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Purpose: Biomarkers that predict response to immune checkpoint inhibitors (ICI) in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are needed. This retrospective study assessed tumor mutational burden (TMB) and outcomes in the phase II HAWK and CONDOR and phase III EAGLE studies of durvalumab with or without tremelimumab in platinum-resistant R/M HNSCC. Patients and Methods: Tumor samples from HAWK/CONDOR (N = 153) and blood samples from EAGLE (N = 247) were analyzed for TMB. Associations with survival were evaluated for tissue TMB (tTMB) at cutoffs from 10 to 20 mutations/megabase (mut/Mb) and for blood plasma TMB (bTMB) at cutoffs from 8 to 24 mut/Mb. Results: In HAWK/CONDOR, overall survival (OS) with durvalumab with or without tremelimumab was longer for high versus low tTMB: statistically significant differences were observed with durvalumab plus tremelimumab at tTMB ≥ 10 mut/Mb [HR, 0.52 (95% confidence interval, CI, 0.28–0.98)] and tTMB ≥ 12 mut/Mb [HR, 0.46 (95% CI, 0.24–0.86)]. In EAGLE, a significant OS benefit versus chemotherapy was observed with durvalumab and durvalumab plus tremelimumab at bTMB≥16 mut/Mb [HR, 0.39 (95% CI, 0.20–0.76) and 0.38 (95% CI, 0.19–0.78), respectively] but not bTMB < 16 mut/Mb [HR, 0.92 (0.61–1.37) and 0.92 (95% CI, 0.62–1.36), respectively]. A significant progression-free survival benefit was also observed in the ICI arms versus chemotherapy at bTMB ≥ 16 mut/Mb. Conclusions: Findings support TMB as a biomarker for predicting survival in patients with platinum-resistant R/M HNSCC treated with ICIs. The analysis of EAGLE demonstrated that bTMB was predictive of survival with ICI treatment versus chemotherapy in a large, randomized controlled study population.

Identification of tumours harbouring an overall active immune phenotype may help for selecting patients with advanced head and neck squamous cell carcinomas (HNSCC) and non-small cell lung cancer (NSCLC) who may benefit from immunotherapies. Our objective was to develop a reliable and stable scoring system to identify those immunologically active tumours.Using gene expression profiles of 421 HNSCC, we developed a score to identify immunologically active tumours. Validation of the 'HOT' score was done in 40 HNSCC and 992 NSCLC. Stability of the 'HOT' score was tested in paired HNSCC samples from diagnostic biopsies versus surgically resected specimens, untreated versus recurrent samples, and pre-versus post-cetuximab samples in a total of 76 patients. The association between the 'HOT' score with overall survival (OS) and progression-free survival (PFS) was tested in 184 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors.A 27-gene expression based 'HOT' score was correlated with: (i) PD-L1 and IDO1 expression, (ii) TCD8 infiltrate and (iii) activation of the IFN-γ pathway. The HOT score concordance when comparing diagnostic biopsies and surgically resected specimens was higher than in untreated samples versus recurrent or pre-versus post-cetuximab samples. In 102 and 82 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors, the HOT score was associated with an improved OS and PFS in multivariate analysis.The 'HOT' score is a simple and robust approach to identify real-world patients with HNSCC and NSCLC immunologically active tumours who may benefit from PD-1/PD-L1 inhibitors.

Indications of adjuvant radiotherapy (RT) for high-risk cutaneous squamous cell carcinoma (cSCC) are not clearly defined. We aimed to identify factors predicting relapse in cSCC patients treated with surgery or RT alone and to assess in which clinical setting adjuvant RT was beneficial in term of progression free survival (PFS).This retrospective analysis included patients with resectable primary cSCC treated with surgery and/or RT in curative intent, managed at Centre Léon Bérard (Lyon, France) from April 2010 to September 2020.A total of 303 patients with 529 cSCC were included. 31 (5.9%) cSCC were treated with surgery and adjuvant RT. With a median follow-up of 54 (0.2-126) months, 103 (19.5%) cSCC relapsed. In multivariate analysis, the highest predictive factor of relapse in cSCC was the number of risk factors (HR = 15.110 [95% CI: 3.91-58.40] for ≥3 risk factors p 0.001), followed by poor differentiation (HR = 4.930 [95% CI: 2.47-9.86], p 0.001) and perineural invasion (HR = 2.442 [95% CI: 1.11-5.38], p = 0.027). For cSCC with ≥3 risk factors, PFS was significantly higher in cSCC treated with surgery and adjuvant RT compared to those treated with surgery or RT alone (the 36-month PFS was 74% [95% CI: 43-90%] and 31% [95% CI: 10-54%] respectively, p = 0.008).An increased number of risk factors was identified as being the highest predictive factor of relapse in cSCC. Adjuvant RT improved PFS for high-risk cSCC with ≥3 risk factors.

FIG S2. Kaplan-Meier plot of OS in the durvalumab monotherapy, durvalumab plus tremelimumab and SoC treatment arms in the NLR ≤ 7 subgroup (A) and NLR > 7 subgroup (B) in EAGLE.

Supplementary Data

Purpose:Biomarkers that predict response to immune checkpoint inhibitors (ICI) in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are needed. This retrospective study assessed tumor mutational burden (TMB) and outcomes in the phase II HAWK and CONDOR and phase III EAGLE studies of durvalumab with or without tremelimumab in platinum-resistant R/M HNSCC.Patients and Methods:Tumor samples from HAWK/CONDOR (N = 153) and blood samples from EAGLE (N = 247) were analyzed for TMB. Associations with survival were evaluated for tissue TMB (tTMB) at cutoffs from 10 to 20 mutations/megabase (mut/Mb) and for blood plasma TMB (bTMB) at cutoffs from 8 to 24 mut/Mb.Results:In HAWK/CONDOR, overall survival (OS) with durvalumab with or without tremelimumab was longer for high versus low tTMB: statistically significant differences were observed with durvalumab plus tremelimumab at tTMB ≥ 10 mut/Mb [HR, 0.52 (95% confidence interval, CI, 0.28–0.98)] and tTMB ≥ 12 mut/Mb [HR, 0.46 (95% CI, 0.24–0.86)]. In EAGLE, a significant OS benefit versus chemotherapy was observed with durvalumab and durvalumab plus tremelimumab at bTMB≥16 mut/Mb [HR, 0.39 (95% CI, 0.20–0.76) and 0.38 (95% CI, 0.19–0.78), respectively] but not bTMB < 16 mut/Mb [HR, 0.92 (0.61–1.37) and 0.92 (95% CI, 0.62–1.36), respectively]. A significant progression-free survival benefit was also observed in the ICI arms versus chemotherapy at bTMB ≥ 16 mut/Mb.Conclusions:Findings support TMB as a biomarker for predicting survival in patients with platinum-resistant R/M HNSCC treated with ICIs. The analysis of EAGLE demonstrated that bTMB was predictive of survival with ICI treatment versus chemotherapy in a large, randomized controlled study population.

Extra-cellular galectins 1, 3 and 9 (gal-1, -3 and -9) are known to act as soluble immunosuppressive agents in various malignancies. Previous publications have suggested that their expression is dependent on the metabolic status of producing cells and reciprocally that they can influence metabolic pathways in their target cells. Very little is known about the status of gal-1, -3 and -9 in patients bearing head and neck squamous cell carcinomas (HNSCC) and about their relationships with the systemic metabolic condition. This study was conducted in plasma samples from a prospective cohort of 83 HNSCC patients with advanced disease. These samples were used to explore the distribution of gal-1, -3 and -9 and simultaneously to profile a series of 87 metabolites assessed by mass spectrometry. We identified galectin and metabolic patterns within five disease categories defined according to the primary site and human papillomavirus (HPV) status (HPV-positive and -negative oropharyngeal carcinomas, carcinomas of the oral cavity, hypopharynx and larynx carcinomas). Remarkably, samples related to hypopharyngeal carcinomas displayed the highest average concentration of gal-9 (

Mammalian target of rapamycin (mTOR) regulates cellular functions by integrating intracellular signals and signals from the tumor microenvironment (TME). The PI3K-AKT-mTOR pathway is activated in 70% of head and neck squamous cell carcinoma (HNSCC) and associated with poor prognosis. This phase I-II study investigated the effect of mTOR inhibition using weekly everolimus (30 mg for dose level 1, 50 mg for dose level 2) combined with weekly induction chemotherapy (AUC2 carboplatin and 60 mg/m2 paclitaxel) in treatment-naïve patients with locally advanced T3-4/N0-3 HNSCC. Patients received 9 weekly cycles before chemoradiotherapy. Objectives were safety and antitumor activity along with tissue and blood molecular biomarkers. A total of 50 patients were enrolled. Among 41 evaluable patients treated at the recommended dose of 50 mg everolimus weekly, tolerance was good and overall response rate was 75.6%, including 20 major responses (≥50% reduction in tumor size). A significant decrease in expression of p-S6K (p-value: 0.007) and Ki67 (p-value: 0.01) was observed in post-treatment tumor tissue. Pro-immunogenic cytokine release (Th1 cytokines IFN-γ, IL-2, and TNF-β) was observed in the peripheral blood. The combination of everolimus and chemotherapy in HNSCC was safe and achieved major tumor responses. This strategy favorably impacts the TME and might be combined with immunotherapeutic agents.

PURPOSEMutations in the HRAS (m HRAS) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function. We evaluated the efficacy of tipifarnib in patients with R/M m HRAS HNSCC.METHODSWe enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m HRAS malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with m HRAS variant allele frequency (VAF) data, enrollment was limited to those with a m HRAS VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles.RESULTSOf the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%).CONCLUSIONTipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with HRAS mutations for whom limited therapeutic options exist ( NCT02383927 ).

Background: Hyperprogressive disease (HPD) rate in head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint inhibitors (ICI) was determined using tumor growth kinetics (TGK) and compared with rapidly progressive screen-failure (SF) patients. The impact of TGK on outcomes with salvage chemotherapy (SCT) was also evaluated. Results: HPD was found in 22/120 (18%) patients. Median TGK before the onset of immunotherapy (TGKpre) was 2.7 for SF patients and 4.8 for HPD patients, with no significant difference (p = 0.17). Disease control rate after initial progressive disease on ICI was 86% with SCT in case of tumor growth deceleration vs 39% in case of tumor growth acceleration. Conclusions: HPD was frequent, but TGK of HPD patients treated with ICI did not differ from SF patients, suggesting that there is no relevant causal relationship between HPD and ICI. After initial PD with ICI, tumor growth deceleration was associated with better outcomes, indicating that TGKR might be useful to detect late responders, meriting prospective investigations. Materials and Methods: TGK ratio (TGKR) was defined as the ratio of TGK on ICI (TGKpost) to TGKpre. HPD was defined as TGKR ≥ 2. TGKR >1 indicated tumor growth acceleration, while 0 < TGKR < 1 indicated tumor deceleration.

EGFR is a known driver of cancer growth, and leucine-rich, repeat-containing, G-protein coupled receptor 5 (LGR5) is a transmembrane receptor expressed on cancer stem cells. Petosemtamab is a human, common light chain, IgG1 bispecific antibody with ADCC-enhanced activity, targeting EGFR and LGR5, which has shown potent antitumor activity in patient (pt)-derived HNSCC xenograft models. In the dose escalation part of an ongoing phase 1/2 study, the RP2D was established at 1500 mg Q2W, 4 week cycle (JCO 2021:39.3 Sup 62). Petosemtamab is being investigated in the expansion part in pts with selected advanced solid tumors. Promising activity was seen in HNSCC pts previously treated with both platinum-based chemotherapy and checkpoint inhibitors (MCT 2021:20 Sup12 P185). We present data of the expanded HNSCC cohort treated at the RP2D. Primary objective (expansion): investigator-assessed ORR per RECIST 1.1. Secondary objectives: ORR, DOR, PFS (per investigator and central review), OS and safety/tolerability. Key eligibility criteria: advanced/metastatic HNSCC, prior standard therapy, ECOG PS 0-1, measurable disease (RECIST 1.1), baseline tumor biopsy. At the data cutoff date (28 Nov 2022), 49 HNSCC pts were treated. Median age was 63 years (range 31-77), ECOG PS 0/1: 13/35 pts, and 78% were male. Most frequent primary tumor locations were oropharynx (35%), oral cavity (31%), and larynx (16%). Pts received a median of 2 (range 1-4) lines of prior systemic therapy, including anti-PD-1/PD-L1 in 96% of pts and platinum-based chemotherapy in 92% of pts; 2 pts received prior cetuximab. A median of 4 treatment cycles (range 1-21) was administered, with 17 pts continuing on therapy at the cutoff. Among 42 pts evaluable for efficacy (≥2 cycles and ≥1 postbaseline scan, or early PD), ORR per investigator was 35.7% (15/42), including 1 CR (ongoing after 18 months), 12 PRs, and 2 unconfirmed PRs with treatment ongoing at the cutoff. 15 pts had SD and DCR was 71.4%. Median DOR was 6.0 months (95%CI=3.3-not calculable). Median PFS was 5.0 months (95%CI=3.2-6.8). Of 78 pts treated at the RP2D (escalation and all expansion cohorts), the most frequent AEs regardless of causality (all grades/G3-4) were rash (33%/0%), hypotension (26%/6%), dyspnea (26%/4%), nausea (26%/1%), dermatitis acneiform (24%/1%), blood magnesium decreased (19%/5%), erythema (19%/0%), diarrhea (19%/0%); IRRs (composite term) were reported in 74%/21% of pts, mostly at the first infusion, and all resolved. 5 pts (6%) discontinued treatment due to IRRs on Day 1. 1 esophageal cancer pt died due to unrelated G5 GI bleeding. Retrospective biomarker analyses will be presented. Petosemtamab demonstrates promising clinical efficacy with a manageable safety profile in pretreated HNSCC pts. Further clinical development in HNSCC is planned with petosemtamab monotherapy and in combination with SOC. Citation Format: Ezra E. Cohen, Jérôme Fayette, Amaury Daste, Caroline Even, Christophe Le Tourneau, Irene Brana, Esma Saada, Elisa Fontana, Lara Iglesias, Shumei Kato, Rocio Garcia-Carbonero, Josep Tabernero, Guillem Argilés, Marina Magin, Yu-Ming Shen, Renée de Leeuw, Mohamed Bekradda, Eduardo Pennella, Ernesto Wasserman, Viktoriya Stalbovskaya, Jeroen Lammerts van Bueren, Lokesh Jain, Andrew Joe, Antoine Hollebecque. Clinical activity of MCLA-158 (petosemtamab), an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell cancer (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT012.

Background For patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), surgery (S) followed by radiotherapy (RT) is a standard of care. Randomized controlled trials have shown that postoperative chemoradiation (CRT) increased the locoregional control (LRC) and overall survival (OS) in patient with R1-resection margin and/or extranodal extension (ENE). ENE has been introduced in the 8th TNM staging classification since its presence has been shown to have an independent adverse prognostic impact. The data supporting this finding were however mainly collected in the pre-CRT era. Objectives The objective of this study was to challenge the adverse prognostic factor of ENE in the era of CRT. Methods A retrospective cohort study was performed to evaluate patients diagnosed with LAHNSCC and undergoing a treatment by S and postoperative RT or CRT in Centre Leon Berard, Lyon, France between 2003 and 2018. Patients with oral cavity, oropharyngeal, laryngeal and hypopharyngeal SCC were included. Results 439 patients were included in the study. For patients with non-oropharyngeal p16-positive tumors without ENE, five-year OS, local control, and regional control (RC) reached 63.7%, 86.1%, and 94.9%, respectively; corresponding figures for patients with ENE reached, 42.6%, 77.5%, and 81.1%, respectively (p-value of 0.0006, 0.167, and 0.0005). In multivariable analysis, for non-oropharyngeal p16-positive tumors, ENE remained a poor prognostic factor for OS (RR = 1.74, 95%, CI = 1.16–2.61, p = 0.0069) and RC (RR 3.60, 95% CI =: 1.64–7.87, p = 0.0013). Conclusion In the era or postoperative chemoradiation, pathological ENE remains an adverse prognostic factor for OS and RC.

International audience; BackgroundGenome analysis could provide tools to assess predictive molecular biomarkers of radioresistance.MethodsHead and neck squamous cell carcinoma patients included in ProfiLER study and who underwent a curative radiotherapy were screened. Univariate and Cox multivariate analyses were performed to explore the relationships between molecular abnormalities, infield relapse and complete tumor response after radiation.ResultsOne hundred and forty-three patients were analyzed. PIK3CA mutation and genomic instability of MAP kinases pathway were found to be prognostic factors of loco-regional relapse in multivariate analysis with respectively HR 0.33, 95% CI 0.13–0.83, p = 0.005 and HR 0.61, 95% CI 0.38–0.96, p = 0.025. Instability of apoptosis pathway was found to be a prognostic factor of complete response after radiotherapy with HR 0.24, 95% CI 0.07–0.88, p = 0.04.ConclusionThis sub analysis suggests that PIK3CA mutation, variation of copy number of MAP kinases and apoptosis pathways play a significant role in the radioresistance phenomenon

There are few studies available on melanoma in Afro‐Caribbean and Amerindian populations of South America. French Guiana deserves a study due to its specific health system and diversity of phototypes. The objectives of this study were to evaluate the incidence, histological and clinical characteristics of melanoma in French Guiana. A retrospective study was conducted from October 2007 to January 2018 on all primary melanomas observed at the Cayenne Hospital Centre. Thirty‐nine patients were included. The incidence rate (1.61/106 inhabitants/year) was low compared with mainland France. Median age was 58, and gender ratio 1 : 16. Clear phototype (I/II) patients were the most frequent (38.5%), but a significant amount of melanoma also occurred in darker skin. Median Breslow was higher in dark phototypes than in fair‐skinned patients. Superficial spreading melanoma (SSM) was the most common histological type (33.3%), particularly in patients with clear phototype (61.5%). Acral lentiginous melanoma was found only in darker‐skinned patients (29.1%). The trunk was involved in 66.6% in the clearest group whereas foot was the most common location in the darkest group (60% in V/VI phototypes). Surgery was the most frequently used treatment (79.5%). At the end of the study period, 53.8% had been lost to follow‐up. In conclusion, the incidence of melanoma in French Guiana is lower than in mainland France but remains a public health concern, as dark‐skinned populations often present with advanced diseases. Awareness and prevention in these communities must be improved.

Purpose: Cetuximab, which modulates immune responses, may affect the efficacy of subsequent immunotherapy. Here, we assessed outcomes with nivolumab, by prior cetuximab exposure, in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) who had experienced progression within 6 months of platinum-containing chemotherapy. Patients and Methods: In the randomized, open-label, phase III CheckMate 141 trial, patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator's choice (IC) of single-agent chemotherapy, with stratification by prior cetuximab exposure. The primary endpoint was overall survival (OS); additional endpoints were progression-free survival, objective response rate, and safety. Results: In patients with prior cetuximab exposure, the median OS was 7.1 months with nivolumab versus 5.1 months with IC (HR, 0.84; 95% CI, 0.62–1.15); OS benefit with nivolumab was maintained across most demographic subgroups. In patients without prior cetuximab exposure, the median OS was 8.2 months with nivolumab versus 4.9 months with IC (HR, 0.52; 95% CI, 0.35–0.77); OS benefit with nivolumab was maintained across patient baseline subgroups including tumor programmed death ligand 1 (PD-L1) expression ( Conclusions: Nivolumab appeared to improve efficacy versus IC regardless of prior cetuximab use, supporting its use in patients with R/M SCCHN with or without prior cetuximab exposure. The reduction in risk of death with nivolumab compared with IC was greater in patients without prior cetuximab exposure versus with prior cetuximab exposure.

Objectives: Many patients with squamous cell carcinoma of the head and neck (SCCHN) are ≥65 years old; comorbidities and other age-related factors may affect their ability to tolerate traditional chemotherapy. Nivolumab is the only immunotherapy to significantly improve overall survival (OS) versus investigator’s choice (IC) of single-agent chemotherapy at primary analysis in a phase 3 trial (CheckMate 141) in patients with recurrent/metastatic SCCHN post-platinum therapy. In this post hoc analysis, we report efficacy and safety by age. Patients and methods: Eligible patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks (n = 240) or IC (methotrexate, docetaxel, or cetuximab n = 121). The primary endpoint of the trial was OS. For this analysis, outcomes were analyzed by age < 65 and ≥65 years. The data cut-off date was September 2017 (minimum follow-up 24.2 months). Results: At baseline, 68 patients (28.3%) receiving nivolumab and 45 patients (37.2%) receiving IC were ≥65 years. Baseline characteristics were generally similar across age groups. OS and tumor response benefits with nivolumab versus IC were maintained regardless of age. The 30-month OS rates of 11.2% (< 65 years) and 13.0% (≥65 years) with nivolumab were more than tripled versus corresponding IC rates of 1.4% and 3.3%, respectively. The nivolumab arm had a lower rate of treatment-related adverse events versus IC regardless of age, consistent with the overall patient population. Conclusion: In CheckMate 141, nivolumab resulted in a higher survival versus IC in patients < 65 and ≥65 years, with a manageable safety profile in both age groups. ClinicalTrials.gov: NCT02105636.

BACKGROUND Prognosis of recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) remains poor. The addition of cetuximab, to platinum and fluorouracil chemotherapy (EXTREME regimen) has been shown to improve patients’ outcomes in first‐line settings. METHODS We conducted a retrospective, multicenter study, including HNSCC that progressed after a first line of platinum‐based chemotherapy and cetuximab, treated either by paclitaxel + cetuximab (PC) or paclitaxel alone (P), between January 2010 and April 2018. The end points were overall survival (OS), progression‐free survival (PFS), and overall response rates (ORR). Patients were matched according to their propensity scores, estimated with a logistic regression model. The secondary objectives were to study the safety profile and to look for prognostic and predictive factors of effectiveness. RESULTS Of the 340 identified patients, 262 were included in the analysis, 165 received PC, and 97 received P. In unmatched population, ORR was 16.4% with PC and 6.2% for P. Median PFS was 2.9 months [95% Confidence Interval 2.7–3.0] for PC versus 2.5 months [2.2–2.7] for P, hazard ratio (HR) = 0.770 [0.596–0.996]. Median OS was 5.5 months [4.4–6.9] for PC versus 4.2 months [3.4–4.8] for P, HR = 0.774 [0.590–1.015]. In multivariate analysis, PC was associated with better PFS and OS. These results were consistent in matched‐paired population. Previous cetuximab maintenance for more than 3 months was predictive of better OS with PC. CONCLUSION Although the continuation of cetuximab in combination with paclitaxel after EXTREME provides moderate benefit, it could be an interesting option for selected patients., In this propensity score‐adjusted, multi‐institutional series, cetuximab in association with paclitaxel showed better outcomes than paclitaxel alone for patients who had disease progression after EXTREME regimen, particularly for patients who benefit the most from cetuximab in first‐line setting. This study should raise the question of the place of this association with the arrival of immune checkpoint inhibitors in first line with or without chemotherapy.

Background Programmed death-ligand 1 (PD-L1) is the most validated predictive biomarker used for the treatment of head and neck squamous cell carcinoma (HNSCC) with immune checkpoint inhibitors (ICI). Several gene expression-based signatures surrogate of the activation of IFN-gamma pathway and of the presence of tertiary lymphoid structures (TLS) have also been proposed as potential biomarkers. While they may have a potential therapeutic implication, the longitudinal changes of either PD-L1 or gene expression profiles between the initial and recurrent HNSCC lesions is unknown. Methods PD-L1 immunohistochemistry (IHC) and targeted RNA-sequencing of 2,549 transcripts were analyzed on paired specimens from the initial diagnosis and recurrent HNSCC. PD-L1 status was defined using the combined positive score (CPS). PD-L1 mRNA levels were compared with protein expression levels by IHC. Enrichment scores of surrogate signatures for TLS and IFN-gamma (IFN-γ) pathway activation were computed using the single sample gene set enrichment analysis (ssGSEA). Results PD-L1 status was 64% (21/33) concordant between the initial and recurrent lesions using a CPS 1 threshold and 67% (22/33) concordant using a CPS 20 threshold. CPS score was associated with PD-L1 gene expression levels. There was a 43% (15/35) and 66% (23/35) concordance for the IFN-γ and TLS signature scores, respectively. Conclusion Our study reveals temporal heterogeneity of PD-L1 status and TLS/IFN-γ gene expression surrogates in HNSCC that need to be considered when interpreting biomarker studies.

Background: Head and neck (HN) cancer is the 7th most common cancer and 7th leading cause of cancer death worldwide with approximately 930,000 new cases and 470,000 deaths in 2020.1 HN squamous cell carcinoma (HNSCC) accounts for around 90% of HN cancers.2 Options for first-line treatment of patients (pts) with recurrent/metastatic (R/M) HNSCC include cetuximab (anti-epidermal growth factor receptor) in combination with (+) platinum-based chemotherapy (CT) and 5-fluorouracil (5- FU), or immune checkpoint inhibitor (ICI) therapy with single-agent pembrolizumab (anti-programmed cell death-1) or + CT and 5-FU.3-5 Pts who progress on/after CT may receive single-agent cetuximab, ICI pembrolizumab, or ICI nivolumab.3 However, treatment for pts who progress on/after ICI is not clearly defined and rechallenge is not recommended. Thus, there is a need to assess combination immunotherapy approaches. In a Phase 2 study, monalizumab (anti-NKG2A) + cetuximab combination therapy showed encouraging antitumor results in pts with R/M HNSCC who received prior CT and an ICI.6 INTERLINK-1 (NCT04590963) is a Phase 3 global study evaluating the efficacy and safety of monalizumab + cetuximab in pts with R/M HNSCC previously treated with CT and an ICI. Methods: Approximately 624 pts will be randomized 2:1 to monalizumab + cetuximab or placebo + cetuximab until disease progression or another discontinuation criterion is met. All pts will be followed for survival after discontinuation. Eligible pts will have measurable R/M HNSCC (per RECIST v1.1) of the oral cavity, oropharynx, hypopharynx or larynx, which is not amenable to curative therapy and has progressed on/after previous CT. They will have received 1-2 prior systemic regimens for R/M HNSCC, had prior treatment with a PD-(L)1 inhibitor, an ECOG performance status of 0 or 1, and must provide a fresh/recently acquired tumor sample. Key exclusion criteria include prior cetuximab therapy for R/M HNSCC, autoimmune/inflammatory disease or any concurrent anticancer treatment. The primary objective is overall survival (OS) in human papillomavirus-unrelated pts. Key secondary objectives include OS in all randomized pts, progression-free survival, objective response rate, duration of response, disease-related symptoms, functioning and quality of life, pharmacokinetics, safety and tolerability. Study enrollment is ongoing at 210 sites in 25 countries. References: 1. Sung et al. CA Cancer J Clin 2021; 71: 209-49 2. UICC. Head and Neck Cancer. 2014. who.int 3. NCCN®. Head and Neck Cancers. 2021. nccn.org/guidelines 4. Machiels et al. Ann Oncol 2020; 31: 1462-75 5. Keam et al. ESMO Open 2021; 6: 100309 6. Cohen et al. J Clin Oncol 2020; 38 (15 suppl): Abst 6516. Study Sponsor: AstraZeneca. Citation Format: Jérôme Fayette, Tanguy Seiwert, Robert L. Ferris, Kevin Harrington, Robert Haddad, Makoto Tahara, Lisa Licitra, Lillian L. Siu, Jean-Pascal Machiels, Malgorzata Dominiewska, Julia Xiong, Paramjit Kaur, Dario Ruscica, Roger B. Cohen. INTERLINK-1: A phase 3, randomized, double-blind, placebo-controlled, multicenter, global study of monalizumab in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma previously treated with an immune checkpoint inhibitor [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 CT236.

EVIDENS is an ongoing, prospective, non-interventional study evaluating the effectiveness and safety of nivolumab in lung cancer patients in France (ClinicalTrials.gov NCT03382496). Adults with a pathologically confirmed diagnosis of lung cancer and initiating treatment with nivolumab were recruited from 146 sites in France. This analysis included only patients with non-small cell lung cancer (NSCLC) who received ≥1 nivolumab infusion, and evaluated patient characteristics at the time of nivolumab initiation and its effectiveness and safety after a median follow-up of 18 months. A total of 1,420 patients with NSCLC were included, most of whom had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1 (82.9%), non-squamous histology (69.2%) and stage IV disease (91.4%). Brain metastases were present in 19.9% of patients. Nivolumab was a second-line or ≥third-line regimen in 73.6% and 26.1% of patients, respectively. Almost all patients had prior chemotherapy (99.7%). Median overall survival was 11.2 months (95% confidence interval [CI]: 10.0–12.4). ECOG PS, smoking status, corticosteroids at baseline, epidermal growth factor receptor mutation status, presence of symptomatic brain metastases and treatment-related adverse events (TRAEs) were independent predictors of survival. Grade 3 and 4 TRAEs were reported in 105 (7.4%) and 12 (0.8%) patients, respectively; no treatment-related deaths were reported. Preliminary results of the EVIDENS study confirm the effectiveness and safety of nivolumab, mostly in pre-treated advanced NSCLC patients, with similar benefits to those observed in the phase III randomized clinical trials, despite a broader study population.

Purpose Rare cancers are defined by an incidence of

Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug–related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29–44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398.

BackgroundAlthough the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Therefore, we aimed to characterize the effect of MEK1/2 inhibition on the tumor microenvironment (TME) of MAPK-driven HNC, elucidate tumor-host interaction mechanisms facilitating immune escape on treatment, and apply rationale-based therapy combination immunotherapy and MEK1/2 inhibitor to induce tumor clearance.MethodsMouse syngeneic tumors and xenografts experiments were used to analyze tumor growth in vivo. Single-cell cytometry by time of flight, flow cytometry, and tissue stainings were used to profile the TME in response to trametinib (MEK1/2 inhibitor). Co-culture of myeloid-derived suppressor cells (MDSC) with CD8+T cells was used to measure immune suppression. Overexpression of colony-stimulating factor-1 (CSF-1) in tumor cells was used to show the effect of tumor-derived CSF-1 on sensitivity to trametinib and anti-programmed death- 1 (αPD-1) in mice. In HNC patients, the ratio between CSF-1 and CD8A was measured to test the association with clinical benefit to αPD-1 and αPD-L1 treatment.ResultsUsing preclinical HNC models, we demonstrated that treatment with trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the antitumor immunity of CD8+T cells. Activation of CD8+T cells by supplementation with αPD-1 antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to αPD-1-supplementation by attenuating the expression of tumor-derived CSF-1, which reduced the abundance of two CSF-1R+CD11c+MDSC populations in the TME. In contrast, prolonged treatment with trametinib abolished the antitumor activity of αPD-1, because tumor cells undergoing the epithelial to mesenchymal transition in response to trametinib restored CSF-1 expression and recreated an immune-suppressive TME.ConclusionOur findings provide the rationale for testing the trametinib/αPD-1 combination in HNC and highlight the importance of sensitizing tumors to αPD-1 by using MEK1/2 to interfere with the tumor–host interaction. Moreover, we describe the concept that treatment of cancer with a targeted therapy transiently induces an immune-active microenvironment, and supplementation of immunotherapy during this time further activates the antitumor machinery to cause tumor elimination.

Resume La vague de l’immunotherapie n’epargne pas les cancers de la tete et du cou. En situation de recidive locale ou metastatique, des inhibiteurs de checkpoint (anti-PD-1/PD-L1) ont l’AMM en deuxieme ligne avec un benefice net, tant en survie globale qu’en qualite de vie. Nombre d’etudes sont en cours, en situation palliative, mais aussi curative, en association ou non avec d’autres inhibiteurs de checkpoint (anti-CTLA4) ou avec des therapies validees (radiotherapie, chimiotherapie). Il est necessaire de definir des biomarqueurs robustes permettant de selectionner efficacement les patients eligibles. En effet, le risque d’effet indesirable grave n’etant pas negligeable, l’enjeu est la selection des patients chez qui l’immunotherapie aura le plus de benefices. Nous ferons ici le point sur l’etat des connaissances en 2018 de l’immunotherapie dans les cancers epidermoides ORL.

Nivolumab significantly improved overall survival (OS) vs investigator's choice (IC) of chemotherapy at the primary analysis of randomized, open-label, phase 3 CheckMate 141 in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). Here, we report that OS benefit with nivolumab was maintained at a minimum follow-up of 11.4 months. Further, OS benefit with nivolumab vs IC was also noted among patients who received first-line treatment for R/M SCCHN after progressing on platinum therapy for locally advanced disease in the adjuvant or primary (i.e., with radiation) setting.

Summary Background Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigator's choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs). Methods CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigator's choice (n=121) of methotrexate (40–60 mg/m 2 of body surface area), docetaxel (30–40 mg/m 2 ), or cetuximab (250 mg/m 2 after a loading dose of 400 mg/m 2 ) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigator's choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigator's choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life–5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636. Findings Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigator's choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from −2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigator's choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, −24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigator's choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigator's choice group (7·3 vs −7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigator's choice for 13 (37%) of 35 domains assessed across the three questionnaires. Interpretation In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting. Funding Bristol-Myers Squibb.

Head and neck squamous cell carcinoma (HNSCC) is among the 10 most common cancers worldwide, with increasing incidence.1 Approximately 10% of patients with HNSCC will be diagnosed with metastatic disease, and even when treated early, around half will have disease recurrence.2,3 The platinum-based doublet chemotherapy with cetuximab regimen has been the most widely-used therapy and considered standard of care (SoC) since it was proven effective in 2007 for recurrent/metastatic (R/M) HNSCC in the first-line setting.3,4 However, patients typically progress even after aggressive first-line therapy, and, until recently, the available options (e.g. cetuximab, methotrexate, and taxanes) have delivered limited survival benefits.3 Durvalumab is an immunotherapeutic agent that blocks the interaction between programmed cell death ligand 1 (PD-L1) and its receptors.5 Durvalumab demonstrated encouraging response rates and duration of response (DoR) with a manageable safety profile in patients with HNSCC.6 Although monotherapy agents that block the programmed cell death protein 1 (PD-1)/PD-L1 axis have shown clinical activity, immunotherapy combinations have the potential to improve upon monotherapy activity.7e9 Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and PD-L1/PD-1 pathways have largely non-redundant roles, suggesting that blockade of both could have additive or synergistic effects.10 Indeed, the combination of durvalumab and tremelimumab, an anti-CTLA-4 monoclonal antibody, was explored based on improved efficacy over monotherapy in other solid tumor types.7 This observation, in addition to the activity demonstrated by durvalumab in earlier R/M HNSCC studies, served as the rationale to evaluate durvalumab and tremelimumab in patients with R/M HNSCC. Several studies, including the EAGLE study, were initiated to evaluate combination immunotherapy regimens in various patient groups.11,12 The EAGLE study was the first phase III study to investigate durvalumab and tremelimumab in patients with R/M HNSCC who had progressed after platinumbased therapy. During the conduct of the EAGLE study, anti-PD-1 monoclonal antibodies were approved for use for R/M HNSCC progression following a platinum-based regimen. Treatment with these immunotherapies resulted in a median overall survival (OS) of 7.5e8.4 months.13,14 These immunotherapies are now recommended for second-line treatment as monotherapies for patients with R/M HNSCC.3,13,14 More recently, immunotherapy alone or in combination with platinum-based chemotherapy has shown improvements in OS in the first-line setting, underscoring the clinical utility of immunotherapy in HNSCC.15 Here, we report the results of the randomized phase III EAGLE trial evaluating durvalumab and durvalumab plus tremelimumab versus SoC therapies in patients with R/M HNSCC who have progressed following a platinumcontaining regimen.

Chemoradiotherapy as an alternative to surgery can be offered to patients affected by loco-regionally advanced head and neck cancer (HNC). Induction chemotherapy is a valid option, supported by few positive trials, but its real efficacy is still a matter of debate. The standard regimen for induction chemotherapy in Europe is a combination of docetaxel (75 mg/m2) and reduced dose doses of cisplatin (75 mg/m2) and 5-fluorouracil (750 mg/m2 day, for five consecutive days) (TPF). It is less toxic and more effective than the historical therapy PF (cisplatin 100 mg/m2 and fluorouracil 1,000 mg/m2/day for five consecutive days). However, in some studies treatment-related mortality has been reported to be as high as 6%. Therefore, some less toxic combinations, such as a modified TPF regimen and the combination of carboplatin plus paclitaxel have been studied. These regimens are showing promising results but deserve further validation in comparative trials. Furthermore, several trials are underway in order to enhance TPF with immune checkpoints inhibitors. Compared to chemoradiotherapy, induction chemotherapy followed by chemoradiation was shown to be non-inferior, and it could decrease the distant metastatic progression, especially in high-risk populations. For selected patients, induction chemotherapy could be a strong option. The chemoselective process that leads to immediate surgery for non-responders, the high response rate (complete responses are sometimes observed), and the survival data, are all arguments in favor of induction chemotherapy, if performed in experienced centers involving health professionals in the context of a skilled multidisciplinary team.

Standard treatment for locally advanced head and neck squamous cell carcinoma (LAHNSCC) consists mainly of concurrent chemoradiation (CCR) but induction chemotherapy (IC) by docetaxel-cisplatin-fluorouracil (TPF), followed by CCR, is a strong option. Comparative trials suggest that IC and CCR are equivalent, and some trials suggest superiority of IC, whereas none shows inferiority. IC might have less interest in oropharyngeal cancer (more often linked to HPV infection). When functional laryngeal preservation is the patient's priority, essays strongly suggest that IC is the best treatment. There is little data about a less toxic regimen of IC, but several schemes are promising and need to be developed. An early selection of responders to IC by metabolic imaging must be considered. Intensification attempts with cetuximab were too toxic and unsafe, but trials with immunotherapy are ongoing to enhance TPF efficacy. After IC, CCR either with cetuximab or cisplatin seems to be equally effective.

TPF (docetaxel, cisplatin, fluorouracil) is the standard chemotherapy used for induction in locally advanced head and neck squamous cell carcinoma (LAHNSCC). Its toxicity limits it to younger patients with good functional status and without significant comorbidity. Since modified TPF (mTPF) demonstrated higher tolerability with similar efficacy in gastric cancer, we tested this scheme on frail patients. From July 2010 to July 2014, the files of the 48 patients treated for LAHNSCC with mTPF in three French institutions were retrospectively collected. mTPF was chosen because of age>70 years, or severe denutrition, or PS>1, or severe comorbidities or after severe toxicity of standard TPF. During the first 4 cycles, 2 patients died, 14 secondary hospitalizations were required and 10 patients stopped treatment due to no lethal toxicity. Two patients died during radiotherapy. The response rate was 83% (19% complete response). With a median follow-up of 15.2 months, 4 patients died during treatment, 8 died of non-head and neck cancer related disorders, 18 progressed (17 deaths) and 18 were free of disease. The median overall survival was 18.5 months (95% IC: 16.9-30.0). mTPF is effective in terms of response rate compared with the standard TPF and could become a new option in induction for frail patients with LAHNSCC.

6516 Background: Monalizumab is a first-in-class immune checkpoint inhibitor targeting Natural Killer Group 2A (NKG2A), which is expressed on subsets of Natural Killer (NK), gd T and tumor-infiltrating CD8+T cells. NKG2A blockade promotes innate anti-tumor immunity mediated by NK and CD8+T cells and enhances NK cell antibody-dependent cell-mediated cytotoxicity induced by cetuximab. In a Phase I study, the combination of monalizumab and cetuximab was well tolerated. In an initial expansion cohort 1 of 40 patients (pts) who had progressed after platinum-based therapy, we reported an overall response rate (ORR) of 27.5%, a 4.5 month median PFS and an 8.5 month median OS. In a subset of patients (n=18) previously treated with PD-(L)1 inhibitors (IO), corresponding results were 17%, 5.1, and 14.1 months, respectively (ESMO 2019). Here we present data from a second expansion cohort 2 (n=40) conducted specifically in the post-IO setting to independently confirm the cohort 1 results. Methods: Eligible patients had R/M SCCHN previously treated with platinum and a PD-(L)1 inhibitor. Pts received monalizumab 750 mg q2weeks and cetuximab according to the label until progression or toxicity. Cohort 2 was designed as a confirmatory multicenter single arm phase II study, with a pre-planned total of 40 patients. The primary endpoint was ORR assessed per RECIST 1.1. Results: As of January 31, 2020, 40 pts have been treated in cohort 2. Median follow-up is 7.3 months (range, 1.9-13.6+). Eight (8) pts have a confirmed partial response (PR); ORR is 20% [95% confidence interval: 11-35]. Median time to response is 1.6 months [1.6-5.3]. At the time of data analysis, 3 pts were still in PR and 3 pts had stable disease continue on treatment. PFS and OS are still immature. Conclusions: In pts previously treated with platinum and PD-(L)1 inhibitors, the combination of monalizumab and cetuximab demonstrated promising activity. The second extension cohort confirmed prospectively the ORR reported in cohort 1. A randomized phase III trial of monalizumab and cetuximab is planned in this platinum and IO-pretreated SCCHN population. Clinical trial information: NCT02643550 .

6507 Background: TPExtreme trial comparing EXTREME regimen to the taxane-based TPEx confirmed the encouraging survival results of the TPEx regimen, despite lack of significant overall survival (OS) increase, with a significantly lower toxicity than the EXTREME regimen. Herein, the QoL and exploratory analyses of survival according to 2nd line treatments focusing on immunotherapy (IO) are presented. Methods: Randomized (1:1), open-label trial. Main inclusion criteria were R/M HNSCC not suitable for loco-regional treatment, age 18-70 years, PS < 2, creatinin clearance > 60ml/min, prior cisplatin < 300 mg/m². 539 pts were enrolled over a period of 37 months (mo). QoL was evaluated with QLQ-C30 questionnaire at baseline, week(W)12, W18, W26 and analyzed by linear mixed model. The primary QoL endpoint was the Global Health Status score. 2nd line treatments were collected for 501 (93%) patients (pts), 256 in the EXTREME arm and 245 in the TPEx arm. Results: The percentage of QLQ-C30 questionnaires filled at baseline, W12, W18 and W26 were similar in the 2 arms, 89%, 52%, 43%, and 39% in the EXTREME arm and 91%, 59%, 40%, and 37% in the TPEx arm, respectively.. Higher scores of Global Health Status (p = 0.02), physical functioning (p = 0.009) and role functioning (p = 0.013) and lower scores of appetite loss (p = 0.041) were observed in the TPEx arm than in the EXTREME arm. No significant difference was observed for the other scores. In 2nd line treatment, 120 (47%) pts in the EXTREME arm and 109 (44%) in the TPEx arm received chemotherapy +/- cetuximab (CT); 41 (16%) pts in the EXTREME arm and 41 (17%) in the TPEx arm received IO, mainly anti-PD-1/PD-L1. 79% and 85% of these 2nd line treatments were given after progression in EXTREME and TPEx arms respectively. Median OS (95%CI) since randomization was 17.6 (15.2 – 19.5) mo with CT and 19.4 (13.4 – 22.3) mo with IO in the EXTREME arm vs 14.9 (13.0 – 16.3) and 21.9 (15.9 – 35.0) mo in the TPEx arm (interaction test p = 0.077) respectively. Median OS since start of 2nd line was 9.3 mo with CT and 8.3 mo with IO in the EXTREME arm, and 7.1 and 11.6 mo respectively in the TPEx arm. Conclusions: An improvement in the QoL of patients was observed in the TPEx arm compared to that of the EXTREME arm. Exploratory analysis showed that the taxane-based TPEx regimen followed by IO in 2nd line could provide interesting median OS for pts who need CT in 1st line, with less toxicity than EXTREME. This sequential treatment deserves to be compared to a strategy that starts with Platinum+5FU+pembrolizumab. Clinical trial information: NCT02268695 .

6548 Background: Baseline tumor and germline biomarkers in R/M HNSCC were analyzed for predictive potential in pts benefitting from D or D+T. Methods: In HAWK (NCT02207530), 112 pts (PD-L1 tumor cells [TC]≥25%) received D (10 mg/kg Q2W for ≤12 m); in CONDOR (NCT02319044), 67 pts (PD-L1 TC < 25%) received D (10 mg/kg Q2W for ≤12 m), 133 pts received D+T (D 20 mg/kg Q4W, T 1 mg/kg Q4W for ≤12 m), and 67 pts received T (10 mg/kg Q4W [7 doses] then Q12W [2 doses] for ≤12 m) VENTANA PD-L1 (SP263) Assay determined PD-L1 status. Paired FFPE archival tumor and PBMC samples (as germline control) in the HAWK and CONDOR trials were evaluated by whole exome sequencing (WES). Tumor mutation burden (TMB) was number of somatic mutations/megabase. HLA class I types were obtained via WES of PBMCs (CONDOR only). HPV and neutrophil-to-lymphocyte ratio (NLR) were tested locally in CONDOR. Wilcoxon, log-rank tests, and COX-PH models were used. Pooled D & D+T data were analyzed unless noted. Results: 153 pts had paired evaluable FFPE tumor and PBMC samples (HAWK, n = 48; CONDOR, n = 105). TMB distributions were similar between studies ( P= 0.43). TMB correlated with smoking ( P= 0.02) but not HPV ( P= 0.24), NLR ( P= 0.66), or PD-L1 status ( P= 0.43). Overall, high TMB (≥upper tertile) trended with longer OS vs low TMB in all evaluable pts (N = 153; 9.0 vs 5.6 m; HR = 0.70; 95% CI = 0.48-1.01); P= 0.06). In HAWK, there was no association of TMB with OS. In CONDOR, pts (D and D+T arms) with high TMB vs low had significantly longer OS (N = 76; 16.3 vs 5.3 m; HR = 0.53; 95% CI = 0.31-0.92). TMB and OS association was further assessed by increasing TMB cutoffs. Improved HRs trended with higher cutoffs; cutoffs ≥upper quartile significantly linked to OS.TMB was not associated with PFS or ORR. Pts with low PD-L1 and low TMB had worse OS compared to pts with high PD-L1 or high TMB. Pts with high NLR (≥median) and low TMB had significantly worse OS than pts with low NLR and high TMB (HR = 2.63, P< 0.001). Analysis of germline HLA alleles revealed significantly poorer survival for carriers of the HLA-B*15:01 allele (9.4%) (HLA-B variant status did not affect TMB and OS association in CONDOR). Germline HLA heterozygosity did not impact OS. Pts with mutations in ATM (5%), a DNA damage repair gene, also trended with prolonged OS. Conclusions: TMB is a possible predictive biomarker of IO HNSCC therapy. Combined analysis of NLR and TMB may provide additional PD-L1 data in assessing pts most likely to have long-term benefit. Clinical trial information: NCT002207530, NCT02319044 .

The importance of occupational exposures in patients with head and neck squamous cell carcinomas (HNSCC) has received little attention. In a single-center study, we prospectively characterized occupational exposures in 154 HNSCC cancer patients in a systematic occupational consultation and examined the association between most frequent exposures, HNSCC stage and localization. Patients occupied a mean of 3.3 different positions during their working life. The prevalence of asbestos, the most frequent exposure (46 patients; 29.9%) was higher than in the French population > 50 years. Other frequent exposures were solvents (n = 26; 16.9%) and silica (n = 19; 12.3%). For 37 patients (24%) a possible link was identified between occupational exposures and HNSCC. Duration of asbestos exposure was significantly higher (p = 0.04) in patients with hypopharyngeal and laryngeal cancer compared to other localizations. Occupational exposures are frequent in patients with HNSCC and should receive increased attention by physicians.