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AIM: To build and externally validate an [18F]FDG PET radiomic model to predict overall survival in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Two multicentre datasets of patients with operable HNSCC treated with preoperative afatinib who underwent a baseline and evaluation [18F]FDG PET/CT scan were included (EORTC: n = 20, Unicancer: n = 34). Tumours were delineated, and radiomic features were extracted. Each cohort served once as a training and once as an external validation set for the prediction of overall survival. Supervised feature selection was performed using variable hunting with variable importance, selecting the top two features. A Cox proportional hazards regression model using selected radiomic features and clinical characteristics was fitted on the training dataset and validated in the external validation set. Model performances are expressed by the concordance index (C-index). RESULTS: In both models, the radiomic model surpassed the clinical model with validation C-indices of 0.69 and 0.79 vs. 0.60 and 0.67, respectively. The model that combined the radiomic features and clinical variables performed best, with validation C-indices of 0.71 and 0.82. CONCLUSION: Although assessed in two small but independent cohorts, an [18F]FDG-PET radiomic signature based on the evaluation scan seems promising for the prediction of overall survival for HNSSC treated with preoperative afatinib. The robustness and clinical applicability of this radiomic signature should be assessed in a larger cohort. ispartof: CANCERS vol:15 issue:10 ispartof: location:Switzerland status: published

shows an estimation of copanlisib exposure variables following first infusion or at first tumor size assessment

Shows supplementary methods

Cell-cycle pathway impairments resulting in CDK4 and 6 activation are frequently observed in human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN). We investigated the activity of ribociclib, a CDK4/6 inhibitor, in SCCHN models with the aim of identifying predictive biomarkers of response. HPV-negative or HPV-positive SCCHN cell lines (n = 8) and patient-derived tumor xenograft (PDTX) models (n = 6) were used. The models were classified according to their sensitivity to ribociclib to investigate potential predictive biomarkers. Ribociclib had a cytostatic effect in some HPV-negative SCCHN models but had no effect in HPV-positive models. In SCCHN cell lines and PDTXs, the retinoblastoma (Rb) protein expression level correlated with ribociclib activity. Rb knockdown was, however, not sufficient to block G0–G1 arrest induced by ribociclib in Detroit-562 where p107, p130, and Forkhead BOX M1 (FOXM1) were also implicated in ribociclib activity. Cell lines harboring epithelial-to-mesenchymal transition (EMT) features were less sensitive to ribociclib than those with an epithelial phenotype. Rb downregulation induced EMT in our Rb-expressing SCCHN cell lines. However, ribociclib still had significant activity in one PDTX model with high Rb and vimentin expression, suggesting that the presence of vimentin alone is not enough to induce ribociclib resistance. These findings suggest that CDK4/6 inhibitors should be investigated in patients with HPV-negative SCCHN with high Rb expression and an epithelial phenotype. Although these biomarkers are not predictive in all cases, they may enrich the population that could benefit from CDK4/6 inhibitors.

shows copanlisib plasma concentration over time following infusion during the first week

Figure S2 shows the protein expression of Cyclin E1 in HPV-negative SCCHN human cell lines.

Table S2. Confirmed best overall response per RECIST-1.1 by tumor type

Figure S4. Changes in intratumoral immune markers after treatment

Purpose:Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) tumors. However, 50%–60% do not respond to single-agent anti–programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6–12 months. This phase Ib trial evaluated safety and antitumor activity of anti–PD-L1 antibody LY3300054 monotherapy or in combination with anti–TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors.Patients and Methods:Eligible patients ≥18 years without prior anti–PD-1/PD-L1 therapy received LY3300054 monotherapy (N = 40) or combination (N = 20); patients with PD-1/PD-L1 inhibitor–resistant/refractory tumors received the combination (N = 22). LY3300054 (700 mg) and anti–TIM-3 antibody (cycles 1–2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability.Results:Eighty-two patients were enrolled. Most had colorectal (n = 39, 47.6%) or endometrial (n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort.Conclusions:LY3300054 monotherapy and combined LY3300054/anti–TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor–naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor–resistant/refractory MSI-H/dMMR tumors.

Purpose: This phase I/II study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin (IL)-6 monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line in patients with advanced/refractory solid tumors.Experimental Design: In the phase I dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously (i.v.). In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor (EGFR) refractory/resistant non–small cell lung cancer (NSCLC), colorectal, or H&N cancer received 15 mg/kg every 3 weeks. The phase II primary efficacy endpoint was complete response, partial response, or stable disease >6 weeks.Results: Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of three (range, 1–45) cycles. One dose-limiting toxicity occurred at 5.5 mg/kg. Common grade ≥3 adverse events were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade ≥3 adverse events. Neutropenia (4%) was the only possibly related adverse event grade ≥3 reported in >1 patient. Serious adverse events were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appears similar to the previous cell line. No objective responses occurred; 5 of 84 patients had stable disease >6 weeks. Hemoglobin increased ≥1.5 g/dL in 33 of 47 patients. At 11 and 15 mg/kg, completely sustained C-reactive protein suppression was observed.Conclusions: Siltuximab monotherapy appears to be well tolerated but without clinical activity in solid tumors, including ovarian and KRAS-mutant cancers. The recommended phase II doses were 11 and 15 mg/kg every 3 weeks. Clin Cancer Res; 20(8); 2192–204. ©2014 AACR.

PDF file - 99KB, Supplementary Methods: The supplemental material contains additional detail on the pharmacokinetic and pharmacodynamic methods used during the study as well as a summary table of safety events and a figure detailing patient disposition. Supplemental Table 1: Summary of safety events in all study cohorts.

PDF file - 883K, Patient disposition by treatment group. IP, investigational product; MP, mitoxantrone and prednisone. *Patient had a decrease in hemoglobin prior to administration of IP on day 1 of cycle 1. �Patient had delays to cycles prior to cycle 12.

Supplementary Data from Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors

PDF file - 1418K, Forest plot of the treatment effect of rilotumumab compared with placebo on OS by covariate subgroups in the intention-to-treat analysis set. ECOG, Eastern Cooperative Oncology Group; PD, progressive disease.

PDF file - 28K, Kaplan-Meier plot of OS (A) and PFS (B) by tumor MET expression in all treatment arms combined.

Supplementary Data

PDF file - 28K, Waterfall plot of the maximum change in the sum of the longest diameters of tumors from baseline in patients with evaluable tumor response per investigator assessment who received rilotumumab (A) or placebo (B). Fifteen patients in the rilotumumab group and five patients in the placebo group were omitted because post-baseline data were not available. PD, progressive disease; SD, stable disease; UE, unevaluable.

PDF file - 25KB, Supplementary Figure S1. Patient disposition: AE, adverse event. KRAS, Kirsten rat sarcoma-2. PD, progressive disease. q2w, every 2 weeks. q3w, every 3 weeks.

PDF file - 54K, Drug exposure

PDF file - 31K, Waterfall plot of the maximum change of PSA levels from baseline in patients who received rilotumumab (A) or placebo (B) in the intention-to-treat analysis set. A PSA response was defined as ≥50% decline in two consecutive PSA levels ≥3 weeks apart. Six patients in the rilotumumab group were omitted because post-baseline data were not available.

Purpose: To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC).Experimental Design: This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m2 i.v. day 1, 5 mg twice a day orally days 1–21, respectively) plus 15 mg/kg rilotumumab, 7.5 mg/kg rilotumumab, or placebo (i.v. day 1) every 3 weeks. The primary endpoint was overall survival (OS).Results: One hundred and forty-four patients were randomized. Median OS was 12.2 versus 11.1 months [HR, 1.10; 80% confidence interval (CI), 0.82–1.48] in the combined rilotumumab versus control arms. Median progression-free survival was 3.0 versus 2.9 months (HR, 1.02; 80% CI, 0.79–1.31). Treatment appeared well tolerated with peripheral edema (24% vs. 8%) being more common with rilotumumab. A trend toward unfavorable OS was observed in patients with high tumor MET expression regardless of treatment. Soluble MET levels increased in all treatment arms. Total HGF levels increased in the rilotumumab arms. Rilotumumab showed linear pharmacokinetics when co-administered with MP.Conclusions: Rilotumumab plus MP had manageable toxicities and showed no efficacy improvements in this estimation study. High tumor MET expression may identify patients with CRPC with poorer prognosis. Clin Cancer Res; 19(1); 215–24. ©2012 AACR.

PDF file - 1076K, Kaplan-Meier plot of PFS by tumor MET subgroups in the combined rilotumumab and control arms (A) and forest plot of the biomarker effect of high versus low tumor MET expression on PFS within the combined rilotumumab and control arms (B). MP, mitoxantrone and prednisone; NA, not applicable.

Purpose:Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody–drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623).Patients and Methods:Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity.Results:Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab + doublet chemotherapy. Fifty-one percent of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% [95% confidence interval (CI): 13%−37%]. Median duration of response (DOR) was 4.2 months (range: 1.0+−9.7); four patients responded for >8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%−43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%−35%), median DOR of 6.0 months (range: 1.0+−9.7), and 6-month PFS rate of 40% (95% CI: 24%−55%). Tissue factor expression was confirmed in most patients; no significant association with response was observed.Conclusions:Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer.

Purpose:To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody–drug conjugate (ADC) ± nivolumab, in patients with selected tumors.Patients and Methods:In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1–1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability.Results:In CA008-002, the most common (≥ 10%) treatment-related adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected.Conclusions:BMS-986148 ± nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.

Supplementary Methods and References. Description of additional methods and procedures used in the study. Also includes supplementary references.

Supplementary Tables S1-S8. S1: Antibodies used for western blotting, immunoprecipitation and immunofluorescence S2: siRNA libraries and individual siRNAs used in this study S3: Sequences of qPCR primers S4: Z' values in primary siRNA screens S5: Candidate resistance mediators tested in second round screens S6: Validation of screen hits S7: DVL3 expression and clinical parameters in breast and prostate cancer S8:DVL3 IPS on tumor tissue from 22 patients recruited to trials of IGF-1R antibodies

Supplementary Figure Legend. Legends for Supplementary Figures S1-S6.

Supplementary Figures S1-S6. S1: Sensitivity to IGF�1R inhibitor AZ12253801 is influenced by levels of DVL3 protein but not IGF�1R or INSR S2: Effects of HUNK depletion on IGF signalling S3: Sensitivity to IGF�1R inhibition is enhanced by proximal but not distal WNT pathway inhibition S4: Investigating effects of DVL3 on IGF�induced ERK activation in prostate and breast cancer cells S5: ERK activation induced by DVL inhibition is independent of EGFR and IRS�1, and involves complex formation with adaptor proteins Grb2, DAB2 and SOS S6: DVL3 immunohistochemistry

INTRODUCTION: Fibroblast growth factor receptor (FGFR)-4/FGF19 pathway dysregulation is implicated in hepatobiliary and other solid tumors. INCB062079, an oral, selective, FGFR4 inhibitor, inhibits growth in FGF19/FGFR4-driven liver cancer models. METHODS: This was a two-part, phase I study (NCT03144661) in previously treated patients with advanced solid tumors. The primary objective was to determine safety, tolerability, and maximum tolerated dose (MTD), while secondary objectives included pharmacokinetics, pharmacodynamics (plasma FGF19; bile acid salts/7α-hydroxy-4-cholesten-3-one [C4] levels), and preliminary efficacy. In Part 1, patients received INCB062079 starting at 10 mg once daily, with 3 + 3 dose escalation. Part 2 (dose expansion) was not conducted because of study termination. RESULTS: Twenty-three patients were treated (hepatobiliary, n = 11; ovarian, n = 9; other, n = 3). Among six patients receiving 15 mg twice daily, two patients had dose-limiting toxicities (DLTs; grade 3 diarrhea, grade 3 transaminitis). Both had high pretreatment C4 concentrations, prompting a protocol amendment requiring pretreatment C4 concentrations

Pembrolizumab and nivolumab, two monoclonal antibodies (mAbs) targeting programmed cell death protein-1 (PD-1), improve the overall survival of patients with inoperable recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). For curable HNSCC, the role of immunotherapy is under investigation. In this chapter, we briefly review the current use of immunotherapy with surgery or radio(chemo)therapy in the treatment of HNSCC with curative intent.

Contains fulltext : 290894.pdf (Publisher’s version ) (Open Access) BACKGROUND: Talazoparib has shown antitumor activity with a manageable safety profile in men with metastatic castration-resistant prostate cancer (mCRPC) and DNA damage response (DDR)/homologous recombination repair (HRR) alterations. OBJECTIVE: To evaluate patient-reported health-related quality of life (HRQoL) and pain in patients who received talazoparib in the TALAPRO-1 study, with a special interest in patients harboring breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. DESIGN, SETTING, AND PARTICIPANTS: TALAPRO-1 is a single-arm, phase 2 study in men with mCRPC DDR alterations either directly or indirectly involved in HRR, who previously received one to two taxane-based chemotherapy regimens for advanced prostate cancer and whose mCRPC progressed on one or more novel hormonal agents. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Men completed the European Quality-of-life Five-dimension Five-level scale (EQ-5D-5L), EQ-5D visual analog scale (VAS), and Brief Pain Inventory-Short Form at predefined time points during the study. The patient-reported outcome (PRO) population included men who completed a baseline and one or more postbaseline assessments before study end. Longitudinal mixed-effect models assuming an unstructured covariance matrix were used to estimate the mean (95% confidence interval [CI]) change from baseline for pain and general health status measurements among all patients and patients with BRCA1/2 mutations. RESULTS AND LIMITATIONS: In the 97 men in the PRO population treated with talazoparib (BRCA1/2, n = 56), the mean (95% CI) EQ-5D-5L Index improved (all patients, 0.05 [0.01, 0.08]; BRCA1/2 subset, 0.07 [0.03, 0.10]), as did the EQ-5D VAS scores (all patients, 5.42 [2.65, 8.18]; BRCA1/2 subset, 4.74 [1.07, 8.41]). Improvements in the estimated overall change from baseline (95% CI) in the mean worst pain were observed in all patients (-1.08 [-1.52, -0.65]) and the BRCA1/2 subset (-1.15 [-1.67, -0.62]). The probability of not having had experienced deterioration of worst pain by month 12 was 84% for all patients and 83% for the BRCA1/2 subset. CONCLUSIONS: In heavily pretreated men with mCRPC and DDR/HRR alterations, talazoparib was associated with improved HRQoL in all patients and the BRCA1/2 subset. In both patient groups, worst pain improved from baseline and the probability of not experiencing a deterioration in worst pain with talazoparib was high. PATIENT SUMMARY: We show that talazoparib was associated at least with no change or improvements in health-related quality of life (HRQoL) and pain burden in men with metastatic castration-resistant prostate cancer and DNA damage response/homologous recombination repair gene alterations in the TALAPRO-1 study. These findings in patient-reported HRQoL and pain complement the antitumor activity and tolerability profile of talazoparib. 01 april 2023