant OS benefit versus chemotherapy was observed with durvalumab and durvalumab plus tremelimumab at bTMB≥16 mut/Mb [HR, 0.39 (95% CI, 0.20-0.76) and 0.38 (95% CI, 0.19-0.78), respectively] but not bTMB < 16 mut/Mb [HR, 0.92 (0.61-1.37) and 0.92 (95% CI, 0.62-1.36), respectively]. A significant progression-free survival benefit was also observed in the ICI arms versus chemotherapy at bTMB ≥ 16 mut/Mb. CONCLUSIONS: Findings support TMB as a biomarker for predicting survival in patients with platinum-resistant R/M HNSCC treated with ICIs. The analysis of EAGLE demonstrated that bTMB was predictive of survival with ICI treatment versus chemotherapy in a large, randomized controlled study population.

Population Pharmacokinetics of Monalizumab in Patients With Advanced Solid Tumors.

Monalizumab is a novel, first-in-class humanized immunoglobulin G4 monoclonal antibody immune checkpoint inhibitor that targets the inhibitory CD94/NKG2A receptors. The objectives of this analysis were to develop a population pharmacokinetic (PK) model of monalizumab, evaluate the impact of clinically relevant covariates on monalizumab PK, and provide dose justification for clinical trials. We developed a monalizumab population PK model to characterize the PK properties of monalizumab in patients with advanced solid tumors or head and neck squamous cell carcinoma. Data from clinical studies D419NC00001 (NCT02671435) and IPH2201-203 (NCT02643550) were pooled for the analysis, resulting in a data set of 3066 PK samples derived from 507 subjects. The PK of monalizumab were reasonably described by a 2-compartment model with first-order elimination. Monalizumab generally exhibited linear PK over a dose range of 22.5-750 mg or 10 mg/kg every 2 weeks. The estimate of clearance was ≈0.255 L/day, and apparent volume of distribution was 6.36 L for a typical individual, consistent with previous findings for endogenous immunoglobulin Gs and other therapeutic monoclonal antibodies. Baseline albumin and body weight were identified as significant covariates of clearance; body weight, sex, and smoking status had a significant impact on volume of distribution; and none of these covariates had impact on peripheral volume of distribution. Although these covariates were identified as statistically significant, they are considered to be not clinically meaningful, as changes in monalizumab exposure were <30%. Therefore, no dose adjustments of monalizumab based on patient or disease characteristics are recommended.

Association of circulating protein biomarkers with clinical outcomes of durvalumab in head and neck squamous cell carcinoma.

The potential for durvalumab, a programmed cell death ligand-1 (PD-L1)-blocking monoclonal antibody, to treat head and neck squamous cell carcinoma (HNSCC) is being evaluated in multiple clinical trials. We assessed circulating proteins at baseline to identify potential biomarkers and to understand pathways related to clinical outcomes for durvalumab. Prior to treatment, 66 serum proteins were measured using multiplex immunoassays for 158 durvalumab-treated HNSCC patients in the phase II HAWK and CONDOR trials as a discovery dataset and 209 durvalumab-treated HNSCC patients in the phase III EAGLE trial as a validation dataset. Multivariate Cox modeling of HAWK and CONDOR datasets established that higher baseline concentrations of interleukin-6 (IL-6), C-reactive protein, S100 calcium-binding protein A12, and angiopoietin-2 (ANGPT2) were associated with shorter overall survival (OS), while higher concentrations of osteocalcin correlated with longer OS after durvalumab treatment (p < .05). All five proteins remained significantly correlated with OS after adjusting for baseline clinical factors, with consistent results across clinical efficacy endpoints based on univariate correlation analyses. The validation dataset from the EAGLE trial confirmed the independent association of IL-6 and osteocalcin with OS, and preserved directional trends for the other biomarkers identified in the discovery dataset. Our results demonstrate the important role of immunosuppressive proteins in the resistance of HNSCC to durvalumab treatment. Osteocalcin showed a positive correlation with clinical outcomes, which remains to be further investigated.

Early predictions of response and survival from a tumor dynamics model in patients with recurrent, metastatic head and neck squamous cell carcinoma treated with immunotherapy.

We developed and evaluated a method for making early predictions of best overall response (BOR) and overall survival at 6 months (OS6) in patients with cancer treated with immunotherapy. This method combines machine learning with modeling of longitudinal tumor size data. We applied our method to data from durvalumab-exposed patients with recurrent/metastatic head and neck cancer. A fivefold cross-validation was used for model selection. Independent trial data, with various degrees of data truncation, were used for model validation. Mean classification error rates (90% confidence intervals [CIs]) from cross-validation were 5.99% (90% CI 2.98%-7.50%) for BOR and 19.8% (90% CI 15.8%-39.3%) for OS6. During model validation, the area under the receiver operating characteristic curves was preserved for BOR (0.97, 0.97, and 0.94) and OS6 (0.85, 0.84, and 0.82) at 24, 18, and 12 weeks, respectively. These results suggest our method predicts trial outcomes accurately from early data and could be used to aid drug development.

Efficacy and Tolerability of Tremelimumab in Locally Advanced or Metastatic Urothelial Carcinoma Patients Who Have Failed First-Line Platinum-Based Chemotherapy.

PURPOSE: Patients with advanced urothelial carcinoma who fail platinum-containing chemotherapy (treatment fails) have a poor prognosis and limited treatment options. Recent approvals of immune-checkpoint inhibitors confirmed the value of immunomodulatory therapy in urothelial carcinoma. Tremelimumab is a selective human immunoglobulin G2 (IgG2) monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 with demonstrated durable response rate in metastatic melanoma. This is the first study to report the efficacy and safety of tremelimumab in urothelial carcinoma. PATIENTS AND METHODS: We report the results of the urothelial carcinoma cohort from a phase II, open-label, multicenter study of patients with advanced solid tumors (NCT02527434). Patients with locally advanced/metastatic urothelial carcinoma were treated with tremelimumab monotherapy (750 mg via intravenous infusion every 4 weeks for seven cycles, then every 12 weeks for two additional cycles) for up to 12 months or until disease progression, initiation of other anticancer therapy, unacceptable toxicity, or consent withdrawal. RESULTS: In 32 evaluable patients with metastatic urothelial carcinoma, objective response rate was 18.8% (95% confidence interval, 7.2-36.4), including complete response (CR) in 2 (6.3%), and partial response in 4 patients (12.5%). Median duration of response has not been reached. Stable disease of ≥12 months was reported in 1 patient (3.1%), yielding a disease control rate at 12 months of 21.9%. Overall, tremelimumab was generally well tolerated; safety results were consistent with the known safety profile. CONCLUSIONS: Tremelimumab monotherapy demonstrated clinical activity and durable responses in patients with metastatic urothelial carcinoma. This study is the first in which CR has been observed with tremelimumab as a single agent in urothelial carcinoma.

An open-label feasibility study of nintedanib combined with docetaxel in Japanese patients with locally advanced or metastatic lung adenocarcinoma after failure of first-line chemotherapy.

PURPOSE: This open-label feasibility study assessed the tolerability of nintedanib 200 mg in combination with docetaxel 75 mg/m2 as a starting dose in Japanese patients with a body surface area (BSA) < 1.5 m2 and locally advanced or metastatic lung adenocarcinoma. METHODS: Eligible patients received docetaxel 75 mg/m2 every 21 days and nintedanib administered at 200 mg twice daily (bid), starting on day 2 of each cycle. Treatment was continued until disease progression or undue toxicity. The primary endpoint was the number of patients experiencing dose-limiting toxicities (DLTs) in cycle 1 (days 1-21). RESULTS: Of 10 treated patients, 2 patients (20%) experienced DLTs during cycle 1. These DLTs were grade 3 liver enzyme elevations [alanine aminotransferase (2 patients) and aspartate aminotransferase (2 patients)], and grade 2 hyperbilirubinemia (1 patient). Nine patients met the predefined criteria for nintedanib 200 mg bid plus docetaxel 75 mg/m2 to be considered a tolerable starting dose. All patients experienced ≥ 1 adverse event (AE) during the treatment period (all drug-related), but no patients experienced AEs that led to discontinuation of nintedanib. Of the five serious AEs reported during treatment, none were drug-related. There was no apparent effect of nintedanib on the pharmacokinetics of docetaxel. The objective response and disease control rates were 40 and 70%, respectively. CONCLUSION: Nintedanib 200 mg bid plus docetaxel 75 mg/m2 is a tolerable starting dose in Japanese patients with a BSA < 1.5 m2 with locally advanced or metastatic lung adenocarcinoma. CLINICALTRIALS. GOV NUMBER: NCT02300298.

Nintedanib Plus Pemetrexed/Cisplatin in Patients With Malignant Pleural Mesothelioma: Phase II Results From the Randomized, Placebo-Controlled LUME-Meso Trial.

Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Patients and Methods Chemotherapy-naïve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Results Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), which was confirmed in updated PFS analyses (HR, 0.54; 95% CI, 0.33 to 0.87; P = .010). A trend toward improved overall survival also favored nintedanib (HR, 0.77; 95% CI, 0.46 to 1.29; P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70; 95% CI, 0.40 to 1.21; P = .197; median [nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49; 95% CI, 0.30 to 0.82; P = .006; median [nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade ≥ 3 adverse event (AE; nintedanib 43.2% v placebo 12.2%); rates of febrile neutropenia were low (4.5% in nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus 17.1% of those in the placebo group. Conclusion Addition of nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing.

LUME-Meso: Design and Rationale of the Phase III Part of a Placebo-Controlled Study of Nintedanib and Pemetrexed/Cisplatin Followed by Maintenance Nintedanib in Patients With Unresectable Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare but aggressive disease: median survival is 6 to 9 months if untreated. Standard first-line treatment for patients with unresectable MPM is cisplatin/pemetrexed, with a median overall survival (OS) of approximately 1 year. Improvements in first-line treatment options are needed. With the benefit of combining bevacizumab with standard therapy shown in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS), vascular endothelial growth factor (VEGF) pathway inhibition has gained renewed interest as a treatment approach. Nintedanib is an oral angiokinase inhibitor targeting multiple signaling pathways implicated in the pathogenesis of MPM, including the VEGF receptor. The phase III part of the international, phase II/III LUME-Meso study is evaluating the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with unresectable epithelioid MPM. Originally, this was a double-blind, randomized, phase II exploratory study and was amended to include a confirmatory phase III part following the recommendation of an internal Data Monitoring Committee and review of phase II data. The phase III part plans to enroll 450 chemotherapy-naive patients, who will be randomized to receive pemetrexed/cisplatin on day 1 and nintedanib or placebo on days 2 to 21, for a maximum of 6 cycles. Patients without disease progression who are eligible to continue study treatment will receive maintenance treatment with nintedanib or placebo until disease progression or undue toxicity. The primary end point is progression-free survival; OS is the key secondary end point. The study will use an adaptive design, including an interim analysis to reassess the number of OS events required to ensure sufficient power for OS analysis. The study is currently enrolling patients.

Safety of BLP25 liposome vaccine (L-BLP25) in Japanese patients with unresectable stage III NSCLC after primary chemoradiotherapy: preliminary results from a Phase I/II study.

Preliminary safety findings are presented from the open-label Phase I part of a combined Phase I/II study of BLP25 liposome vaccine (L-BLP25) in Japanese patients with unresectable Stage III non-small-cell lung cancer after primary chemoradiotherapy. Six patients received four or more once-weekly vaccinations with L-BLP25 1000 µg subcutaneously prior to a preliminary safety evaluation. Treatment continued with once-weekly vaccinations with L-BLP25 1000 µg subcutaneously until week 8, then maintenance vaccinations every 6 weeks until progressive disease. Cyclophosphamide (300 mg/m(2) i.v. single dose) was given 3 days before first vaccination. Median age was 63.5 years and performance status was 0-1. No serious adverse events occurred; none necessitated discontinuation. L-BLP25-related adverse events (Grade 1) were myalgia, arthralgia and nausea; cyclophosphamide-related adverse events comprised dysgeusia, anorexia and nausea. The first evaluation of L-BLP25 in Japanese patients shows that it is well tolerated, and the safety profile is consistent with that seen in previous studies of Caucasian patients.

Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract.

PURPOSE: Vinflunine (VFL) is a new microtubule inhibitor that has activity against transitional cell carcinoma of urothelial tract (TCCU). We conducted a randomized phase III study of VFL and best supportive care (BSC) versus BSC alone in the treatment of patients with advanced TCCU who had experienced progression after a first-line platinum-containing regimen. PATIENTS AND METHODS: The study was designed to compare overall survival (OS) between patients receiving VFL + BSC (performance status [PS] = 0: 320 mg/m(2), every 3 weeks; PS = 0 with previous pelvic radiation and PS = 1: 280 mg/m(2) subsequently escalated to 320 mg/m(2)) or BSC. RESULTS: Three hundred seventy patients were randomly assigned (VFL + BSC, n =253; BSC, n = 117). Both arms were well balanced except there were more patients with PS more than 1 (10% difference) in the BSC arm. Main grade 3 or 4 toxicities for VFL + BSC were neutropenia (50%), febrile neutropenia (6%), anemia (19%), fatigue (19%), and constipation (16%). In the intent-to-treat population, the objective of a median 2-month survival advantage (6.9 months for VFL + BSC v 4.6 months for BSC) was achieved (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12) but was not statistically significant (P = .287). Multivariate Cox analysis adjusting for prognostic factors showed statistically significant effect of VFL on OS (P = .036), reducing the death risk by 23% (HR = 0.77; 95% CI, 0.61 to 0.98). In the eligible population (n = 357), the median OS was significantly longer for VFL + BSC than BSC (6.9 v 4.3 months, respectively), with the difference being statistically significant (P = .040). Overall response rate, disease control, and progression-free survival were all statistically significant favoring VFL + BSC (P = .006, P = .002, and P = .001, respectively). CONCLUSION: VFL demonstrates a survival advantage in second-line treatment for advanced TCCU. Consistency of results exists with significant and meaningful benefit over all efficacy parameters. Safety profile is acceptable, and therefore, VFL seems to be a reasonable option for TCCU progressing after first-line platinum-based therapy.