Background

Although antibodies that block PD-1/PD-L1 axis improve survival in patients with recurrent and/or metastatic HNSCC, safety and efficacy of neoadjuvant immunotherapy with PD-L1 with or without CTLA-4 blockade has not been explored. Here, we evaluate the safety and efficacy of a single dose of preoperative D with or without T (D+/-T) in patients with resectable HNSCC.

Methods

Patients with locally advanced but resectable HNSCC were eligible. Enrolled patients were randomized into D or D+T, stratified by primary site and human papilloma (HPV) infection status. A single dose of preoperative D (1500mg) or D+T (1500mg+75mg) was administered, with surgery planned 2 to 8 weeks later for curative resection. Postoperative (chemo) radiation was prescribed based on standard guidelines, followed by maintenance with D every 4 weeks for 1 year. The primary objective was to determine the local recurrence rate. Secondary endpoints included pathologic response, safety, tolerability, survival outcome, and exploration of immune dynamics.

Results

As of May 14, 2021 for interim analysis, a total of 44 patients were enrolled and received surgical resection with available data for pathologic response (D: 20 patients, D+T: 24 patients). Oropharyngeal cancer was most common (n=22), followed by hypopharyngeal (n=9), oral cavity (n=8), and laryngeal cancer (n=5). Human papilloma virus-mediated cancer was observed in 20 patients (45.4%). Neaoadjuvant D+/-T had an acceptable safety profiles and was not associated with delays in surgery or unexpected adverse events. Tumor shrinkage was observed in 31 patients (70.5%), with 16.0% of average tumor shrinkage (95% CI; 4.7% to 27.3%) in the overall population. Major pathologic response (no more than 10% of viable tumor cells) was achieved in 3 patients (6.8%), including 2 cases with pathologic complete response (4.5%). During median follow-up duration of 176 days after surgery, local recurrence was documented in 2 patients (4.5%).

Conclusions

These early data suggested that preoperative D+/-T was safe and feasible and had the potential to provide clinical benefits for patients with resectable HNSCC. The trial is ongoing and the updated outcomes with immune correlates will be presented with ESMO.

Clinical trial identification

NCT03737968.

Legal entity responsible for the study

The authors.

Funding

AstraZeneca, MedImmune.

Disclosure

All authors have declared no conflicts of interest.

Background

Anti-PD-L1 Immune checkpoint inhibition shows promise. Durvalumab (D) is an anti-PD-L1 monoclonal antibody with effect in solid tumors. Metformin (M) alters immunity in the tumor microenvironment, but clinical benefit has yet to demonstrated. Multiplex immune profiling has shown utility in predicting outcomes in HNSCC. We examine the distribution of CD8+ and FoxP3+ tumor-infiltrating T-cells and digital spatial genomic profiling (DSP) in response to therapy with D ± M.

Methods

In a single-center phase I, 4-week window of opportunity trial of resectable HNSCC, patients were randomized 3:1 to a single dose of D +/- daily M (up to 1000 mg BID). We analyzed CD8+ and FoxP3+ T-cell composition at the primary site pre- and post-therapy in the tumor and stromal interface. Whole slide images (WSI) were digitally analyzed (Aperio Technologies, Vista, CA). Image analysis algorithms were employed for CD8+ & FoxP3+ T cell counts (CC) and respective distances. A subset of samples were analyzed by NanoString GeoMX^TM DSP for CD8+, FoxP3+, and cytotoxic T-cell gene set transcripts.

Results

Of 32 evaluable patients, 37.5% (n = 12) had primary site pathologic response. Pre-treatment mean CD8-FoxP3 distance was greater in responders (20.5 μm vs 15.5 μm; p < 0.001). Mean CD8-FoxP3 distance showed a 15.4% decrease in responders (p < 0.001) and a 28.8% increase in non-responders (p < 0.001). Mean CD8-FoxP3 distances increased by 4.54% with D+M (p < 0.001) and 29.6% with D alone (p < 0.001). Relative CD8+ CC/μm² decreased within the tumor by 21.4% in responders (p = 0.003) and 14.9% with D+M (p = 0.004). DSP analysis of a subset of patients suggested an increase in cytotoxic T-cell signatures with therapy. Pre-treatment samples from responders showed higher cytotoxic T-cell signatures.

Conclusions

Greater pre-treatment mean CD8-FoxP3 distance and decreases in mean CD8-FoxP3 distances post-treatment were associated with pathologic response. Increased cytotoxic T-cell activity as determined by DSP were observed with therapy. This preliminary data suggests spatial analysis of T-cell subsets may be a biomarker for treatment response.

Clinical trial identification

NCT03618654.

Editorial acknowledgement

Legal entity responsible for the study

J.M. Curry.

Funding

AstraZeneca.

Disclosure

J.M. Curry: Financial Interests, Personal, Advisory Role: Rakuten Medical; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Funding: Castle Biosciences. A. South: Financial Interests, Personal, Stocks/Shares: Krystal Biotech; Financial Interests, Personal and Institutional, Funding: Zikani Therapeutics; Financial Interests, Personal, Stocks/Shares: Zikani Therapeutics; Non-Financial Interests, Personal, Advisory Role: Zikani Therapeutics. D. Cognetti: Non-Financial Interests, Personal, Advisory Board: Rakuten Medical; Non-Financial Interests, Personal, Other, Proctor: Intuitive Surgical. M.G. Mahoney: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb; Financial Interests, Personal, Royalties: Bristol Myers Squibb. A. Argiris: Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Debiopharm Group; Financial Interests, Personal, Advisory Role: Aspyrian Therapeutics; Financial Interests, Personal, Advisory Role: Seattle Genetics; Non-Financial Interests, Personal, Speaker’s Bureau: Merck Serono; Non-Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Merck Serono; Financial Interests, Personal, Funding: Genentech/Roche; Financial Interests, Personal, Funding: Bristol Myers Squibb. J.M. Johnson: Financial Interests, Personal, Funding: Bristol Myers Squibb ; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Funding: Merck; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb ; Financial Interests, Personal, Advisory Role: Rakuten Medical; Financial Interests, Personal, Advisory Role: Foundation Medicine. All other authors have declared no conflicts of interest.

Background

Despite the introduction of immune checkpoint inhibitors (ICI) in the management of recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), only a small subset of patients achieves long-term survivorship. In order to identify predictors of outcome, we evaluated gene expression profiles in patients at opposite ends of the spectrum of overall survival (OS) after ICI therapy.

Methods

In this retrospective, multicenter study, we analyzed gene expression (Clariom D, Affymetrix, Thermofisher) from histological samples of platinum-resistant RM-HNSCC patients treated with ICI alone. Each long-term survivor (LTS), defined as OS >18 months since the start of ICI, was matched with at least one short-term survivor (STS), defined as OS <6 months, according to site of recurrence (distant metastases only, or locoregional recurrence with/out metastases). We applied the Prediction Analysis for Microarrays classifier to infer six molecular HNSCC subtyping clusters, including immune related subtypes (De Cecco, Oncotarget 2015). Subsequently, a score was determined between each sample and the centroids for “Cl6-Immunereactive”.

Results

We analyzed a total of 26 LTS and 38 STS (clinical characteristics shown in table). We applied our six-subtype stratification to determine the samples belonging to the immune related clusters. In detail, LTS showed a positive association with Cl6 subtype score, while STS showed a negative association (p-value= 3.97E-06). The accuracy was investigated in terms of ROC analysis, reaching the significance with AUC = 81.3%; 95% CI: 71%-91.6% (DeLong-test). Table: 862MO

Conclusions

These preliminary data indicate the presence of underlying differences in gene expression profiles between LTS and STS after treatment with ICI for platinum-refractory RM-HNSCC. These observations need further study and may have translational implications improving treatment selection.

Legal entity responsible for the study

The authors.

Funding

AIRC (Associazione Italiana Ricerca sul Cancro) - IG 21740.

Disclosure

All authors have declared no conflicts of interest.

Background

The prognostic implication of HPV-mediated head and neck squamous cell carcinoma (HNSCC) is changing the approach to this disease in the cisplatin-based chemoradiation era. More recent trials provide new data to analyze factors influencing survival in this cohort. We aimed to find prognostic factors for survival in patients with HNSCC, assess outcomes by sex, and generate nomograms using data from 3 randomized trials.

Methods

This secondary analysis of 3 phase III randomized trials included patients age 18+ with pathologically confirmed HNSCC of the oral cavity, oropharynx, larynx, or hypopharynx. Training data from RTOG 0522/1016 were used to generate 3 models using different analytic approaches for both overall survival (OS) and progression-free survival (PFS) that were internally validated using cross-validation. The models with the highest C-indices were the Cox proportional hazards (CPH) models, which were then externally validated using data from RTOG 0129. Nomograms for OS and PFS at 2, 3, and 5 years were generated. Substaging for T/N categories was excluded to minimize heterogeneity between AJCC staging editions.

Results

721 patients from RTOG 0129, 891 from 0522, and 406 from 1016 met criteria for inclusion. The final multivariable CPH models for OS and PFS included age, sex, race, smoking history, primary site, p16 status, T category, N category, anemia (hemoglobin <= 13.5 g/dL for males, <= 12.5 g/dL for females), and Zubrod performance status. Nomograms to predict OS and PFS will be made publicly accessible at the time of manuscript publication. Both nomograms showed moderate to high predictive accuracy on validation dataset (C-index: OS 0.70, PFS 0.68).

Conclusions

Using a large cohort from 3 randomized trials of HNSCC patients receiving cisplatin-based chemoradiation, we developed internally and independently validated nomograms for prognostication of outcomes for individual patients using pretreatment clinical and patient characteristics. There was no association of sex with OS or PFS. To facilitate use and further validation of our nomograms, a free web-based tool is made available.

Legal entity responsible for the study

The authors.

Funding

NRG Oncology.

Disclosure

M. Machtay: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca. J. Caudell: Financial Interests, Personal, Research Grant, Grants and Honoraria: Varian Medical Systems. All other authors have declared no conflicts of interest.

Background

Approximately 45% of head and neck squamous cell carcinoma (HNSCC) patients are ≥65 years old, and this rate is expected to increase. We prospectively evaluated the role of comprehensive geriatric assessment (CGA) as a tool to personalize therapeutic approach in the elderly with locally advanced (LA) HNSCC.

Methods

We enrolled patients aged ≥65 years old, with stages III-IVb HNSCC according to the AJCC 7^th, and potentially suitable for curative treatment. At first, the HN multidisciplinary team (HN-MDT) defined a therapeutic indication driven by clinical judgement and standard evidence-based recommendations, and a geriatrician performed CGA, preceded by a G8 screening tool. Later, the same HN-MDT re-discussed the curative strategy in light of the CGA results. Primary objective was to define the proportion of changes in therapeutic indications after CGA. Secondary aims were to assess the distribution of elderly LA-HNSCC patients into three geriatric categories (fit, vulnerable, and frail) according to CGA and the accuracy of the G8 geriatric screening tool in this setting.

Results

Between December 2017 and March 2021, we enrolled 101 patients: 33.7% were fit, 39.6% vulnerable, and 26.7% frail. After geriatric assessment, the major therapeutic strategy changed in 12 cases (11.8%): in 7 it was de-intensified, in 4 intensified, and in one it changed from surgery to chemoradiation. Furthermore, CGA resulted in an increased demand for certain supportive care needs, such as nutritional (27.7% at first HN-MDT evaluation vs. 49.5% after CGA), psychological support and psychiatric treatments (3.9% vs. 19.8%), and chronic therapy modification (1% vs. 9%). G8 score >14 corresponded to fit patients at CGA in 83.3%, whereas ≤14 to vulnerable/frail in 87.3%. G8 score with cut-off ≤14 had sensitivity and specificity of 92.5% and 73.5%, respectively.

Conclusions

Geriatric intervention changed major therapeutic choices in about one out of 10 patients. In addition, CGA played an important role in tailoring elderly patients supportive care needs. Moreover, G8 can be used as a screening tool in LA-HNSCC, with a good sensitivity in identifying unfit patients who then need a complete geriatric evaluation, even if with limited specificity.

Legal entity responsible for the study

Gruppo Oncologico Nord-Ovest (GONO).

Funding

Associazione Italiana Oncologia Medica (AIOM).

Disclosure

All authors have declared no conflicts of interest.

Background

Adjuvant re-chemoradiation after salvage surgery improves disease-free survival in recurrent head and neck cancer. However, most patients are not eligible for re-irradiation and are kept under observation. We investigated the efficacy of metronomic adjuvant chemotherapy (MAC) in this group of patients in comparison with observation.

Methods

This is a randomized integrated phase II/III clinical trial. Adults with recurrent head and neck cancer, who underwent salvage surgery, and were not eligible for adjuvant re-irradiation were randomized in a 1:1 ratio to either MAC arm or observation. MAC consisted of oral methotrexate (at a dose of 15 mg per square meter of body surface area, weekly) and celecoxib (at a dose of 200 mg orally twice daily) for 6 months. The primary endpoint of phase II was disease-free survival (DFS), while that of phase III was overall survival (OS). For phase II, to detect an improvement in the hazard ratio (HR) with MAC, with a target HR of 0.67, type 1 error of 10% (1-sided) & type 2 error of 30%, 105 patients were required. For phase III, with a target HR of 0.77, type 1 error of 5% & type 2 error of 20%, 318 patients were required.

Results

We are reporting the results of the phase II part of the trial. The median DFS was 15.8 months (95% CI, 9.67-24.3) versus not reached (95% CI, 9.33-NA) in the MAC and observation arm, respectively (P=0.19). At a median follow up of 30.2 months (95% confidence interval (CI), 25.3 to 35.1) the 1-year and 2-year DFS was 59.4% (95% CI, 44.8 to 71.4) and 38.9% (95% CI, 25.1 to 52.5) in MAC arm, while the corresponding numbers were 62.3% (95% CI, 47.8 to 73.8) and 54.2% (95% CI, 39.8 to 66.5) in the observation arm (HR for progression, 1.42; 95% CI, 0.84 to 2.4; P=0.2). In the MAC arm the 1 year & 2- year OS was 78.7% (95% CI, 64.9 to 87.6) and 48% (95% CI, 34.1 to 62) respectively. In the observation arm the 1- year & 2- year OS was 79.2% (95% CI, 65.7 to 87.9) and 65.5% (95% CI, 50.9 to 76.7) (HR for death, 1.7, 95% CI, 0.94 to 3.08; P=0.08).

Conclusions

The adjuvant 6-month metronomic chemotherapy schedule was ineffective in improving outcomes in recurrent head and neck cancer patients post salvage surgery who are not eligible for re-radiation.

Clinical trial identification

Clinical Trials Registry- India (CTRI): CTRI/2016/04/006872.

Editorial acknowledgement

None

Legal entity responsible for the study

Kumar Prabhash.

Funding

Tata Memorial Center Research Administration Council (TRAC).

Disclosure

V. Noronha: Non-Financial Interests, Institutional, Research Grant, Research grants from Dr Reddy’s Laboratories, Amgen, and Sanofi, outside of the submitted work: Tata Memorial Centre. K. Prabhash: Non-Financial Interests, Institutional, Research Grant, Research grant from Glenmark Pharmaceuticals, Dr Reddy’s Laboratories, Fresenius Kabi India and Roche Holding, outside the submitted work: Tata Memorial Centre. All other authors have declared no conflicts of interest.