Resolution of Immune Checkpoint Inhibitors-Induced Inflammatory Arthritis while Maintaining Active Treatment with Checkpoint Inhibitors and After Its Discontinuation: an Observational Study.

INTRODUCTION: Immune checkpoint inhibitors-induced inflammatory arthritis (ICI-IA) affects about 5% of ICI recipients. We aimed 1) to characterize the resolution of ICI-IA during ICI treatment and after ICI discontinuation and 2) to assess how ICI-IA influences ICI management across time. METHODS: All ICI-treated patients referred to rheumatology at Bordeaux University Hospital were identified and patients with ICI-IA with a follow-up of ≥ 6 months after ICI-IA onset were included. Resolution of ICI-IA was defined by discontinuation of ICI-IA medications without recurrence of ICI-IA symptoms. RESULTS: Resolution of ICI-IA occurred in 13 of 80 patients (16%) while maintaining active ICI treatment, mainly in patients with polymyalgia rheumatica (PMR)-like clinical presentation (p=0.03). Synovitis was more frequent in those whose ICI-IA persisted throughout ICI treatment. In patients with persistent ICI-IA throughout ICI treatment, 34 (50%) and 47 (70%) resolved at 6- and 12-months post ICI discontinuation, respectively. Reason for terminating ICI was more frequently cancer stable or in remission in those who still had active ICI-IA at 6- and 12- months post ICI discontinuation. Both progression-free survival and overall survival were longer in the groups with active ICI-IA at 6- and 12-months after ICI discontinuation. DISCUSSION: In this cohort, ICI was safely continued in most patients experiencing ICI-IA. About one sixth of ICI-IA resolved despite maintaining active ICI treatment and allowing ICI-IA treatment discontinuation without recurrence of symptoms, mainly in those with PMR-like presentation. Larger studies are needed to determine predicting factors of resolving ICI-IA to minimize exposure to immunosuppressive treatment.

Immunotherapy for head and neck squamous cell carcinoma: current status and perspectives.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several solid cancers, including head and neck squamous cell carcinoma (HNSCC). First approved for second-line settings, ICIs are now used for the first-line treatment of HNSCCs, mainly in combination with standard chemotherapy. This review focuses on the results of the main phase III studies evaluating ICIs in recurrent or metastatic HNSCCs. The efficacy and indications according to the PD-L1 status, the main predictive biomarker, are discussed. The results of trials assessing ICI efficacy for locally advanced disease, including the neoadjuvant setting are also discussed. Finally, therapeutic combinations that are potential treatments for HNSCCs, including ICIs and targeted therapies such as anti-EGFR agents, are presented.

Head and neck (HN) cancer is common and challenging to treat, especially when it relapses locally (recurrence) or in a different organ (metastatic). Immunotherapy, which strengthens the immune system's ability to target tumor cells, has revolutionized the treatment of several cancers, including metastatic HN cancers. Pembrolizumab, an immunotherapy drug, is now combined with chemotherapy as standard treatment for recurrent or metastatic HN cancers; it has a manageable toxicity profile. However, some patients do not respond to treatment, and the disease may relapse after several injections. Efforts are currently underway to improve the efficacies of these immunotherapy treatments by combining them with other therapies, such as anti-EGFR treatment. Current studies seek biomarkers to identify patients likely to benefit from these treatments and those who may require alternative treatments.

Immune checkpoint inhibitor rechallenge in patients who previously experienced immune-related inflammatory arthritis: a multicentre observational study.

OBJECTIVE: Another course of immune checkpoint inhibitors (ICIs) is often considered in patients with cancer progression and previous immune-related adverse events, including inflammatory arthritis (ICI-IA), but there are limited data regarding safety of ICI rechallenge in this setting. We aimed to assess the rate and clinical features associated with ICI-IA flare/recurrence on ICI rechallenge. METHODS: We conducted a multicentre observational study including cancer patients with ICI-IA who started a second course of ICI more than 3 months after ICI discontinuation in four French university hospitals. Primary outcome was the frequency of ICI flare/recurrence after ICI rechallenge. RESULTS: Twenty-three patients were included. At the time of ICI rechallenge, 18 patients reported no symptoms of ICI-IA (78%) and 5 had grade 1 (22%), 11 patients (48%) were not receiving any ICI-IA treatment, 11 (48%) were still on prednisone, 2 (9%) were on conventional synthetic disease-modifying antirheumatic drugs and 1 (4%) on anti-IL-6. ICI-IA flare/recurrence occurred in 12 patients (52%) with a median time of 1 month after ICI rechallenge. ICI-IA phenotype, disease activity and ICI-IA treatment at the time of ICI rechallenge did not differ according to ICI-IA flare/recurrence status. CONCLUSION: In this first observational study of ICI-IA patients rechallenged with ICI, about half of the patients experienced ICI-IA flare/recurrence with a similar phenotype but occurring earlier than the initial ICI-IA, warranting close monitoring during the first month of retreatment. Risk of flare did not differ according to baseline immunosuppressive treatment at the time of rechallenge.

Management of 80 sinonasal undifferentiated carcinomas. Retrospective multicentre study of the French Network of Rare Head and Neck Cancers (REFCOR).

OBJECTIVES: Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive disease requiring multimodal treatment, and multiple new entities once included in the spectrum of SNUC, such as SWI/SNF-deficient carcinomas, are emerging. We aimed to provide new data regarding the role of chemotherapy and surgery and the prognostic factors of disease-free survival. METHODS: This study was based on data from the REFCOR database and included patients with SNUC treated with curative intent from 2007 to 2021 across 22 centres in France. RESULTS: A total of 80 patients were included in the analysis. Among the entire cohort, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 58% and 63%, respectively. Of 100% of the patients treated with irradiation, 29% underwent surgery, 56% neoadjuvant chemotherapy (82% had either a partial or a complete response) and 76% chemoradiotherapy. No treatment modality was associated with a better OS or DFS, including surgery (p = 0.34). There was a trend for a better DFS for the patients treated with chemotherapy (neoadjuvant or concomitant, p = 0.062). Overall survival at 3 years was 58% for SWI/SNF deficient group and 86% for non deficient group (p = 0.14). The locoregional relapse rate without distant metastases was 21% in the exclusive radiotherapy group and 26% in the surgery group. Grade 3 or higher toxicities concerned 9%, 32% and 29% of patients for surgery, radiotherapy and chemotherapy respectively. CONCLUSION: In the management of localised SNUC among all patients treated with irradiation, surgery yielded no benefit, whereas the addition of chemotherapy tended to improve disease-free survival.

Efficacy of second-line chemotherapy or immune checkpoint inhibitors for patients with a prolonged objective response (≥ 6 months) after first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma: a retrospective study.

BACKGROUND: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) have a poor prognosis and limited therapeutic options. Immune checkpoint inhibitors (ICIs) are effective in patients with tumor progression < 6 months following first-line, platinum-based chemotherapy (PBC), but data are missing for patients with progression ≥ 6 months after the last platinum dose. METHODS: Retrospective analysis (six French centers, 2008-2019) of all consecutive R/M-HNSCC patients. treated first-line with PBC and tumor progression ≥ 6 months after the last platinum dose. PRIMARY ENDPOINT: progression-free survival after second-line therapy (PFS2). Additional endpoints: overall survival from Day 1 of first-line (OS1) and second-line (OS2) therapy. RESULTS: R/M-HNSCC patients (n = 144) received cisplatinum (n = 67, 47%) or carboplatinum (n = 77, 53%) first-line. Response after first-line: complete response (CR; n = 16, 11%); partial response (PR; n = 77, 53%); stable disease (n = 22, 15%). Second-line therapy: PBC (n = 95, 66%); platinum-free regimen (PFR) (n = 25, 17%); ICI (n = 24, 17%). Median [95% confidence interval] PFS (months): PBC 5.0 [3.8-6.2]; PFR 4.0 [1-7.0]; ICI 2.0 [0.4-3.6] (p = 0.16). For PBC, PFR, and ICI, respectively: OS1 30, 23, and 29 months (p = 1.02); OS2 14, 10, and 16 months (p = 0.25); PR, 26%, 16%, and 21% patients; CR, 0%, 8%, and 4% patients. For subsequent lines, ICIs were administered for PBC (n = 11, 12%) and PFR (n = 2, 8%). No predictive factor for efficacy (PFS, OS) was identified. CONCLUSIONS: Our retrospective study suggests similar efficacy regarding OS2 for second-line chemotherapy or ICI in R/M-HNSCC patients with progression ≥ 6 months after the last first-line platinum dose.

Plasma galectins and metabolites in advanced head and neck carcinomas: evidence of distinct immune characteristics linked to hypopharyngeal tumors.

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 (p = .017) and a trend toward higher concentrations of kynurenine, a potential factor of tumor growth and immune suppression. In contrast, there was a tendency toward higher concentrations of fatty acids in samples related to oral cavity. These observations emphasize the diversity of HPV-negative HNSCCs. Depending on their primary site, they evolve into distinct types of immune and metabolic landscapes that seem to be congruent with specific oncogenic mechanisms.

Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651.

PURPOSE: CheckMate 651 (ClinicalTrials.gov identifier: NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance) in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). METHODS: Patients without prior systemic therapy for R/M SCCHN were randomly assigned 1:1 to nivolumab plus ipilimumab or EXTREME. Primary end points were overall survival (OS) in the all randomly assigned and programmed death-ligand 1 combined positive score (CPS) ≥ 20 populations. Secondary end points included OS in the programmed death-ligand 1 CPS ≥ 1 population, and progression-free survival, objective response rate, and duration of response in the all randomly assigned and CPS ≥ 20 populations. RESULTS: Among 947 patients randomly assigned, 38.3% had CPS ≥ 20. There were no statistically significant differences in OS with nivolumab plus ipilimumab versus EXTREME in the all randomly assigned (median: 13.9 v 13.5 months; hazard ratio [HR], 0.95; 97.9% CI, 0.80 to 1.13; P = .4951) and CPS ≥ 20 (median: 17.6 v 14.6 months; HR, 0.78; 97.51% CI, 0.59 to 1.03; P = .0469) populations. In patients with CPS ≥ 1, the median OS was 15.7 versus 13.2 months (HR, 0.82; 95% CI, 0.69 to 0.97). Among patients with CPS ≥ 20, the median progression-free survival was 5.4 months (nivolumab plus ipilimumab) versus 7.0 months (EXTREME), objective response rate was 34.1% versus 36.0%, and median duration of response was 32.6 versus 7.0 months. Grade 3/4 treatment-related adverse events occurred in 28.2% of patients treated with nivolumab plus ipilimumab versus 70.7% treated with EXTREME. CONCLUSION: CheckMate 651 did not meet its primary end points of OS in the all randomly assigned or CPS ≥ 20 populations. Nivolumab plus ipilimumab showed a favorable safety profile compared with EXTREME. There continues to be a need for new therapies in patients with R/M SCCHN.

Effect of prior immunotherapy on the efficacy of chemotherapy in advanced non-small cell lung cancer: A retrospective study.

BACKGROUND: The effect of the sequential combination of chemotherapy and immune checkpoint inhibitors (ICIs) remains unclear. Here, we evaluated the efficacy of different chemotherapy regimens administered after ICIs in advanced non-small cell lung cancer (NSCLC), compared to the same regimens administered without previous ICIs. METHODS: We retrospectively included all patients treated between 2015 and 2019 for an advanced NSCLC, receiving a salvage chemotherapy just after ICI (CAI group) comparing them to ICI naive patients (CWPI group) undergoing the same chemotherapy at Bordeaux University Hospital. The primary outcome was the time to treatment discontinuation (TTD), and secondary endpoints were overall survival (OS) and overall response rate (ORR). RESULTS: A total of 152 patients were included, with 34/23 (CAI/CWPI) receiving paclitaxel/bevacizumab (PB), 24/11 paclitaxel (P), 27/12 gemcitabine (G) and 6/15 pemetrexed (PE). Characteristics were comparable, except for CAI treated with PB (more patients with an ECOG PS ≤1 [p <0.001]). Median number of lines received was higher in CAI for all groups. There was no difference between CAI and CWPI for TTD, OS and ORR. However, PB was associated with a nonsignificant increase in OS in the CAI group (HR = 0.65; 95% CI: 0.38-1.2, p = 0.17]. CONCLUSION: Our data showed no difference in TTD, OS and ORR regardless of chemotherapy, but a trend towards an increased OS with PB when given after an ICI, while patients received chemotherapy later in the CAI group. This suggests that a sequential combination of ICI followed by chemotherapy could be an interesting strategy in advanced NSCLC for selected patients.

A phase II study of monalizumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: The I1 cohort of the EORTC-HNCG-1559 UPSTREAM trial.

PURPOSE: Monalizumab is a monoclonal antibody targeting the inhibitory natural killer group 2A (NKG2A) receptor localised on natural killer (NK) and T cells. Its ligand, the human leukocyte antigen E (HLA-E), is overexpressed in squamous cell carcinoma of the head and neck (SCCHN). By targeting the HLA-E-NKG2A pathway, monalizumab may enhance NK and T cell activity. EXPERIMENTAL DESIGN: The UPSTREAM trial is a biomarker-driven umbrella trial studying targeted therapies and immunotherapies in patients with recurrent/metastatic (R/M) SCCHN progressing after platinum therapy. The immunotherapy 1 (I1) cohort was a phase II, single-arm substudy evaluating monalizumab (10 mg/kg intravenously on day 1 of a 14-day cycle). The primary end-point was the objective response (OR) rate (Response Evaluation Criteria in Solid Tumours 1.1) over the first 16 weeks. A two-stage Simon design was used (H1 15%, H0 3%, α 8%, power 90%) with pre-planned interruption of accrual if no OR was observed after the first 25 patients. RESULTS: Twenty-six eligible patients were enrolled. Seventeen (65%) patients had received ≥2 previous lines of systemic treatment, and 15 (58%) patients were PD(-L)1 inhibitor pretreated. No OR was observed. Stable disease was observed in 6 patients (23%) with a median duration of 3.8 months (95% confidence interval [CI]: 2.7-NE). The median progression-free survival and overall survival were 1.7 months (95% CI: 1.5-1.8) and 6.7 months (95% CI: 3.0-9.6), respectively. The most frequent treatment-related adverse event was grade I/II fatigue (19%). CONCLUSIONS: Monalizumab monotherapy has limited activity in R/M SCCHN. The I1 cohort did not meet its primary objective. Monalizumab combined with durvalumab is under investigation within UPSTREAM.

Avelumab for platinum-ineligible/refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck: phase Ib results from the JAVELIN Solid Tumor trial.

BACKGROUND: Recurrent and/or metastatic (R/M) disease develops in approximately 65% of patients with squamous cell carcinoma of the head and neck (SCCHN) and is associated with a poor prognosis. Immune checkpoint inhibitors have proven effective in multiple tumor types, including R/M SCCHN. We report the efficacy and safety of avelumab (antiprogrammed death ligand 1 antibody) in an expansion cohort of patients with platinum-refractory/ineligible R/M SCCHN enrolled in the phase I JAVELIN Solid Tumor trial (NCT01772004). METHODS: Eligible patients with R/M SCCHN were aged ≥18 years and had received ≥1 line of platinum-based chemotherapy with disease progression or recurrence within 6 months of the last dose or were ineligible for platinum-based chemotherapy. All patients received avelumab 10 mg/kg every 2 weeks. Tumor assessments were carried out by a blinded independent review committee (IRC) and investigators according to Response Evaluation Criteria in Solid Tumors V.1.1 (RECIST 1.1). Key endpoints included best overall response, duration of response (DOR) and progression-free survival (PFS) assessed by IRC and investigator per RECIST 1.1, overall survival (OS), and safety. RESULTS: Between April 24, 2015, and November 13, 2015, 153 patients were enrolled. Patients had a median of two prior lines of therapy for metastatic or locally advanced disease (range 0-6); 12 patients (7.8%) were not eligible for platinum-based chemotherapy. At data cut-off (December 31, 2017), the confirmed objective response rate was 9.2% (95% CI 5.1% to 14.9%) assessed by IRC and 13.1% (95% CI 8.2% to 19.5%) assessed by investigator. Median DOR was not reached (95% CI 4.2 to not estimable) based on IRC assessment. Median PFS was 1.4 months (95% CI 1.4 to 2.6) assessed by IRC and 1.8 months (95% CI 1.4 to 2.7) assessed by investigator; median OS was 8.0 months (95% CI 6.5 to 10.2). Any-grade treatment-related adverse events (TRAEs) occurred in 83 patients (54.2%) and were grade ≥3 in 10 patients (6.5%). The most common TRAEs were fatigue (n=19, 12.4%), fever (n=14, 9.2%), pruritus (n=12, 7.8%), and chills (n=11, 7.2%), and there were no treatment-related deaths. CONCLUSION: Avelumab showed clinical activity and was associated with a low rate of grade ≥3 TRAEs in heavily pretreated patients with platinum-refractory/ineligible R/M SCCHN.

Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events.

PURPOSE: As gut microbiota composition is an important determinant of response to immune checkpoint inhibitors (ICIs), we examined the effect of various co-medications known for their interaction with microbiota, when given at ICI initiation. PATIENTS AND METHODS: We identified patients with advanced cancer treated with ICI between May 2015 and September 2017 in our institution. Co-medications given within 1 month before or 1 month after the first administration of ICI were reviewed from medical records. Survival data were analysed with univariable Cox regression, and the combined effect of multiple factors was assessed with factor analysis of mixed data (FAMD). The impact of co-medications on immune-related adverse events (irAEs) occurrence was also assessed. RESULTS: A total of 635 patients were included. Psychotropic drugs (41%), proton pump inhibitors (PPIs; 38%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs; 32%), glucocorticoids (26%), antibiotics (24%), statins (21%) and morphine (20%) were the most prescribed co-medications. Baseline use of antibiotics, glucocorticoids >10 mg/day, PPIs, psychotropic drugs, morphine and insulin was associated with significantly shortened overall survival and decreased tumour response, whereas coadministration of statins, ACEs and/or ARBs, non-steroidal anti-inflammatory drugs, aspirin and oral antidiabetic drugs did not impact patient outcomes. Treatments that altered the response to ICI were also associated with a decreased incidence of irAEs. FAMD revealed the respective weight of each factor or co-medication on the oncological outcomes. CONCLUSION: Co-medications must be carefully assessed at the time of ICI initiation and clinicians aware of their possible deleterious effect, notably for PPIs, glucocorticoids, antibiotics and psychotropic drugs.

Combining immune checkpoint inhibitors with chemotherapy in advanced solid tumours: A review.

The use of immune checkpoint inhibitors (ICIs), especially anti-programmed cell death 1 (PD1) and anti-programmed cell death ligand 1 (PD-L1), has changed practices in oncology, becoming a new standard of care in first or subsequent lines for several cancer subtypes. Recent data have highlighted the ability of standard chemotherapy to enhance immunogenicity and/or to break immunoresistance of the tumour and its microenvironment, leading to a rationale for the use of ICIs in combination with the standard chemotherapy regimen to improve efficacy of cancer treatment. Here, we propose to review randomised clinical trials evaluating concomitant administration of ICIs and chemotherapy, to assess clinical efficacy and safety profiles in advanced solid tumours. Association of these two modes of action on treatments has shown improved overall survival and better objective response rates than standard chemotherapy, especially in first-line treatment of non-small cell lung cancer (NSCLC) and for PD1/PD-L1 enriched tumours, highlighting a potential synergistic effect of this treatment combination in certain tumour types. However, improved survival results with the use of anti-PD-L1 avelumab as a maintenance schedule for bladder cancer raises the question of the most appropriate approach between sequential and concomitant administration of chemoimmunotherapy. To date, no trials have compared in a head-to-head protocol the administration of concomitant chemoimmunotherapy with chemotherapy, used for tumour debulking, followed by administration of ICIs. Regarding the tolerance profile, no new safety signals were found with the combination tested to date. Interestingly, recent results have shown an improved Progression Free survival 2 (PFS2) (defined as the progression after the next line of therapy) in head-and-neck cancers or NSCLC after a first-line pembrolizumab-chemotherapy combination, suggesting a potential long-lasting effect of ICIs when used in combination in the first-line setting.

The impact of sarcopenia on the efficacy and safety of immune checkpoint inhibitors in patients with solid tumours.

BACKGROUND: Evidence suggests that sarcopenia is a significant predictive factor of worst outcomes and treatment-associated toxicities in patients with metastatic solid tumours. The aim of this study was to explore the relationship between low muscle mass and clinical outcomes and immune-related severe toxicities (IrST) in patients treated with immune checkpoint inhibitors (ICIs). METHODS: A retrospective cohort of 261 consecutive metastatic solid tumour patients treated with ICIs were included in our study. Low muscle mass was defined as skeletal muscle index <41 cm2/m2 for females and <43 cm2/m2 for males if body mass index (BMI) <25 kg/m2 or <53 cm2/m2 if BMI ≥ 25 kg/m2. Severe toxicities (ST), including grade III-IV toxicities and side effects leading to treatment interruption, were recorded. RESULTS: The majority of patients (n = 179; 69%) included in this study had metastatic lung cancer. The prevalence of low muscle mass was 47%. The median progression-free survival (PFS) was 32.2 weeks for low muscle mass patients and 24.3 weeks for non-low muscle mass patients (adjusted HR, 0.80; 95% CI, 0.60-1.055; p = 0.11). For low muscle mass and non-low muscle mass lung cancer patients, median PFS was 24.0 weeks and 18.8 weeks (adjusted HR, 0.70; 95% CI, 0.50-0.98; p = 0.04) and median overall survival was 50.7 weeks and 41.1 weeks (adjusted HR, 0.77; 95% CI, 0.54-1.10, p = 0.15) respectively. Immune-related severe toxicities occurred in 3.3% and 9.4% of low muscle mass and non-low muscle mass patients respectively (adjusted OR, 0.69; 95% CI: 0.31-1.49; p = 0.35). CONCLUSION: No difference in outcomes and safety was observed for low muscle mass and non-low muscle mass patients treated with ICIs.

Efficacy and safety of immune checkpoint inhibitors in elderly patients (≥70 years) with squamous cell carcinoma of the head and neck.

BACKGROUND: Recent meta-analysis showed that immune checkpoint inhibitors (ICIs) have comparable activity between younger and older patients. However, little is known about efficacy and safety of ICI in elderly patients with relapsed/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). The aim of this study is to compare the efficacy of ICI for patients aged ≥70 y to that for younger patients, while taking into account potential confounding factors. METHODS: A retrospective study was conducted at four hospitals in France. Patients treated with ICI for R/M SCCHN between September 2014 and December 2018 were eligible. Patients' charts were reviewed for clinical and radiological data as well as oncologic outcomes. RESULTS: We included 226 patients, of whom 67 were aged ≥70 years. Objective response rate (ORR), median overall survival (OS) and median progression-free survival (PFS) were 23%, 9.7 months and 2.7 months, respectively, for elderly patients, compared to 13%, 8.7 months and 1.9 months for younger patients (respective p-values: 0.071, 0.87 and 0.21). After adjustment for performance status, site of progression, number of ICI drugs, time between initial diagnosis and ICI start and number of previous lines, age ≥70 years was significantly associated with a better PFS (hazard ratio [HR], 0.66; p = 0.021) but not OS (HR, 0.91; p = 0.59). Grade 3-5 adverse events (AEs) occurred in 15% of patients aged ≥70 years and in 8% of younger patients (p = 0.13). CONCLUSION: Patients aged ≥70 years with R/M SCCHN may respond to ICI similarly as younger patients in terms of ORR, OS and PFS, while maintaining comparable rate of AEs.

Cetuximab combined with paclitaxel or paclitaxel alone for patients with recurrent or metastatic head and neck squamous cell carcinoma progressing after EXTREME.

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.

Colitis presenting 5 months after the final dose of anti-PD-1: long-term monitoring is warranted after adjuvant therapy.

Immune checkpoint inhibitors have been approved as adjuvant therapy. Adverse immune events occurred during the administration of treatment, and delayed immune-related events have low incidence. A 66-year-old man was treated for hypopharynx cancer in 2012. In 2019, he was treated for a new oropharynx cancer. After undergoing surgery and complete response, the patient received nivolumab as adjuvant treatment. 5 months after the last dose of nivolumab, he presented with grade III diarrhea and abdominal pain for 3 weeks. Rectoscopy showed infiltration of mucous by lymphocytes. Corticosteroid was started resulting in a rapid decrease in symptom severity. With the increasing immune checkpoint inhibitors in adjuvant therapy, strict surveillance and education of patient in remission is necessary.

Lay abstract Immune checkpoint inhibitors have changed the outcomes of several cancers and have been approved after local treatment for melanoma or lung cancer. The toxicities of this treatment were immune-related adverse events and any organ can be involved. Usually, toxicity occurred during the administration of treatment and delayed immune-related events have low incidence. Here, we presented a case report of a patient treated with anti-programmed cell death protein 1 after loco-regional treatment for head and neck cancer and presented with severe diarrhea 5 months after the last dose of treatment. Corticosteroid was started, resulting in a rapid decrease in symptom severity. With the increasing immune checkpoint inhibitors in adjuvant therapy, strict surveillance and education of patient in remission is necessary.

Systemic treatment of metastatic squamous cell carcinoma of the head and neck: proposal for management changes.

PURPOSE OF REVIEW: Worldwide, head and neck carcinomas account for 5% of all malignancies. Two-thirds of patients relapse after initial multimodal therapy. Until early 2010, the median overall survival (OS) of metastatic patients was about 10 months. RECENT FINDINGS: New drugs have been incorporated in patient management, thus enabling an increase in OS. Several first and second line protocols are now available but the lack of direct comparison makes the choice difficult between them. SUMMARY: This work aims to define the comprehensive medical management of patients with relapsing head and neck carcinoma. In September 2020, the French head and neck groups GORTEC, Unicancer head and Neck group, GROCC and GETTEC decided to promote a one-day meeting to propose how to incorporate these new regimens in first and second line treatment for recurrent and metastatic head and neck cancer (R/M SCCHNC). Twelve French medical oncologist involved in the management of R/M SCCHNC for more than 10 years examined the literature and proposed a simple and practical management based on five criteria: age, delay from last platinum injection, combined positive score expression level, FIT or UNFIT patient according to physician decision, fast response needed or not.

Management of Immune Checkpoint Inhibitor Toxicities.

Immune checkpoint inhibitors (ICIs) have radically changed the clinical outcome of several cancers with durable responses. CTLA-4 (cytotoxic T lymphocyte antigen-4), PD-1 (programmed cell death protein 1) or PDL-1 (programmed cell death ligand protein 1) represent ICIs that can be used as monotherapy or in combination with other agents. The toxicity p\rofiles of ICIs differ from the side effects of cytotoxic agents and come with new toxicities like immune-related adverse events. Typically, these toxicities occur in all organs. However, the main organs affected are the skin, digestive, hepatic, lungs, rheumatologic, and endocrine. Most of the immune toxicity that occurs is low grade but some more severe toxicities can occur that require a rapid diagnosis and appropriate treatment. The recognition of symptoms by physicians and patient is necessary to resolve them rapidly and adapt treatment to allow the toxicity to resolve.

Current management and future perspectives of penile cancer: An updated review.

Penile cancer (PeCa) is a rare disease worldwide, accounting for less than one percent of all malignancies in men. It usually presents as a painless ulcer or lump on the head of the penis. Squamous cell carcinoma represents the most common histological subtype of PeCa, with pathogenesis intimately linked to chronic Human Papilloma Virus (HPV) infection. Surgery is the cornerstone for the treatment of primary PeCa with potential mutilating outcome depending on the nodal extension of the disease. However, in case of extensive lymph node involvement, multidisciplinary treatment including perioperative chemotherapy and inclusion in clinical trial should be considered. To date, advanced or metastatic disease still have poor prognosis and are a therapeutic challenge with limited options, highlighting the need of new treatments and further investigations. Growing efforts to identify molecular alterations, understand the role of HPV and characterize immune contexture have expanded over the past years, providing further perspectives in prognostication, predictive biomarkers and therapeutic intervention. In this review, we provide an updated overview of current management of PeCa focusing on perioperative strategy. We discuss about new insights of the biology of PeCa and comment future directions in the field.