Head And Neck Squamous Cell Carcinoma Pts Research Articles

Recent safety and efficacy findings from a phase 1b/2 open-label combination study of ASP-1929 photoimmunotherapy with anti-PD-1 therapy in EGFR-expressing advanced head and neck squamous cell carcinoma (HNSCC).

6083 Background: In the challenging landscape of advanced HNSCC, patients (pts) have overall low survival and high locoregional (LR) recurrence rates. While LR progression is a key contributor to morbidity and mortality, LR control remains low despite aggressive therapy including surgery, radiation, chemotherapy, and immunotherapy. ASP-1929 photoimmunotherapy (PIT) combines EGFR-targeting cetuximab, with a light-activatable dye, IRDye 700DX, and a laser light for localized drug activation. This novel approach has demonstrated rapid and selective tumor necrosis in preclinical studies, and a manageable safety profile in HNSCC early clinical trials. Phase I/II and preclinical data indicate a potential synergy in anti-tumor activity of PIT when combined with anti-PD-1 therapy. Here we present updated interim evaluation findings based on a recent data cut from this study initially presented at the 2023 American Head and Neck Society meeting. Methods: A phase 1b/2 open-label study of pts with recurrent locally advanced (rLA) and/or metastatic (m) HNSCC evaluating the safety and efficacy of ASP-1929 PIT in combination with anti-PD-1 (pembrolizumab) therapy (NCT04305795). Pts with measurable disease by modified RECIST 1.1, at least 1 lesion accessible to light illumination, combined positive score (CPS) ≥1, and who were not candidate for LR therapy could be eligible for the study. Treatment included ASP-1929 PIT (infusion day 8, target tumors illuminated 24±4 hours later) plus anti-PD-1 (days 1&22) during a 6-week cycle for up to 24 months. Primary objectives: safety/tolerability; objective response rate (ORR). Secondary objectives: overall survival (OS); progression-free survival (PFS); duration of response (DOR). Planned sample size: 26 HNSCC pts. Results: Of the 19 r/m HNSCC pts enrolled, 18 pts received both study therapies (PIT-evaluable). Data cut-off was August 31, 2023 (previously reported data cut-off: October 4, 2022). Efficacy results updated for the 18 PIT-evaluable pts: ORR of 33.3% (95% CI 13.3-59.0), including 4 CRs (22.2%) and 2 PRs (11.1%). Median OS not reached; 24-month OS rate estimate was 52.4% (95%CI 25.9-73.4). No change in median PFS, 2.9 months (95%CI 1.4-14.6). Median DOR was not reached at data cut-off (range 2.8+ to 18.0+ months). Safety data remained consistent with the data previously presented. Most common serious adverse reactions were dysphagia (10.5%) and tongue edema (10.5%). There were two grade 4 events: laryngeal edema (PIT-related) and tumor hemorrhage due to advanced disease, and no fatal events. Conclusions: ASP-1929 PIT in combination with anti-PD-1 therapy was generally well tolerated. Initial data demonstrate promising overall survival and response rates with this combination therapy in pts with rLA and/or m HNSCC lacking LR treatment options. Clinical trial information: NCT04305795 .

The potential prognostic value of the head and neck advanced lung inflammation index (HN-ALI) for patients treated with immunotherapy.

6052 Background: The ALI is recognized as a potential prognostic and predictive biomarker for patients (pts) treated with immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer. In head and neck squamous cell carcinoma (HNSCC) its prognostic role has been acknowledged in locally advanced setting. We evaluated whether HN-ALI could provide similar value in pts with recurrent/metastatic (R/M) HNSCC undergoing treatment with ICIs. Methods: We conducted a multicentric observational retrospective study including R/M HNSCC pts treated with ICIs alone or in combination with chemotherapy from April 2016 to November 2023. The ALI was calculated as follows: BMI (kg/m2) × serum albumin (g/dL)/neutrophil-to-lymphocyte ratio (NLR). Using the bibliographic cut off value of 18, pts were divided into two groups: ALI < 18 (high inflammation) and ALI > 18 (low inflammation). The primary outcomes were overall survival (OS) and progression free survival (PFS), evaluated with the Kaplan-Meier estimator. Cox proportional hazard regression models were employed to perform multivariate analysis. Results: A total of 145 pts [105 males, median (m) age 66 years, 128 with ECOG PS < 1] were treated with ICIs (35% nivolumab, 64% pembrolizumab) across two Italian centers. Primary tumor sites were: oral cavity (35%), oropharynx (33%), larynx (14%), hypopharynx (7%), other (9%). ICIs were administered as single agents in 86 pts and in combination with chemotherapy in 59 pts. The HN-ALI was collected for 92 pts. The mPFS was 6 months (95%CI, 2.16-9.83) within the ALI group > 18 versus 1 month for the ALI group < 18 (95%CI, 0.26-1.73) (p< .001); analogously, the mOS was 17 months (95%CI, 11.63-22.36) versus 2 months (95%CI, 0.68-3.32) for the ALI group > 18 and < 18, respectively (p< .001). At the multivariate analysis, high ALI score represented an independent risk factor for better OS, also including ECOG PS and PD-L1 expression [HR 0.38; (95% CI,0.15 – 0.96), p= .042], while showing a trend towards longer disease progression [HR 0.52; (95% CI, 0.26 - 1.02), p= .058]. Conclusions: In our experience, ALI value >18 is associated with better prognosis in pts treated with ICIs alone and in combination with chemotherapy. Further analyses are warranted to validate the prognostic relevance of the ALI value in pts with HNSCC undergoing ICIs.

Safety and immunogenicity of TG4050: A personalized cancer vaccine in head and neck carcinoma.

6082 Background: Despite adjuvant therapy, over 50% of surgically treated head and neck squamous cell carcinoma (HNSCC) patients (pts) experience a recurrence of disease. Systemic stimulation of cellular immunity against tumor mutations using a viral vaccine may be an ideal modality to clear residual cancer cells. For this purpose, we developed a pipeline for the design of TG4050, a personalized cancer vaccine (PCV) using a Modified Vaccinia Ankara (MVA) viral vector. We report here preliminary safety and immunogenicity data from a phase I TG4050 study. Methods: Surgically resected stage III or IV, HPV negative HNSCC pts were enrolled in the study. pts must have achieved clinical remission after adjuvant chemoradiotherapy. A PCV for each pt was manufactured with up to 30 neoantigens identified using a state-of-the-art machine learning algorithm, from next generation sequencing (NGS) data. Pts randomized to arm A received the PCV after completion of primary treatment. Pts randomized to arm B received the PCV in the event of relapse, in conjunction with second line therapy. The PCV schedule consisted of an induction period of 6 weekly administrations, followed by booster doses once every 3 weeks for up to one year. Immune cells were collected by leukapheresis at baseline and at day 64. Primary endpoint was safety. Secondary endpoints included feasibility, disease free survival and immune response as assessed by ex-vivo IFNg-ELISPOT. Results: At the time of data cut-off, a total of 31 pts were randomized, 15 in arm A and 16 in arm B. A vaccine was successfully designed for all randomized pts. Pts had no evidence of disease at baseline either at the clinical or molecular level, as assessed by ctDNA assessment. All adverse events (AEs) were mild to moderate and most were injection site reactions. Median follow-up was 9.2 months in arm A vs 7.6 months in arm B. None of the pts in arm A experienced relapse vs. 2 in the arm B. Immune monitoring demonstrated priming of a polyepitopic T cell response against the PCV in 100% of pts in arm A, among pts evaluated to date, with a mean of 9 responses per pt (6-19). Responses were observed regardless of HLA genotype, and without cross-reactivity to the wildtype antigen. Baseline tumor analyses revealed challenging genomic and immune profiles such as low TMB (avg of 3.06 ± 0.86 Mut/Mb), a majority of immune-desert tumors, and a low expression of important immune related factors including PD-L1 (16 pts out of 17 had a negative to moderate PD-L1 expression). Conclusions: Our preliminary data demonstrate that TG4050 is safe, well tolerated, and capable of inducing T cell responses in cold tumors. In summary viral based, PCVs designed to induce tumor-specific neoantigen may be associated with a safe tolerance and an improved outcome in HNSCC pts. Clinical trial information: NCT04183166 .

A phase 1/2a study of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody, administered via intratumoral (IT) injection as monotherapy in advanced solid tumors.

2520 Background: T3011, a replication-competent, genetically modified, next-generation oncolytic herpes simplex viruses (oHSV), deletes one copy of ICP34.5 and retains ICP47, thus maximizing replication activity and virulence attenuation of the virus. Moreover, T3011 was inserted with biologically active IL-12 and anti-PD-1 antibody genes. Therefore, while lysing tumor cells, T3011 can significantly improve the tumor microenvironment and elicit the body's specific anti-tumor immunity. Methods: An open-label, dose escalation and expansion study of T3011 administered via IT injection as a single agent in patients (pts) with advanced solid tumors. Pts who progressed on or were intolerable to the standard of care were eligible and received T3011 IT therapy Q2W in several dose cohorts (2.5×105 ~ 1×108 PFU/mL). The primary endpoints were safety and tolerability. Key secondary endpoints were PK/PD profile, efficacy endpoints including ORR, DCR, DOR, PFS by investigator per RECIST1.1 and OS. Results: As of 18 Jan. 2023, 90 Pts received T3011 monotherapy. Median follow-up time is 5.7(0.5-22.5) months. No DLT events were reported. Treatment-related adverse events (TRAEs) were observed in 66.7% pts (≥G3 TRAEs and treatment discontinuation both in 2.2% [2/90]), and treatment-related SAEs occurred in 2.2% (2/90) pts. The most frequently reported TRAEs (≥5%) were pyrexia (21.1%, 19/90), influenza like illness (8.9%, 8/90), TSH increased (6.7%, 6/90), proteinuria (6.7%, 6/90), facial edema, white blood cell count decreased, AST increased and anemia (5.6%, 5/90, each). MTD was not reached, RP2D was determined as 1x108 PFU/mL. Over 80% of pts had viral DNA un-detected in their blood, urine and saliva after injection. Moreover, almost all injection site and occlusive dressing samples that tested positive for viral DNA were confirmed to be free of viral activity. The confirmed ORR was 11% (6/55), DCR was 49% (27/55) in 55 pts (HNSCC, sarcoma, melanoma, breast cancer, etc.) treated under RP2D evaluable for tumor response.The median PFS was 2.8 mos (95%CI: 1.84, 4.60) in all 76 Pts received T3011(RP2D). 19 head and neck squamous-cell carcinoma (HNSCC) pts progressed on platinum-based chemotherapy and anti-PD-1/PD-L1 therapy treated with T3011(RP2D), median PFS was 3.9 mos (95%CI: 0.89, NA;1 pt failed from chemotherapy only for PFS analysis set). 12 HNSCC pts had at least one tumor evaluation post-dose, the confirmed ORR and DCR was 25% (3/12) and 50% (6/12) respectively. Conclusions: The safety profile and clinical compliance of T3011 IT therapy are excellent. T3011 injected locally will not spread to blood, urine and saliva, regional shedding doesn't raise the possibility of transmission to the local and systemic environment. The encouraging anti-tumor activity of T3011 monotherapy in advanced HNSCC pts supports further evaluation in phase II studies. Clinical trial information: NCT05602792 .

Dynamic change of immune phenotype assessed by artificial intelligence (AI)-powered analysis of tumor-infiltrating lymphocytes (TILs) during neoadjuvant durvalumab with or without tremelimumab (D+/-T) in head and neck squamous cell carcinoma (HNSCC).

2578 Background: The results of a phase II trial evaluating preoperative durvalumab with or without tremelimumab (D+/-T) in resectable HNSCC (NCT03737968) suggest that the neoadjuvant immunotherapy is associated with pathologic tumor regression with manageable safety profiles. Here, we applied AI-powered spatial TIL analyzer, Lunit SCOPE IO, to tumor specimens of the patients included in the trial to assess the impact of spatial TIL density and inflamed immune phenotype (IIP) on immunotherapy responses. Methods: H&E-stained whole-slide images (WSIs) of pre- and post-treatment tumor specimens from HNSCC pts enrolled in the aforementioned D+/-T trial were collected. Patients with locally advanced but operable HNSCC were randomly assigned in 1:1 to receive a single dose of D (1,500mg) or D+T (1,500mg+75mg) followed by surgery, at Severance Hospital in Seoul, Korea. Lunit SCOPE IO was used to segment tumor epithelium and stroma to identify and quantify intratumoral TIL (iTIL) and stromal TIL. IIP was defined as the proportion of high iTIL area more than 33.3% of analyzable area. Clinical data and the combined positive scores (CPS) of PD-L1 were also collected. Results: A total of 39 paired tumor samples of pre- and post-treatment WSI (23 from D+T and 16 from D) were included. Overall, tumor regression grade 2 (TRG2, ≥ 50% of tumor regression) was achieved in 15.4% (6/39) pts, and downstaging after treatment was achieved in 35.9% (14/39) pts. By pre-treatment WSIs, 38.5% (15/39) samples were classified as IIP, and subgroups of D+T and D had 34.8% (8/23) and 43.8% (7/16), respectively. In the D+T arm, the proportions of TRG2 were 25% (2/8) in IIP versus 13.3% (2/15) in non-IIP, whereas D arm had 28.6% (2/7) TRG2 in IIP, but no TRG2 in non-IIP (0/9), respectively. Comparing the WSI of pre- and post- D+/-T samples, the proportion of IIP was significantly increased to 66.7% from 38.5 ( p = 0.015). The increase in IIP proportion was prominent in the D+T arm (34.8% to 69.6%, p = 0.043), but not in the D arm (43.8% to 62.5%, p = 0.37). Similarly, PD-L1 CPS increased after therapy, especially in the D+T group (mean CPS 6.0 to 20.7, p = 0.009). Interestingly, pts who remained non-IIP in both pre- and post-treatment (25.6%, 10/39) had significantly poor prognosis compared to the others, as the 12-month disease-free survival (DFS) rate was 50.0% vs 93.1% (median DFS 13.4m vs not reached, hazard ratio [HR] 4.26, 95% confidence interval [CI] 1.32-13.8, p = 0.009). This prognostic impact was prominent in the D+T arm (HR 6.75, 95% CI 1.49-30.6, p = 0.004). Conclusions: Neoadjuvant durvalumab +/- tremelimumab promotes dynamic change toward inflamed immune phenotype, resulting in favorable clinical outcomes. Resistance mechanism of stand-still-non-inflamed patients even on D+/-T should be further investigated. Clinical trial information: NCT03737968 .

Abstract 5463: The PD-L1 protein expression in Chinese patients with recurrent or metastatic head and neck squamous cell carcinoma: A multi-center retrospective study

Abstract Programmed death-ligand 1 (PD-L1) is a trans-membrane protein and co-inhibitory factor of the immune response. PD-L1 can combine with its receptor (PD-1) to reduce the proliferation of PD-1-positive cells and induce apoptosis. Therefore, PD-L1 was employed as a prognostic marker and a target for anti-cancer immunotherapy in blocking the PD-1 and PD-L1 checkpoints. PD-L1 is highly expressed in various malignancies, including head and neck squamous cell carcinoma (HNSCC). HNSCC is the sixth most common cancer worldwide, with high incidence and mortality rates in China. Although PD-L1 expression has been widely investigated, the PD-L1 expression status in Chinese HNSCC patients (pts) is largely unrevealed. The primary objective of this study was to determine the prevalence of PD-L1 expression with the Combined Positive Score (CPS) ≥20 in Chinese pts with recurrent or metastatic (R/M) HNSCC. The secondary objectives were to determine the prevalence of CPS≥1 in pts with R/M HNSCC and to study the difference in the demographic characteristics, clinicopathological parameters, treatment status, and other available biomarkers between the PD-L1 CPS≥20 group and the PD-L1 CPS<20 group. This study was a multi-center retrospective analysis of data from six centers in China from August 9, 2021, to February 28, 2022. Pts with histologically/cytologically confirmed diagnoses of R/M HNSCC were included. PD-L1 expression was assessed by IHC using the 22C3 PharmDx assay (Agilent, Santa Clara, CA, USA) and was determined using a CPS. The Chi-square test, Fisher’s exact test, or Wilcoxon rank sum test would be used to compare the prevalence of these variables among pts between the PD-L1 CPS≥20 group and the PD-L1 CPS<20 group. Out of 406 enrolled pts with R/M HNSCC, 402 testing pts were included in the final analysis. For all testing R/M HNSCC pts, 168 pts (41.8% [95% CI 36.92-46.78]) had PD-L1 expression with CPS ≥20. In addition, 337 pts (83.8% [95% CI 79.86-87.29]) had PD-L1 expression (CPS≥1). For the testing pts, there were statistically significant differences in variables of gender (P < 0.001), smoking habit (P = 0.0138 for non-smokers versus current smokers), and primary tumor site (P < 0.001 for hypopharynx versus oral cavity and P = 0.0304 for larynx versus oral cavity) between the PD-L1 CPS≥20 group and the PD-L1 CPS<20 group. In summary, in Chinese R/M HNSCC pts, most pts (83.8%) had PD-L1 expression, and two-fifths (41.8%) had PD-L1 expression with CPS ≥20. Prevalence of PD-L1 among Chinese pts with R/M HNSCC was consistent with that reported in the global KEYNOTE-048 study. PD-L1 expression was significantly associated with gender, smoking history and primary tumor site. Our findings of the variables related to the PD-L1 expression levels can supply adjuvant evidence for clinical practice and are a solid basis for future research on immunotherapy. Citation Format: Haizhen Lu, Dong Kuang, Lili Jiang, Jingping Yun, Qingxin Xia, Jian Wang, Pei Duan, Ping Zhou, Shengbing Zang, Yiping Jin, Xiangnan Jiang, Jielin Li, Wenmin Tang, Jiansong Zhou, Jihua Chen, Jianming Ying. The PD-L1 protein expression in Chinese patients with recurrent or metastatic head and neck squamous cell carcinoma: A multi-center retrospective study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5463.

Variation in Body Mass and Skeletal Muscle Indices in Head and Neck Cancer Patients Undergoing (Chemo)Radiotherapy and Nutritional Intervention.

The aim of this study was to analyze variation in body mass index (BMI) and skeletal muscle index (SMI) in head and neck squamous cell carcinoma (HNSCC) patients who underwent exclusive radiotherapy (RT) or concurrent chemo-radiotherapy (RT-CHT). We enrolled 73 HNSCC pts treated with definitive or post-operative RT (14 pts) or RT-CHT (59 pts). At the time of diagnosis (t0) and 3 months after treatment completion (t3), CT scans were retrieved to measure skeletal muscle at the level of the C3 vertebra. Median follow-up was 16 months. Nine disease progressions with distant metastases and eleven local relapses were observed. Fifty-three pts were free from progression at 1 year. At t0, average BMI was 25.8 (SD 4.1), while at t3 it was 24.5, with no reduction in 54 pts. A BMI decrease of -1.3 (p-value < 0.0001) between t0 and t3 was found with the Wilcoxon signed-rank test. SMI was 57.1 and 59.2 at t0 and t3, respectively (p-value = 0.005). According to our analysis, SMI variation seems to reflect the effect of an appropriate nutritional intervention and may represent a reliable, simple tool for muscle mass analysis.

Radiotherapy with Durvalumab vs. Cetuximab in Patients with Locoregionally Advanced Head and Neck Cancer and a Contraindication to Cisplatin: Phase II Results of NRG-HN004

<h3>Purpose/Objective(s)</h3> The optimal treatment for patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) and contraindication to cisplatin is uncertain. This trial (NCT03258554) tested the primary hypothesis that radiation therapy (RT) with concurrent and adjuvant durvalumab, a PD-L1 inhibitor, improves progression-free survival (PFS) compared to standard RT with cetuximab. <h3>Materials/Methods</h3> This phase II/III randomized trial enrolled patients ≥ 18 years of age who had previously untreated AJCC 8^th stage III-IVB SCC of the larynx, hypopharynx, oral cavity, p16- oropharynx/unknown primary (OPC/UP) or stage III and selected stage I-II p16+ OPC/UP, with a contraindication to cisplatin: ECOG performance status (PS) 2; renal or hearing impairment; peripheral neuropathy; age ≥ 70 with moderate/severe comorbidity; age < 70 with severe comorbidity. Favorable-risk p16+ HNSCC, PS >2, inadequate end-organ function, or active autoimmune disease were exclusion criteria. Patients were randomized 2:1 to RT (70 Gy, 35 fractions, 7 weeks) plus either: (arm A) durvalumab 1500 mg IV q4 weeks starting 2 weeks before RT (7 cycles) or (arm B) cetuximab 400 mg/m² IV 1 week prior to RT then 250 mg/m² weekly (8 cycles). The primary phase II endpoint was PFS with planned sample size of 234 randomized patients (69 PFS events, hazard ratio 0.65, 80% power, 1-sided alpha 0.20). The difference in PFS between arms was tested using a log-rank test. <h3>Results</h3> This study enrolled 190 patients (186 randomized; 123 arm A; 63 arm B) from Mar 2019-Jul 2021. Following planned interim futility analysis, the trial was temporarily closed to accrual, pending analysis based on total required phase II PFS events (met in Jun 2022). Median age was 72 years (59% ≥ 70). 95% had ≥ 3 comorbidities (median 5); 58% had T3-4; 49% had N2-3; 47% had p16+ OPC/UP. 87% in arm A and 89% in arm B completed RT. 89%/63% completed concurrent/adjuvant durvalumab and 81% completed ≥ 7 cycles of cetuximab. At median follow-up of 1.2 years, PFS was not improved and locoregional failure (LRF) was higher with durvalumab (Table). Grade ≥ 3 adverse events were 69%/79% for arm A/B. Grade ≥ 3 dysphagia, mucositis, and dermatitis rates were 22%/30%, 11%/20%, and 5%/13% for arm A/B, respectively. <h3>Conclusion</h3> Novel eligibility criteria and feasibility of accrual were established. However, RT with durvalumab did not show a signal toward improved PFS and led to significantly worse LRF, compared to RT with cetuximab in HNSCC pts with a contraindication to cisplatin. The trial will not move to phase III.

704TiP SAR445256 (KY1044) in combination with atezolizumab in patients (pts) with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)

SAR445256 (KY1044) is a fully human IgG1 targeting ICOS with a dual mechanism of action: dose dependent depletion of ICOShigh Tregs in tumor microenvironment and activation of ICOSlow Teff. NCT03829501 is the first in human study testing safety, efficacy, and pharmacological properties of SAR445256 with/without atezolizumab in PD-L1 naïve or pretreated pts with advanced malignancies. Dose escalation part was guided by an adaptive dose-finding method and Ph 1 enrichment part was included for a better understanding of safety, tolerability, preliminary anti-tumor efficacy and PK/PD relationships of SAR445256 in combination with atezolizumab. Selected Ph2 dose was 8mg with atezolizumab 1200mg, both given IV, Q3W. In Ph1, a 59-year-old male pt with HPV+ HNSCC who progressed on 5 prior lines of therapy (including nivolumab), experienced a PR (42% tumor shrinkage), still holding as of C26D1, and on treatment for >20 months as of 10Feb2022. Strong expression of ICOS on intratumoral Tregs in head and neck cancer as well as the promising clinical activity previously reported suggest HNSCC to be favorable indication for SAR445256. Ph2 cohorts (2 cohorts, PD-L1 naïve and pretreated) are being initiated in HNSCC pts. Approximately 40 pts will be enrolled in each cohort. Key inclusion criteria: anti -PD-L1 therapy naïve and pretreated, 1-2 prior lines of systemic therapy for advanced disease, histologically documented advanced/metastatic malignancies, measurable disease by RECIST 1.1, site of disease amenable to biopsy. Key exclusion criteria: CNS metastases, active autoimmune disease, significant heart disease and/or QT prolongation, steroid therapy, or any immunosuppressive therapy. Efficacy measures will be performed as per RECIST 1.1 Q8W for the first 16 weeks and then Q12W, while AEs will be classified according to CTCAE v5. SAR445256 was well tolerated and showed initial signs of activity, in a HNSCC pt who received multiple prior lines of therapy. Ph2 assessment is planned in 2 cohorts: HNSCC pts PD-L1 naïve and pretreated. Note: Atezolizumab will continue to be provided by Roche for the RP2D part of this study as well. 1. Sainson R et al 2020. 2. Patel MR et al 2021. NCT03829501. Mukul Rastogi, PhD of Sanofi. Sanofi.

686P Next generation sequencing (NGS) helps predict response to immunotherapy (IO) in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients (pts)

Immunotherapy has changed the treatment of HNSCC pts since the introduction of immune checkpoint inhibitors (ICI). Genomic instability increases neo-antigen production, which has been related with sensitivity to IO. We investigated whether single-gene alterations in TP53, cell-cycle and other mutations (mut) or copy number gains (CNG) predict outcomes in R/M HNSCC pts treated with IO.

Phase 1 studies of personalized neoantigen vaccine TG4050 in ovarian carcinoma (OC) and head and neck squamous cell carcinoma (HNSCC).

2637 Background: Mutation-associated neoantigens (MANAs) constitute attractive antigens for the design of cancer vaccines. However, clinical implementation remains challenging because of the patient specific nature of MANAs, hereby requiring that a bespoke vaccine is designed for each subject. We developed a pipeline for the genomic characterization and the design of tailored vaccine using a modified vaccinia Ankara viral vector. Methods: Immunogenicity, safety and early clinical activity of personalized cancer vaccines are being assessed in two phase I trials, respectively in high grade serous OC and HPV-negative HNSCC. Patients (Pts) at high risk of relapse are enrolled in the study being in remission following surgical primary treatment. High risk is defined as stage IIIC or IVA for OC and stage III or IVA for HNSCC. A vaccine is manufactured for each patient. OC pts are treated at asymptomatic relapse based on radiological finding or elevation of CA-125 with the vaccine alone; HNSCC pts in complete remission after surgery and adjuvant therapy are randomized to receive the vaccine either at the end of locoregional treatment or in combination with standard of care at relapse. The vaccine was administered weekly for 6 weeks and a booster dose every three weeks over a year or until progression, whichever occurred first. Results: At the time of the data cut-off, a total of 8 pts were treated: 4 relapsing OC pts, 3 HNSCC pts in complete remission and 1 relapsing HNSCC pt. AE attributable to the vaccine were mainly grade 1 injection site reactions and fatigue. One OC pt displayed an objective response 6 weeks after initiation of vaccine and for 9 months with a normalization of CA-125 until death from an unrelated cause; 1 other OC pt remains on treatment with a stable radiological disease for 11 months. The 2 other OC progressed at the first evaluation on day 43. HNSCC pts treated in complete remission received respectively 20, 15 and 4 doses, and remain on treatment and disease free. One HNSCC patient received 9 doses of vaccine after relapse in conjunction with chemotherapy and anti-PD-1 therapy and remains on treatment with stable disease after 5 months. Immune monitoring demonstrates priming of a polyepitopic T cell response against class I and II antigens. Responses were observed regardless of HLA and without cross-reactivity to the germline protein. Adaptive response was associated with a shift of CD4 and CD8 T cells toward an effector phenotype and innate cellular immunity was activated with a strong maturation and activation of NK cells. Immune changes were stronger in pts with controlled disease versus progressors. Conclusions: Data demonstrate that TG4050 is safe, well tolerated and able to induce T cell responses whatever the HLA haplotype. Early signs of clinical activity were observed in OC pt. These data pave the way for further development and synergistic immunotherapeutic combinations. Clinical trial information: NCT04183166.

Immune-related gene expression signature in patients with recurrent/metastatic head and neck cancer treated with immunotherapy.

6051 Background: In platinum-resistant recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients (pts), survival improvements have been achieved with immune checkpoint inhibitors (ICI), however this benefit is limited to a relatively small subgroup of pts. Predictive biomarkers are still under investigation and their contribution to the clinic has been limited. An immune-related cluster (Cl6) has been defined by means of a metanalysis in locally advanced HNSCC. Methods: Gene expression profiling was performed on two cohorts of platinum resistant R/M HNSCC pts treated with ICI alone: i) 20 patients as training set, divided in long-term (OS &gt;18 months; n=12) and short-term (OS &lt; 6 months; n=8) survivors matched according to site of recurrence (distant metastases only, or locoregional recurrence with/out metastases); ii) 80 patients enrolled in a phase II trial (EudraCT number: 2017-000562-30; NIVACTOR study) as testing set. The molecular subtyping stratification (De Cecco, Oncotarget 2015) was applied. Subsequently, a score was determined between each sample and the centroids for the 6 clusters previously identified. The threshold point was imputed in the training set as the closest value to the observed prevalence. A Cox multivariable analysis including TMB, CPS and TPS PD-L1 status, age, tumoral subsite and performance status (PS) was performed. Results: Among all the clusters, Cl6 turned out to be significant and applied to training set it provided evidence to discriminate pts’ survivals (AUC=0.86, 95%CI=0.7-1.0; p=2E-05). The stratification based on Cl-6 along with the cut-off point defined in the training set were challenged in the testing set: samples were divided in 28 (35%) having high Cl-6 scores and 52 (65%) with low scores, reaching HR=0.46 (95% CI= 0.27-0.76; p=0.0024). Multivariate analysis showed that only Cl6 (high vs low, HR=0.44; p=0.00443) and PS (1,2 vs 0, HR 1.85; p=0.02686) resulted to be significant on pts’ OS. Conclusions: By analysing two series of pts receiving immunotherapy alone, we identified an immune-related gene expression signature, able to discriminate the prognosis of platinum-resistant R/M HNSCC pts. The multivariate analysis confirmed the immune-related Cl6 as factor linked to outcome in pts treated with immunotherapy, as well as it confirmed the importance of PS. An analysis of the signature on pts receiving first line treatment with immunotherapy is currently ongoing. [Table: see text]

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.

872P Association between event-free (EFS) and overall survival (OS) in newly diagnosed patients (pts) with locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) ineligible for surgery

Improvement in OS is the gold standard for assessing treatment efficacy. To avoid delays in novel treatment approval, early treatment decisions may be based on validated surrogate endpoints which predict OS. A prior meta-analysis of clinical trials in LA HNSCC pts by Michiels 2009 showed a strong correlation of EFS with OS, supporting EFS as a surrogate endpoint in LA HNSCC. This study aimed to assess whether the correlation between EFS and OS is maintained with updated literature in pts with LA HNSCC ineligible for surgery and receiving chemoradiation therapy (CRT).

Expansion cohort validation of a clinical predictive model for head and neck cancer survival in patients treated with immune checkpoint inhibitors.

6030 Background: Immune checkpoint inhibitors (ICI) therapy is approved for patients (pts) with recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). The majority of pts will die within two years of diagnosis. We have shown that pretreatment clinical characteristics may predict overall survival (OS). Here, we expand our analysis to a total of 201 pts. Methods: Between January 15,2016 and April 9, 2020, 201 pts with R/M HNSCC were treated with ICI as first, second line and beyond. Data on p16 status, hemoglobin (Hb), albumin, lactate dehydrogenase (LDH), neutrophil, platelet and lymphocyte count was recorded initially. OS was defined from the start of ICI to death. Progression Free Survival (PFS) was defined from the start of ICI to disease progression (PD) or death. A nomogram was created using the rms package to generate individualized survival prediction. Results: 201 pts were analyzed, sex: 154 male (77%), 47 female (23%), median age 61 (IQR: 55-68). ICI drug: pembrolizumab 100 (50%), nivolumab 91 (45%), ipilimumab+nivolumab 10 (5%). Line of therapy: First: 98 (49%), second and beyond: 103 (51%). Tumor site: oropharynx 84 (42%), oral cavity 45 (22%), others 72 (36%). p16 status: negative 132 (66%), positive 69 (34%). Laboratory values: Median neutrophil count: 4.58 (IQR: 3.43-6.47), Median lymphocyte count: 0.69 (IQR: 0.47-1.08), Median Platelet count: 229 (IQR: 187-300), hemoglobin (Hb) normal/low 101/100 (50%/50%), albumin: normal/low 156/45 (78%/22%), LDH: normal/high 124/77 (62%/38%). Overall response rate: 36 (18%). Median OS: 12 months (CI: 9.4-14.8), median PFS: 4 months (CI: 3.5-5.7). The variables associated with OS were neutrophil count (high) [HR 1.28 (1.08 – 1.51), p=0.004], lymphocyte count (high) [HR 0.75 (0.60 – 0.95), p=0.015], albumin (low) [HR 2.06 (1.37 – 3.10), p&lt;0.001], hemoglobin (low) [HR 1.64 (1.14 – 2.35), p=0.007], LDH (high) [HR 1.78 (1.23 – 2.56), p=0.002] and p16 status (positive) [HR 0.58 (0.39-0.87), p=0.009]. Using the prognostic index of the chosen model, we stratified patients into three risk groups at the 33rd and 66th percentile. Median OS in the good risk group was 24 months (CI: 18.5-NR), average risk group 13.8 months (CI: 11-20), poor risk group 2.3 months (CI: 1.7-4.4). The discrimination of the model after internal validation was c-index of 0.72. Conclusions: A small percentage of R/M HNSCC pts treated with ICI have good long-term survival outcomes. In a larger cohort, we internally validated the utilization of a simple, inexpensive and widely accessible nomogram based on clinical and laboratory variables which can predict OS in this patient population.

A combined genomic and immune profile in patients with head and neck squamous cell carcinoma treated with immunotherapy: A pilot study.

e18506 Background: In head and neck squamous cell carcinoma (HNSCC) only a small subset of patients (pts) really benefits from immunotherapy, suggesting the need of validated molecular and immunological predictive biomarkers. The aim of the study was to evaluate both the genomic and immune profile of HNSCC correlating it to early progression to immunotherapy. Methods: This is a pilot study evaluating immune and molecular profile in platinum-refractory HNSCC pts treated with Nivolumab. Blood samples were collected at baseline (T0) and at second cycle of therapy (T1). The immune profile was studied by multiplex assay, evaluating circulating: CD137, CTLA4, PD1, PDL1, PDL2, CD27, TIM3, LAG3, GITR, HVEM, BTLA, CD80, CD28 and IDO. The comprehensive genomic profile was evaluated at baseline on formalin-fixed paraffin-embedded samples of the tumor through Foundation One Cdx test. The results obtained were correlated with early progression (within 3 months from the start of therapy). Results: Ten pts were enrolled in the study. Early progression occurred in 6 pts (60%). Median progression free survival and overall survival were 3 months (1-11) and 6.5 months (1-12), respectively. In all patients ≥ 5 genetic mutations were detected; median number of mutation was 6 (5-14); 8/10 pts had a tumor mutational burden less than 10 Muts/mb. The more frequent genetic alterations involved the cycline-dependent-kynase pathway (9/10), the transcription factor associated gene TP53 (8/10) and the PI3K-Akt-PTEN signaling pathways (5/10). Less frequent alterations involved FGFR family (4/10), NOTCH signaling pathway (3/10) and TERT (4/10). Early progression was slightly associated with the number of mutations detected (p = 0.06). The rising or falling trend of circulating levels of biomarkers were detected in 9/10 pts and included modification in IDO (1/10), LAG3 (3/10), GITR (3/10), BTLA (3/10), CD137 (4/10), CTLA4 (4/10), PD1 (2/10), Tim3 (3/10), CD28 (3/10), HVEM (3/10), CD80 (2/10). No modifications were recorded in PDL1, PDL2 and CD27. Conclusions: Our results, although in a small cohort, highlighted the complexity and heterogeneity of landscape in HNSCC pts. A novel evaluation that combines molecular and immune profile is needed. In the context of a poor prognosis disease the combination of personalized molecular and immune approaches could represent a promising strategy to improve survival.

A phase I/Ib study of lenvatinib and cetuximab in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

6541 Background: Despite overexpression of EGFR in HNSCC, cetuximab monotherapy has limited benefit. Fibroblast growth factor receptor (FGFR) signaling is a known resistance mechanism to EGFR inhibition. Lenvatinib is a multi-targeted receptor tyrosine kinase inhibitor (RTKI) and has unique activity against FGFR 1,2,3, and 4. We are evaluating inhibition of EGFR and RTKs including FGFR through the combination of cetuximab and lenvatinib in patients (pts) with R/M HNSCC. Methods: In this phase I/Ib, single-institution study, pts with measurable disease per RECIST v1.1 that is incurable with surgery and radiation are eligible regardless of prior cetuximab therapy. The dose de-escalation phase included pts with HNSCC and cutaneous squamous cell carcinoma (cSCC) treated with standard cetuximab dosing and lenvatinib in 3 potential dose levels (DL): (0) 24mg, (-1) 20mg, (-2) 14mg oral daily in a standard 3+3 design. The primary objective was to determine the MTD of lenvatinib in combination with cetuximab. The expansion phase included an additional 5 pts with HNSCC treated at the MTD. Exploratory endpoints include ORR and PFS in HNSCC pts treated at the MTD. Results: 12 evaluable pts were treated on the dose de-escalation phase. There were no DLTs on DL 0; however, 3/6 pts were removed immediately following the 28-day DLT period due to toxicity that included extensive thrombotic events and athlerosclerotic disease. On DL -1, 0/6 pts (5 HNSCC/1 cSCC) had a DLT establishing lenvatinib 20mg daily as the MTD. 7 pts were enrolled onto the expansion phase; 4 are currently evaluable for response and 2 are unevaluable because of withdrawal due to a cetuximab reaction and required surgery. Of the 9 evaluable HNSCC pts treated with lenvatinib 20mg daily, 6 pts had a PR with a 67% ORR. For the 8 pts who have completed treatment, the median PFS is 3.6 months (range 1.6-10.4). Grade 3 AEs regardless of attribution included hypertension (3), oral mucositis (3) and oral cavity fistula (1). The most common AEs were acneiform rash (7), fatigue (6), and hypertension/hypothyroidism/oral mucositis (5 each). Conclusions: The MTD of lenvatinib 20mg daily with cetuximab appears to be active in R/M HSNCC with an impressive preliminary ORR, warranting further evaluation of the efficacy of this combination. Clinical trial information: NCT03524326 .

The AIM-HN and SEQ-HN study: A pivotal study evaluating the efficacy of tipifarnib in patients with head and neck squamous cell carcinoma (HNSCC) with hras mutations (AIM-HN) and the impact of hras mutations on response to first line systemic therapies for HNSCC (SEQ-HN).

TPS6593 Background: HRAS mutations define a unique molecular subset of ~ 5% of HNSCC. Evidence suggests that these tumors respond poorly to standard systemic therapy but the impact of HRAS missense mutations on clinical outcomes has not been formally characterized. Tipifarnib is a potent and selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity. Phase 2 Proof of concept for tipifarnib in HRAS mutant HNSCC was recently achieved in study KO-TIP-001 (NCT02383927, Ho et. al. ESMO 2018). Methods: The AIM-HN and SEQ-HN Study (KO-TIP-007, NCT03719690) is an ongoing international, multicenter, open-label, 2 cohort (AIM-HN and SEQ-HN), pivotal trial designed to determine the Overall Response Rate (ORR) of tipifarnib in patients (pts) with HRAS mutant HNSCC (AIM-HN). SEQ-HN will retrospectively investigate how the ORR to first line treatment compares between the accrued HRAS mutant pts to matched-case control HRAS wild type (wt) HNSCC pts. Information on subsequent lines of therapy for HRAS mutant and wt pts will also be collected. AIM-HN will enroll at least 59 pts (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) who are refractory or have relapsed from at least one prior line of systemic platinum-based therapy and have measurable disease by RECIST 1.1. AIM-HN pts must have tumors with &gt;35% HRAS mutant variant allele frequency (VAF) or &gt;20% VAF if serum albumin is &gt;3.5 g/l. AIM-HN pts will receive treatment with tipifarnib at 600 mg bid on days 1-7 and 14-21 of 28-day cycles. Using Simon's Two-Stage Minimax design, if true ORR is &gt; 30%, the study will have 80% power to detect ORR &gt; 15% at 0.025 significance level. Both interim (after first 31 pts) and final analysis, 2-sided 95% CI on ORR, will be performed on the modified intent to treat population. The SEQ-HN observational cohort will enroll ~225 control pts who will receive standard of care treatment. A subset of SEQ-HN pts will be matched to the HRAS mutant AIM-HN pts according to defined patient characteristics and compared for responses to therapy. Clinical trial information: NCT02383927 .

Single-arm study of bimiralisib in head and neck squamous cell carcinoma (HNSCC) patients (pts) harboring NOTCH1 loss of function (LOF) mutations.

TPS6590 Background: Effective targeted therapies are needed for HNSCC that is lethal despite recent advances with immunotherapy. A major challenge to personalize treatment is that most genomic alterations are in tumor suppressors, including NOTCH1 that is mutated in ~20% of HNSCC. We recently published that HNSCC cell lines harboring NOTCH1 LOF mutations undergo cell death in vivo and in vitro following PI3K inhibition, in contrast to PIK3CA mutant cell lines that merely undergo cell cycle arrest when exposed to the same drugs. Based on these results we initiated a novel genomic biomarker-driven phase II clinical trial treating NOTCH1 mutant HNSCC pts with the dual PI3K/mTOR inhibitor bimiralisib (PQR309). Methods: The primary objective is to determine the objective response rate (ORR) of recurrent/metastatic HNSCC harboring NOTCH1 LOF mutations to bimiralisib. Pts who have already received standard platinum chemotherapy and immunotherapy will receive bimiralisib orally twice per wk unless progression or intolerable toxicity occurs. Tumors will be evaluated using RECIST q 6 wks. A Simon’s optimal two-stage design is used. To have 80% power to detect an ORR of 30%, (one-sided α = 0.05, β = 0.20) 10 pts will be enrolled in the first stage. If ≤1 pts respond, the trial will be closed for futility. If ≥2 pts have an OR, the study will enroll an additional 19 pts in the second stage. The null hypothesis (ORR ≤ 10%) will be rejected if ≥ 6 in 29 pts have an OR. Seven pts have enrolled. The algorithm for determining NOTCH1 mutation function is based on the patterns of mutations in HNSCC vs. leukemia where mutations are activating. It may be difficult to determine whether NOTCH1 mutations are homo- or heterozygous due to normal cell contamination. Therefore, levels of activated NOTCH1 in pretreatment tumors may be assessed by IHC with an antibody against activated NOTCH1 (NICD). In parallel with the trial, to further confirm NOTCH1 LOF, we can use site-directed mutagenesis to re-create NOTCH1 mutations from trial pts that will then be introduced into NOTCH1-null cell lines to assay for NICD and growth inhibition with culture on NOTCH1 ligand. All pts will have serial collection of blood for pharmacokinetics and for ctDNA to examine clonal evolution associated with acquired resistance. Samples with high NOTCH1 mutation ctDNA VAF will be analyzed by WES and compared with pretreatment tissue. In the second stage, IHC and WES may be performed on pre- and post- treatment (day 15 and progression) tissue to examine pharmacodynamics and mechanisms of resistance. Clinical trial information: NCT03740100 .

Efficacy of Cetuximab Based Chemotherapy after Immunotherapy Treatments (IT) in Recurrent/Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC) Patients (pts)

Abstract Background A combination therapy based on chemotherapy (CT) and Anti-PD1 is the new standard FDA-approved first-line treatment for (R/M) HNSCC PD-L1 negative pts. The addition of pembrolizumab to cetuximab has been proved feasible in a recent Phase II trial for anti-PD-1/PD-L1 and cetuximab naive HNSCC pts. The efficacy of cetuximab-based CT regimens in the post-IT setting, has not been assessed. Methods We analyzed 27 R/M HNSCC pts treated at the Vall d´Hebron Hospital from 2015-2019 with CT post-IT, including cetuximab-based CT (CT+cetu post-IT) and non-cetuximab CT regimens (CT post-IT). Clinicopathological features and treatment modalities were correlated with outcomes. Overall survival (OS) was calculated from the first cycle of CT post-IT until death or last follow-up with Kaplan-Meier method. Results Out of 27 pts, median age was 62y, all ECOG ≤1, treated with CT+cetu post-IT 20 pts (74%) or CT post-IT 7 pts (26%). P16 immunohistochemistry was present in 3 pts (17%). Median prior lines was 1 (range 1 - 4) and median follow-up was 6 months (m). Median OS was 8 m (CI95% 5 - 23) and median progression free survival (PFS) 5 m (CI95% 3 - 7). No significant differences were found in OS according to cetuximab addition (P = 0.252 log-rank test). In the CT post-IT cohort, 2 pts (29%) had a partial response (PR) and 5 (71%) had progressive disease. Clinical benefit rate (CBR, defined as complete + partial + stable disease) was 29%. Among pts treated with CT+cetu post-IT, 2 pts (11%) achieved a complete response (CR), 10 (52%) achieved a PR and 2 (11%) stable disease (CBR= 74%). A significantly higher CBR was observed for cetuximab based CT regimens following IT (P = 0.036 chi-square test). Among CR pts in the CT+cetu post-IT cohort, all were cetuximab naive. Interestingly, both pts achieving a CR had PD as best response on previous IT. Conclusion In our cohort, the addition of cetuximab to CT post-IT was associated with promising CBR. These results suggest that CT+cetu post-IT regimens may have a role in (R/M) HNSCC pts. Future prospective trials are needed to assess the sensitization effect of IT on cetuximab-based CT and the optimal sequence of treatments in (R/M) HNSCC. Legal entity responsible for the study Vall d´Hebron Institute of Oncology. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.