Advanced HNSCC Research Articles

Long term results of a randomized phase III study of nimotuzumab in combination with concurrent radiotherapy and cisplatin versus radiotherapy and cisplatin alone, in locally advanced squamous cell carcinoma of the head and neck.

LBA6092 Background: The addition of nimotuzumab to weekly cisplatin as a radiosensitizer had improved progression-free survival (PFS) in a phase 3 study in locally advanced head and neck squamous cell carcinoma (LA HNSCC). However, whether it leads to an improvement in long-term OS is unknown. Hence this analysis was performed to evaluate the efficacy (in terms of OS) and late-term adverse events of the addition of nimotuzumab to concurrent chemoradiation in LA HNSCC. Methods: This was an open-label, investigator-initiated, phase 3 randomized trial conducted from 2012 - 2018. 536 adult patients with LA HNSCC, fit for radical chemoradiation were randomly assigned. Primary sites in the nasopharynx, salivary gland, nasal cavity, and paranasal sinus were excluded. Randomized 1:1 to either radical radiotherapy (66-70 Gy) with concurrent weekly cisplatin (30 mg/m2) (CRT) or the same schedule of chemoradiation with weekly nimotuzumab (200 mg) (NCRT). The primary endpoint was a 10-year OS; the key secondary endpoint was late adverse events. Intent to treat analysis was performed. OS was defined as the time from randomization till death. Kaplan Meier method will be used for the estimation of OS. Landmark analysis was performed to compare 10 OS between the 2 arms. COX proportional hazard model will be used for the calculation of hazard ratio (HR). The adverse events between the 2 arms were compared using a Fisher's test. A p-value of 0.05 will be considered as significant. Results: The median follow-up was 8.86 years (95% CI 8.59-9.16). The primary site of the primary was the oropharynx (269,50.2%) and only 24 cases were HPV positive. The 10-year OS was 22.5% (95% CI 16.7-28.8) versus 33.5% (95% CI 27.6-39.4) in the CRT and NCRT arm respectively (Hazard ratio=0.811; 95%CI 0.664-0.995, P=0.044). The median OS was 2.78 years (95% CI 2.31-3.69) versus 3.69 years (95% CI 2.90-4.49) in the CRT and NCRT arm respectively (P value by log-rank test=0.04). The median OS in HPV negative oropharynx was 1.8 years (95% CI 1.51-2.09) versus 2.48 years (95% CI 1.79-3.16) in the CRT and NCRT arm respectively (P value by log-rank test=0.02; HR 0.724 95%CI 0.546-0.959). Long-term adverse events were captured in 380 patients. There was no statistically significant difference in late-term adverse events between the 2 arms and will be presented at the conference. Conclusions: The addition of nimotuzumab to weekly cisplatin leads to improvement in long-term overall survival in locally advanced HNSCC without any additional increase in late-term adverse events. These results are largely applicable in HPV-negative patients. Clinical trial information: CTRI/2014/09/004980 .

Analysis of PD-L1 expression in locally advanced head and neck squamous cell carcinoma and its correlation with the efficacy of neoadjuvant immunotherapy + chemotherapy: A retrospective real-world study.

6074 Background: The incidence rate of HNSCC in Hunan China are notably higher than in other regions, likely due to the high prevalence of betel nut chewing. Therefore, we conducted a study to examine the PD-L1 expression in newly diagnosed locally advanced (stage III-IVB) HNSCC patients. Methods: 1. We conducted a retrospective analysis of the PD-L1 expression (represented as CPS) in pre-treatment biopsy tissues from locally advanced HNSCC. 2. 57 patients received neoadjuvant treatment consisting of nab-paclitaxel+ cisplatin+ pembrolizumab. The efficacy of the treatment was evaluated using pathology assessments. Results: 1. A total of 373 patients were included. The top five primary sites of the tumors were the tongue(32.17%), Buccal oris (20.91%), oropharynx (10.19%), hypopharynx(9.92%), and gingiva(7.77%). The proportion of patients with PD-L1 CPS≥20 (55.23%) was significantly higher than the 43.20% reported in the KEYNOTE-048 study. Furthermore, the subgroup was even higher in the buccal oris (70.51%) and gingiva (72.41%). 2. A total of 57 patients were tested for PD-L1 CPS and received neoadjuvant treatment.After surgery, 22/57 (38.60%) achieved pathological complete response (pCR) or major pathological response (MPR), 29/57 (50.88%) achieved partial pathological response (pPR), resulting in an overall response rate (ORR) of 89.47%. In the PD-L1 CPS ≥20 group, the ORR was as high as 91.89% (34/37). 3. Among the 57 patients, 36 patients had lymph node metastasis. After treatment, 15/36 patients (41.67%) achieved pCR/MPR in lymph nodes, 7/36 patients (19.44%) achieved pPR, resulting in an ORR was 61.11% (22/36). Conclusions: 1. The oral cavity is the most common primary in HNSCC in Hunan,China. In the locally advanced , the proportion of PD-L1 CPS ≥20 is higher than reported in other studies. 2. Regardless of PD-L1 expression, neoadjuvant treatment with nab-paclitaxel+ cisplatin+ pembrolizumab has shown a high rate of local disease control in newly diagnosed HNSCC patients. Additionally, the use of neoadjuvant therapy has improved the delineation of surgical safety margins, leading to 100% R0 resections in all 57 patients. 3. The response of the primary lesion in patients treated with neoadjuvant therapy is better than that of the lymph node. Patients with a well-responding primary lesion but multiple lymph node metastases should be closely monitored for the possibility of short-term systemic metastasis. [Table: see text]

Can TTMV clearance predict recurrence in HPV HNSCC?

6066 Background: Patients with locally advanced (LA) HPV HNSCC are treated with various types of induction chemotherapy (IC) followed by standard (sd) or reduced (rd) chemoradiation (CRT). Tumor tissue-modified viral HPV DNA (TTMV) pairs with PET-CT in predicting an early detection of treatment failure in HPV-related HNSCC. Mid-treatment TTMV assessment in HPV-related HNSCC can help identify patients who are eligible to receive a lower dose of IC and/or CRT or those who may require close follow-up. Methods: Patients with LA HPV+ HNSCC with high-risk features (radiographic ECE, T4 primary, >N2c) and <20 pack-year (py) smoking history were treated with IC followed by rdCRT (56 Gy); sdCRT (70 Gy) was used in non-responders. 16/23 received IC with TPF, 1/23 TP, and 6/23 TP-PD1, and all patients received carboplatin weekly with their CRT. Regeneron trial patients who received TP-Cemiplimab (PD1) IC followed by sdCRT are also continuing adjuvant Cemiplimab alone for 6 months (NCT05376553). PET-CT-confirmed residual, recurrent, or metastatic diseases were defined as treatment failures; TTMV + patients only if PET-CT confirmed. Results: 23 subjects treated with IC followed by CRT between 2/4/21-1/26/24, who had pre- and post-treatment TTMV were included in our analysis. The median pre-IC TTMV was 8082 (27 – 90770). The median follow-up time from treatment start was 21 months. 9/23 patients had full clearance TTMV after 1 cycle of IC defined as rapid responders (RR). 11/23 patients still had positive TTMV after 1st cycle of IC were defined as slow responders (SR). 1 patient had no TTMV done after 1 cycle of IC but was elevated after 2nd IC; he was defined as SR. 2 patients had a positive pre-IC TTMV, but no TTMV was drawn during IC to see if RR. 1 of 2 patients was TTMV negative prior to CRT, and 2/2 had a 1st post IC negative TTMV done 1 week after CRT started. They were both included in the analysis but defined as unknown response status. TTMV testing was done for all 23 subjects after CRT; all were negative. All subjects have TTMV testing done during their surveillance visits. Among 9/23 RR, none developed a failure. Among 12/23 SR, 3 patients developed a failure: 1/3 was TTMV+ but PET-, being followed with TTMV and PET-CT; and 2/3 were confirmed failures, TTMV+ and PET+; 1 locoregional, 1 metastatic. 2 patients were not known to be a SR or RR and had no recurrence. Among 23 patients, NPV of TTMV to detect failure was 100%, but PPV was 96% (1/23). Conclusions: IC followed in rapid clearance of TTMV in 39% of patients, and all remained disease-free. 3/11 (27%) with persistently elevated TTMV after cycle 1 relapsed as of this time point. This small study was not large enough to be practice-changing. However, this is significantly hypothesis-generating and should be tested in a larger trial to help identify patients for de-escalation (RR) or closer surveillance (SR).

Identification of MUC1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas.

This work reports a previously unrecognized role for MUC1-C in driving STAT1-mediated chronic inflammation with the progression of HNSCC and identifies MUC1-C as a druggable target for advanced HNSCC treatment.

Abstract LB413: A newly developed patient-derived culture panel identifies precision therapies and pan-effective agents for head and neck squamous cell carcinoma

Abstract Head and neck squamous carcinoma (HNSCC) is an aggressive cancer with few treatment options. Its well-known genetic heterogeneity presents a major challenge for precision medicine development. We report a newly developed panel of 20 HNSCC patient-derived cultures (HNSCC-PDCs) from advanced or recurrent HNSCC, with comprehensive somatic and germline characterization for precision medicine (PM) discovery. The PDCs retain genetic heterogeneity of the original patient tumors, and xenografts of which also phenocopied HNSCC patient tumors. Importantly, somatic and germline events that were never or seldom captured by long-established HNSCC cell lines are represented by the PDC panel, including HRAS-CASP8 co-mutations, EGFR-AS1 germline mutation, exonic germline PIK3CA mutation, sonic hedgehog (SHH) pathway and FGFR pathway mutations. We hypothesize that drug screening with this newly developed HNSCC-PDC panel that recapitulates HNSCC patient genetics may identify new gene-drug sensitivity relationships for precision medicine development in advanced HNSCC. Here, data from our pilot drug screen of 38 selected FDA approved/Phase I-II clinical trial agents first reveal: 1) HNSCC-PDC with the hotspot HRASp.G13R, together with CASP8p.L183S, is sensitive to tipifarnib vs. tipifarnib-resistance in a long-established HNSCC cell line, SNU899 with the same HRAS mutation. Subsequent high-content imaging cell death assay further demonstrates a dose-dependent tipifarnib-induced cell death in HRASp.G13R-mutated PDC, but not in SNU-899; 2) TP53-EP300 co-mutated HNSCC-PDCs are most sensitive to cisplatin with ~340 nM sensitivity (mean IC50) among all PDCs tested, which is 22 times more sensitive than that reported in Genomics of Drug Sensitivity in Cancer (GDSC) HNSCC cell lines; 3) EGFR-AS1 (c.2361G>A)-germline mutated PDCs, and MAPK1-mutated PDCs, are both hypersensitive to EGFR inhibitors (EGFRi: erlotinib and mobocertinib), which independently credentialed gene-drug sensitivity relationships reported in exceptional responders in HNSCC clinical trials. Further signaling investigation in PDC models demonstrates phospho-MAPK activation as a reliable surrogate biomarker for EGFRi sensitivity in HNSCC; 4) FRS3-mutated PDCs are sensitive to FDA-approved FGFR pathway inhibitors; and 5) TP53-wildtype HNSCC-PDCs are 150-fold more sensitive to novel p53-MDM2 interaction inhibitors vs. TP53-mutated PDCs, a phenomenon that cannot be captured in long-established TP53-wildtype HNSCC cell lines. Lastly, 4 pan-PDC effective agents are identified with nM sensitivities and high drug activities (i.e. drug-induced growth inhibition) in more than half of our PDC models. These include 3 FDA-approved agents, TAK-981, Selinexor (a novel XPO1 inhibitor), and trametinib, as well as the preclinical agent JQ1. In conclusion, our pilot HNSCC-PDC drug screen identifies new gene-drug sensitivity relationships for HNSCC PM development and new pan-effective agents for advanced HNSCC. Citation Format: Yuen Keng Ng, Hui Li, Wenying Piao, Cecilia Pik Yuk Lau, Peony Hiu Yan Poon, Tin Yu Samuel Law, Jason Ying Kuen Chan, Yuxiong Su, Chin Wang Lau, Zigui Chen, Laura Ren Huey Ip, Thomas Chung-Kit Yeung, Sai Fung Yeung, Jason Hoi-Lam Ngan, Zoey Wing Yee Liu, Noah R. Wiese, Vivie Vo, Zoey Patel, Jeremia Onyekachi, Laili Afzali, Jasmine Zohal Afzali, Jack Nimitz Smith, Vivian Wai Yan Lui. A newly developed patient-derived culture panel identifies precision therapies and pan-effective agents for head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB413.

Abstract CT112: An off-the-shelf multivalent vaccine containing cancer’s dark matter, DPV-001, combined with PD-1 +/- GITR in head & neck cancer: safety, efficacy, and immunodynamics from the phase 1 GITRVax trial

Abstract Background: Immune responses to shared cancer antigens have correlated with durable clinical responses. DPV-001 is a novel microvesicle vaccine that contains >300 proteins for genes commonly overexpressed by cancer and is enriched for short-lived proteins (SLiPs), and defective ribosomal products (DRiPs), including non-canonical peptides, representing potential shared non-mutated alternative cancer neoantigens (dark matter). Preclinical studies identified increased therapeutic efficacy when this vaccine strategy was combined with anti-PD-1 and anti-GITR, leading to this clinical trial for patients with advanced or metastatic HNSCC. Methods: Following safety run-in, eligible pts were randomly assigned 1:1 to receive DPV-001 +/- GITR agonist mAb (INCAGN-1949; q2wks). All received sequenced PD-1 mAb (retifanlimab; q4wks) starting D15. Safety was evaluated as the primary endpoint and efficacy was evaluated as a secondary endpoint. Tumor biopsies were taken pre-treatment, Wk 2 and 8, and assessed by CITE-seq, scRNA-seq, BCR-seq, and TCR-seq. Multiplex immunofluoresence was performed on biopsies. Blood samples were taken pre-treatment and at multiple timepoints and analyzed by flow cytometry and seromics. Results: 18 pts received backbone therapy of DPV-001 + sequenced PD-1; of these, 9 pts also received GITR starting D1 (Arm 2). G3 irAE's included: hypothyroidism & mucositis (Arm 1, same pt); pneumonitis and adrenal insufficiency (Arm 2, separate pts). No G4 toxicity was observed. Combining both arms, the response rate (RR) for PD-1 naïve pts was 55% (5/9), and 33% (3/9) for PD-1 experienced pts. Two CR's have been observed in Arm 2. Durability of response (DOR) and progression-free survival (PFS) will be reported at the meeting. DPV-001 induced increased Ki67+ CD4 EM (p<0.042) by D15, prior to first dose of PD-1. Addition of GITR at D1 further increased Ki67+ CD4 (p=0.008) & CD8 EM cells (P=0.0006) by D15. Activated or proliferating CD4 and CD8 EM were significantly increased in both arms by D30 (p<0.025). Across above specified analyses, pts receiving GITR had the greatest increase. Evaluable pts had significantly (all p<0.032) increased numbers of TIL expressing IFN-γ and/or GZMB, LAG-3, and TIM3 in on-treatment biopsies. TCR, BCR, and seromic analyses, as well as studies to identify targets of anti-cancer immunity, are ongoing. Conclusions: This 18 pt trial of DPV-001 and sequenced PD-1 +/- GITR shows a promising RR and evidence of increased activation and expansion of effector T cells in PBL and tumor. Upregulation of LAG-3 and TIM3 by T cells that infiltrate the tumor and have increased in number, provide a rationale for including inhibitors for both in this treatment strategy. Current efforts include evaluating whether immune responses target shared non-canonical alternative neoantigens, or Dark Matter, contained in DPV-001, and whether synchronized antibody and cellular response is evidenced. Acknowledgements: Incyte, Providence Portland Medical Foundation, Steve and Cindy Harder, Trial Registry: NCT04470024, Ethics Approval: PSJH IRB# 2020000480 Citation Format: Rom S. Leidner, Christopher Paustian, Shawn M. Jensen, Tarsem Moudgil, Yoshinobu Koguchi, Noah Simons, Venkatesh Rajamanickam, Ryan Meng, Marcus A. Couey, Quyen Vu, Matthew H. Taylor, Anne Long, Abigail J. Staeck, Lakhvir Kaur, Tijana Jovanovic, Brady Bernard, Tanisha Christie, Noriko Iwamoto, Yuriko Minegishi, Koji Ueda, William Redmond, Lessli M. Rushforth, Takashi Shimada, Patrick Rethwisch, Ashish Patel, Richard B. Bell, Carlo B. Bifulco, Traci L. Hilton, Hong-Ming Hu, Brian Piening, Walter J. Urba, Bernard A. Fox. An off-the-shelf multivalent vaccine containing cancer’s dark matter, DPV-001, combined with PD-1 +/- GITR in head & neck cancer: safety, efficacy, and immunodynamics from the phase 1 GITRVax trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT112.

Abstract 5188: Defining PD-1/PD-L1 receptor-ligand interactions in the head and neck cancer tumor microenvironment identifies unique ‘immune cell rivers’ of cellular interactions

Abstract Head and neck squamous cell carcinoma (HNSCC) is the 7th most common cancer globally with a poor 5-year survival rate of ~50%. With the emerging successes with immune checkpoint blockade (ICB) in the metastatic and recurrent setting, there is a need for predictive biomarkers to identify patients likely to achieve clinical benefit. Whilst PD-L1 expression on tumour cells and PD-1 on immune cells have been investigated, these remain inconclusive biomarkers. To better understand and map the PD-L1/PD-1 receptor-ligand interactions, we evaluated a novel in situ proximity ligation assay (is PLA) across whole tissue sections of pre-treatment HNSCC patients to received ICB therapy. Pre-treatment FFPE whole tissue samples were collected from n=25 advanced stage HNSCC patients across two major Queensland Hospitals (Royal Brisbane and Women’s Hospital and the Princess Alexandra Hospital). Tissues were stained with multiplex immunofluorescence and the Navinci Diagnostics fluorescent is PLA assay for PD-1/PD-L1. Tissues were incubated with the PD1/PD-L1 antibodies and subsequent incubation with oligonucleotide-tagged secondary probes enabled PLA, which highlights PD1 and PD-L1 interactions. Following the application of secondary probes, the sections underwent a ligation step, then a post-blocking, and an amplification process to enhance the detection of protein interactions. Next, the sections were treated with a detection solution to visualize the amplification product. The PLA assay findings were measured against clinical endpoints (PFS/OS criteria). In n=5/25 HNSCC tissues, positive PD-1/PD-L1 interactions were measured across the tumour microenvironment (TME), specifically in the immune rivers on the immediate tumour periphery. These cells showed highly specific binding of the PLA product. These areas positive by the PLA assay were in stark contrast to the tumour bulk/nests which were absent in PD-1/PD-L1 interactions. Notably, the PLA PD-1/PD-L1 do not correlate with tumour PD-L1 expression or tumour proportion scores (TPS). Rather, our study highlighted the difference in spatially mapping PD-1/PD-L1 interactions which may better recapitulate the tumour-immune recognition and activity in the TME. Taken together, these data provide a novel approach for determining clinically relevant receptor/ligand interactions in the HNSCC TME. Citation Format: Habib Sadeghirad, Vahid Yaghoubi Naei, James Monkman, Subham Basu, Agata Wicher, Rahul Ladwa, Brett GM Hughes, Arutha Kulasinghe. Defining PD-1/PD-L1 receptor-ligand interactions in the head and neck cancer tumor microenvironment identifies unique ‘immune cell rivers’ of cellular interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5188.

Abstract 1111: Poor radiation sensitivity and potential radiosensitizers for betel-nuts related head and neck squamous cell carcinoma in Taiwan

Abstract Background: Betel nut chewing might contribute to strong invasion & treatment refractoriness in HNSCC from Taiwan. Betel-nuts exposed HNSCC cell line, TW2.6, had high PDL1, defective p53 mutation, p16 loss, & BCL2 overexpression. In our studies, PI3K/AKT/mTOR inhibitors, anti-angiogenesis therapies, CDK4/6 inhibitors, DDR interventions, epigenetic modifications, and immunotherapy-containing regimens will be future combination options. The genomic signature of TW2.6 has been figured out in our study(AACR2020 & 2023), too, mainly with PIK3CA H1047R mutation, high TMB(8.42 muts/Mb)/MSS, VEGF-A amplification, p53/MYC/HRAS/DDR2/PDGFRbeta/EPHB1/ATM mutations, FAT1 loss, amplification of TERT/FGF10/CCND3/SOX9/IL-7R/SDHA/RICTOR/FLCN, CDK12/PTPRD loss of function, CDK8 mutation, & deletions of STK11/ARID1B/MITF/TNFAIP3 and molecularly-guided novel interventions will be designed. Purpose & Methods: Polo-like kinase 1 inhibitor(volasertib), gluconate(blocking citrate transport & glucose metabolism), IAP inhibitor(Debio1143), glutaminase 1 inhibitor(CB839) were tested on TW2.6 to evaluate synergistic effects with radiation. Results: TW2.6 was resistant to volasertib, gluconate, or radiation alone; but sensitive to Debio1143 and CB839. Volasertib significantly enhanced radiation. The flow cytometry revealed volasertib and radiation resulted in a significant G2/M arrest. Western blotting showed volasertib and radiation increased p-histone3, p-CDK1, & cyclin B levels and induced apoptosis. Gluconate, CB839, or Debio1143 each had significant synergistic effects with radiation. The radiosensitization efficacy would be volasertib>gluconate>CB839>Debio1143. Conclusions: In Taiwan, patients with R/M HNSCC progressing within 3 months after CCRT could be rescued by early ICIs. Recently, sequential CCRT followed by ICI or Debio-1143 with CCRT showed potential survival benefits. In our studies, novel agents such as PLK inhibitor, gluconate, and CB839 had even better radiosensitization compared with Debio1143. Sequential CCRT with novel agents followed by ICI will be the future trend, esp. in biology-aggressive betel-nuts related locally advanced HNSCC in Taiwan. Citation Format: Jo-Pai Chen, Jui-Ying Chang, Ruey-Long Hong. Poor radiation sensitivity and potential radiosensitizers for betel-nuts related head and neck squamous cell carcinoma in Taiwan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1111.

Novel Radioenhancer NBTXR3 Activated by Radiotherapy in Cisplatin-Ineligible Locally Advanced HNSCC Patients: Final and Exploratory Results of a Phase I Trial

Novel Radioenhancer NBTXR3 Activated by Radiotherapy in Cisplatin-Ineligible Locally Advanced HNSCC Patients: Final and Exploratory Results of a Phase I Trial

175 Induction radiochemotherapy with low dose fractionation XRT in patients with advanced HNSCC.

175 Induction radiochemotherapy with low dose fractionation XRT in patients with advanced HNSCC.

The Heterogeneous Impact of Prediagnostic Folate Intake for Fluorouracil-Containing Induction Chemotherapy for Head and Neck Cancer.

Fluorouracil (FU) exerts its antitumor activity by inhibiting folate-mediated one-carbon metabolism. Evidence that folate may play a role in the carcinogenic process via folate-mediated one-carbon metabolism has given rise to the hypothesis that pre-diagnostic folate intake may induce heterogeneous chemosensitivity to FU-containing induction chemotherapy (IC) in head and neck cancer. To assess this hypothesis, we conducted a cohort study to investigate whether the association between prediagnostic dietary folate intake and cancer survival differed between treatment regimens with and without FU-containing IC in 504 cases of locally advanced (stage III/IV) HNSCC, using an epidemiologic database combined with clinical data. In total, 240 patients were treated with FU-containing IC followed by definitive treatment, and 264 patients were treated with definitive treatment alone. Definitive treatment is defined as (1) the surgical excision of a tumor with clear margins, with or without neck lymph node dissection; or (2) radiotherapy with or without chemotherapy. In the overall cohort of the FU-containing IC group, a higher folate intake was significantly associated with better overall survival (adjusted hazard ratios (HRs) for the highest compared to the lowest folate tertiles (HRT3-T1) = 0.42, 95%CI, 0.25-0.76, Ptrend = 0.003). Conversely, no apparent association between prediagnostic folate intake and survival was observed with definitive treatment alone (HRT3-T1: 0.83, 95%CI, 0.49-1.42, Ptrend = 0.491)). A consideration of the cumulative dose of FU-containing IC showed that the survival impact of prediagnostic folate intake differed statistically significantly by treatment regimen (Pinteraction = 0.012). In conclusion, an association between prediagnostic folate intake and HNSCC survival significantly differed by FU-containing IC. This finding indicates that in the carcinogenic process, folate status causes HNSCC to be heterogenous in terms of one-carbon metabolism.

Management of Synchronous Locally Advanced Carcinoma Oropharynx and Early Stage Carcinoma Esophagus in a Tertiary Cancer Center: A Case Report

Risk factors for squamous cell carcinomas (SCCs) of the head and neck (HN) and oesophagus are similar. As such, synchronous primary tumors in these areas are not entirely uncommon. Definitive chemoradiation (CRT) is standard care for locally advanced HNSCC and is a preferred option for inoperable oesophageal SCC. Simultaneous treatment of both primaries with CRT can present technical challenges. We report a case of synchronous oropharyngeal and oesophageal SCC primary tumors treated simultaneously with definitive chemoradiotherapy.

Apatinib potentiates the therapeutic effect of anti-PD-1 in locally advanced head and neck cancers.

Antiangiogenic inhibitors have been shown to synergize with immune checkpoint blockade, but the underlying mechanisms of the synergistic response are not fully understood. We investigate the impact of VEGFR2 inhibition on tumor-infiltrating immune cells invivo and the activity of the combination of apatinib and anti-PD-1 in synergistic mouse model of HNSCC. A patient with squamous cell carcinoma of the left tongue with cervical lymph node were received with combined induction treatment of camrelizumab and apatinib to validate the efficacy of neoadjuvant immunotherapy before surgery. We found that apatinib increased the infiltration of CD8+T cells and decreased the population of Tregs in a preclinical syngeneic mouse model. The proportions of CD8+PD1+T cells were significantly increased in apatinib-treated tumors. The combined treatment of apatinib and anti-PD-1 demonstrated better therapeutic benefit than each treatment alone. The patient with squamous cell carcinoma of the left tongue with cervical lymph node achieved major pathologic response (MPR) after two cycles of combined induction treatment. Our study demonstrated that apatinib therapy synergized with an anti-PD-1 antibody in preclinical cancer models and in patient with advanced HNSCC. These results provide a new rationale for advancing this neoadjuvant immunotherapy in large scale of clinical trials of HNSCC.

887P Antitumor activity of the radioenhancer NBTXR3 on injected lesions to estimate overall survival: Exploratory analyses from a phase I in cisplatin-ineligible locally advanced HNSCC patients

887P Antitumor activity of the radioenhancer NBTXR3 on injected lesions to estimate overall survival: Exploratory analyses from a phase I in cisplatin-ineligible locally advanced HNSCC patients

Novel Radioenhancer NBTXR3 Activated by Radiotherapy in Cisplatin-Ineligible Locally Advanced HNSCC Patients: Final Results of a Phase I Trial

New approaches are needed for frail or elderly patients with locally advanced head and neck squamous cell carcinoma (LA HNSCC) who are unfit to receive cisplatin with concurrent radiotherapy (RT). NBTXR3 is a first-in-class radioenhancer, composed of functionalized hafnium oxide nanoparticles, administered by a single intratumoral (IT) injection and activated by RT. NBTXR3 locally amplifies the anti-tumoral response of RT without adding toxicity to surrounding healthy tissue as shown in a randomized trial in soft tissue sarcoma. This two-part study: dose-escalation followed by the dose-expansion part reported here, evaluated the safety and preliminary efficacy for NBTXR3 activated by RT in elderly or frail patients ineligible to cisplatin. This trial enrolled patients who had previously untreated AJCC 8th Stage III-IVA or T3, T4 SCC of the oral cavity or oropharynx (OPC) ineligible to cisplatin. Eligible patients received a single IT injection of NBTXR3 at the recommended dose (22% of the baseline tumor volume) followed by RT (IMRT 70 Gy in 35 fractions). The primary objectives of the dose expansion part were to test the recommended dose, to confirm its safety, and obtain preliminary evidence of efficacy. The secondary objectives included the evaluation of progression-free survival (PFS) and overall survival (OS). Fifty-sixpatients in the dose expansion part were treated from April 2019-January 2022; 44 patients were evaluable for objective tumor response. In the all-treated population, median age was 71.9 years. 64.3% had age-adjusted Charlson Comorbidity Index scores ≥4, 55.4% had OPC (45.2% HPV+) and 80% had T3-4. Median injected volume of NBTXR3 was 13.6 [0.5-57.1] mL. Grade ≥ 3 adverse events reported as potentially related to NBTXR3 or to injection procedure were 1.2% and 0.4% of all AEs reported, respectively. In the evaluable population, the best objective response rate of the NBTXR3 injected lesion was 81.8% with a complete response rate of 63.6%. The best overall response rate (injected and non-injected lesions) was 79.5%. Final analyses on PFS and OS with long-term follow-up will be presented. NBTXR3 IT injection followed by activation with RT was confirmed to be feasible and well tolerated in elderly or frail patients with LA HNSSC and significant comorbidities. The high rate of best overall response suggests that NBTXR3+RT is effective in this elderly population ineligible to cisplatin with a high unmet medical need. These results support our ongoing phase III study comparing NBTXR3/RT ± cetuximab vs. RT ± cetuximab in platinum-based chemotherapy ineligible elderly patients with LA-HNSCC: NANORAY 312 (NCIT04892173).

Automatic Segmentation of Head and Neck Cancer from PET-MRI Data Using Deep Learning

PurposeHead and neck squamous cell carcinoma (HNSCC) is one of the most common cancer types globally. Due to the complex anatomy of the region, diagnosis and treatment is challenging. Early diagnosis and treatment are important, because advanced and recurrent HNSCC have a poor prognosis. Robust and precise tools are needed to help diagnose HNSCC reliably in its early stages. The aim of this study was to assess the applicability of a convolutional neural network in detecting and auto-delineating HNSCC from PET-MRI data.Methods2D U-net models were trained and tested on PET, MRI, PET-MRI and augmented PET-MRI data from 44 patients diagnosed with HNSCC. The scans were taken 12 weeks after chemoradiation therapy with a curative intention. A proportion of the patients had follow-up scans which were included in this study as well, giving a total of 62 PET-MRI scans. The scans yielded a total of 178 PET-MRI slices with cancer. A corresponding number of negative slices were chosen randomly yielding a total of 356 slices. The data was divided into training, validation and test sets (n = 247, n = 43 and n = 66 respectively). Dice score was used to evaluate the segmentation accuracy. In addition, the classification capabilities of the models were assessed.ResultsWhen true positive segmentations were considered, the mean Dice scores for the test set were 0.79, 0.84 and 0.87 for PET, PET-MRI and augmented PET-MRI, respectively. Classification accuracies were 0.62, 0.71 and 0.65 for PET, PET-MRI and augmented PET-MRI, respectively. The MRI based model did not yield segmentation results. A statistically significant difference was found between the PET-MRI and PET models (p = 0.008).ConclusionAutomatic segmentation of HNSCC from the PET-MRI data with 2D U-nets was shown to give sufficiently accurate segmentations.

Real-world study of patients with locally advanced HNSCC in the community oncology setting.

There is a need to understand the current treatment landscape for LA HNSCC in the real-world setting. This retrospective study assessed real-world outcomes and treatment patterns of 1,158 adult patients diagnosed with locally advanced (stage III-IVB) HNSCC initiating chemoradiotherapy (CRT) within the period January 2015 to December 2017 in a large network of US community oncology practices. Structured data were abstracted from electronic health records. Demographic, clinical and treatment characteristics were analyzed descriptively overall and stratified by index treatment (cisplatin + radiotherapy [RT], cisplatin + other chemotherapy + RT, or cetuximab + RT). Time to next treatment (TTNT) and overall survival (OS) were measured using the Kaplan-Meier method, and median duration of treatment was assessed. OS was compared across treatment cohorts using multinomial logistic regression with inverse probability treatment weighting. To identify covariates associated with OS, a multivariable adjusted Cox proportional hazard model was used. This study examined 22,782 records, of which 2124 had stage III to stage IVB and no other cancers, and 1158 met all eligibility criteria. Among the treatment cohorts analyzed (cisplatin + RT, cisplatin + other chemotherapy + RT, or cetuximab + RT), cisplatin + RT was the most common concurrent chemotherapy (65.8%). Among 1158 patients, 838 (72.4%) did not initiate subsequent treatment and 139 (12.0%) died. The median TTNT and median OS were only reached by the cetuximab + RT cohort. Among patients with oropharynx primary tumor location, patients with human papilloma virus (HPV) positive status had the longest time on treatment and highest survival at 60 months. Covariates associated with improved survival were never/former tobacco use, HPV positive status, and overweight or obese body mass index. Covariates associated with poorer survival were age of 60+ years, primary tumor location of hypopharynx or oral cavity and Eastern Cooperative Oncology Group performance status score of 2+. These data describe real-world treatment patterns in locally advanced head and neck squamous cell cancer and sets the baseline to assess outcomes for future studies on the community oncology population.

The smart options of induction therapy for locally advanced betel-nuts related HNSCC in Taiwan.

e18080 Background: The treatment of HNSCC in Taiwan is still very challenging and might be related to betel-nuts use. Betel nut chewing might contribute to strong angiogenesis/invasion and treatment refractoriness. In western countries where HPV+ oropharyngeal cancer prevalence is high, induction TPF (TAX323/324) response rate in locally advanced HNSCC is around 70%; Erbitux and TP (Argiris in JCO2008) induction response rate is 86%. In the analysis from KGMH in Taiwan, induction chemotherapy response for locally advanced HNSCC was 55% in betel-nuts chewers compared with 75% in non-users ( p=0.038; From Su in World Journal of Surgical Oncology 2016). In further studies from Taiwan, Avastin-PF induction benefit (ORR 80%) was also prominent from NTUH (Huang in ESMO Asia2016); Erbitux-TPF induction response rate was 88% from VGH by Lu in Head & Neck2019. Neoadjuvant biochemotherapy seemed to bring more benefits in betel-nuts related HNSCC. In the era of incorporating immunotherapy to neoadjuvant setting of HNSCC, triple therapy of bio-chemoimmunotherapy deserves more attention. Methods: From 2012 to 2022, 111 unresectable stage IVA & IVB betal-nuts related HNSCC patients (OSCC 69, Hypopharynx 26, OPC 13) had ever received induction Bio-chemotherapy or triple therapy (Bio-chemoimmunotherapy) in Yun-lin Branch of National Taiwan University Hospital. We have reviewed basic characteristics, therapeutic regimens, induction response, and final outcomes of these patients. Results: See table. Conclusions: Induction TPF response in locally advanced betel-nuts related HNSCC in Taiwan was not so prominent. Flexible chemotherapy backbones, such as TP/DP-HDFL(weekly docetaxel or paclitaxel with cisplatin and 24-hr high dose 5-fluorouracil/leucovorin infusion), might produce acceptable response rates with less toxicity. Bio(EGFR or VEGFR-targeting)-chemotherapy or Bio-chemoimmunotherapy has brought encouraging induction response with favorable toxicity profiles to conversion surgery or definite CCRT. Further investigation and clinical trials will be urgently warranted. [Table: see text]

DURTRERAD: A phase II open-label study evaluating feasibility and efficacy of durvalumab (D) and durvalumab plus tremelimumab (DT) in combination with radiotherapy (RT) in non-resectable locally advanced HPV-negative head and neck squamous cell carcinoma (LA-HNSCC).

2611 Background: Concurrent platinum-based chemo-RT is the standard treatment for LA-HNSCC, despite of limited efficacy in poor-risk patients and long-term toxicity. Targeting PD-L1 with D has activity in recurrent/metastatic (RM)-HNSCC, and the combination with the CTLA4 targeting agent T was considered to augment the immunotherapy efficacy of a chemotherapy-free regimen. Thus DURTRERAD was designed as a randomized two-arm phase II study to investigate, whether D or DT combined with RT was feasible in the patient population and a 1-year progression free survival rate of 50% was reached. Methods: The phase II study planned to enroll 60 patients in each treatment arm. Key selection criteria were patients with advanced HPV negative unresectable HNSCC planned for definitive radiotherapy. Treatments: First dose of immunotherapy 14 days prior to start of RT (70Gy over 7 weeks). D (1500mg q 3 weeks x 13) or DT (D: 1500mg q 3 weeks x 13 + T: 4 x 75 mg in weeks 5,9,13,17). Planned treatment duration was 51 weeks in both arms. Treatment was considered feasible in case of <10% treatment discontinuations. An interim analysis for feasibility was planned after treatment of 6 patients per arm and a futility analysis was performed after treatment of 18 patients, resulting in premature closure of the trial. Results: Patient accrual in 4 centers in Germany from 9/2018 - 9/2020. The interim feasibility analysis of DT revealed that 5/6 patients stopped treatment due to 1 grade 5 and 1 grade 4 immune related AE and 3 non-immune related AEs, respectively. Thus, the DT arm was prematurely terminated, and only the D monotherapy arm continued. Futility analysis of D monotherapy: One of 12 patients stopped treatment due to immune related toxicity, and 7 patients experienced disease progression on treatment or died within the first year. The median PFS was 39 weeks, the 1 year PFS rate was 42%. Conclusions: Even though D was previously proven as an active agent in RM-HNSCC, and there DT was not associated with increased toxicity, DT in combination with RT was not feasible in our poor prognostic, vulnerable patient cohort of HPV negative LA-HNSCC. D monotherapy in combination with RT was well tolerated, but revealed a low level of efficacy, when administered in the trial schedule, starting 2 weeks prior to RT. Similar to results in lung cancer, start of immunotherapy after completion of radiotherapy may be of interest. Clinical trial information: NCT03624231 .

Efficacy and safety of induction chemotherapy with docetaxel + cisplatin in selected groups of patients with HNSCC.

e18059 Background: We investigated the efficacy and safety of docetaxel + cisplatin (DC) induction chemotherapy vs TPF in patients with locally advanced HNSCC. Methods: Under our observation there were 22 patients in HNSCC (63,6% men and 36,4% women, aged 43 to 74 years (58.7±9.4 (95% CI 55.0-62.4)). The control group consisted of 18 patients (72,2% men and 27,8% women, aged 43 to 73 years (53.9±8.8 (95% CI 49.6-58.3). Both groups were comparable in terms of location, stage (III-IVA) and tumor differentiation. The patients of group 1 received DC (docetaxel 75 mg/m2 + cisplatin 75 mg/m2; q3w) as induction chemotherapy (ICT), while patients in the control group received TPF. Results: The planned number of ICT cycles (No. 3) in group 1 was received by 100% pts. and in the control group - 77.78% pts. (p = 0.02). At the control assessment according to RECIST 1.1, PR was registered in 77.3% pts. of group 1 vs 55.5% pts. in control group (p = 0.14), SD - in 22.7% vs 33.3: (p = 0.45), PD was registered only in patients of the control group - in 11.2% (p = 0.11). The frequency of registration of AEs: diarrhea gr.1-3 - 9.1% pts. group 1 vs 33.3% of pts. the control group (p = 0.06), nausea gr.1 -2 - 9.1% vs 22.2% (p= 0.25), asthenia gr. 1-2 - 4.5% versus 16.7% (p = 0.20), anemia gr. 1-2 - 9.1% vs. 16.7% (p = 0.47), neutropenia gr. 3-4– 4.5% versus 16.7% (p = 0.20). Reduction of doses of cytostatic up to 50% was performed in 4.5% pts. in group 1 and 16.7% pts. in the control group (p = 0.20). Conclusions: Induction chemotherapy in DC mode may be an effective and safe regimen in certain groups of patients with HNCH (for example, in patients with contraindications to 5-FU infusions, as well as in patients with high-risk HHNH for alternative surgical treatment or concurrent CRT as initial treatment of localized and locally advanced HNSCC.