Advanced Squamous Cell Research Articles

Circular RNA MTCL1 promotes advanced laryngeal squamous cell carcinoma progression by inhibiting C1QBP ubiquitin degradation and mediating beta-catenin activation

BackgroundCircular RNAs (circRNAs) are involved in regulatory processes of ubiquitination and deubiquitination in various tumors at post-transcriptional epigenetic modification level. However, the underlying mechanism and its biological functions of circRNAs in the advanced laryngeal squamous cell carcinoma (LSCC) remain obscure.MethodsRNA sequencing and quantitative real-time PCR (qRT-PCR) assays were applied to screen for circRNAs differentially expressed in LSCC tissues and cell lines. The candidate RNA-binding proteins and target signalling pathway were detected by RNA pull-down and mass spectrometry, in situ hybridization (ISH), immunohistochemistry (IHC), qRT-PCR assays, and bioinformatics analysis. The functional roles of these molecules were investigated using in vitro and in vivo experiments including EdU, transwell, wound healing, western blot assays, and the xenograft mice models. The molecular mechanisms were identified using RNA pull-down assays, RNA immunoprecipitation (RIP), Co-IP, ISH, Ubiquitination assay, bioinformatics analysis, and the rescue experiments.ResultsHere, we unveil that microtubule cross-linking factor 1 circRNA (circMTCL1, circ0000825) exerts its critical oncogenic functions by promoting complement C1q-binding protein (C1QBP)-dependent ubiquitin degradation and subsequently activating Wnt/β-catenin signalling in laryngeal carcinoma initiation and development. Specifically, circMTCL1 was remarkably up-regulated in the paired tissues of patients with LSCC (n = 67), which predicted a worse clinical outcome. Functionally, circMTCL1 exerted oncogenic biological charactersistics by promoting cell proliferative capability and invasive and migrative abilities. Ectopic circMTCL1 augumented cell proliferation, migration, and invasion of LSCC cells, and this effect could be reversed by C1QBP knocking down in vitro and in vivo. Mechanistically, circMTCL1 directly recruited C1QBP protein by harboring the specific recognized sequence (+ 159 − + 210), thereby accelerating the translation of C1QBP expression by inhibiting its ubiquitin–proteasome-mediated degradation. Importantly, the direct interaction of C1QBP with β-catenin protein was enhanced via suppressing the β-catenin phosphorylation and accelerating its accumulation in cytoplasm and nucleus.ConclusionOur findings manifested a novel circMTCL1-C1QBP-β-catenin signaling axis involving in LSCC tumorigenesis and progression, which shed new light on circRNAs-ubiquitous acidic glycoprotein mediated ubiquitin degradation and provided strategies and targets in the therapeutic intervention of LSCC.

Prophylactic contralateral neck dissection has no advantage in patients with early stage HPV-positive tonsil cancer

ABSTRACT Background Patients with locally advanced HPV-positive tonsil cancer would benefit from prophylactic contralateral neck dissection (pCND). Aims/Objectives The aim of this study was to analyze rates of contralateral lymph node metastases (LNM) and their prognostic effects on locally advanced HPV-positive tonsillar squamous cell carcinoma. Materials and methods Medical records of 54 patients who underwent upfront primary surgery and pCND were retrospectively reviewed. Results Six (11.1%) patients had contralateral LNM in 54 locally advanced HPV-positive tonsil cancer. Of these, five patients had contralateral level II LNM and one patient had contralateral level II and III LNM. Contralateral LNM showed significant positive correlations with advanced T stage (p = .017) and the presence of extracapsular spread (p = .007). Contralateral lymph node metastasis had no significant association with five-year disease-specific survival. Conclusions and significance This study demonstrated no advantage in performing pCND in early stage HPV-positive tonsil cancer.

A Case of Amelanotic Melanoma in the Setting of Cemiplimab Therapy for Invasive Squamous Cell Carcinoma

Cemiplimab is the first PD-1 inhibitor approved in the United States for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), but not melanoma. We describe a case of amelanotic melanoma (AM) developing in a patient on cemiplimab therapy for invasive SCC. Cutaneous AM is a rare subtype of cutaneous melanoma that shows little or no melanin pigmentation on clinical and histological examination thus often leading to a high misdiagnosis rate. Physicians should consider atypical presentations of melanoma, including amelanotic melanoma, during surveillance of patients managed with immune checkpoint inhibitor therapy.

A phase 2 study of the efficacy and safety of INCMGA00012 in advanced penile squamous cell carcinoma (PSqCC): ORPHEUS.

TPS8 Background: PSqCC is a rare tumor with poor prognosis and limited therapeutic options. The current standard of care for advanced disease has been palliative platinum-based chemotherapy, with only marginal survival benefit. Recent data has shown that the majority of PSqCC patients present high levels of programmed death-ligand 1 (PD-L1). The ORPHEUS trial is evaluating the efficacy and safety of INCMGA00012 –a programmed cell death 1 (PD-1) antagonist– in patients with unresectable, locally advanced or metastatic PSqCC. Methods: ORPHEUS is an international, multicenter, open-label, single-arm, phase 2 clinical trial. Eligible patients are male aged ≥18 years with locally advanced or metastatic PSqCC, ECOG performance status of 0-1, adequate organ function, a life expectancy of ≥12 weeks, and with no prior treatment with PD-1 or PD-L1/2 agents. A total of 18 patients will be enrolled to receive INCMGA00012 500 mg administered intravenously on day 1 of each 28-day cycle. Treatment will continue until progressive disease or unacceptable toxicity. Tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune-related RECIST will be performed approximately every 8 weeks for the first 6 months and every 12 weeks thereafter until progressive disease. The primary endpoint is objective response rate. Secondary objectives include additional efficacy outcomes (clinical benefit rate, progression-free survival (PFS), 6-month PFS, duration of response, time to progression, overall survival, and maximum tumor shrinkage) and safety evaluated as per NCI-CTCAE 5.0. Exploratory objectives will evaluate efficacy based on immune-related RECIST; predictive and prognostic biomarkers; impact of INCMGA00012 on human immunodeficiency virus (HIV) control in patients known to be HIV-positive. The sample size calculation is based on an exact binomial test. At least 4 responders (22.2%) among 18 patients will be adequate to justify further investigation of this strategy. The analyses were designed to attain an 80% power, with a 10% dropout rate assumption, at a nominal one-sided α level of 5%. The response probabilities for null (H0) and alternative hypotheses (H1) were H0: ≤ 5% and H1: ≥ 25%, respectively. All 18 planned patients have been enrolled since the trial began in March 2020. Clinical trial information: NCT04231981.

Randomized, phase 3 study of second-line tislelizumab versus chemotherapy in advanced or metastatic esophageal squamous cell carcinoma, RATIONALE 302: Asia subgroup.

279 Background: In the global Phase 3 study RATIONALE 302 (NCT03430843), tislelizumab (TIS) demonstrated statistically and clinically significant improvement in overall survival (OS) vs chemotherapy (chemo) (median OS 8.6 vs 6.3 months; HR 0.70, 95% CI 0.57–0.85; p=0.0001) in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). Here, we report data from the Asia subgroup. Methods: Eligible patients who had disease progression after first-line systemic therapy were randomized 1:1 to receive TIS 200 mg intravenously once every three weeks or chemo (paclitaxel, docetaxel, or irinotecan) until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was OS in all randomized patients (Intent-to-treat population). The key secondary endpoint was OS in patients with PD-L1 Tumor Area Positivity Score* ≥ 10%; other secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), health-related quality of life, and safety. Results: Of the 512 randomized patients, 404 (79%) were enrolled from China, Taiwan, Japan, and Korea and constituted the Asia subgroup (n=201 TIS, n=203 chemo). At data cut-off (December 1, 2020), median follow-up was 6.9 months in the Asia subgroup. Median OS was 8.5 months with TIS vs 6.3 months with chemo (HR 0.73; 95% CI 0.59, 0.90). Median PFS was 1.5 months with TIS vs 1.7 months with chemo (HR 0.81; 95% CI 0.64, 1.02). TIS resulted in a higher ORR (20.4% [95% CI 15.1, 26.6] vs 9.4% [95% CI 5.7, 14.2]) and longer median DoR (7.4 vs 4.0 months; HR 0.42, 95% CI 0.21, 0.84) vs chemo. In the safety analysis set (n=201 TIS, n=191 chemo), patients treated with TIS had fewer treatment-related adverse events (TRAEs) (74.1% vs 95.3%), fewer ≥ Grade 3 TRAEs (19.4% vs 57.1%), fewer serious TRAEs (15.4% vs 20.9%), and a similar incidence of TRAEs leading to death (2.5% vs 2.6%) vs chemo. Conclusions: In the Asia subgroup, TIS improved OS and tumor response vs chemo as second-line treatment in patients with advanced or metastatic ESCC and showed a well-tolerated safety profile. These findings were consistent with published results in the overall population. *The TAP score methodology has been previously referred to as visually-estimated combined positive score (vCPS) and was previously presented at the American Society of Clinical Oncology 2021, June 4–8, 2021, ESMO World Gastrointestinal Congress 2021, June 30–July 3, 2021, and The Chinese Society of Clinical Oncology 2021, September 25–29, 2021. Clinical trial information: NCT03430843.

Efficacy and safety of definitive chemoradiotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma.

252 Background: The standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is platinum-based definitive chemoradiotherapy (dCRT). Previous clinical trials have indicated a clinical complete response (cCR) rate of 11%-25% and median overall survival (OS) of 9-10 months. The cCR rate is strongly correlated with good prognosis, however the predictive factors have not been elucidated. Methods: In this multi-institutional retrospective study, we evaluated the efficacy and safety of dCRT in patients with unresectable locally advanced ESCC. “Unresectable” was defined as the primary lesion (T4b) invading adjacent structures such as the aorta, vertebral body, and trachea, or the regional and/or supraclavicular lymph nodes (LNT4b) invading unresectable adjacent structures. cCR was determined by both computed tomography and endoscopy based on the Response Evaluation Criteria in Solid Tumors (version 1.1) with modifications and Japanese Classification of Esophageal Cancer (11th edition), respectively. Results: A total of 175 patients who started dCRT between January 2013 to March 2020, were included in this study. The overall median age was 68 (31-86). A total of 95 (54%) patients had a performance status of 0. Of these, 124 (71%) patients had T4b and 81 (46%) had LNT4b. The clinically involved site were as follows: thoracic aorta (22%), tracheobronchial tree (73%), and others (14%). The median tumor length was 6 (2-22) cm. 56 (32%) patients were tube-fed owing to obstructive tumors. 165 (96%) patients completed at least one cycle of chemotherapy with 60 Gy of radiation. Further, 84 (48%) patients received consolidation chemotherapy following dCRT. The confirmed cCR rate was 24% (42/175). At a median follow-up interval of 20 months, the 2-year OS and progression-free survival (PFS) rates of cCR cases vs. non-cCR cases were 90% vs. 31% (log-rank p < 0.001) and 59% vs. 2% (log-rank p < 0.001), respectively. Multivariate analysis of the clinicopathological factors contributing to cCR revealed that a tumor length of≥6 cm (OR, 0.4; 95% CI, 0.2–0.9 p = 0.03) was the only a significant predictive factor. The primary adverse events of grade 3 or above were esophagitis (32%), pneumonitis (13%), fistula formation (10%), febrile neutropenia (9%), and dyspnea (6%). Among 22 patients who originally presented with fistula formation, fistula disappeared in 14 (64%), including 3 cCR cases. Two (1%) sudden deaths secondary to severe hemorrhage and suspected aortic fistula were observed during the treatment period. Conclusions: dCRT is feasible for patients with unresectable locally advanced ESCC. The cCR rate of dCRT is consistent with that reported in previous clinical trials, and favorable OS and PFS rates were observed in patients with cCR. Tumor length was observed to be a significant predictive factor of cCR. Research Sponsor: None.

AdvanTIG-203: A randomized phase 2 study comparing anti-TIGIT ociperlimab plus tislelizumab versus tislelizumab plus placebo as second-line treatment in patients with advanced or recurrent esophageal squamous cell carcinoma (ESCC) expressing programmed death-ligand 1 (PD-L1).

TPS370 Background: The programmed death-1 (PD-1)/PD-L1 pathway plays an important role in tumor induced immunosuppression. PD-L1 overexpression is observed in approximately 30–60% of esophageal cancers and is associated with poor prognosis. Anti-PD-1 agents demonstrate moderate efficacy in PD-L1-positive esophageal cancer in terms of response rate and overall survival, however, long-term outcomes remain poor due to primary and secondary resistance driven by tumor immune escape. The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is upregulated on T-cells and natural killer cells in multiple solid tumors, which can inhibit anticancer immune responses. Ociperlimab (BGB-A1217) is a novel, humanized, monoclonal antibody that binds TIGIT with high specificity and affinity, blocking the interaction with its ligands on tumor cells. Preclinical and clinical studies suggest that dual targeting with anti-TIGIT and anti-PD-1 antibodies produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-203 is a Phase 2, global, randomized, double-blind, placebo-controlled study (NCT04732494) of patients with unresectable, locally advanced, recurrent or metastatic ESCC, who progressed on or after 1st line systemic therapy and whose tumors express PD-L1 (visually-estimated combined positive score ≥ 10%). After stratification by Eastern Cooperative Oncology Group performance status (0 or 1), number of metastatic sites (≤ 1 or ≥ 2) and region (Asian or non-Asian), 280 patients will be randomized (1:1) to either ociperlimab 900 mg intravenous (IV) plus tislelizumab 200 mg IV every 3 weeks (Q3W), or tislelizumab plus placebo Q3W, until disease progression (per RECIST v1.1), unacceptable toxicity, death or withdrawal of consent. Co-primary endpoints are investigator-assessed overall response rate (ORR) and overall survival (OS) in the intention-to-treat population. A sample size of 280 patients was estimated to provide approximately 94.8% power to detect a 20% difference in ORR at a one-sided significance level of 0.025. With 198 deaths, the study was estimated to provide approximately 86% power to detect a hazard ratio of 0.65 for OS. Secondary endpoints are ORR by independent review, progression-free survival, duration of response, disease control rate, and clinical benefit rate per investigator and independent assessment, cancer-specific health-related quality of life (HRQoL), and safety. Exploratory endpoints include but are not limited to expression of TIGIT, CD226, CD155, CD112, and PD-L1, pharmacokinetics, immunogenicity, and generic HRQoL measures. Clinical trial information: NCT04732494.

Multicenter, randomized double-blind placebo-controlled trial of definitive concurrent chemoradiotherapy plus megestrol acetate/placebo in local-advanced esophageal cancer.

275 Background: To determine Quality-of-Life (QoL) improvement by Megestrol Acetate (MA) in local advanced esophageal squamous cell carcinoma (ESCC) with definitive concurrent chemoradiotherapy (DCRT). Secondary aims were to examine the safety and the impact of MA on the efficacy of DCRT. Methods: Patients (with previously untreated T1bN+M0 or T2-4aN0-2M0 ESCC) were randomly assigned at a one-to-one ratio to receive MA or placebo (blind). All received 5-FU based chemotherapy with concurrent radiotherapy (50Gy/25F). QoL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaires at pretreatment and 3, 6, 16 weeks of DCRT. The good status (GS) rate of appetite loss (AL), nausea and vomiting (NV), weight (WT) and performance status (PS) were chosen as predefined primary end points. GS defined as the score were ≤ 0 for AL or NV and ≥ 0 for WE or PS when the designed time points compared with last one. Secondary end points were the comprehensive QoL (remaining items of QLQ-C30 changes analysis at 16th week), myelosuppression (MS), and deep vein thrombosis (DVT). The exploratory end points were the objective response rate (ORR), 1-year overall survival (OS) and progression-free survival (PFS). Results: 84 completed the follow-up and were analyzed from which 120 patients randomly assigned. The GS rates of AL (3th week: P = 0.011; 6th week: P < 0.001; 16th week: P = 0.001), NV (6th week: P = 0.001) and PS (6th week: P = 0.01) were higher in MA than Placebo. There were no statistical differences between MA and Placebo on WT. At 16th week, the change degree analysis shown the fatigue was worse in MA than Placebo ( p = 0.031). There were no differences on MS, DVT, ORR, OS and PFS between two arms. Nevertheless the rate of DVT was slightly higher in MA than Placebo (12.5% vs. 2.8%, P = 0.113). Conclusions: MA is helpful for ESCC patients receiving DCRT as well as the risk of DVT needed be careful.

Circulating tumor DNA-based molecular residual disease detection and recurrence monitoring in patients with advanced or metastatic anal squamous cell carcinoma.

6 Background: For patients with anal squamous cell carcinoma (ASCC), the current standard of care involves curative-intent definitive chemoradiation. For those that recur locally, salvage surgery maybe a consideration. ASCC, however, still lacks a non-invasive blood-based biomarker, which can be of value in this patient population for monitoring recurrence and/or response to immunotherapy later. Circulating tumor DNA (ctDNA) is a promising non-invasive tool to assess molecular residual disease (MRD) and recurrence in ASCC. Here, we evaluated real-world utility of ctDNA status to identify MRD and recurrence in ASCC patients across all stages. Methods: This is a retrospective analysis of patients with any stage ASCC receiving SOC or/and immunotherapy with immune checkpoint inhibitors. A personalized tumor-informed PCR/NGS-based assay (Signatera) was used for ctDNA detection, in the pre/on/post-treatment and surveillance setting. Results: In this study, plasma samples (n=105) were collected from 25 ASCC patients (13 females, 12 males; median age 66 years) at various timepoints for a median follow-up of 315 days (range: 59-1717), post-diagnosis; 12 patients were HPV-positive, 1 patient was HPV-negative, and 12 had unknown HPV status; 88% (22/25) of the patients had serial timepoints (≥2) available. ctDNA-positivity rates, test results, and ctDNA quantification by stage are summarized in Table. The quantitated ctDNA values (mean tumor molecules (MTM)/mL) increased in concordance with the stage of the disease, with values trending higher in stage III and IV. In addition, complete clinical outcome information was available for 22/25 patients at the time of releasing this data. Of the 96 plasma samples drawn from these patients, 68 (70%) were in the surveillance setting (post-definitive therapy). No recurrences were observed among 15 patients who cleared ctDNA on treatment and/or tested negative post-treatment, whereas, 6/7 ctDNA-positive patients were confirmed to have disease recurrence and 1 was pending confirmatory imaging. This often predated recurrence on scans. Conclusions: Measuring and monitoring MRD in patients with ASCC is feasible and has the potential to impact clinical decision making. Our study is the first to set the benchmark for the feasibility of using a tumor-informed assay in ASCC. Larger prospective studies are needed to explore the clinical utility of ctDNA status to guide disease surveillance and management of ASCC.[Table: see text]

Impact of CT-assessed changes in tumor size after neoadjuvant chemotherapy on pathological response and survival of patients with esophageal squamous cell carcinoma.

Neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for advanced esophageal squamous cell carcinoma (ESCC) in Japan. Computed tomography (CT) is usually used to assess the therapeutic effect of NAC; however, there are no reliable criteria for predicting pathological response or patient prognosis. We included 84 patients who underwent esophagectomy between January 2009 and December 2018 and retrospectively reviewed their CT scans performed before and after NAC. The reduction rate of the largest tumor area (TA), long diameter (LD), and short diameter (SD) were measured on a transverse CT image. The pathological response and cutoff values were calculated using the receiver operating characteristic curve, and the most suitable ones for determining the effect were examined. The areas under the curve for predicting responders to NAC based on the reduction rate of the TA, LD, and SD were 0.755, 0.761, and 0.781, respectively. The optimal cutoff value of the SD reduction rate for predicting responders to NAC was 22%. An SD reduction ≥ 22% was an independent prognostic factor for overall survival in univariate (p = 0.005, hazard ratio [HR] = 2.755) and multivariate analyses (p = 0.030 HR 2.690). Furthermore, an SD reduction of ≥ 22% was also an independent prognostic factor for relapse-free survival in the univariate (p = 0.007, HR = 2.491) and multivariate analyses (p = 0.007, HR = 0.030). The reduction rate of the tumor SD is a simple predictor of pathological response and patient prognosis.

Cemiplimab for the treatment of advanced cutaneous squamous cell carcinoma

Introduction Cutaneous squamous cell carcinoma (CSCC) is the second most frequent malignant skin cancer, with an increasing worldwide incidence. Cemiplimab is a human monoclonal antibody directed against programmed cell death-1 receptor that acts by blocking T-cell inactivation. It is the first drug approved for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation. Areas covered The aim of this review is to analyze the mechanism of action, including pharmacokinetic and pharmacodynamic properties, clinical efficacy, safety, and tolerability of cemiplimab for squamous cell carcinoma. Expert opinion The introduction of immune checkpoint inhibitors has revolutionized the therapeutic scenario of advanced skin cancers. Many challenges regarding the use of cemiplimab for locally advanced and metastatic CSCC still exist. The use of combination treatments, including the association of different immune checkpoint inhibitors, could be a strategy to increase treatment response, reducing the possibility of therapeutic failure. Also, different schemes of treatment or dose adjustments should be considered in order to reduce toxicity, avoiding treatment discontinuation and increasing patient´s quality of life.

Efficacy of some selected neo-adjuvant chemotherapy regimens in the treatment of advanced oral squamous cell carcinoma, and their effects on immune function

Purpose: To investigate the clinical efficacy of different neo-adjuvant chemotherapy (NACT) regimens in the treatment of advanced oral squamous cell carcinoma (OSCC), and their influence on immune function of the patients.Methods: Advanced OSCC patients (n = 94) who received NACT served as subjects in this study. They were assigned to 2 different treatment groups. Forty patients received docetaxel and fluorouracil regimen (DF group), while 54 patients received taxotere, cisplatin and fluorouracil regimen (TPF group). Surgery was performed after NACT. Changes in clinical efficacy and immune function were monitored in both groups. The clinical baseline data of patients were assessed prior to the treatments. Independent indicators of prognosis were determined using Cox regression analysis (CRA).Results: Clinical treatment efficacy was higher in TPF group than in DF group (p < 0.05). Objective remission rate (ORR) in DF group was lower than that in TPF group (p < 0.05). After chemotherapy, both groups had increased levels of CD4+ and CD4+/CD8+, and reduced level of CD8+, when compared with pre-chemotherapy values, with higher levels of CD4+ and CD4+/CD8+ ratio, and lower level of CD8+ in TPF group than in DF group (p < 0.05). Multivariate CRA revealed that the independent factors for prognosis of oral carcinoma (OC) were tumor node metastasis (TNM) stage and lymph node metastasis.Conclusion: These results indicate that TFP regimen improves clinical efficacy and immune function in patients with advanced OSCC.

Abstract P185: Preliminary antitumor activity of MCLA-158, an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell carcinoma

Abstract In the expansion part of an ongoing phase 1 study, MCLA-158 is being investigated at the recommended phase 2 dose (RP2D) in patients (pts) with advanced solid tumors, including head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor (EGFR) and WNT signaling are known oncogenic and mitogenic drivers in several cancers, including HNSCC. MCLA-158 is a human common light chain IgG1 bispecific antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. It targets EGFR and the leucine-rich, repeat-containing, G-protein coupled receptor 5 (LGR5), a transmembrane receptor associated with tumor initiating cells, particularly cancer stem cells. Potent antitumor activity was seen with MCLA-158 in pt-derived HNSCC xenograft models. The RP2D of MCLA-158 was determined to be 1500 mg every 2 weeks (q2w), with 4-week cycles, during the dose escalation part of the study, based on safety, PK and receptor occupancy prediction. A maximum tolerated dose was not reached. The primary objective of the expansion part is to characterize the safety and tolerability of single-agent MCLA-158 and confirm the RP2D. Secondary objectives include assessment of antitumor activity (investigator-assessed overall response rate [ORR] per RECIST 1.1 and duration of response). Key eligibility criteria include prior exposure to standard therapy, ECOG performance status (PS) 0-1, measurable disease (RECIST 1.1), and availability of a baseline tumor biopsy. At the interim data cutoff date of 15 June 2021, 7 pts with advanced recurrent/metastatic HNSCC were enrolled and treated in the expansion phase. Median age was 63 years (range 50-74), ECOG PS 0/1: 2/5. Primary tumor locations were oropharynx (2 pts), hypopharynx (1 pts), larynx (3 pts), and unknown primary (1 pt). All pts had a histology of squamous cell carcinoma. Prior treatment included platinum-based chemotherapy in all pts, and anti-PD-1/PD-L1 in 6 pts. No pts received prior cetuximab. A median of 3 treatment cycles (range 1-8) were administered to the 7 pts, 4 of whom were continuing with therapy at the cutoff. Of the 5 pts who had a postbaseline assessment, 2 had confirmed partial responses (5+ and 8 cycles initiated), and 2 pts had stable disease (reduction in the sum of target lesions of 7% and 17%; 4+ and 5 cycles initiated, respectively). Scheduled first postbaseline tumor assessments for 2 pts occurred after the data cutoff date. Among 26 pts who were treated at the RP2D in the dose escalation and expansion cohorts, the most frequent adverse events regardless of causality (all grades/grade 3) were infusion-related reactions (73%/8%), rash (39%/0%), asthenia (35%/4%), decreased appetite (27%/4%), nausea (27%/4%), and acneiform dermatitis (23%/4%). There were no treatment-related grade 4 or 5 adverse events. In conclusion, MCLA-158 shows promising signs of antitumor activity in pretreated HNSCC, and a well-tolerated and favorable safety profile. Citation Format: Antoine Hollebecque, Irene Brana, Lara Iglesias, Caroline Even, Kato Shumei, Marc Díez García, Mateo Bover, Patricia Martin-Romano, Rocio Garcia-Carbonero, Guillen Argilés, Josep Tabernero, Rajan Khanna, Viktoriya Stalbovskaya, Jeroen Lammerts van Bueren, Kees Bol, Mohamed Bekradda, Andrew Joe, Ernesto Wasserman, Ezra E.W. Cohen. Preliminary antitumor activity of MCLA-158, an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P185.

Abstract P045: LUMINOS-103: A basket trial evaluating the safety and efficacy of PVSRIPO and PVSRIPO in combination with anti-PD-1/L1 checkpoint inhibitors in patients with advanced solid tumors

Abstract Background: PVSRIPO, a novel intratumoral viral immunotherapy, infects cells via CD155, which is widely expressed on solid tumors and antigen-presenting cells (APC). Infection is lethal in malignant cells, but a unique, activating, nonlethal infection of local APCs yields type-I/III interferon (IFN)-dominant inflammation with subsequent anti-tumor T-cell priming and activation. In preclinical models, PVSRIPO-dependent inflammation upregulated the PD-1/L1 pathway, and greater anti-tumor response was observed with PVSRIPO + anti-PD-1/L1 (αPD-1/L1). Promising clinical activity with PVSRIPO monotherapy was observed in patients (pts) with recurrent glioblastoma and advanced αPD-1–refractory melanoma (Desjardins 2018 NEJM, Beasley 2021 JITC). Collectively, these results warrant further clinical investigation of PVSRIPO ± αPD-1/L1. Trial design, objectives, and eligibility criteria: LUMINOS-103 (NCT04690699) is a phase (Ph) 1/2, open-label, multi-center, single-arm basket trial evaluating repeat administration of PVSRIPO ± αPD-1/L1 in adults with solid tumors. Trial objectives are to assess the safety and tolerability of PVSRIPO monotherapy in each cohort in Ph 1 and the safety, tolerability, and antitumor efficacy of PVSRIPO + αPD-1/L1 in each cohort in Ph 2. The first two study cohorts include pts with muscle-invasive bladder cancer being treated in the neoadjuvant setting (A) and pts with metastatic bladder cancer being treated in the 1st/2nd line setting (B); these cohorts have been described previously (Inman 2021 Virtual AACR Annual Meeting). Cohort C includes pts with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) being treated in the neoadjuvant setting; Cohort D includes pts with recurrent/metastatic HNSCC with a PD-L1 Combined Positive Score ≥1 being treated in the 1st line setting. Eligibility: HNSCC pts must have histologically or cytologically proven SCC of the oral cavity, oropharynx, hypopharynx, or larynx. All pts must have prior and boosted PV immunization and tumors amenable to injection and biopsy. Key exclusion criteria: Requirement for oxygen supplementation, systemic or intratumoral therapy ≤6 months prior to the first dose of study drug, CNS metastases requiring immediate treatment, systemic immunosuppressive medications ≤4 weeks prior to the first dose of study drug, and severe active comorbidities. Pts who are HIV+, HBV+ or HCV+ are eligible provided they meet certain criteria. Endpoints: Primary endpoints include safety (all), tolerability (all), surgical complication rate (A, C), pathologic treatment effect/response (A, C), and objective response rate (B, D). Secondary endpoints include overall survival (all), pathologic downstaging and relapse-free survival (A, C), duration of response and progression-free survival (B, D), and assessment of tumor/blood biomarkers (all). Citation Format: Brant A. Inman, Matthew I. Milowsky, Raj S. Pruthi, Marshall Posner, Melissa J. Polasek, Shannon R. Morris, Lori Mixson, Kristin Orr, Elizabeth M. H. Woodson, Andrea T. Kelly, W. Garrett Nichols, Arjun V. Balar. LUMINOS-103: A basket trial evaluating the safety and efficacy of PVSRIPO and PVSRIPO in combination with anti-PD-1/L1 checkpoint inhibitors in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P045.

Identification of factors related to immunotherapy efficacy and prognosis in patients with advanced head and neck squamous cell carcinoma

BackgroundImmunotherapy is an important treatment in oncology, but only a fraction of patients with head and neck squamous cell carcinoma (HNSCC) benefit from it. Therefore, the aim of this study was to identify predictive biomarkers of immunotherapy response for HNSCC in order to improve treatment outcomes.MethodsSurvival analyses and comparative efficacy evaluation were performed to investigate prognostic and therapeutic impact factors in patients with advanced HNSCC following immunotherapy, and to examine the effects of factors including gene mutations, tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), and immune cell infiltration on the survival and efficacy.ResultsAnti-PD-1 treatment led to a prolonged overall survival (OS) in HNSCC patients with gene mutations compared with those without the mutations, while no significant difference in the OS was found between the two groups of patients. And no marked association between the MATH value and OS was detected in HNSCC patients, whereas patients with either high TMB scores in tissues and blood or high immune cell infiltration displayed a significantly longer OS. Further analysis with efficacy as the primary endpoint revealed no significant differences in the tissue TMB, blood TMB, and MATH value between the patients who responded to immunotherapy and those who did not. Moreover, no significant differences in the expression percentages of positive immune cells in tumor, stroma, and total regions were identified between the above two groups of patients.ConclusionHNSCC is characterized by high mutation rate, high mutation burden, and high level of immune cell infiltration, and a subset of HNSCC patients respond to immunotherapy. Here, we showed that high mutation burden and immune cell infiltration may improve the prognosis of HNSCC patients with immunotherapy, while there was no remarkable effect on the efficacy.

Real-world effectiveness of second-line Afatinib versus chemotherapy for the treatment of advanced lung squamous cell carcinoma in immunotherapy-na\xefve patients

BackgroundLimited treatment options exist for relapsed advanced lung squamous cell carcinoma (SCC), leading to poor outcomes compared with adenocarcinoma. This study aimed to investigate the efficacy of second-line afatinib versus chemotherapy in patients with advanced lung SCC who progressed after first-line chemotherapy.MethodsIn this retrospective, multisite cohort study, we recruited patients with initial locally advanced or metastatic lung SCC from four institutes in Taiwan between June 2014 and October 2020. The primary endpoint of this study was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and overall survival (OS).ResultsThe present study enrolled 108 patients: 19 received second-line afatinib, and 89 received second-line chemotherapy. The median ages were 71 and 67 years, respectively. PFS was significantly longer among patients who received afatinib than among those who received chemotherapy (median 4.7 months [95% confidence interval (CI), 0.1–7.5] vs. 2.6 months [95% CI, 0.9–6.7]; hazard ratio (HR) 0.53 [95% CI 0.32–0.88], p = 0.013). Compared with the chemotherapy group, OS was longer in the afatinib group but did not reach significance (median 16.0 months [95% CI, 6.1–22.0] vs. 12.3 months [6.2–33.9]; HR 0.65 [95% CI 0.38–1.11], p = 0.112).ConclusionsAfatinib offered a longer PFS and comparable OS to chemotherapy in advanced lung SCC patients in a real-world setting, it may be considered as a 2nd line alternative treatment choice for immunotherapy unfit advanced lung SCC patients.

CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation

BackgroundCisplatin-based chemotherapy is a mainstay systematic therapy for advanced esophageal squamous cell carcinoma (ESCC), and cisplatin resistance, which is not uncommon, is the major barrier to improving patient outcomes. Circular RNAs (circRNAs) are novel noncoding RNAs that are implicated in cancer progression, but their involvement in modulating cisplatin responsiveness in ESCC remains unknown.MethodsBioinformatics analysis was used to profile and identify the circRNAs involved in cisplatin responsiveness in ESCC. The chemosensitive role of cDOPEY2 was confirmed both in vitro and in vivo. The molecular mechanism of cDOPEY2 was investigated by mass spectrometry, immunoprecipitation, and ubiquitination analyses.ResultsWe report that a novel circRNA (cDOPYE2, hsa_circ_0008078) was markedly downregulated in cisplatin-resistant ESCC cells (ESCC-CR) compared with parental chemosensitive cells. Re-expression of cDOPEY2 substantially enhanced the cell-killing ability of cisplatin by augmenting the apoptotic process in ESCC-CR cells, which was achieved by decreasing the abundance of the antiapoptotic protein Mcl-1. Mechanistically, we showed that cDOPEY2 acted as a protein scaffold to enhance the interaction between the cytoplasmic polyadenylation element binding protein (CPEB4) and the E3 ligase TRIM25, which in turn facilitated the ubiquitination and degradation of CPEB4. The increased Mcl-1 expression in ESCC-CR cells was dependent on the binding of CPEB4 to its untranslated mRNA, and depletion of CPEB4 mediated by cDOPEY2 reversed this effect. Rescue experiments confirmed that the critical role of cDOPEY2 in maintaining cisplatin sensitivity was dependent on the depletion of CEPB4 and its downstream target Mcl-1. Clinical and in vivo data further corroborated the significant relevance of cDOPEY2 to cisplatin responsiveness in ESCC.ConclusionsWe provide evidence that cDOPEY2 inhibits CPEB4-mediated Mcl-1 translation by promoting the ubiquitination and degradation of CPEB4 to alleviate cisplatin resistance, indicating that cDOPEY2 may serve as a valuable biomarker and potential therapeutic target in ESCC.

PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis

BackgroundAim to establish the inhibitors of programmed cell death protein 1 (PD-1) as second-line therapy for advanced esophageal squamous cell carcinoma (ESCC).MethodsPublished clinical trials in the PubMed, Medline, Embase databases on PD-1 inhibitors for the treatment of ESCC were searched, along with an additional search on abstracts from the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) from inception to September 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) were synthesized using STATA.ResultsA total of 1970 patients (PD-1 inhibitors: 987; chemotherapy: 983) were enrolled in five randomized controlled trials. Compared with conventional chemotherapy, second-line PD-1 inhibitors significantly improved the OS (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.66–0.81; P < 0.001) and ORR (relative risk [RR] = 1.89, 95% CI: 1.16–3.05; P = 0.01) of advanced ESCC patients, especially significantly prolonged the OS in the patients with positive programmed death-ligand 1 (PD-L1) status (HR = 0.64, 95% CI: 0.53–0.77; P < 0.001); but did not better PFS (HR = 0.88, 95% CI: 0.68–1.14; P = 0.330) and DCR (RR = 0.89, 95% CI: 0.59–1.37; P = 0.603). Moreover, PD-1 inhibitors were associated with statistically lower incidences of grade 3–5 TRAEs.ConclusionSecond line PD-1 inhibitors significantly improved the OS and ORR of patients with advanced ESCC, especially the OS of those with positive PD-L1 expression, and did not result in significant improvement in PFS and DCR. Compared to chemotherapy, second-line PD-1 inhibitors had superior safety profiles for the treatment of advanced ESCC.

Predicting response to immunotherapy plus chemotherapy in patients with esophageal squamous cell carcinoma using non-invasive Radiomic biomarkers

ObjectivesTo develop and validate a radiomics model for evaluating treatment response to immune-checkpoint inhibitor plus chemotherapy (ICI + CT) in patients with advanced esophageal squamous cell carcinoma (ESCC).MethodsA total of 64 patients with advance ESCC receiving first-line ICI + CT at two centers between January 2019 and June 2020 were enrolled in this study. Both 2D ROIs and 3D ROIs were segmented. ComBat correction was applied to minimize the potential bias on the results due to different scan protocols. A total of 788 features were extracted and radiomics models were built on corrected/uncorrected 2D and 3D features by using 5-fold cross-validation. The performance of the radiomics models was assessed by its discrimination, calibration and clinical usefulness with independent validation.ResultsFive features and support vector machine algorithm were selected to build the 2D uncorrected, 2D corrected, 3D uncorrected and 3D corrected radiomics models. The 2D radiomics models significantly outperformed the 3D radiomics models in both primary and validation cohorts. When ComBat correction was used, the performance of 2D models was better (p = 0.0059) in the training cohort, and significantly better (p < 0.0001) in the validation cohort. The 2D corrected radiomics model yielded the optimal performance and was used to build the nomogram. The calibration curve of the radiomics model demonstrated good agreement between prediction and observation and the decision curve analysis confirmed the clinical utility.ConclusionsThe easy-to-use 2D corrected radiomics model could facilitate noninvasive preselection of ESCC patients who would benefit from ICI + CT.

Outcomes of esophagectomy for patients with esophageal squamous cell carcinoma accompanied by recurrent laryngeal nerve palsy at diagnosis

BackgroundHoarseness is one of the classical symptoms in patients with locally advanced thoracic esophageal squamous cell carcinoma (ESCC), and it results from recurrent laryngeal nerve palsy, which is caused by nodal metastasis along the recurrent laryngeal nerve or by main tumors. We reviewed the short-term and long-term results of esophagectomy for patients with locally advanced ESCC and hoarseness at diagnosis.PatientsPatients who initially presented with hoarseness from recurrent laryngeal nerve palsy between 2009 and 2018 and underwent esophagectomy for thoracic ESCC were eligible for this study. Pharyngolaryngectomy or cervical ESCC were exclusionary.ResultsA total of 15 patients were eligible, and 14 underwent resection of the recurrent laryngeal nerves. The remaining patient had nerve-sparing surgery. Nine patients (60%) had post-operative complications ≥ Clavien–Dindo class II and, pulmonary complications were most common. Two patients (13%) died in the hospital. The 5-year overall survival rate for all patients was 16%. Age (≤ 65 years), cT1/T2 tumor, and remarkably good response to neoadjuvant treatment were likely related to longer survival; however, these relationships were not statistically significant.ConclusionsEsophagectomy for ESCC patients who are diagnosed with recurrent laryngeal nerve paralysis at initial presentation could be a treatment option if the patient is relatively young, has a cT1/T2 tumor, or shows a remarkably good response to neoadjuvant treatment. However, clinicians should be aware of the possibility of postoperative pulmonary complications, which were frequently observed with the procedure.