Abstract only
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 .
Summary Objective Worldwide, head and neck carcinomas account for 5% of all malignancies. Two-thirds of patients relapse after initial multimodal therapy. Until early 2000, the median overall ...survival (OS) of metastatic patients was about 6 months. Recently, new drugs have been incorporated in patient management, thus enabling an increase in OS. This review aims to define the comprehensive medical management of patients with relapsing head and neck carcinoma. Methods A comprehensive review of the literature was made targeting four topics: first- and second-line treatment, supportive care, and management of elderly patients. Results The choice of first- or second-line treatments is mainly based on performance status. In the elderly, geriatric assessment could be helpful. For PS 0.1 patients, the standard first-line treatment is 6 cycles of cisplatin-5FU-cetuximab. In the event of response, cetuximab alone is prolonged until progression or unacceptable toxicity. For second-line treatment, several options are currently available: enrolment in clinical trials, single-agent therapy (methotrexate, taxane, cetuximab), and best supportive care (BSC). Supportive care has to be initiated very early in the course of the disease to prevent pain, dysphagia and malnutrition. In elderly patients, the therapeutic options are: first-line treatment with the EXTREME regimen replacing cisplatin by carboplatin for patients in good general condition or methotrexate alone for other patients. BSC continues to be given to all patients (i.e. poor general conditions). Conclusion In spite of numerous pending issues requiring further investigation, these recommendations seem to be routinely applicable.
Abstract only
11541
Background: About 47% and 10% of HNSCC occur in pts aged ≥65 or ≥80 respectively. This population being heterogeneous, balancing efficacy with toxicity is challenging. As the G8 ...screening tool includes 3 nutritional items, we need to evaluate its usefulness in HNSCC pts and to establish an adapted tool for HNSCC pts. Methods: ONCOVAL is the first step of the ELAN program for pts ≥70 with HNSCC not amenable to surgery. Pts were assessed for geriatric frailties before inclusion in appropriate trials (ELAN-RT, FIT, UNFIT) depending on curative or palliative setting and fit or unfit status. The aim was to evaluate the G8 tool and EGE usable by oncologists to classify pts as fit or unfit. The EGE was elaborated by the French GERICO group for HNSCC pts, evaluating functional status, comorbidity, cognition/mood, social status. To estimate sensitivity and specificity of G8 and EGE, we used comprehensive geriatric assessment (CGA) performed by geriatricians as gold standard. Results: From 06/2013 to 08/2018, 633 pts were included in 44 centers. Data are available for 613 pts. Median age 79 years (70-97) with 45% ≥ 80. 75% males. G8 score was ≤14, i.e. at risk of geriatric frailty, in 82% pts. Assessment by EGE was done by physicians (64%), nurses (11%), ELAN staff (21%) in 20 minutes of median time. After EGE, oncologists classified 71% pts as unfit. 49% of pts were assessed by CGA. The G8 score with cut-off ≤ 14 has sensitivity 91% and specificity 30%. Lowering cut-off to 12 increased specificity to 56% but decreased sensitivity to 75%. Sensitivity of EGE was 95% and specificity 60%. Multidisciplinary interventions were more frequently implemented in pts assessed by geriatricians than in others (71% vs 47%), even after adjusting for frailty. 58% of pts included in ONCOVAL were further included in ELAN therapeutic trials. Assessment by geriatricians did not modify the rate of inclusion in trials. Conclusions: The G8 screening tool is not appropriate for HNSCC pts. The EGE was feasible and had better sensitivity and specificity. Oncologists and geriatricians must continue such collaboration to propose tailored treatments. Clinical trial information: NCT03614936.
Abstract only
6083
Background: SGCHN are rare tumors including adenoid cystic carcinoma (ACC) and non-ACC, with no standard systemic treatment for R/M pts. We evaluated N monotherapy in R/M SGCHN ...pts. Methods: R/M SGCHN pts (ACC or non-ACC) not eligible to local treatment and with centrally confirmed RECIST 1.1 disease progression over the last 6 months were enrolled and received N 3 mg/kg IV, every 2 weeks for a maximum of 12 months (mo). Possibility was given to re-start N in case of progression during the 2-year follow-up phase. Primary endpoint was 6-mo non-progression Rate (NPR
6m
) as per RECIST 1.1. Secondary endpoints included ORR, PFS, OS, and safety. Considering that N would be uninteresting if NPR
6m
≤ 20% and promising if ≥ 40% and using a Fleming’s single-stage design (α: 5% unilateral, power: 90%), at least 14 successes/42 evaluable pts were required for each cohort to be positive. Results: 46 ACC and 52 Non-ACC pts (median age 61 yrs (range 29-81), 43.9% female, 55.1% PS1 and 2.0% PS2) were enrolled and received at least one dose of N. Median treatment duration was 5.5 mo (ACC) and 3.3 (Non-ACC). Median FU was 10.8 mo (ACC) and 8.3 mo (Non-ACC). 95 patients were evaluable for the primary endpoint. NPR
6m
was 15/45 pts (33.3%, 90%CI :21.8;46.6) and 7/50 pts (14.0%, 90%CI:6.8;24.7) for ACC and non-ACC pts respectively. 4 (8.7%) partial responses (PR) and 26 (56.5%) stable diseases (SD) were observed in ACC cohort while 2 (3.8%) PR and 22 (42.3%) SD were observed in non-ACC. Median PFS was 4.9 mo (95%CI = 3.4;5.6) in ACC pts and 1.8 mo (95%CI = 1.7;3.5) in non-ACC pts. The most common related adverse events (AE) ( > 10% by cohort) were asthenia, hyperthyroidism, diarrhea, rash, pruritus and hypothyroidism. 7/98 pts (7.1%) presented at least one related AE Grade 3-4 (mainly hepatic) and 9 pts (9.2%) prematurely discontinued Nivolumab due to toxicity. Conclusions: Limited efficacy was observed with N in R/M SGCHN pts. N in combination might be of interest and deserves exploration in ACC pts. Clinical trial information: NCT03132038.
Abstract only
6002
Background: After promising results from the GORTEC TPEx phase II trial, the role of taxane instead of 5FU in 1st-line R/M HNSCC chemotherapy (CT) remained to be confirmed by ...comparing TPEx to the reference EXTREME regimen. Methods: Randomized (1:1), open-label trial. Main inclusion criteria were R/M HNSCC not suitable for locoregional treatment, age 18-70 years, PS <2, creatinine clearance >60ml/min, prior cisplatin <300 mg/m². Reference EXTREME regimen (arm A: 6 cycles every 3 weeks (Q3W) of 5FU–cisplatin-cetuximab (cetux) followed by weekly cetux maintenance) was compared to TPEx regimen (arm B: 4 cycles Q3W of docetaxel 75mg/m²–cisplatin 75mg/m²- cetux 250mg/m² with mandatory G-CSF support followed by every 2W cetux 500mg/m² maintenance). The primary endpoint was Overall Survival (OS). To detect a hazard ratio (HR) of 0.72 (median OS increase from 10.1 to 14.0 months (mo) with 88% power, 2-sided significance level of 0.05, 374 deaths were required. 540 patients (pts) were planned to enroll. Results: 539 pts were enrolled in 37 mo. Median age was 60 years, 93% were smokers, 40% had oropharyngeal tumor (p16 or HPV DNA was done in 85%, positive in 28%). In arm A, 44% of pts received all CT cycles vs 72% in arm B. Delays in administration were more frequent in arm A (27% vs 10%). Cisplatin was more frequently switched to carboplatin in arm A (34% vs 9%). Toxicity was lower in arm B: 34% pts had grade ≥4 adverse events during CT in arm B vs 50% in arm A (p<0.001). Less pts in arm A started maintenance than in arm B (53% vs 73%). At time of analysis, the median follow-up duration was 30 mo and 406 pts had died. OS was not significantly different between arms: HR=0.87 (95%CI: 0.71-1.05), p=0.15. Median OS was 13.4 mo in arm A vs 14.5 in arm B. 2-year OS rate was 21.0% in arm A vs 28.6% in arm B. Conclusions: This large randomized trial confirmed the encouraging survival results of the TPEx regimen observed in the first phase II. OS in both arms was higher than observed in previous randomized CT or immunotherapy combination trials. Despite lack of significant OS increase, taxane based TPEx regimen appears to be a new option in 1st line R/M HNSCC, with a shorter time on CT and significantly lower toxicity than the EXTREME regimen. Clinical trial information: NCT02268695.
Abstract only
6032
Background: In the randomized phase III Study CA209141, Nivolumab (N) demonstrated significant overall survival (OS) benefit with favorable safety profile for platinum refractory ...R/M SCCHN and is now approved for these patients (pts). The objectives of the study are to provide additional insight into the frequency of high-grade AEs related to N and the efficacy of N in real life. Methods: Between August and December 2017, 203 pts were included in the multicenter, non-controlled phase II TOPNIVO. The main inclusion criteria were patients with platinum refractory R/M SCCHN with progressive disease, ECOG 0-2. Pts received N 3mg/kg every 2 weeks intravenously over 30 minutes. Four pts did not receive N. We report here the safety during the first 6 months (mo) after inclusion and OS results on the first 199 treated pts. Results: Median age was 62 yr, 83% were male, 84% were ECOG 0-1, 16% 2. The primary site of cancer was oral cavity 26%, oropharynx 38%, larynx 16%, hypopharynx 21%. 33% had loco regional relapse, 32% metastatic disease and 35% both. 49% had received one prior line of chemotherapy and 30% two prior lines. 157 (79%) pts ended their treatment within the first six mo: 5 for AE related to N (pneumonitis 3 pts, hepatitis 1 pt, diarrhea 1 pt), 107 for progression, 33 for death (24 related to progression, 9 to intercurrent disease), 12 other. 132 pts (66%) experienced at least 1 AE grade ≥3. On the 226 AEs grade 3-4, 21 (mainly pneumopathy, lipase increase and asthenia) were related to N and occurred in 18 pts. On the 51 AEs grade 5, 3 were considered related to N (2 pneumonitis, 1 cardiac arrest). The median OS was 7.7 mo (CI 95% 6.0; 9.5) in the whole population; 9.2 mo 6.8; 12.1 in the 167 pts with ECOG 0-1, 3.0 mo 1.1; 6.0 in the 32 pts with ECOG 2; 12.1 mo 7.6; NR in the 64 pts with metastatic disease, 7.7 mo 5.0; 9.6 in the 66 pts with locoregional disease and 4.6 mo 3.1; 7.9 in the 69 pts with both. OS was similar in pts older or younger 70 yr. Conclusions: The interim analysis of the TOPNIVO study shows no additional toxicities of N compared to what has been described previously, confirms the previous results of OS and provides new survival data in subgroups of pts. Clinical trial information: NCT03226756.
At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of ...cetuximab to those of methotrexate (the reference regimen) in this population.
This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m2 intravenously every 2 weeks or methotrexate 40 mg/m2 intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis.
Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8–52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months 95% CI 1·0–2·1 in the cetuximab group vs 1·9 months 1·1–2·6 in the methotrexate group; adjusted HR 1·03 95% CI 0·66–1·61, p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3–4 adverse events in the cetuximab group were fatigue (four 10% of 41 patients), lung infection (four 10%), and rash acneiform (four 10%), and those in the methotrexate group were fatigue (nine 22% of 41), increased gamma-glutamyltransferase (seven 17%), natraemia disorder (four 10%), anaemia (four 10%), leukopenia (four 10%), and neutropenia (four 10%). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause).
The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation.
French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé.
For the French translation of the abstract see Supplementary Materials section.
