Locally Advanced Squamous Cell Carcinoma Of The Head And Neck Research Articles

LBA37 Final results: Randomized assessment of cisplatin dosing interval for ototoxicity (RADIO) trial comparing chemoradiation (CRT) with cisplatin q3weekly to weekly for locally advanced squamous cell carcinoma of the head and neck (LASCCHN)

LBA37 Final results: Randomized assessment of cisplatin dosing interval for ototoxicity (RADIO) trial comparing chemoradiation (CRT) with cisplatin q3weekly to weekly for locally advanced squamous cell carcinoma of the head and neck (LASCCHN)

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step 40 Gy with 56 Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck: A phase III trial (JCOG1912, NEW BRIDGE).

TPS6121 Background: Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. Methods: This study is a multicenter, two-arm, open-label, randomized phase III trial. The main inclusion criteria are as follows: (i) Primary lesions are located in the oropharynx, hypopharynx, or larynx. (ii) Histologically proven SCC on biopsy specimens of the primary lesion. Immunohistochemistry reveals p16 negativity in patients with oropharyngeal cancer. (iii) Clinical stage of III, IVA, or IVB (excluding N3a) based on the 8th UICC-TNM classification. Patients are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score.Patient accrual was started in May 2021 and the study is now open for accrual. A total of 186 patients have been enrolled as of January 2024. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100. Clinical trial information: jRCTs031210100 .

Study of late toxicity biomarkers of locally advanced head and neck cancer patients treated with radiotherapy plus cisplatin or cetuximab points to the relevance of skin macrophages (TOX-TTCC-2015-01).

Radiotherapy (RT) with concomitant cisplatin (CRT) or cetuximab (ERT) are accepted treatment options for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Long-term adverse events (AEs) have a vast impact on patients' quality of life. This study explored tissue biomarkers which could help predict late toxicity. Single-institution prospective study including patients aged ≥ 18 with histologically confirmed newly diagnosed LA-SCCHN treated with RT and either concomitant cisplatin q3w or weekly cetuximab, according to institutional protocols. All patients underwent pre- and post-treatment skin biopsies of neck regions included in the clinical target volume. Angiogenesis, macrophages, and extracellular matrix (ECM) markers were evaluated by immunohistochemistry (IHC). From April 15, 2016, to December 11, 2017; 31 patients were evaluated [CRT = 12 (38.7%) and ERT = 19 (61.3%)]. 27 patients (87%) had received induction chemotherapy. All patients finished RT as planned. IHC expression of vasculature (CD34) and collagen (Masson's Trichrome) did not differ significantly between and within CRT and ERT arms. Conversely, an increased CD68 and CD163 macrophage infiltration expression was observed after treatment, without significant impact of treatment modality. Patients with higher late toxicity showed lower expression of macrophage markers in pre-treatment samples compared with those with lower late toxicity, with statistically significant differences for CD68. Angiogenesis and ECM biomarkers did not differ significantly between CRT and ERT. Macrophage markers increased after both treatments and deserve further investigation as predictors of late toxicity in LA-SCCHN patients. [Protocol code: TOX-TTCC-2015-01/Spanish registry of clinical studies (REec): 2015-003012-21/Date of registration: 27/01/2016].

Abstract CT009: IMvoke010: A phase III, double-blind randomized trial of atezolizumab (atezo) after definitive local therapy vs placebo in patients (pts) with high-risk locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN)

Abstract Background: Treatment (tx) for LA SCCHN includes a combination of surgery, radiation and/or chemotherapy followed by monitoring for local recurrence/distant metastases as standard of care. Given poor outcomes, there remains a clear unmet need in this pt population. IMvoke010 (NCT03452137) evaluated the efficacy and safety of atezo in pts with LA SCCHN who are at high-risk for disease progression following multi-modal definitive tx. Methods: Eligible pts with LA SCCHN (Stage IVa or IVb involving the oral cavity, larynx, hypopharynx, HPV negative oropharynx or Stage III HPV positive oropharynx [per AJCC 8th edition]) with no disease progression after multi-modal definitive tx were randomized (1:1) to receive atezo 1200 mg or placebo. Tx was given every 3 weeks for 1 year or until disease progression, unacceptable toxicity or consent withdrawal. Primary endpoint: investigator-assessed event-free survival (INV-EFS). Other key endpoints: overall survival (OS, secondary for efficacy) and safety. Results: A total of 406 pts were randomized to receive either atezo (n=203) or placebo (n=203). 156 (38.4%) pts underwent surgery as part of definitive tx. At clinical cutoff (27 September 2023), median follow-up was 46.5 months (mos). Median INV-EFS was 59.5 mos with atezo vs 52.7 mos with placebo (HR, 0.94; 95% CI, 0.70-1.26). INV-EFS results were generally consistent across all subgroups. OS showed no difference between arms for atezo vs placebo. Safety data are reported (Table). Conclusion: This study did not meet the primary endpoint of INV-EFS, a numerical improvement in INV-EFS was observed for atezo in pts with LA SCCHN, but this was not statistically significant. Atezo was generally well tolerated, and no new safety signals were identified. Table: Key efficacy and safety results Efficacy Atezo (n=203)* Placebo (n=203) Median INV-EFS, mos 59.5 52.7 HR (95% CI) 0.94 (0.70-1.26) P-value 0.6804† Median OS, mos NE NE HR (95% CI) 0.96 (0.68-1.36) Safety, n (%) Grade 3-4 AEs 55 (27.2) 43 (21.2) TRAEs Grade 3-4 20 (9.9) 12 (5.9) Grade 5 AEs 3 (1.5) 5 (2.5) SAEs 32 (15.8) 32 (15.8) AEs leading to tx discontinuation 18 (8.9) 9 (4.4) CI, confidence interval; HR, hazard ratio; *safety-evaluable pts (n=202); †α boundary: 0.0427 Citation Format: Deborah J. Wong, Jérôme Fayette, Maria Teixeira, Kumar Prabhash, Ricard Mesia, Andrzej Kawecki, Arunee Dechaphunkul, José Dinis, Ye Guo, Muneyuki Masuda, Ching-Yun Hsieh, Maria Grazia Ghi, Claudia Vaz de Melo Sette, Tao Jiang, Yibing Yan, Monika Kaul, Ritika Jagtiani, Christina Matheny, Vaikunth Cuchelkar, Robert Haddad. IMvoke010: A phase III, double-blind randomized trial of atezolizumab (atezo) after definitive local therapy vs placebo in patients (pts) with high-risk locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT009.

Acute Toxicity Results from the Randomized Assessment of Cisplatin Dosing Interval for Ototoxicity (RADIO) Trial Comparing Chemoradiation (CRT) with Cisplatin Q3weekly to Weekly for Locally Advanced Squamous Cell Carcinoma of the Head and neck (LASCCHN)

Acute Toxicity Results from the Randomized Assessment of Cisplatin Dosing Interval for Ototoxicity (RADIO) Trial Comparing Chemoradiation (CRT) with Cisplatin Q3weekly to Weekly for Locally Advanced Squamous Cell Carcinoma of the Head and neck (LASCCHN)

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step40 with 56-Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck, an intergroup phase III trial (JCOG1912, NEW BRIDGE)

BackgroundChemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN.MethodsThis study is a multicenter, two-arm, open-label, randomized phase III trial. Patients with LA-SCCHN excluding p16 positive oropharynx cancer are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score.DiscussionIf the experimental arm is non-inferior to the standard arm in terms of TTF and superior on the safety endpoints, the 2-step40 procedure is the more useful treatment than SIB56 for definitive CRT.Trial registrationThis trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100 (https://jrct.niph.go.jp/latest-detail/jRCTs031210100). Date of Registration: May 2021.

Long-term results from a clinical study of xevinapant plus chemoradiotherapy in people with high-risk locally advanced squamous cell carcinoma of the head and neck: a plain language summary.

Squamous cell carcinoma of the head and neck (SCCHN) is the most common type of head and neck cancer. About half of the people with locally advanced (LA) SCCHN will have surgery to remove their cancer. For people who do not have surgery, chemoradiotherapy is the standard treatment, with the aim of fully removing the cancer. However, in many people, this treatment does not completely kill the cancer. This summary presents the main results of a phase 2 study of a medicine called xevinapant, which is under investigation as a potential future medicine for people with this type of cancer. In this study, researchers wanted to find out whether xevinapant plus chemoradiotherapy could stop the cancer from growing back or getting worse in the years after treatment completion in people with LA SCCHN. They also looked at whether people with this type of cancer had side effects from taking this medicine. Short-term results were collected 18months after treatment with chemoradiotherapy ended. These results showed that people who received xevinapant plus chemoradiotherapy were less likely to have their cancer grow back, or get worse in the part of the body where it was first found, than people who received liquid placebo-which looked and tasted the same as the active medicine (in this case, xevinapant), but did not contain any medicine-plus chemoradiotherapy. Researchers then continued to collect information for a longer amount of time (at least 3years). They wanted to see if treatment with xevinapant plus chemoradiotherapy was stopping the cancer from growing back or getting worse and helping people live longer. After this, people were monitored for a further 2years to see if they were alive 5years after treatment. The results showed that people with this type of cancer who were treated with xevinapant plus chemoradiotherapy were less likely to die, lived longer on average, and were less likely to have their cancer get worse. A phase 3 study, named TrilynX, in a larger group of people, is currently taking place to confirm the results of this study. Clinical Trial Registration: NCT02022098 (Debio 1143-201 Dose-finding and Efficacy Phase I/II Trial) (ClinicalTrials.gov).

Randomized phase 3 noninferiority trial of radiotherapy and cisplatin vs radiotherapy and cetuximab after docetaxel-cisplatin-fluorouracil induction chemotherapy in patients with locally advanced unresectable head and neck cancer

ObjectivesConcurrent chemoradiotherapy is the standard treatment for patients with unresectable, locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN); induction chemotherapy (ICT) may provide survival benefits in some patients. This study aimed to demonstrate the noninferiority of concomitant cetuximab plus radiotherapy (cet+RT) vs cisplatin plus radiotherapy (cis+RT) in patients with unresectable LA-SCCHN who were responsive to ICT. Materials and methodsThis randomized, open-label, phase 3 trial studied patients with unresectable LA-SCCHN who received 3 cycles of ICT (docetaxel, cisplatin, and 5-fluorouracil; TPF) followed by cis+RT (standard arm) or cet+RT (experimental arm). The primary endpoint was noninferiority of the experimental arm vs the standard arm in terms of overall survival (OS), based on a hazard ratio (HR) of < 1.3. Secondary endpoints included progression-free survival, overall response, safety, and quality of life (QOL). ResultsBetween July 15, 2008, and July 5, 2013, 519 patients were recruited and started ICT; 407 patients received post-ICT treatment (cis+RT, n = 205; cet+RT, n = 202). At a median follow-up of 43.9 (cis+RT) and 41.1 (cet+RT) months, median OS was 63.6 and 42.9 months with cis+RT and cet+RT, respectively (HR [90% CI] = 1.106 [0.888–1.378], P =.4492). There were no differences in progression-free survival, overall response rates, or adverse event rates between groups. There was greater late neurotoxicity with cis+RT than cet+RT (P =.0058). Several QOL dimensions improved with cet+RT vs cis+RT (physical functioning, P =.0287; appetite loss, P =.0248; social contact, P =.0153). ConclusionNoninferiority of cet+RT over cis+RT was not demonstrated.

693P Impact of one-week hydration after each three-weekly concurrent cisplatin on the tolerance among locally advanced head and neck cancer patients receiving chemoradiotherapy

Three-weekly high-dose cisplatin (100 mg/m2) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Concurrent chemoradiation (CRT) with high-dose cisplatin is associated with 30% of acute kidney injury (AKI). The aims of this study were to investigate the impact of our outpatient protocol of 7 day hydration after each cisplatin administration on the tolerance.

671P Postoperative chemoradiation in combination with cetuximab followed by 6-months cetuximab maintenance in squamous cell carcinoma of the head and neck with high risk of locoregional recurrence

Post-surgery chemoradiation (pCRT) is standard in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), although there is still a need to improve the outcome. We performed an open-label, single-arm, multicenter trial (EudraCT No. 2007-002659-17) and investigated safety and efficacy of escalating the multimodal therapy by adding concomitant and maintenance cetuximab (CTX).

SY17-3 Current status and perspective of the combination of immunotherapy and chemoradiotherapy for locally advanced head and neck cancer

The standard treatment for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is surgery ± postoperative (chemo)radiation therapy [(C)RT] or definitive CRT. The standard concurrent chemotherapy regimen is tri-weekly cisplatin. In the postoperative setting, weekly cisplatin is an alternative option. For laryngeal preservation, induction docetaxel, cisplatin, and 5-FU followed by (C)RT is the treatment option. Recently, the efficacy of combined immunotherapy and CRT for curative intent has been reported.

Abstract 3443: The IAP antagonist xevinapant, in combination with high-dose cisplatin chemoradiotherapy, induces NF-kB and apoptotic pathway biomarkers in patients with high-risk locally advanced squamous cell carcinoma of the head and neck

Abstract Introduction: Inhibitor of Apoptosis Proteins (IAPs) regulate apoptosis and modulate NF-kB signaling, which in turn drives the expression of genes involved in immune and inflammatory responses. Xevinapant (XVT) (a.k.a Debio 1143) is an orally available IAP antagonist shown to enhance tumor response to radiation through the proapoptotic cytokine TNFα and caspase activation. Results from a double-blind, multicenter, randomized, phase II trial in patients with high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) revealed significant improvement in overall survival (OS), progression free survival (PFS) and duration of response with XVT in combination with high-dose cisplatin chemoradiotherapy (CRT) vs CRT alone (NCT02022098). We analyzed XVT pharmacodynamic (PD) biomarker time-concentration profiles and explored the association of PD changes over time with clinical efficacy and safety parameters. Methods: Three serum PD biomarkers were measured during cycle 1: caspase-cleaved cytokeratin 18 fragment (CKM30), a biomarker of epithelial apoptosis, MCP1 and TNFα, both NF-kB target genes. Time course changes in PD biomarker exposure, measured by their Area Under the Curve (AUC), were tested for association with clinical efficacy and safety endpoints, by linear, logistic, and Cox Proportional Hazard models. Clinical response parameters included locoregional control (LRC) at 18 months from end of treatment (EOT), PFS, duration of LRC, time to distant relapse (TTDR), OS and complete response (CR) 6 months after EOT. Results: The biomarker analysis set was composed of all patients with baseline PD assessments and at least one post-baseline measurement and included 35 and 40 patients in the XVT and placebo (PBO) arms, respectively. All three serum PD biomarkers increased upon administration of CRT + XVT during cycle 1. The increase in CKM30 and MCP1 levels was significantly higher in the CRT + XVT arm vs the CRT + PBO arm, as tested by linear mixed effect models (CKM30: p = 0.0167; MCP1: p = 0.0135). Interestingly, CKM30 AUC appeared to be correlated with response in CRT + XVT but not CRT + PBO (based on LRC at month 18 or CR at month 6). No associations between any of the three biomarkers were observed with the safety endpoints explored. Conclusions: Xevinapant has demonstrated promising activity in combination with CRT in LA-SCCHN. The outcome of the exploratory PD analyses indicates that XVT modulates NF-kB signaling, leading to serum increases in MCP1 and TNFα while further augmenting CRT-induced apoptotic marker CKM30. Our findings further characterize the mechanism of action of XVT and how it may ultimately result in enhanced clinical responses to CRT. Citation Format: Luke Piggott, Bruno Gavillet, Franck Brichory, Kathrin Gollmer, Florilene Bouisset, Gregoire Vuagniaux. The IAP antagonist xevinapant, in combination with high-dose cisplatin chemoradiotherapy, induces NF-kB and apoptotic pathway biomarkers in patients with high-risk locally advanced squamous cell carcinoma of the head and neck [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 3443.

The RADIO trial: Randomized assessment of cisplatin dosing interval for ototoxicity with curative concurrent chemo-radiation for locally advanced head and neck squamous cell carcinoma.

TPS12144 Background: Patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) receive curative chemoradiation (CRT) with Cisplatin, as a standard of care. A meta-analysis of 52 randomized trials comparing Low Dose (LD) and High Dose (HD) schedules demonstrated differing toxicity profiles but hearing effects were not rigorously studied. Hearing loss associated with HD Cisplatin can result in survivorship challenges. A local study suggested a protective effect for LD Cisplatin in relation to ototoxicity and pharmacogenomic markers, MATE1 and COMT, to be associated with risk for ototoxicity. We hypothesize that LD cisplatin is associated with reduced frequency of hearing loss when compared to the standard HD cisplatin in LASCCHN patients on CRT and that differences in MATE1/COMT can predict for cisplatin-related ototoxicity and be identified prior to treatment. Our goal is to develop an innovative personalized treatment pathway incorporating predictive pharmacogenomics markers to improve the tolerability and survivorship outcomes of curative CRT for LASCCHN. Methods: This is a prospective, open-label, randomized clinical trial. Following informed consent, eligible LASCCHN patients planned for primary CRT will be stratified by tumor p16 status and then randomized in 1:1 fashion to either concurrent LD Cisplatin (40mg/m2 every week) or HD cisplatin (100mg/m2 every 3 weeks). The primary outcome is to measure the change in incidence of CTCAE grade ≥2 hearing loss and hearing-related quality of life (QOL) at 1 year. As part of secondary and exploratory outcomes, differences in survival, loco-regional control, global QOL and other toxicities (e.g. nephrotoxicity, neurotoxicity) will be assessed. The relationship between MATE1 and COMT, as predictors for cisplatin-related ototoxicity will be evaluated. Cost-effectiveness analyses comparing the two regimens will be assessed. Statistical plan: Based on rates of CTCAE grade ≥2 hearing loss in an earlier study (Winquist et al., 2016), assuming a conservative rate of hearing loss, amongst treated patients, of 60% with HD cisplatin and 30% with LD cisplatin, a total sample size of 92 patients would achieve &gt; 80% statistical power, (two-sided, alpha = 0.05 test of two proportions) to detect these differences. 100 patients would be targeted to accrual for an assumed 5% noncompliance rate. For hearing related QOL, a two-sided, alpha = 0.05, two-sample t-test with 50 patients per group would achieve &gt; 80% statistical power to detect an effect size of 0.60 and &gt; 95% power to detect an effect size of 0.75. All analyses will be based primarily on the intent-to-treat population. An arms-length data and safety monitoring committee (DSMC) will review safety data bi-annually. Trial accrual status: 60 participants have been accrued. Clinical trial information: NCT03649048.

Current Aspects and Future Considerations of EGFR Inhibition in Locally Advanced and Recurrent Metastatic Squamous Cell Carcinoma of the Head and Neck

Simple SummarySquamous cell carcinoma of the head and neck (SCCHN) is a debilitating disease that affects hundreds of thousands of individuals worldwide and has a high mortality rate. Mainstay treatment largely consists of surgery, radiation, and chemotherapy which has been met with significant morbidity. The epidermal growth factor receptor is one that which plays a major role in cell signaling and has been extensively studied in locally advanced (LA) and recurrent metastatic (RM) SCCHN. This review paper details the major roles of the epidermal growth factor receptor (EGFR), previous and current EGFR inhibition therapeutics, resistance mechanisms, and the possible integration of immunotherapy and EGFR inhibition in this disease process. Recurrent metastatic (RM) and locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) are devasting disease states with limited therapeutic options and poor overall survival. Targeting the epidermal growth factor receptor (EGFR) is one area that has helped improve outcomes in this disease. Anti-EGFR based therapies have been shown to improve overall survival and mitigate the significant toxicities incurred from standard radiation, chemotherapy, and/or surgical options. Cetuximab, the most well-studied anti-EGFR monoclonal antibody, has demonstrated a positive impact on outcomes for RM and LA SCCHN. However, the development of early resistance to cetuximab highlights the need for a wider arsenal of therapy for RM and LA diseases. The use of immune checkpoint inhibitors has recently transformed the treatment of recurrent SCCHN. Drugs such as pembrolizumab and nivolumab have demonstrated success in recent clinical trials and have been approved for the treatment of advanced disease. Given the positive results of both EGFR targeted agents and immune checkpoint inhibitors, ongoing trials are studying their synergistic effects.

PCN72 An EARLY Cost-Effectiveness Analysis of Xevinapant in Combination with Chemo-Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck in United States.

To assess the cost-effectiveness of xevinapant in combination with cisplatin-based chemoradiotherapy (CRT) compared to CRT in the treatment of patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) from the perspective of a US third-party payer.

Nivolumab and Ipilimumab Combined with Definitive Radiation Therapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: In-field Toxicity Analysis of a Phase I Clinical Trial

Cisplatin added to radiation therapy (RT) for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is associated with a modest improvement in survival at the cost of increased toxicity, highlighting the need for newer agents. Immune checkpoint inhibitors (ICI) have a favorable safety profile and are the standard of care in recurrent/metastatic SCCHN, but their role in the definitive setting with RT remains to be determined. We conducted a single institution clinical trial assessing the safety of combined nivolumab (Nivo), a PD-1 inhibitor, and ipilimumab (Ipi), a CTLA-4 inhibitor, with concurrent RT in patients with high risk LA-SCCHN. Newly diagnosed, chemotherapy eligible patients (pts) with stage IVA-IVB p16(-) SCC of the oral cavity, oropharynx, larynx, and hypopharynx, or T4, N2c, or N3 p16(+) SCC of the oropharynx (AJCC 7th edition) were enrolled. Nivo (3 mg/kg Q2 weeks IV x17 doses) and Ipi (1 mg/kg Q6 weeks IV x6 doses) were administered 2 weeks prior to the start of RT. RT (70 Gy in 2 Gy daily fractions) was delivered to the primary tumor using VMAT and daily cone-beam CT IGRT. The primary objective was safety of combined ICI and RT. Between July 2017 and July 2019, 24 pts were enrolled with a median follow-up of 15 months (range 7-31); median age 60 (range 48-77); 20 male; 16 oropharynx (14 HPV+), 6 larynx, and 2 hypopharynx. All pts completed RT with no treatment delays. Seventeen out of twenty-four pts (71%) experienced grade 3 acute in-field adverse events (AE) consisting of mucositis (9), dysphagia (6), dermatitis (5), odynophagia (4), and dysphonia (1) during concurrent ICI-RT; there were no grade 4/5 AEs during ICI-RT. Five pts (22%) developed soft tissue ulcers (STU) at the primary tumor site during the ICI maintenance phase, one of which was not treated and led to a fatal carotid rupture. All STUs developed at a median of 91 (range 50-107) days post RT and were negative for viable tumor. Four primary site STUs were managed with either hyperbaric oxygen (HBO) (2), lingual artery embolization (1), or surgical debridement (1). One pt treated with HBO healed after 189 days while the pt who underwent debridement healed after 285 days. Two additional pts developed areas of necrosis at adjacent sites not involved by tumor, underwent surgical debridement, and healed after an average of 18.5 days. Two other pts experienced osteoradionecrosis (ORN) at sites of prior teeth extractions and were treated with HBO. Two pts experienced persistent inflammation without ulceration (PI). Six out of eleven pts (55%) with STU, necrosis, ORN, or PI discontinued maintenance ICI. Locoregional PFS is 100%. Combined PD-1 and CTLA-4 blockade with concurrent RT is associated with excellent locoregional control in high risk LA-SCCHN, albeit at the cost of in-field complications. Patients treated with such an approach should be closely monitored for soft tissue ulceration.

LBA39 3-years follow-up of double-blind randomized phase II comparing concurrent high-dose cisplatin chemo-radiation plus xevinapant or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck

This was a double-blind, randomized phase 2 study of 96 patients with poor prognosis locally advanced, squamous cell carcinoma of the head and neck (LA-SCCHN). Previously reported data showed significant improvements of xevinapant (Debio 1143) versus placebo in addition to chemoradiation (CRT) for the primary endpoint of locoregional control (LRC) rate at 18 months, and demonstrated that addition of Debio 1143 was feasible, safe and did not compromise backbone therapy. Here we report up-dated data on PFS and overall survival (OS). Patients, stratified by node involvement, tumor localization and HPV-16 status, were randomized (1:1) to receive Debio 1143 or matching placebo at 200 mg/day, oral once daily D1–14 q3w (3 cycles) when added to standard high-dose cisplatin CRT. PFS and OS were analyzed using a Cox model in the intention-to-treat population. Median and survival rates at 36 months were estimated by the Kaplan-Meier method. As of 21 Jul 2020, the median follow-up was 33 months. Debio 1143 combined with CRT showed a statistically significant improvement in OS vs placebo by reducing the risk of mortality by 51% (HR=0.49, [95%CI: 0.26-0.92], P=0.0261). The 3 years OS rate was 66% (95% CI: 49–78) in the Debio 1143 arm versus 51% (95% CI: 34–65) in the placebo arm; the median OS is not reached with Debio 1143 vs. 36.1 months with placebo (95%CI: 21.8-46.7). Statistically significant improvement in PFS was demonstrated, reducing the risk of disease progression or death by 66% (HR=0.34 [95%CI, 0.17-0.68], p=0.0023) and improving probability of PFS at 36 months to 72% in the Debio 1143 arm compared to 36% in the placebo arm. The predictable and manageable safety profile observed with Debio 1143 + CRT after 2 years remained unchanged after 3 years. These results with extended follow-up confirm those previously reported, showing now in addition a statistically and clinically significant OS benefit by adding Debio 1143 to standard CRT. The confirmatory phase III Trilynx study (EudraCT Number: 2020-000377-25) is ongoing.

Feasibility and efficacy of chemoradiotherapy with concurrent split-dose cisplatin after induction chemotherapy with docetaxel/cisplatin/5-fluorouracil for locally advanced head and neck cancer.

Chemoradiotherapy (CRT) with concurrent high-dose cisplatin (CDDP) is a standard treatment for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Docetaxel plus CDDP and 5-fluorouracil (TPF) induction chemotherapy (ICT) prior to CRT is considered for patients at high risk of distant metastases. The purpose of the current study was to evaluate the feasibility and efficacy of CRT with split-dose CDDP after TPF-ICT for LA-SCCHN. A total of 21 LA-SCCHN patients treated with TPF-ICT followed by concurrent CRT with split-dose CDDP between January 2011 and December 2017 were retrospectively analysed. The patients' characteristics were i) median age 66 years (48-75 years); ii) male/female, 21/0; iii) performance status 0-1/2, 20/1; iv) larynx/hypopharynx/oropharynx/oral cavity, 4/8/8/1 and v) clinical stage III/IV, 3/18. The numbers of TPF-ICT cycles 1/2/3 were 2/3/16. Median cumulative doses of CDDP in TPF-ICT and CRT were 180.0 and 206.7 mg/m2, respectively. All patients completed 70 Gy RT. The complete response rate was 76.2%. At a median follow-up of 51.5 months, median PFS and OS were not reached and 65.5 months, respectively. The most common grade 3 or worse toxicities during CRT-ICT were stomatitis (48%), dysphagia (21%), anorexia (17%) and leukopenia (14%). However, no grade 2 or worse nephrotoxicity, neurotoxicity or ototoxicity was observed. The results demonstrated that concurrent CRT with split-dose CDDP after TPF-ICT is feasible and effective for LA-SCCHN.

Phase II/III trial of post-operative chemoradiotherapy comparing 3-weekly cisplatin with weekly cisplatin in high-risk patients with squamous cell carcinoma of head and neck (JCOG1008).

6502 Background: The standard treatment for post-operative high-risk patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (CDDP) (100 mg/m2, q3wk, 66 Gy/33Fr; 3-weekly CDDP+RT). However, one concern with 3-weekly CDDP+RT is insufficient CDDP compliance due to high-dose-related toxicities. Weekly CDDP+RT (40 mg/m2, qwk, 66 Gy/33Fr; weekly CDDP+RT) is an alternative regimen with better compliance. Here, we conducted a phase II/III trial of weekly CDDP+RT in post-operative high-risk LA-SCCHN. Methods: This is a multi-institutional randomized phase II/III trial to confirm the non-inferiority of weekly CDDP+RT (Arm B) compared with 3-weekly CDDP+RT (Arm A). The trial enrolled pts aged 20-75 years with post-operative high-risk features (microscopically positive margin and/or extranodal extension) and ECOG-PS 0-1. Pts were randomized in a 1:1 ratio to Arm A or Arm B. Primary endpoint of phase II was the proportion of treatment completion and that of phase III was overall survival (OS). A non-inferiority margin of hazard ratio (HR) was set at 1.32. Results: Between Oct 2012 and Dec 2018, 261 pts were enrolled (Arm A 132 pts, Arm B 129 pts). At the planned second interim analysis in phase III with 76/161 events, the Data and Safety Monitoring Committee recommended terminating the trial and publishing the results because the statistical boundary for OS non-inferiority had met the pre-specified stop criteria. With a median follow-up of 2.2 years in all randomized pts, 3-year OS was 59.1% in Arm A and 71.6% in Arm B with a HR of 0.69 (99.1% CI, 0.374-1.273 [ &lt; 1.32], one-sided p for non-inferiority = 0.00272 &lt; 0.00433). 3-year RFS was 53.0% in Arm A and 64.5% in Arm B with a HR of 0.71 (95% CI, 0.48-1.06). Regarding acute adverse events, neutropenia (≥ grade 3), increased creatinine (≥ grade 2), hearing impairment (≥ grade 2) and mucositis (≥ grade 2) occurred in 48.8%, 8.5%, 7.8% and 55.0% in Arm A and 35.3%, 5.7%, 2.5% and 59.0% in Arm B, respectively. For compliance, median total dose of CDDP was 280 mg/m2 (IQR, 250-299) in Arm A and 239 mg/m2 (IQR, 199-277) in Arm B. Total radiation dose was 66 Gy (IQR, 66-66) in both arms. Proportion of treatment completion was 93.2% in Arm A and 86.8% in Arm B. Conclusions: Weekly CDDP+RT is non-inferior to 3-weekly CDDP+RT for post-operative high-risk LA-SCCHN pts and has a favorable toxicity profile. Weekly CDDP+RT should be considered the new standard treatment option for these pts. Clinical trial information: 000009125 .

PCN340 TREATMENT OUTCOMES IN LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF HEAD AND NECK PATIENTS WHO SUBSEQUENTLY PROGRESSED: REAL-WORLD EVIDENCE FROM EUROPE AND THE US

To describe outcomes of treatment for locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) in patients who completed frontline, locoregional treatment. A real-world cross-sectional survey was conducted in France, Germany, the UK, Spain, Italy (EU5) and the US from April–September 2016. Inclusion criteria considered oncologists, qualified for 5-35 years, who made treatment decisions for ≥10 SCCHN patients/month. Physicians provided information on their next 8 consecutive SCCHN patients receiving 1L R/M treatment after previously receiving treatment for locally advanced disease. All analyses are descriptive. Physicians (n=213) provided data on 557 patients (n=458 EU5, n=99 US). Mean patient age was 63.1 years; 68% of patients were male. 68% (n=377) of patients did not receive surgery (un-resected), of whom 78% had Eastern Cooperative Oncology Group scores (ECOG) of 0-1 at diagnosis. At initiation of subsequent R/M treatment, 66% of patients who were un-resected in LA setting had ECOG 0-1. 53% of un-resected patients received chemoradiation (CRT) in the LA setting: 29% achieved complete response; 36% had partial response/stable disease; and 32% had progressive disease. In un-resected patients who did not receive CRT (non-CRT) in the LA SCCHN setting, the respective percentages were 17%, 35% and 35% of patients. Mean duration of therapy was 14.1 weeks in patients who received CRT and 14.6 weeks in non-CRT patients. Median time to next treatment was 23.7 weeks in patients who received CRT in the LA setting, and 5.9 weeks in non-CRT patients. CRT is used as frontline treatment for the majority of un-resected LA SCCHN patients who subsequently progressed. While physicians reported improved treatment outcomes and longer time to initiation next treatment in CRT vs. non-CRT patients, achievement of complete response remains low (<50%). Therefore, there remains a need for more efficacious treatment modalities in the frontline LA SCCHN setting.