Background: Mipsagargin (G-202) is a thapsigargin-based prodrug with cytotoxic activity masked by a peptide that is cleaved by prostate-specific membrane antigen (PSMA), a protease expressed in prostate cancer cells and the endothelium of tumor vasculature. It was hypothesized that PSMA-mediated activation of mipsagargin would result in disruption of the tumor vasculature, leading to a decrease in blood flow, and in direct cytotoxic effects on tumor cells, resulting in anti-tumor activity. Method: In this open-label, Phase II study, mipsagargin was administered intravenously on Days 1, 2, and 3 of a 28-day cycle to patients with hepatocellular carcinoma (HCC) who progressed on or after treatment with sorafenib or intolerant of sorafenib. Assessments included time to disease progression (TTP), response rate, progression-free survival (PFS), overall survival (OS), and safety. Blood flow metrics in hepatic lesions were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Of 25 treated patients, 19 were evaluable for efficacy. None had an objective response, 12 (63.2%) had a best response of stable disease, and 12 (63.2%) showed radiologic progression; seven patients (36.8%) were censored. The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days. Of five patients with DCE-MRI data for 11 HCC lesions, all demonstrated a reduced Ktrans (mean, 52%). The most common treatment-emergent AEs were Grade 1–2 and consisted of increased blood creatinine (68.0%), fatigue (56.0%), and nausea (44.0%). Conclusions: Mipsagargin is relatively well tolerated and promotes prolonged disease stabilization in patients with advanced HCC that had progressed on prior treatment with sorafenib. A significant decrease in Ktrans upon treatment suggests mipsagargin reduces blood flow in hepatic lesions.
Abstract. Chemokines play an important role in cancer metastasis by modulating the directional cell movement and migration of tumor cells. The most commonly overexpressed chemokine receptor in human cancer is CXCR4. Once activated by its ligand CXCL12 (stromal cell-derived factor-1 ligand/SDF1), CXCR4 stimulates several key migratory, proliferative and survival signaling cellular pathways. CXCR4 is expressed in small-cell lung carcinoma (SCLC) cells and other tumors. To further characterize the role of chemokines in tumor-to-tumor metastasis, we analyzed the tissue expression of CXCR4 and CXCL12 in the surgical specimen of a patient with this phenomenon. We performed immunohistochemical analysis for the expression of CXCR4 and CXCL12 in metastatic tumor tissue of a 69-year-old Caucasian male with extensive SCLC metastatic to a renal oncocytoma. The oncocytoma tissue harboring SCLC showed CXCL12 expression, but not CXCR4. A high expression of the two molecules was found in a normal renal parenchymal control. Our results suggest that CXCR4 and CXCL12 plays a role in this condition, but their expression may be affected by the microenvironment of the harboring malignancy. Further characterization of these phenomena is needed to shed light on the biological mechanisms of tumor metastasis.
BackgroundEftilagimod alpha (efti) is a soluble LAG-3 protein targeting a subset of MHC class II, thus mediating antigen presenting cell (APC) and CD8 T-cell activation. Such stimulation of the dendritic cell network and resulting T cell recruitment by efti may lead to stronger anti-tumor responses than observed with pembrolizumab alone. We hereby report results of the 2nd line metastatic head and neck squamous cell carcinoma (HNSCC) cohort (part C) of the TACTI-002 phase II trial (NCT03625323).MethodsEligible patients (pts) with HNSCC, unselected for PD-L1 expression with disease progression on or after 1st line platinum-based therapy, received 30 mg subcutaneous efti Q2W for 24 weeks and 200 mg pembrolizumab Q3W for up to 2 years or until disease progression. The study used a Simon’s 2-stage design with objective response rate (ORR) as the primary endpoint (EP). Secondary EPs included tolerability, progression free survival (PFS), overall survival (OS), pharmacokinetics, pharmacodynamics, and immunogenicity. Tumor response was assessed Q9W. PD-L1 was assessed centrally (22C3 clone). The study was approved by ethic committees and institutional review boards.ResultsBetween Mar 2019 and Jan 2021, 39 pts were enrolled (cut-off Apr 2021). The median age was 62 yrs (range 37–84) with 90% male pts. ECOG was 0 and 1 in 33% and 67%, respectively. Primary tumor location at diagnosis was oropharynx (36%), oral cavity (31%), hypopharynx (18%) and larynx (15%) with all PD-L1 subgroups (CPS< 1, ≥1 to ≤19; ≥20) being represented. All pts were pre-treated with platinum-based chemotherapy. Thirty-seven (37) pts were evaluated for response with ORR (iRECIST) of 30% (95% CI 16–47%) with 5 (14%) CRs; 6 (16%) PRs; 3 (8%) SDs; 17 (46%) PDs and 6 (16%) pts not evaluable. Median PFS was 2.1 months and 30+% were progression-free at 6 months. One patient (3%) discontinued due to pembro-related adverse event. The most common (>10%) treatment emergent adverse events were hypothyroidism (21%), cough (18%), asthenia (15%), fatigue (13%), anemia (13%), diarrhea (13%) and weight decreased (13%).ConclusionsEfti in combination with pembrolizumab is safe, showing encouraging antitumor activity in platinum pre-treated, 2nd line HNSCC patients. For further investigation of this combination, a 1st line HNSCC trial (NCT04811027) has been initiated.Trial RegistrationNCT03625323Ethics ApprovalThe study was approved by relevant ethic committees and institutional review boards
Purpose: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and then CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses than observed with pembrolizumab alone. Combining an APC activator with an immune checkpoint inhibitor aims to increase efficacy without additional toxicity. We hereby report initial results of a phase II trial (NCT03625323). Methods: A predefined number of patients (pts) are recruited into this umbrella trial irrespective of PD-L1 expression. In part A: 1st line, PD-X naïve NSCLC; in part B: 2nd line, PD-X refractory NSCLC and in part C: 2nd line PD-X naive HNSCC. The study has a Simon's 2-stage design, with objective response rate (ORR) as primary endpoint. Secondary endpoints include progression free and overall survival, PK, PD and immunogenicity. Additional pts (N2) will be recruited for each part if the pre-specified threshold for ORR is met. Up to 109 pts will be enrolled. Efti is administered as 30 mg subcutaneous injection every 2 weeks for 8 cycles and then every 3 weeks for 9 cycles. Pembrolizumab is administered at a standard dose (200 mg intravenous infusion every 3 weeks for up to 2 years). The study was approved by ethic committees and institutional review boards. Results: Between 04 Mar 19 and 17 Jan 2020, 46 pts were enrolled and evaluated for safety. The median age was 66 years (range 48-84) and 74 % were male. The ECOG was 0 in 52 % and 1 in 48 % of the pts, respectively. Pts received a median of 5 (7) pembrolizumab (efti) administrations until data cut-off in Jan 2020. The most common (≥ 10%) adverse events (AEs) being cough (28 %), asthenia (24 %), dyspnea (17 %), decreased appetite (17 %), fatigue (15 %), diarrhea (15 %), non-cardiac chest pain (11 %), neck pain (11 %) and hypothyroidism (11 %). Two pts discontinued any study treatment due to AEs. All pts part A (1st line NSCLC) stage 1 (n=17) are evaluable for efficacy. Eight pts (47 %) had a partial response (iPR) and six (35 %) had stable disease according to iRECIST leading to an ORR of 47 %. Ten (10; 59 %) pts are still under therapy (7+ months). In part C (2nd line HNSCC) stage 1 13/18 pts are evaluable and five (39 %) had an iPR so far. Conclusions: Efti s.c. administered every 2 weeks in combination with pembrolizumab is safe and shows encouraging antitumor activity in all comer PD-L1 1st line NSCLC and 2nd line HNSCC. Stage 2 for both parts has been opened and stage 1 for part B is still recruiting. Citation Format: Martin Forster, Enriqueta Felip, Bernhard Doger, Margarita Majem, Enric Carcereny, Julio Peguero, Pawan Bajaj, Tim Clay, Matthew Krebs, Patricia Roxburgh, Leora Horn, Frederic Triebel. Initial results from a phase II study (TACTI-002) in metastatic non-small cell lung or head and neck carcinoma patients receiving eftilagimod alpha (soluble lag-3 protein) and pembrolizumab [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT202.
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