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Purpose This phase I study assessed the safety of first-in-class radioenhancer nanoparticles, NBTXR3, in elderly or frail patients with locally advanced head and neck squamous cell carcinoma (HNSCC), ineligible for chemoradiation. Methods Patients with stage III or IVA (American Joint Committee on Cancer (AJCC) guidelines, 7th edition, 2010) HNSCC of the oral cavity or oropharynx, aged ≥70 or ≥65 years and ineligible to receive cisplatin, amenable to radiotherapy (RT) with curative intent, received NBTXR3 as a single intratumoural (IT) injection followed by activation by intensity-modulated radiation therapy (IMRT; 70 Gy). The NBTXR3 dose corresponded to a percentage of the baseline tumour volume, measured by magnetic resonance imaging. The primary objectives were to determine the recommended phase II dose (RP2D), dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Safety and tolerability were assessed using National Cancer Institute CTCAE version 4.0. Antitumour activity was assessed by Response Evaluation Criteria in Solid Tumours 1.1. Results Nineteen patients were enrolled: 3 at the dose level of 5%, 3 at the dose level of 10%, 5 at the dose level of 15% and 8 at the dose level of 22% of the tumour volume. The MTD was not reached, and no DLTs or serious adverse event (SAEs) related to NBTXR3 were observed. Four adverse events related to NBTXR3 and/or the IT injection were reported (grade I–II). NBTXR3 remained in the injected tumour throughout RT, with no leakage in the surrounding healthy tissues. Specific RT-related toxicity was as expected with IMRT. The RP2D was determined as 22% baseline tumour volume. Preliminary signs of antitumour activity were observed. Conclusion Intratumoural injection of NBTXR3 followed by IMRT is feasible and demonstrated a good safety profile, supporting further evaluation at the RP2D in this patient population. Trial registration ClinicalTrials.gov NCT01946867 .

Although the neutrophil-lymphocyte ratio (NLR) is prognostic in many oncological settings, its significance in the immunotherapy era is unknown. Mechanistically, PD-1/PD-L1 inhibitors may alter NLR. We sought to characterise NLR kinetics in patients with advanced solid tumours treated with PD-1/PD-L1 inhibitors.Electronic records of patients treated with PD-1/PD-L1 inhibitors on phase I trials across three sites were reviewed. A high NLR (hNLR) was predefined as5. Univariate logistic regression models were used for toxicity, response analyses and Cox models for overall survival (OS) and progression-free survival analyses. Landmark analyses were performed (cycle two, three). Longitudinal analysis of NLR was performed utilising a mixed effect regression model.The median OS for patients with hNLR was 8.5 months and 19.4 for patients with low NLR, (hazard ratio [HR] = 1.85, 95% confidence interval [CI] 1.15-2.96, p = 0.01). On landmark analysis, hNLR was significantly associated with inferior OS at all time points with a similar magnitude of effect over time (p 0.05). On multivariate analysis, NLR was associated with OS (HR 1.06, 95% CI 1.01-1.11, p = 0.01). NLR did not correlate with increased immune toxicity. Longitudinally, NLR correlated with response: NLR decreased by 0.09 (95% CI: -0.15 to -0.02; p = 0.01) per month in responders compared with non-responders.hNLR at baseline and during treatment is adversely prognostic in patients with advanced malignancies receiving PD-1/PD-L1 blockade. Importantly, NLR reduced over time in responders to immunotherapy. Taken together, these data suggest that baseline and longitudinal NLR may have utility as a unique biomarker to aid clinical decision-making in patients receiving immunotherapy.

PURPOSE/OBJECTIVE(S) Concurrent radiotherapy (RT) with high-dose cisplatin, or cetuximab in case of intolerance to cisplatin, are the non-surgical standard treatment for locally advanced head and neck squamous cell carcinoma (LA HNSCC). However, elderly patients, patients with poor performance status, comorbidities, and/or intolerance may not benefit from these treatments and represent a high unmet medical need. New approaches are thus needed to improve the patient clinical outcomes without adding toxicity. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected once intratumorally and activated by RT. NBTXR3 increases the RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, without adding toxicity to healthy tissues. We present here current results of the dose expansion part of the phase I study evaluating NBTXR3 plus intensity modulated radiation therapy (IMRT) in this population (ClinicalTrials.gov: NCT01946867). MATERIALS/METHODS Patients with stage III-VA or T3/T4 (AJCC/UICC TNM staging system 8th ed.) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT, received a single intratumoral injection of NBTXR3 and IMRT (70 Gy in 35 fractions /7 weeks). A classical 3 + 3 dose escalation design has tested four doses of NBTXR3, equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume. The RP2D established as 22% of baseline tumor volume is further tested in the dose expansion part of the study. The primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor, by imaging according to RECIST v1.1. Safety is also evaluated. RESULTS As of August 13, 2020, 43 patients have been treated in the dose expansion part of the study. The median age was 70.7 years old (range: 50.7- 89.9), 70% of patients had cardiac disorder risk, 44% had gastrointestinal disorder risk and 44% metabolic and nutrition disorder risk. The median tumor volume was 42.8 mL (range: 1.3 - 222.3). In the evaluable population for efficacy (N = 31), the ORR of the primary lesion was 83.9% and the CRR 67.7% at a median time of 7.8 months after NBTXR3 injection. Three patients (7%) experienced at least one serious adverse event (AE) related to the injection procedure and/or NBTXR3 which represented less than 1% of all reported AEs. RT-related toxicity was as expected with IMRT. Three deaths due to AEs related to RT and other causes were reported. The recruitment is ongoing and updated efficacy and safety results will be presented. CONCLUSION NBTXR3 intratumoral administration followed by IMRT may represent an option in elderly in elderly patients or patients with multiple comorbidities with LA-HNSCC who have limited therapeutic options. NBTXR3 activated by RT showed promising anti-tumor efficacy, supporting further evaluation in a phase III randomized trial.