Background

Head and neck cancer ranks as the sixth most common cancer globally with around 650000 new squamous cell carcinoma cases diagnosed yearly. EGFR is consistently expressed in SCCHN serving as an unfavorable prognostic factor; cetuximab a chimeric monoclonal antibody effectively inhibits EGFR by blocking ligand binding and enhancing immune cell targeting This study evaluates ENZ-124 biosimilarity with cetuximab in Indian patients with recurrent locoregional or metastatic SCCHN.

Methods

This prospective multicenter randomized non-inferiority study enrolled a total of 180 patients with recurrent locoregional or metastatic SCCHN. The patients were stratified based on the type of disease and randomized in a 2:1 ratio to receive either ENZ-124 or innovator cetuximab in combination with platinum-based chemotherapy. The study was conducted at 30 centers across India and PK assessments were performed on 30 patients.

Results

The study enrolled 180 patients, randomized 2:1 for ENZ-124 or innovator cetuximab with platinum-based chemotherapy. The analysis of 141 subjects showed DCR percentages of 94.8% for ENZ-124 and 100% for IC. No significant difference was found (p=0.1773). For ORR, ENZ-124 achieved 55.2%, and IC achieved 60%. Again, no significant difference existed (p=0.5924). All secondary endpoints showed ENZ-124 non-inferior to innovator cetuximab. A total of 1279 treatment-emergent adverse events (TEAEs) were reported. No significant difference existed (p=0.8364) in patients experiencing at least one AE. Out of 1279 TEAEs, 136 events in 77 patients (42.8%) related to the investigational product. 87 AEs in 47 patients (39.2%) were attributed to ENZ-124, while 49 AEs in 30 patients (50%) were related to the reference product safety analysis, including clinical laboratory data, anti-cetuximab antibody assessments, and other parameters, demonstrated comparable safety and immunogenicity.

Conclusions

This study shows ENZ-124 as a biosimilar of innovator cetuximab, the first approved biosimilar cetuximab from India.

Clinical trial identification

CTRI/2019/09/021256 [Registered on: 16/09/2019].

Legal entity responsible for the study

Alkem Lab & Enzene Biosciences.

Funding

Alkem Lab.

Disclosure

N. Dhamne: Non-Financial Interests, Personal, Principal Investigator, I must disclose that I have a conflict of interest in presenting the independent data of Alkems' biosimilar trial, as I was the principal investigator for Alkems' biosimilar trial.: Alkem. M. Jain, R. Nagarkar, S.K.K. Das Majumdar, C.D. Deshmukh, R. Dana, P. Ganesan, K. Chatterjee, S. Chatterjee, K. Prabhash, A. Sharma: Non-Financial Interests, Personal and Institutional, Principal Investigator: Alkem. V.K. Mahobia, R. Kumar, P. S.S., H. Malhotra, S.V. Aagre: Non-Financial Interests, Personal, Coordinating PI: Alkem. M. A, P.K. Chaitnya, V.G. Choudhary, V. Maniar: Financial Interests, Personal, Coordinating PI: Alkem.

Background

Latent EBV is associated with NPC. Nstat is a Class-I selective oral HDAC inhibitor that induces expression of the lytic BGLF4 EBV protein kinase in EBV+ tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-mediated inhibition of viral + cellular DNA synthesis and apoptosis. Nstat + VGCV (prodrug of GCV) had favorable safety with antitumor activity in a study in patients (pts) with R/R EBV+ lymphoma. For this study, phase 1b (P1b) uses 3+3 dose escalation for Nstat + VGCV dose selection in pts with R/M NPC, then expansion at that dose in other EBV+ solid tumors. In phase 2 (P2), up to 60 R/M NPC pts will be randomized 1:1 to receive Nstat and VGCV +/- PEM. Herein we report safety results from P1b in pts with R/M NPC (NCT05166577).

Methods

Pts ≥18y with measurable R/M EBV+ NPC (1-3 prior Tx) and no curative options receive oral Nstat 20-40 mg/d (4d/wk) with VGCV 900-1800 mg/d in P1b. Primary endpoints are dose-limiting toxicities (DLTs) (P1b) and overall response (P2); secondary endpoints include duration of response, disease control rate, progression-free survival, and overall survival.

Results

As of July 2023, 17 pts (median age 49y [19-66y]) were enrolled across 5 dose level cohorts (DLCs): 3, 4, and 3 pts in DLCs 1, 2, and 3 received Nstat 20, 30, and 40 mg QD 4d/wk + VGCV 900 mg QD; 3 and 4 pts in DLCs 4 and 5 received Nstat 10 mg BID and 20 mg QAM/10 mg QPM 4d/wk + VGCV 900 mg BID x 21d then QD. Median 2 prior systemic Tx, and all pts were refractory to last Tx. Related AEs were mostly G1-2 in severity, most commonly nausea and decreased appetite (n=7 each), increased creatinine (n=5), and fatigue (n=4), with no related SAEs or DLTs reported. Of 15 pts evaluable for response, 1 had PR x 6.9+ mos (at DLC3 with stable plasma EBV DNA [pEBVd]), 2 had SD (at DLC4 + DLC5 with pEBVd reduction), and 12 had PD (with rising pEBVd).

Conclusions

The combination of Nstat and VGCV represents a novel approach for the treatment of R/M EBV+ NPC that is tolerated at doses exceeding the RP2D for lymphoma with early signs of antitumor activity at higher DLCs. Further dose escalation with split daily Nstat + VGCV dosing based on recent murine xenograft results is planned.

Clinical trial identification

NCT05166577.

Legal entity responsible for the study

Viract.

Funding

Viract.

Disclosure

A. Elguindy, A. Katkov: Financial Interests, Personal, Other, employee: Viracta. All other authors have declared no conflicts of interest.

Background

ICI have promising activity in phase II trials of patients (pts) with recurrent or metastatic NPC. We investigated whether AI-powered spatial tumor infiltrating lymphocyte analysis (AI-STIL) of NPC TME cell subpopulations correlate with clinical outcome in pts treated with ICI-based therapy.

Methods

A total of 73 NPC pts treated with Nivolumab+Gemcitabine (Niv+Gem; KCSG HN17-11), Niv+Ipilimumab (Niv+Ipi, NCT03097939), Niv alone (Niv, NCT02339558), or Avelumab+Axitinib (Ave+Axi, NCT04562441) who have matched H&E slides before treatment were included in this exploratory post-hoc analysis. Lunit SCOPE IO (Lunit, Korea) was applied to spatially analyze TIL, macrophages (MP), fibroblasts (FB), and endothelial cells (EC) in the intratumoral area and adjacent stroma. Cell populations were analyzed.

Results

In all merged dataset, the median progression-free survival (mPFS) and overall survival (mOS) were 7.3 mo and 30 mo, respectively. ORR/mPFS by each regimen were 38.7%/13.8 m in Niv+Gem (n=31), 36.4%/5.4 m in Niv+Ipi (n=22), 36.4%/3.7 m in Niv (n=11), and 0%/5.4 m in Ave+Axi (n=9), respectively. In TIL subgroup analysis, mPFS was significantly higher in high intratumoral TIL (iTIL) than low iTIL group (hazard ratio, HR 0.44, p=0.0081), but no difference in stromal TIL (sTIL, HR 1.14, p=0.6681). mPFS was longer in the high intratumoral MP subgroup (HR 0.5, p=0.0209), but not the stromal MP subgroup (HR 0.9, p=0.7278). In FB and EC analyses, mOS was lower in high stromal FB (sFB) than low sFB (HR 2.44, p=0.0148), but there were no significant differences in survival outcomes across the other cell subgroups.

Conclusions

Interactive TME analysis powered by AI suggested that intratumoral TIL or macrophage, not stromal residues, are clinically significant in the NPC patients treated with ICI.

Drs. Bhumsuk Keam and Darren Wan-Teck Lim equally contributed to the study.

Clinical trial identification

KCT0003189, NCT03097939, NCT02339558, NCT04562441.

Legal entity responsible for the study

Lunit.

Funding

Lunit.

Disclosure

B. Keam: Financial Interests, Personal, Invited Speaker: Merck, Lily; Financial Interests, Personal, Advisory Board: Handok, TrialInformatics, ImmunOncia, NeoImmunetech, Beigen; Financial Interests, Personal, Coordinating PI: MSD Oncology, AstraZeneca, Ono Pharmaceutical. D.W. Lim: Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim; Financial Interests, Institutional, Advisory Board: MSD, Roche, BeiGene; Financial Interests, Institutional, Trial Chair, Grant funding for investigator-sponsored study: Bristol Myers Squibb; Financial Interests, Institutional, Steering Committee Member: Novartis. C. Ock: Financial Interests, Personal and Institutional, Officer: Lunit. T. Lee, C. Oum: Financial Interests, Personal and Institutional, Officer: Lunit. B. Goh: Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board: Bayer Healthcare; Financial Interests, Personal, Other, Consultancy: Adagene pharmaceutical; Financial Interests, Institutional, Research Grant, Support for investigator initiated trial: MSD; Financial Interests, Institutional, Other, Pharmaceutical support for clinical trial: BMS; Financial Interests, Institutional, Other, Pharmaceutical support for investigator initiated clinical trial: Taiho pharmaceuticals; Financial Interests, Institutional, Coordinating PI: Adagene, Bayer; Financial Interests, Institutional, Local PI: Pfizer; Financial Interests, Institutional, Local PI, Conducting clinical trial: alx; Financial Interests, Institutional, Local PI, Pharmaceutical phase 1 trial: Novartis; Non-Financial Interests, Institutional, Other, Lead clinical trial platform of the Singapore Translational Cancer Consortium: Consortium for Clinical Research and Innovation Singapore; Non-Financial Interests, Personal, Member: ASCO. A.T.C. Chan: Financial Interests, Personal, Advisory Board: MSD, Tessa Therapeutics Ltd; Financial Interests, Personal, Other, Consultancy: MSD; Financial Interests, Personal, Other, Biomarker testing for MK-3475 KN122 program: MSD; Financial Interests, Personal, Writing Engagement: Springer; Financial Interests, Personal, Other, Travel and accommodation expenses to attend conference: Roche; Financial Interests, Institutional, Research Grant, Neoadjuvant Pembrolizumab-Gemcitabine-Cisplatin Followed by Concurrent Pembrolizumab-Chemoradiation and Maintenance Pembrolizumab for Stage IVA Nasopharyngeal Cancer: Merck Sharp & Dohme (Asia) Ltd; Financial Interests, Institutional, Research Grant, Biomarker study for NEO-SPACE MISP-56746: MSD International GmbH; Financial Interests, Institutional, Research Grant, AXEL - Axitinib-Avelumab Combination in Recurrent or Metastatic Nasopharyngeal Cancer - A Multicenter Phase 2 Trial: Pfizer Corporation Hong Kong Limited; Financial Interests, Institutional, Research Grant, Clinical Development of a Urine Test for Screening Urinary Tract Cancers: Angene Biotechnology Limited; Financial Interests, Institutional, Research Grant, NRG Oncology #HN007 An Open-label, Phase II Study of Platinum-Gemcitabine With or Without Nivolumab in the First Line of Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma: NRG OncologyFoundation, Inc.; Non-Financial Interests, Personal, Advisory Role: Immunomic Therapeutics, Inc, Angene Biotechnology Limited, Owlstone Medical Limited. B.B.Y. Ma: Financial Interests, Personal, Invited Speaker, Advisory Board/Consultancy: Novartis, BMS, MSD; Financial Interests, Personal, Advisory Board, Consultancy: Y-biologics, Boehringer Ingelheim, Merck Serono; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board, Ad board and consultancy: Viracta Therapeutics; Financial Interests, Personal, Other, Consultancy: Alentis; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Merck Serono; Financial Interests, Institutional, Research Grant, Research Grant Preclinical: Novartis; Non-Financial Interests, Personal, Principal Investigator, NRG oncology study PI: NRG oncology. All other authors have declared no conflicts of interest.

Background

Clinical trial data have shown that programmed cell death 1 (PD-1) inhibitors can be effective in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). A subset of patients experiences immune-related adverse events (irAEs), several studies have reported the incidence of irAEs as a predictor of the efficacy of αPD-1 antibodies in patients with cancer. However, clinical predictive factors for treatment responses or irAEs risk remain unclear. Our objective was to develop a nomogram that utilizes pre-treatment peripheral blood signatures to predict the risk of irAEs in patients with RM-NPC.

Methods

Clinical data including age, sex, clinical type, metastatic site, treatment course, blood laboratory tests, irAEs and treatment outcome were collected. Data were randomly divided into a training and a validation set (ratio: 7:3). The predictive value of the irAEs nomogram was evaluated using time-dependent area under the curve, decision curve analysis, and calibration curve. According to irAEs nomogram, patients with high risk of irAEs were compared with those with low risk of irAEs in terms of overall survival (OS) and progression-free survival (PFS).

Results

In total, 336 patients were enrolled with 236 and 100 in the training and validation cohorts, respectively. Multivariate logistic regression analysis showed that increased baseline neutrophil lymphocyte ratio (NLR) was significantly associated with high risk of irAEs (odds ratio [OR]: 2.7, P = 0.002, cutoff value = 4.337). Four peripheral blood indicators (monocyte, NLR, free T4, and plasma Epstein-Barr virus (EBV) DNA titer) and ICI duration, were included to construct the irAEs signature. We constructed and validated a irAEs nomogram in combination with five above clinical characteristics, which showed favourable performance. Patients in the high-risk irAEs group had significantly better overall and progression-free survival than patients in the low-risk group in both cohorts (P < 0.05).

Conclusions

This study of irAEs in patients with RM-NPC who are receiving toripalimab suggests that high risk of irAEs was associated with improved survival.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.