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Background: Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. Methods: MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III–IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m2; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016–004403–31). Findings: From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2–29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7–12·1) in the standard group and 9·6 months (7·2–17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65–0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3–4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]). Interpretation: Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted.

Background The prognostic value of the inflammatory indexes (eg. neutrophil-to-lymphocyte ratio, NLR; and systemic immune-inflammation index, SII) was demonstrated among patients with epithelial ovarian cancer (EOC). This study aimed to evaluate their predictive value in terms of platinum-free interval (PFI) as regard to bevacizumab treatment received. Methods A total of 375 EOC patients were retrospectively analyzed, 301 treated with chemotherapy alone and 74 with bevacizumab, with the decision to include this drug in the chemotherapy regimen left to the discretion of the treating physician. The correlation between NLR (defined as the ratio of neutrophil to lymphocyte count) and SII, calculated as (platelet count × neutrophil count)/lymphocyte count, and PFI were analyzed using logistic regression analyses adjusted for baseline patient characteristics. Cutoff values were determined using Receiver Operating Characteristic (ROC) analysis. Results In univariate analysis, patients with high NLR (≥3) and SII (≥730) had a significantly shorter PFI at 6 and 12 months in overall cohort. In multivariate analysis, only NLR was an independent predictive factor for PFI at 6 months (OR = 2.52, 95% CI 1.30–4.87, p = 0.006) and at 12 months (OR = 2.05, 95% CI 1.05–4.01, p = 0.036) in the overall population and in the chemotherapy group (OR = 2.77, 95% CI 1.38–5.56, p = 0.004; HR = 2.27, 95% CI 1.10–4.70, p = 0.027, respectively). Inflammatory indexes were not predictive for PFI in the bevacizumab group (Table). Table: 1020P . PFI at 6 months PFI at 12 months N. pts N. pts OR (95% CI) p N. pts N. pts OR (95% CI) p NLR 74 139 1.00 113 98 1.00 ≥3 80 68 2.52 (1.30-4.87) 0.006 106 37 2.05 (1.05-4.01) 0.036 SII 52 99 1.00 76 73 1.00 ≥730 102 108 0.74 (0.36-1.53) 0.413 143 62 0.91 (0.45-1.84) 0.786 CT NLR 62 115 1.00 98 78 1.00 ≥3 69 48 2.77 (1.38-5.56) 0.004 89 24 2.27 (1.10-4.70) 0.027 SII 41 80 1.00 63 56 1.00 ≥730 90 83 0.76 (0.35-1.67) 0.498 124 46 0.84 (0.39-1.82) 0.663 CT+B NLR 12 24 1.00 15 20 1.00 ≥3 11 20 0.47 (0.04-5.15) 0.538 17 13 0.75 (0.11-5.25) 0.774 SII 11 19 1.00 13 17 1.00 ≥730 12 25 1.65 (0.13-20.56) 0.696 19 16 1.78 (0.21-15.14) 0.599 Conclusions The NLR was an independent predictive factor for platinum-sensitivity in patients with EOC treated with chemotherapy. Its predictive role seems to be lost in patients treated with bevacizumab. Legal entity responsible for the study MITO group. Funding MITO group. Disclosure All authors have declared no conflicts of interest.

Small-cell lung cancer has a high chemotherapeutic sensitivity but with disappointing outcome results. Patients with “sensitive disease” are those who respond to treatment with a long relapse-free interval (RFI): in these cases rechallenge with first-line chemotherapy might represent a therapeutic opportunity. Our largest retrospective experience confirmed that rechallenge is feasible with interesting outcome results; there are no statistical differences between RFI and outcome.Patients with small-cell lung cancer (SCLC) that progresses after first-line (FL) chemotherapy have a poor prognosis and second-line (SL) chemotherapy has limited efficacy. Patients whose disease relapses/progresses90 days after FL platinum-based treatment are considered platinum-sensitive and could be rechallenged with a similar regimen. We conducted a multicenter retrospective analysis to evaluate outcomes of SCLC patients rechallenged with platinum/etoposide.Records of all SCLC patients treated in 7 institutions between January 2007 and December 2011 were reviewed. The primary end point was overall survival from the time of rechallenge (OS-R); secondary end points were progression-free survival (PFS) and overall survival from the time of diagnosis (OS-D). Survival curves were calculated using the Kaplan-Meier method.Of the 2000 SCLC patients identified, 112 (5.6%) had sensitive disease treated with rechallenge platinum/etoposide; 65% were men with a median age of 64 years. At the time of diagnosis, 44% of patients had limited disease, 82% had an Eastern Cooperative Oncology Group performance status of 0 to 1. A median of 4 cycles of rechallenge was administered. Tumor response was 3% for complete response and 42% for partial response, 19% of patients maintained stable disease, 27% progressive disease, and 9% were not evaluable. Median PFS from the time of rechallenge was 5.5 months (95% confidence interval [CI], 4.4-6.3). Median OS-R and OS-D were 7.9 months (95% CI, 6.9-9.7) and 21.4 months (95% CI, 19.8-24.1), respectively. Subgroup analysis according to relapse-free interval (90-119 vs. 120-149 vs.150 days) did not show any statistically significant difference in PFS or OS-R.The outcome for SL chemotherapy for SCLC is poor. Rechallenge platinum/etoposide is a reasonable option with potentially better outcomes than standard chemotherapy.

Purpose/Objective: Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who progress after first-line platinum-based therapy have a dismal prognosis and limited efficacious treatment options. Afatinib, an irreversible ErbB family blocker, showed anti-tumour activity in a phase II trial in this setting (Seiwert et al. Ann Oncol 2014). LUX-Head & Neck 1, a global, openlabel, randomised phase III trial, evaluated second-line afatinib vs methotrexate (MTX) in patients with R/M HNSCC who progressed on/after platinum-based therapy (NCT01345682). Materials and Methods: Patients were randomised 2:1 to 40 mg/day oral afatinib (n=322) or 40 mg/m/week intravenous MTX (n=161), stratified by Eastern Cooperative Oncology Group performance status (0/1) and prior use of anti-EGFR antibody therapy (Yes/No) in the R/M setting. The primary endpoint was progression-free survival (PFS) by independent central review; overall survival (OS) was the key secondary endpoint. Other endpoints included objective response rate (ORR), patient-reported outcomes (PROs), tumour shrinkage, and adverse events (AEs). Disease control rate (DCR) was also assessed. Results: Patient baseline characteristics were well balanced between treatment groups (Table). Afatinib significantly improved the primary endpoint of PFS vs MTX by independent central review (median 2.6 vs 1.7 months; HR=0.80 [95% CI 0.65–0.98; p=0.03]; Figure); similar results were observed by investigator assessment. A trend towards improved PFS with afatinib was observed in a subgroup of patients aged ≥65 years (HR=0.68 [95% CI 0.45–1.03]). OS was not significantly improved with afatinib vs MTX (median 6.8 vs 6.0 months; HR=0.96 [0.77–1.19]). DCR was higher with afatinib vs MTX (49.1% vs 38.5%; p=0.04); ORR was 10.2% vs 5.6%, respectively (p=0.10). Tumour shrinkage was observed in 34.8% of afatinib-treated patients vs 22.4% of MTX-treated patients. Afatinib significantly delayed deterioration of global health status, pain and swallowing (all p≤0.03); significantly less pain over time was observed in afatinib-treated patients (p=0.03). Median duration of treatment was 83 days (range, 2–546) with afatinib and 43 days (range, 1–442) with MTX. The most frequent grade 3/4 treatment-related AEs were rash/acne (9.7%) and diarrhoea (9.4%) with afatinib, and stomatitis (8.1%) and neutropenia (6.9%) with MTX. Fewer treatment-related AEs led to dose reductions (32.2% vs 41.9%), drug discontinuations (7.2% vs 16.3%) or fatal outcome (2 [0.6%] vs 5 [3.1%]) in afatinib-treated patients. Conclusions: In this phase III trial in patients with R/M HNSCC after failure of platinum-based therapy, second-line afatinib significantly improved the primary endpoint of PFS vs MTX, with a manageable safety profile. A significant delay in deterioration of PROs and less pain over time was also observed with afatinib compared to MTX. OC-006 Concomitant treatment (CRT or cetuximab/RT) with or without induction TPF in Locally Advanced head and neck Cancer M.G. Ghi, A. Paccagnella, D. Ferrari, P. Foa, M. Cossu Rocca, E. Verri, F. Morelli, G. Azzarello, C. D'Ambrosio, C. Casanova, M. Guaraldi, E. Massa, C. Rossetto, A. Bonetti, S. Siena, A. Frattegiani, H. Koussis, G. Pieri, A. Gava, I. Floriani, For the GSTTC Italian Study Group Ospedale SS Giovanni e Paolo, Medical Oncology, Venezia, Italy San Paolo Hospital, Medical Oncology Unit, Milano, Italy Medical Oncology Unit of Urogenital and Head and Neck Tumors, European Institute of Oncology, Milano, Italy IRCCS Casa Sollievo della Sofferenza, Medical Oncology, San Giovanni Rotondo, Italy Azienda ULSS 13, Internal Medical Sciences, Mirano, Italy University Hospital, Oncology, Modena, Italy Azienda USL, Medical Oncology, Ravenna, Italy Policlinico Sant'Orsola-Malpighi, Medical Oncology, Bologna, Italy Azienda Ospedaliero Universitaria, Internal Medical Science, Cagliari, Italy University Hospital, Oncology, Udine, Italy Mater Salutis Hospital-AULSS 21 della Regione Veneto, Legnago, Italy Niguarda Ca' Granda Hospital, Milano, Italy Azienda Ospedaliera, Raditation Therapy, Perugia, Italy Istituto Oncologico Veneto IRCCS, Padova, Italy Ospedali Riuniti di Trieste, Oncology, Trieste, Italy Ospedale Ca Foncello, Radiation Therapy Department, Treviso, Italy Laboratorio Trials Clinici, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy

Background CT/RT or CET/RT are standard treatment options for LASCCHN. Strategies to improve the efficacy with the integration of induction chemotherapy are being investigated. Primary endpoints of this study were to compare: 1) the 3 y overall survival (OS) of induction vs. no induction arms; 2) the Grade(G)3-4 in-field toxicity of CT/RT vs. CET/RT. Methods Patients (pts) with unresectable LASCCHN, stage III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1: CT/RT (2 cycles of ciplatin/5fluorouracil); Arm A2: CET/RT; Arm B1: 3 cycles of induction TPF followed by the same CT/RT; Arm B2: 3 cycles of induction TPF followed by CET/RT. A total of 204 deaths (420 ptsincluding the 101 randomized in the phase II part of the study comparing CT/RT with or w/o induction TPF) were required to detect a HR of death of 0.675 (A1 + A2 vs. B1 + B2; 2-sided a = 0.05; b = 0.20) and a 10% difference in G3-4 in-field mucosal toxicity (A1 + B1 vs. A2 + B2). Results Accrual was completed (421 pts) in April 2012. By May 2012, 348 patients were evaluable for toxicity during the planned concomitant treatments. 82% of pts were male; median age was 60y; PS of 0 (77.8%) or 1 (22.2%). Stage was III (31%) or IV (69%). Sites of disease were: oral cavity: 21.7%, oropharynx: 54.8%, hypopharynx: 23.5%. Data on G3-4 in-field toxicity (primary endpoint) and compliance to CT/RT vs CET/RT are shown in table 1. CT/RT N 215 CET/RT N 133 p In-field mucositis Grade 3 Grade 4 37% 4% 35% 2% 0.79 0.45 In-field skin reaction Grade 3 Grade 4 13% 1% 20% 1% 0.07 0.58 RT median dose, Gy (range) 70 (8-70) 70 (14-70) 0.32 RT median duration, weeks (range) 7 (1-13) 8 (1-14) Pts with RT interruption >3days 32% 38% 0.22 RT modification due to acute toxicity 37% 40% 0.58 Conclusions No advantage for CET/RT over CT/RT were observed regarding G3-4 in-field toxicities and feasibility. Pts are still being followed-up to assess OS. Table 1: Disclosure All authors have declared no conflicts of interest.