Advanced Squamous Cell Research Articles

Comparison of Nivolumab with Docetaxel in the Treatment of Advanced Squamous Cell Non-small Cell Lung Cancer

Lung squamous-cell carcinoma poses a significant global health challenge with limited treatment options available. Immune checkpoint inhibitors, particularly nivolumab, have revolutionized cancer therapy, especially in non-small cell lung cancer (NSCLC). Nivolumab, targeting the PD-1 protein, exhibits promise in treating advanced squamous-cell NSCLC. This article critically examines nivolumab’s development and compares its efficacy with docetaxel in this context. Nivolumab’s effectiveness lies in its ability to block the PD-1/PD-L1 immune checkpoint pathway, reinvigorating the immune response against cancer cells. Clinical trials reveal higher overall survival rates and fewer adverse events (AEs) with nivolumab compared to docetaxel, alongside improvements in patient-reported outcomes and mental well-being. However, limitations exist, primarily stemming from clinical trial data’s potential mismatch with real-world scenarios. Short trial durations hinder long-term outcome analysis and delay AE evaluations. Furthermore, the comparison is restricted to nivolumab and docetaxel, overlooking other Food and Drug Administration-approved monoclonal antibodies. Addressing these limitations are crucial for enhancing the utility of these evaluations in clinical decision-making and guiding future research in advanced squamous-cell NSCLC management. Nivolumab emerges as a promising treatment option, offering superior efficacy and safety over traditional chemotherapy, yet its real-world efficacy warrants further exploration.

Survival Impact of Second-Line Immune Checkpoint Inhibitors in Older Patients With Advanced Squamous-Cell NSCLC: Post Hoc Analysis of the CAPITAL Study

IntroductionIn the CAPITAL study, a randomized phase 3 study, wherein carboplatin plus nab-paclitaxel treatment was compared with docetaxel treatment for older patients with squamous-cell lung cancer, the former became the new standard of care for such patients. Our study aimed to evaluate whether the efficacy of second-line immune checkpoint inhibitors (ICIs) affected the primary analysis of overall survival (OS). MethodsHerein, we performed a post hoc analysis of the impact of second-line ICIs on OS, safety in each group of participants aged more than 75 years, and intracycle nab-paclitaxel skip status. ResultsPatients were randomly allocated to the carboplatin plus nab-paclitaxel (nab-PC) arm (n = 95) or the docetaxel (D) arm (n = 95). Of these patients, 74 of 190 (38.9%) were transferred to ICIs for second-line treatment (nab-PC arm: 36, D arm: 38). A survival benefit was numerically observed only for patients for whom first-line therapy was terminated owing to disease progression (median OS [nab-PC arm]: with and without ICIs, 321 and 142 d, respectively; median OS [D arm]: with and without ICIs, 311 and 256 d, respectively). The OS among patients who received ICI after adverse events was similar in the two arms. In the D arm, a significantly higher frequency of grade greater than or equal to 3 adverse events was observed among patients aged more than or equal to 75 years (86.2%) than among those aged less than 75 years (65.6%, p = 0.041), including a significantly higher frequency of neutropenia (84.6% versus 62.5%, p = 0.032); no such differences were observed in the nab-PC arm. ConclusionsWe found that second-line ICI treatment seemed to have a little impact on OS.

MRI-based radiomics value for predicting the survival of patients with locally advanced cervical squamous cell cancer treated with concurrent chemoradiotherapy

BackgroundTo investigate the magnetic resonance imaging (MRI)-based radiomics value in predicting the survival of patients with locally advanced cervical squamous cell cancer (LACSC) treated with concurrent chemoradiotherapy (CCRT).MethodsA total of 185 patients (training group: n = 128; testing group: n = 57) with LACSC treated with CCRT between January 2014 and December 2018 were retrospectively enrolled in this study. A total of 400 radiomics features were extracted from T2-weighted imaging, apparent diffusion coefficient map, arterial- and delayed-phase contrast-enhanced MRI. Univariate Cox regression and least absolute shrinkage and selection operator Cox regression was applied to select radiomics features and clinical characteristics that could independently predict progression-free survival (PFS) and overall survival (OS). The predictive capability of the prediction model was evaluated using Harrell’s C-index. Nomograms and calibration curves were then generated. Survival curves were generated using the Kaplan-Meier method, and the log-rank test was used for comparison.ResultsThe radiomics score achieved significantly better predictive performance for the estimation of PFS (C-index, 0.764 for training and 0.762 for testing) and OS (C-index, 0.793 for training and 0.750 for testing), compared with the 2018 FIGO staging system (C-index for PFS, 0.657 for training and 0.677 for testing; C-index for OS, 0.665 for training and 0.633 for testing) and clinical-predicting model (C-index for PFS, 0.731 for training and 0.725 for testing; C-index for OS, 0.708 for training and 0.693 for testing) (P < 0.05). The combined model constructed with T stage, lymph node metastasis position, and radiomics score achieved the best performance for the estimation of PFS (C-index, 0.792 for training and 0.809 for testing) and OS (C-index, 0.822 for training and 0.785 for testing), which were significantly higher than those of the radiomics score (P < 0.05).ConclusionsThe MRI-based radiomics score could provide effective information in predicting the PFS and OS in patients with LACSC treated with CCRT. The combined model (including MRI-based radiomics score and clinical characteristics) showed the best prediction performance.

Prognostic factors associated with 18FDG-PET/CT in esophageal squamous cell carcinoma after trimodality treatment

PurposeThis study aimed to determine the pathological complete response (pCR), overall survival (OS), and disease-free survival (DFS) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) using post-neoadjuvant chemoradiotherapy (nCRT) F-18-fluorodeoxyglucose (18FDG).MethodsThis is a retrospective study of patients with locally advanced ESCC receiving nCRT and then esophagectomy between January 2011 and December 2018 in the Tri-Service General Hospital, Taipei, Taiwan. A total of 50 patients were enrolled in the study. Survival analysis was performed using the Kaplan–Meier method and Cox proportional hazards model. Univariate and multivariate analysis were used to determine the independent prognostic factors.ResultsFifty patients were enrolled in the study, and 18 had pathological complete response. Post-nCRT SUVmax ≥ 3 is a poor prognostic factor associated with overall survival (HR: 3.665, P = 0.013) and disease-free survival (HR: 3.417, P = 0.011). Poor prognosis was found in the non-pCR plus post-nCRT SUVmax ≥ 3 group compared with pCR plus post-nCRT SUVmax < 3 group.ConclusionsSUVmax ≥ 3 is a poor prognostic factor in esophageal squamous cell carcinoma after trimodality treatment, even in patients having pathological complete response.

Neoadjuvant treatment combined with planned endoscopic surgery in locally advanced sphenoid sinus basaloid squamous cell carcinoma

Introduction: Basaloid squamous cell carcinoma (BSCC) is a rare and aggressive variant of SCC. It often diagnosed at a late clinical stage and is associated with a poor survival rate, and the optimal sequence of treatment modalities remains unclear. Patient concerns: A 45-years-old male patient presented with 3 months history of left side nasal obstruction without rhinorrhea, olfaction loss, epistaxis, loss of visual acuity, and negative for family history of sinonasal carcinoma. Diagnosis: A transnasal biopsy was performed under general anesthesia. The Hematoxylin-eosin staining of the pathological slice and immunohistochemistry findings were consistent with the diagnosis of BSCC. Interventions: The patient was treated with planned endoscopic surgery after preoperative neoadjuvant cisplatin with concurrent radiation therapy. After neoadjuvant therapy, the tumor volume was reduced, facilitating transnasal radical resection. The endoscopic surgery was followed by radiation therapy. Outcome: Follow-up at 24 months post-surgery did not reveal any recurrence of the tumor. Conclusion: Neoadjuvant therapy consisting of radiation and cisplatin is a potentially effective therapeutic option in the treatment of locally advanced BSCC prior to surgical resection. This treatment and concurrent radiation followed by planned surgical resection results in significantly improved survival of the patients.

Parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor type 1 in locally advanced laryngeal cancer as prognostic indicators of relapse and survival

BackgroundParathyroid hormone-related peptide (PTHrP) overexpression and poor patient outcome have been reported for many human tumors, but no studies are available in laryngeal cancer. Therefore, we studied the expression of PTHrP and its receptor, parathyroid hormone-related peptide receptor type 1 (PTH1R), in primary locally advanced laryngeal squamous cell carcinomas (LALSCC) also in relation to the clinical outcome of patients.MethodsWe conducted a retrospective exploratory study, using immunohistochemistry, on PTHrP, PTH1R and HER1 expressions in LALSCC of 66 patients treated with bio-radiotherapy with cetuximab.ResultsThe expressions of PTHrP and PTH1R in LALSCC were associated with the degree of tumor differentiation (p = 0.01 and 0.04, respectively). Poorly differentiated tumors, with worse prognosis, expressed PTHrP at nuclear level and were PTH1R negative. PTHrP and PTH1R were expressed at cytoplasmic level in normal larynx epithelium and more differentiated laryngeal cancer cells, suggesting an autocrine/paracrine role of PTHrP in squamous cell differentiation of well differentiated tumors with good prognosis. Eighty-one percent HER1 positive tumors expressed PTHrP (p < 0.0001), mainly at nuclear level, consistent with the known up-regulation of PTHrP gene by HER1 signaling. In multivariable analyses, patients with PTHrP positive tumors had a higher relative risk of relapse (HR = 5.49; CI 95% = 1.62–22.24; p = 0.006) and survival (HR = 8.21; CI 95% = 1.19–105.00; p = 0.031) while those with PTH1R positive tumors showed a lower relative risk of relapse (HR = 0.18; CI 95% = 0.04–0.62; p = 0.002) and survival (HR = 0.18; CI 95% = 0.04–0.91; p = 0.029).ConclusionsIn LALSCC nuclear PTHrP and absence of PTH1R expressions could be useful in predicting response and/or resistance to cetuximab in combined therapies, contributing to an aggressive behavior of tumor cells downstream to HER1.

Postoperative radiotherapy may not be necessary for locally advanced head and neck squamous cell carcinoma: a case-match multicentre study

BackgroundSome head and neck cancer surgeons found that many patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) without postoperative radiotherapy (PORT) also have a good prognosis. The purpose of this study was to determine the effect of PORT on survival in patients with LA-HNSCC.MethodsA case-match cohort analysis was performed at two institutions on patients with LA-HNSCC. Patients who received surgery alone were case-matched 1: 1 with patients treated by surgery plus PORT based on pT, pN, tumor subsite etc.Results114 patients were matched into 57 pairs, with a median follow-up period of 40.2 months. No difference in overall survival (OS, HR 0.88; 95% CI 0.50–1.58; P = 0.79) or disease-specific survival (DFS, 0.86; 95% CI 0.50–1.50; P = 0.76) was observed with no PORT.ConclusionsPORT isn’t necessary for patients with LA-HNSCC who are treated for the first time as long as the head and neck cancer surgeon adhere to appropriate surgical concepts. The indications of PORT for patients with LA-HNSCC need to be further discussed.

Abstract CT502: Preliminary immunological monitoring of first-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma

Abstract Background: Preclinical studies document that complex cancer vaccines, combined with T cell agonists and anti-PD-1, can augment therapeutic efficacy. Here we report preliminary immunological analyses of patients enrolled in a first-in-human immunotherapy-trio study of multivalent autophagosome vaccine (DPV-001), with sequenced checkpoint inhibition (anti-PD-1; retifanlimab), with/without anti-GITR agonist (INCAGN-1949), in recurrent or metastatic HNSCC (NCT04470024). Methods: Peripheral blood (PB) and sera are collected regularly and PB are evaluated by flow cytometry. Biopsies obtained at baseline, D15 and D45 are analyzed by multiplex IF and 10x Genomics scRNA-Seq. Sera are being analyzed by phage immunoprecipitation (PhIP) sequencing for reactivity against the human proteome. Results: Preliminary results document increases in activated CD4 and CD8 effector memory T cells (TEM) with vaccine alone. Changes in tumor microenvironment (TEM) were also observed with increased infiltration of immune cells. Evaluation of changes to humoral immunity, T cell function and TCR analyses are ongoing. Conclusions: We previously reported immunological monitoring of a phase I/II trial of an autophagosome cancer vaccine (DPV-001) containing more than 300 shared cancer antigens, as adjuvant therapy for NSCLC. Vaccination induced or augmented immune responses to more than 50 cancer antigens shared with head and neck squamous cell carcinoma (HNSCC). Preclinical studies combining this cancer vaccine with αGITR agonist and αPD-1 augmented therapeutic efficacy [PMID: 31747946], and provided the rationale for the current study. This is the first clinical trial to perform such a study with αGITR agonist (INCAGN-1949), in humans. Support: Incyte, Providence Medical Foundation, The Harder Family, Nancy Lematta. Citation Format: Rom S. Leidner, Matthew H. Taylor, Tarsem L. Moudgil, Tanisha L. Christie, Yoshinobu Koguchi, Alexa Dowdell, William L. Redmond, Shawn M. Jensen, Carmen Ballesteros-Merino, Jake A. Vancampen, Venkatesh Rajamanickam, Brady M. Bernard, Christopher Paustian, Traci L. Hilton, Hong-Ming Hu, Richard B. Bell, Walter J. Urba, Carlo B. Bifulco, Brian Piening, Bernard A. Fox. Preliminary immunological monitoring of first-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT502.

Phase 3 randomised study evaluating the addition of low-dose nivolumab to palliative chemotherapy in head and neck cancer.

LBA6016 Background: The regimens approved for the treatment of advanced head and neck squamous cell carcinoma (HNSCC) are accessible to only 1-3% of patients in low and middle-income countries due to cost. In our previous study, metronomic chemotherapy (MC) improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low dose nivolumab to MC improved the overall survival. Methods: This was a randomised phase 3 superiority open-label study. Adult patients with relapsed -recurrent or newly diagnosed advanced HNSCC being treated with palliative intent with ECOG PS 0-1 were eligible. Patients were randomised 1:1 to MC consisting of methotrexate 15 mg/m2 PO weekly, celecoxib 200 mg PO daily and erlotinib 150 mg PO daily, or MC with intravenous nivolumab 20 mg flat dose once-every-3-weeks. Therapy was continued until disease progression or intolerable adverse events. Response assessment (RECIST version 1.1) was performed every 2 months. The primary endpoint was 1-year overall survival (OS) and this was a pre-specified interim analysis with the nominal p-value for efficacy being 0.006. Results: 151 patients were randomised, 75 in MC and 76 in the MC-I arm respectively. The addition of low dose nivolumab led to an improvement in the 1-year overall survival from 16.3% (95%CI 7.95-27.4) to 43.4% (95% CI 30.8-52.3) [Hazard ratio-0.545; 95%CI 0.362-0.82; P=0.00358]. The median overall survival in MC and MC-I arms was 6.7 months (95%CI 5.83 -8.07) and 10.1 months (95%CI 7.37-12.63) respectively (P=0.0052). The median progression-free survival in MC and MC-I arms was 4.57 months (95%CI 4.2 -5.3) and 6.57 months (95%CI 4.43-8.9) respectively (P=0.0021). Response rate in MC and MC-I arm were 49.3% (95% CI 37.8-60.8) and 65.2% (95%CI 53.4-75.4) respectively (P=0.085). The rate of grade 3 and above adverse events was 50% and 46.1% in MC and MC-I arm respectively (P=0.744). Conclusions: In this first-ever randomised study, the addition of low dose nivolumab led to improved overall survival and is an alternative standard of care for those who cannot access full dose nivolumab. Clinical trial information: CTRI/2020/11/028953.

Paclitaxel and cisplatin combined with concurrent involved-field irradiation in definitive chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: a phase II clinical trial

PurposeThis trial aims to explore the efficacy and safety of involved-field irradiation (IFI) combined with paclitaxel plus cisplatin as concurrent chemoradiotherapy for locally advanced esophageal squamous cell carcinoma (ESCC), under the premise of intensity-modulated radiotherapy (IMRT).MethodsEnrolled patients with locally advanced ESCC were treated with definitive concurrent chemoradiotherapy. IFI was administered adopting IMRT and the total dose was 61.2 Gy delivered in 34 fractions. On the first day of radiotherapy, the patients were treated with paclitaxel and cisplatin one cycle per month for 2 cycles followed by the same regimen in consolidation chemotherapy for two cycles. The primary endpoint of the study was the 2-year locoregional recurrence-free survival (LRFS) rate, and secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety.ResultsBetween January 2018 and September 2020, 108 patients participated in the trial. 78.7% (85/108) of patients completed all 4 cycles of chemotherapy. The median follow-up of the surviving patients was 33.9 months (interquartile range, 29.2–41.1). The 2-year LRFS rate, as the primary endpoint, was 64.2%. In addition, the median PFS was 39.2 months, and 1-year and 3-year OS rates of 88.0% and 63.3%, respectively. Among the patients, out-of-field regional failure was seen in only 7 (6.5%) patients. Neutropenia grade 3 and 4 occurred in 21.3% and 37.0% of the patients, respectively.ConclusionsIFI using IMRT combined with paclitaxel and cisplatin concurrent chemotherapy for locally advanced ESCC yields encouraging local control and overall survival, but high hematological toxicity.Trial registration Clinical Trials ChiCTR1800017039.

Cetuximab and anemia prevention in head and neck cancer patients undergoing radiotherapy

BackgroundEpidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels intensifies RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, has been associated with lower rates of anemia for locally advanced head and neck squamous cell carcinoma (HNSCC). We hypothesized that concomitant cetuximab could prevent RT-induced anemia.MethodsWe queried our institutional head and neck cancers database for non-metastatic HNSCC cases that received RT with concomitant cetuximab or RT-only between 2006 and 2018. Cetuximab was administered for some high-risk cases medically unfit for platinum agents per multidisciplinary team evaluation. We only included patients who had at least one complete blood count in the 4 months preceding and after RT. We compared the prevalence of anemia (defined as hemoglobin (Hb) below 12 g/dL in females and 13 g/dL in males) and mean Hb levels at baseline and after RT. Improvement of anemia/Hb (resolution of baseline anemia and/or an increase of baseline Hb ≥1 g/dL after RT), and overall survival (OS) in relation to anemia/Hb dynamics were also compared.ResultsA total of 171 patients were identified equally distributed between cetuximab-plus-RT and RT-only groups. The cetuximab-plus-RT group had more locally-advanced stage, oropharyngeal and high grade tumors (p < 0.001 for all). Baseline anemia/Hb were similar, however anemia after RT conclusion was higher in the cetuximab-plus-RT vs RT-only (63.5% vs. 44.2%; p = 0.017), with a mean Hb of 11.98 g/dL vs. 12.9 g/dL; p = 0.003, for both respectively. This contributed to significantly worse anemia/Hb improvement for cetuximab-plus-RT (18.8% vs. 37.2%; p = 0.007). This effect was maintained after adjusting for other factors in multivariate analysis. The prevalence of iron, vitamin-B12 and folate deficiencies; and chronic kidney disease, was non-different. Baseline anemia was associated with worse OS (p = 0.0052) for the whole study cohort. Nevertheless, improvement of anemia/Hb was only marginally associated with better OS (p = 0.068).ConclusionsIn contrast to previous studies, cetuximab was not associated with lower rates of anemia after RT for nonmetastatic HNSCC patients compared to RT-alone. Dedicated prospective studies are needed to elucidate the effect of cetuximab on RT-induced anemia.

Comparable Clinical Outcome Using Small or Large Gross Tumor Volume-to-Clinical Target Volume Margin Expansion in Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma.

The purpose of this study was to evaluate the feasibility of small primary gross tumor volume (GTV)-to-clinical target volume (CTV) margin expansion in neoadjuvant chemoradiation for esophageal squamous cell carcinoma. Medical records of 139 patients with locally advanced esophageal squamous cell carcinoma who underwent neoadjuvant chemoradiation and radical esophagectomy were retrospectively reviewed. Patients treated with longitudinal primary GTV-to-CTV margin expansion of 2 cm and no additional expansion of the CTV through the esophagus were classified into a small margin (SM) group (37 patients). The remaining 102 patients were classified as a large margin (LM) group. Patterns of recurrence including local and out-field regional recurrence rates were compared between the two groups. Clinical outcomes including rates of local control, regional control, failure-free survival, and overall survival were also compared. More patients in the SM group underwent paclitaxel + carboplatin, Mckeown esophagectomy, and intensity-modulated radiation therapy than in the LM group. With a median follow-up of 25.6 months, there was no significant difference in the crude rate of local recurrence (10.8% vs. 6.9%, P=0.694), out-field regional recurrence (27.0% vs. 19.6%, P=0.480), or out-field regional recurrence without in-field recurrence (10.8% vs. 12.7%, P=0.988) between the two groups. There was no significant difference in failure-free survival (5-year, 34.4% vs. 30.6%, P=0.652) or overall survival (44.1% vs. 38.5%, P=1.000), either. Esophageal fistula was not reported in the SM group (0.0% vs. 7.9%, P=0.176). In conclusion, a radiation field with 2 cm of longitudinal primary GTV-to-CTV was feasible in the neoadjuvant setting for esophageal squamous cell carcinoma treatment.

A randomized, controlled, open-label, phase 2 study of cemiplimab ± RP1 in patients with advanced cutaneous squamous cell carcinoma (CERPASS).

TPS9593 Background: RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity, which is further improved by combining anti-PD-1 therapy. The prognosis for advanced and metastatic cutaneous squamous cell carcinoma (CSCC) remains poor for many patients despite the adoption of cemiplimab and pembrolizumab as a standard treatment. Preliminary results from IGNYTE, a phase I/II clinical study of RP1 in combination with nivolumab showed a high rate of deep and durable responses in patients (pts) with CSCC. This study is evaluating the efficacy and safety of cemiplimab ± RP1 versus cemiplimab alone in advanced CSCC. Methods: This global, multicenter, randomized phase 2 study is enrolling pts with metastatic or unresectable, locally advanced CSCC who are not candidates for/refuse surgery and/or radiation therapy. Key eligibility criteria include no prior treatment with anti-PD1/PD-L1 antibodies or oncolytic viruses. The clinical trial is enrolling approximately 180 pts from centers in the EU, Australia, Canada, and USA. Pts are randomized in a 2:1 ratio to receive combination therapy or monotherapy respectively. Pts receive 350 mg of cemiplimab intravenously (IV) Q3W for up to 108 weeks. In the RP1 + cemiplimab arm, RP1 is injected intratumorally at a starting RP1 dose of 1 × 106 plaque-forming units (PFU)/mL alone, followed by up to 7 doses of RP1 at 1 × 107 PFU/mL Q3W together with the same dose of cemiplimab. Pts in the combination arm may receive up to 8 additional RP1 doses if protocol specific criteria are met. No crossover is allowed. Pts are stratified by disease status (nodal or distant metastatic or locally advanced CSCC) and prior systemic therapy. Tumor assessments are performed every 9 weeks. The dual independent primary endpoints are overall response rate and complete response rate, both by a blinded independent review. Secondary endpoints include safety, progression-free survival, duration of response, and overall survival. Exploratory endpoints include quality of life, and immune biomarker analyses. This trial is currently enrolling pts. Clinical trial information: NCT04050436.

Camrelizumab plus apatinib as induction therapy for locally advanced head and neck squamous cell carcinoma (IMplus): A single-arm phase II study.

6060 Background: Immune checkpoint inhibitor combined with antiangiogenic agent has been investigated in many solid tumors, including advanced head and neck squamous cell carcinoma (HNSCC; NCT02501096), but the evidence is limited. This study was conducted to investigate the efficacy and safety of anti-programmed cell death-1 antibody camrelizumab plus antiangiogenic agent apatinib as induction therapy in patients with locally advanced HNSCC. Methods: In this single-center phase II trial (NCT04440917), patients with untreated locally advanced HNSCC who had inoperable lesions, could not tolerate surgery, or refused surgery were enrolled. Patients received camrelizumab 200 mg once every 2 weeks and apatinib 250 mg once daily for two 28-day cycles, followed by local treatment based on the re-examination results. The primary endpoint was objective response rate (ORR) after induction therapy, as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. Simon’s two-stage design was adopted for this study. Results: Between December 2019 and July 2021, 18 patients were enrolled in the first stage. Eight (44%) patients had oropharyngeal carcinoma, nine (50%) had oral carcinoma, and one (6%) had hypopharyngeal carcinoma. There were six (33%), three (17%), and nine (50%) patients with stage III, IVA, and IVB disease, respectively. After induction therapy, six patients achieved complete response, nine achieved partial response, and three had stable disease, with an ORR of 83%. The study proceeded to the second stage and the enrollment for another 14 patients is ongoing. Two (11%) patients with partial response received surgery and adjuvant radiotherapy, and 16 (89%) received radical radiotherapy. With a median follow-up duration of 18 months (range, 9-26), only one disease recurrence and no deaths occurred. The most common adverse events during induction therapy were hypertension (ten [56%]), oral pain (nine [50%]), and increased aspartate aminotransferase (five [28%]). Only one [6%] grade 3 hypertension and one [6%] grade 3 proteinuria were observed, and no grade 4 or 5 adverse events occurred. Conclusions: Camrelizumab plus apatinib showed promising antitumor activity as induction therapy in patients with locally advanced HNSCC, with acceptable safety profile. Clinical trial information: NCT04440917.

Non-invasive cell-free DNA monitoring for predicting the response to neoadjuvant immunotherapy in locally advanced esophageal squamous cell carcinoma.

e16040 Background: The combined modality therapy including neoadjuvant chemoradiotherapy has been selected as the standard care for locally advanced Esophageal squamous cell carcinoma (ESCC). However, the conclusive evidences to support the effectiveness of neoadjuvant immunotherapy for ESCC are rarely discussed. This study aims to investigate the molecular features of cell-free DNA (cfDNA) and the impact of their dynamic changes on the response to neoadjuvant immunotherapy in locally advanced ESCC patients. Methods: Twenty-four eligible locally advanced ESCC patients with received neoadjuvant immunotherapy were enrolled in this study. 7 patients achieved pathological complete regression (pCR) and the other 17 patients had non-pCR. The baseline, second and third blood samples (before neoadjuvant immunotherapy, at one month and two months after neoadjuvant immunotherapy, respectively) were collected from Cancer Institute and Hospital, Chinese Academy of Medical Sciences. Both cfDNA fragments and genomic DNA were extracted for enrichment of a customized panel covering exon regions of 599 genes. The dynamic analysis of gene alterations, which allows the monitoring of the response to neoadjuvant immunotherapy in locally advanced ESCC patients, were conducted based on multiple blood sampling strategy. Results: The most frequently mutated genes among all cases were TP53, KMT2D, CREBBP and KMT2B. MSI scores of both second and third blood samples were remarkablely higher than those in baseline blood samples (p = 0.002, 0.04). On the contrary, the TMB values and mean variant allele frequency (VAF) of second and third blood samples were significantly decreased compared with the baseline blood (TMB, p = 0.04, 0.03; mean VAF, p = 0.01, 0.02). Moreover, a decreasing trend of mean VAF was observed at the time-series blood samples from ESCC patients with pCR, while the mean VAF of ESCC patients with non-pCR declined in the blood samples from the second time point then increased in the blood samples from the thrid time point. Conclusions: The detection of dynamic changes of mean VAF could distinguish the pCR and non-pCR ESCC patients with neoadjuvant immunotherapy. These findings warrant further expanded prospective cohorts to validate.

Navigation of patients with locally advanced head and neck squamous cell carcinoma during cisplatin-based chemoradiation: A cohort study.

e18613 Background: Cisplatin(DDP)-based chemoradiation (CCR) is currently used to treat locally advanced head and neck squamous cell carcinoma (LAHNSCC), either as an exclusive modality or in the adjuvant setting. Acute, treatment-related toxicities are frequent. In this prospective cohort study, we evaluated the impact of patient (pt) navigation in multidisciplinary care by nurses on adherence to consultations and procedures, number and duration of hospital admissions, admissions to the emergency department, and treatment-related toxicities. Methods: In this prospective, uni-institutional cohort study, pts diagnosed with LAHNSCC (oral cavity, oropharynx, hypopharynx, and larynx) were consecutively included at the beginning of CCR, after informed consent. The navigation program included: (1) referral to multidisciplinary care (Nutrition, Psychology, Social Work); (2) monitoring attendance at multidisciplinary clinical visits; (3) monitoring of possible hospital and emergency admissions; and (4) diagnosis and monitoring of treatment-related toxicities, graded according to CTCAE v5.0. To observe an effect size of 0.50 with a power of 80% and a type I error of 0.05, 64 pts would be needed. Here we present the analysis of the first 26 pts included, with outcomes compared to 130 LAHNSCC pts treated with CCR at the same institution in 2019. Accrual was stopped. Results: 26 pts were included between Mar/2021 and Sep/2021, with a median age of 57 years, being 77% men, with KPS ≥ 80% in 25 pts (96%), and with a primary tumor in the oral cavity or oropharynx in 18 patients (69%). CCR was administered in the adjuvant setting in 9 pts and as an exclusive treatment in 17 pts. 10 pts (39%) experienced DDP discontinuation (mainly for toxicity) in the navigation group, compared to 67% in the control group (p = 0.008); and the duration of radiotherapy was 48d and 49d, respectively (p = 0.483). No grade 4 adverse events were observed in navigated pts. The median number of absences (any visit or treatment) was 1.0 (control) and zero (navigation, p &lt; 0.001). Admission to the emergency department occurred in 6 navigated pts (23%) as compared to 100 control pts (77%, p &lt; 0.001), while hospitalizations occurred in 1 (3.8%) and 50 (38.5%, p &lt; 0.001), respectively, lasting 4.9±9.7d and 1±0.39d (p = 0.001). Conclusions: The navigation program provided better outcomes in comparison to the control group, in terms of a lower number of missed appointments, a higher number of chemotherapy cycles administered, lower frequency of severe toxicities, lower frequency of attendance at emergency and hospitalization services, as well as reduced length of hospital stay.

Camrelizumab in combination with concurrent chemoradiotherapy as first-line treatment for nonoperative head and neck cancer: A comparative study.

6063 Background: We hypothesized that concurrent chemoradiotherapy (CCRT) plus concurrent and adjuvant camrelizumab as first-line treatmentwas associated with improved survival compared with concurrent chemoradiotherapy alone for nonoperative locoregionally advanced head and neck squamous cell carcinoma (HNSCC). The purpose of this comparative study was to compare the efficacy and toxicity of CCRT plus concurrent and adjuvant camrelizumab versus CCRT alone in nonoperative locoregionally advanced HNSCC. Methods: One hundred and eighty patients with nonoperative locoregionally advanced HNSCC (cancer of the oral cavity, oropharyngeal cancer, hypopharyngeal cancer and laryngeal cancer) received either CCRT plus concurrent and adjuvant camrelizumab (camrelizumab + CCRT group, n = 90) or CCRT alone (CCRT alone group, n = 90). Patients in both groups received curative cisplatin-based concurrent chemoradiotherapy. The radiation dose was 70 Gy (2.0 Gy/fraction). In camrelizumab + CCRT group, concurrent camrelizumab (200mg/day on days 1, 22, 43) was added to CCRT, followed by adjuvant camrelizumab (200mg, every 3 weeks for 6 months or until disease progression, unacceptable adverse events or withdrawal of consent). Results: Compared with CCRT alone, the addition of concurrent and adjuvant camrelizumab significantly improved complete response (CR) rates (92.2% vs. 80.0%; P = 0.018), 3-year disease free survival (DFS, 72.2% vs. 56.7%; P = 0.029), locoregional recurrence-free survival (LRRFS, 76.7% vs. 61.1%; P = 0.024), and overall survival (OS, 78.9% vs. 63.3%; P = 0.033). Reactive cutaneous capillary endothelial proliferation was higher in the camrelizumab + CCRT group (6.7% vs. 0.0%; P = 0.013). No statistically significant differences in other acute (mucositis, leukopenia, thrombocytopenia, anemia, etc.) and late toxic effects (mucosal necrosis, trismus, cranial nerve palsy, etc.) were observed between the two groups. The addition of camrelizumab (CCRT plus camrelizumab vs. CCRT alone) was a significant independent prognostic factor for 3-year DFS, LRRFS and OS (P = 0.038, P = 0.032, and P = 0.048, respectively). Conclusions: Concurrent chemoradiotherapy plus concurrent and adjuvant camrelizumab as first-line treatment is associated with a considerable survival benefit, with acceptable adverse events, as compared with concurrent chemoradiotherapy alone, among patients with nonoperative locoregionally advanced head and neck squamous cell carcinoma. Our ongoing prospective clinical trial (registered with chictr.org.cn, number ChiCTR2200056298) will further investigate the efficacy of camrelizumab in combination with chemoradiotherapy for HNSCC.

Outcomes of cisplatin dosing strategies in locally advanced non-nasopharyngeal head and neck squamous cell carcinoma treated with definitive concurrent chemoradiation in a safety-net hospital.

e18064 Background: For patients with locally advanced non-nasopharyngeal head and neck squamous cell carcinoma (HNSCC) not amenable for resection, concurrent chemoradiation with cisplatin is the standard of care. Most popular dosing strategies for cisplatin include bolus dosing once every three weeks for a total of three cycles and once a week for seven cycles. Randomized studies comparing efficacy and tolerability of these dosing strategies have been conflicting. We examined how different dosing strategies affect outcomes in our institution, a safety-net hospital serving the medically underserved population in a large metropolitan area. Methods: We conducted a retrospective chart review of patients diagnosed with HNSCC from January 2015 to July 2021 in our institution. Patients with biopsy proven HNSCC with oral cavity, oropharyngeal, laryngeal, or hypopharyngeal primary tumor sites treated with definitive concurrent chemoradiation with cisplatin were included in the study. Those who received cisplatin bolus dosing were identified as Arm A and weekly dosing identified as Arm B. Primary outcome studied was 12-month event-free survival (EFS). We controlled for stage at diagnosis, age, p16 positivity, smoking status, treatment delay or premature discontinuation, and number of comorbidities. Secondary outcomes were rates of treatment delay or discontinuation, and median cisplatin dose received. To determine whether a preliminary association exists, a Pearson Chi-Square test for association of treatment type to 12-month EFS was utilized. To control for potential confounding variables the Mantel-Haenszel test was used on each confounder. Results: A total of 51 patients were included in the study, 36 (70.6%) with bolus and 15 (29.4%) with weekly cisplatin. After controlling for confounding variables listed above, there was no statistically significant association between Arm A or Arm B and 12-month EFS (p = 0.324). Delay or discontinuation rate for Arm A was 10 out of 36 patients (27.8%) and for Arm B was 5 out of 15 patients (33.3%). The difference in these rates were not statistically significant (p = 0.743). The median cisplatin dose received for Arm A was 300 mg/m2 and 280 mg/m2 for Arm B. Conclusions: In our institution, there was no difference in 12-month EFS or rates of treatment delay or discontinuation between patients who underwent definitive concurrent chemoradiation with bolus versus weekly cisplatin (p = 0.324). This has a significant impact on practical management of concurrent chemoradiation in our resource limited setting.

PEP503 (NBTXR3), a radioenhancer, in combination with concurrent chemoradiation (CCRT) in locally advanced or recurrent head and neck squamous cell carcinoma (HNSCC): Dose-finding of a phase 1b/2 trial.

e18041 Background: PEP503 (aka NBTXR3), a novel radioenhancer composed of functionalized hafnium oxide nanoparticles, is designed for intratumoral injection to increase radiation energy deposition within solid tumors and subsequent tumor cell killing, without increasing toxicity to surrounding healthy tissue. PEP503 nanoparticles plus RT has been tested in elderly HNSCC patients and has demonstrated a good safety profile. The phase 1b part of the study aimed to test the feasibility and the recommended phase 2 dose (RP2D) of PEP503 intratumoral injection when added with low-dose (LD) weekly cisplatin-containing chemoradiation (CCRT) in HNSCC. Methods: Patients who had T3-4 locally advanced HNSCC suitable for CCRT were eligible. An intratumoral single injection of PEP503 was performed 24 to 72 hours before the start of CCRT: consisting of IMRT (70̃72 Gy, 2-2.12 Gy/fraction) and weekly cisplatin (low dose, 40 mg/m2) concurrently during IMRT. Traditional 3+3 design was planned for dose escalation and 5 levels of PEP503 were planned, including 5%, 10%, 15%, 22%, and 33% of the baseline GTV by MRI. PEP503 Intra-tumor dispersion was anayzed by CT-scan. Results: Twelve (12) patients (male/female: 11/1; oral cavity/oropharynx: 11/1) were enrolled, with 3, 6, and 3 patients at 5%, 10%, and 15% PEP503 dose levels, respectively, in combination with LD cisplatin CCRT. DLTs were observed in one patient at 10% dose level which were G3 ALT and G3 AST increased. Common G3 AEs observed across dose levels were stomatitis (50.0%), WBC decreased (33.3%), decreased appetite (16.7%), neutrophil count decreased (16.7%), and leukopenia (16.7%), and only one G4 AE (hyponatraemia) was observed. CT images demonstrated PEP503 within the tumor contour after injection throughout the CCRT period. Hafnium, for all patients, was either not detected or below the Lower Limit of Quantification (LLOQ) in the circulation 60 minutes after PEP503 intratumoral injection, and not found in urine. DCR was achieved in 100% of patients with responding patients for an ORR of 58.3%. No subjects received salvage surgery after study treatment. Study was terminated early before MTD and RP2D could be determined. Conclusions: Adding PEP503, a radioenhancer, via a single intratumoral injection to weekly cisplatin-containing CCRT was feasible and safe for patients with locally advanced or recurrent LA-HNSCC. RP2D was not reached due to study early termination. Clinical trial information: NCT02901483.

Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648.

4035 Background: NIVO + chemo and NIVO + IPI demonstrated significant overall survival (OS) benefit vs chemo in previously untreated patients (pts) with advanced ESCC in the phase 3 CheckMate 648 study. We report expanded results from the primary analysis with 13-month (mo) minimum follow-up. Methods: Pts with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR) in pts with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Secondary endpoints planned for hierarchical testing included OS, PFS, and objective response rate (ORR) per BICR in all randomized pts. Duration of response (DOR) per BICR and PFS2 per investigator (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) were exploratory endpoints. Results: Among all pts randomized to NIVO + chemo (n = 321), NIVO + IPI (n = 325), or chemo (n = 324), PFS2 favored NIVO + chemo (HR 0.64, 95% CI 0.54–0.77) and NIVO + IPI (HR 0.74, 95% CI 0.62–0.88) vs chemo. ORR (95% CI) was 47% (42–53), 28% (23–33), and 27% (22–32), respectively. More responders with NIVO + chemo or NIVO + IPI vs chemo had prolonged DOR (≥12 mo; 39%, 48%, and 23%, respectively). Efficacy data by tumor cell PD-L1 and PD-L1 combined positive score will be presented. Grade 3/4 treatment-related adverse events with potential immunologic etiology (select TRAEs) occurred in ≤ 6% of pts with NIVO + chemo and NIVO + IPI, and non-endocrine select TRAEs resolved in 57%–95% of pts across organ categories (Table). Conclusions: NIVO + chemo and NIVO + IPI demonstrated favorable PFS2 and a higher proportion of pts with prolonged DOR vs chemo, as well as acceptable safety profiles. These results provide further support for each regimen as a new potential 1L standard of care in advanced ESCC. Clinical trial information: NCT03143153. [Table: see text]