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Background: Molecular diagnostics for non-small cell lung cancer (NSCLC) has become the standard of care for personalized treatment. Epidermal growth factor receptor ( EGFR ) mutation and EML4-ALK translocation represent the two most important alterations in first-line treatment decision-making. However, other potentially targetable alterations are also present. Methods: One thousand consecutive NSCLC patients with EGFR wild type (wt) tumors diagnosed by routine molecular analysis were considered. KRAS, BRAF, ERBB2, PIK3CA, NRAS, ALK, MAP2K1, RET and DDR2 gene mutations were analyzed using the multiparametric Sequenom MassARRAY ® platform. EML4-ALK and ROS1 rearrangements were also assessed by fluorescent in situ hybridization. HER4 status was determined by direct sequencing. Results: Three hundred and forty-eight (34.8%), 31 (3.1%), 39 (4.4%), 14 (1.8%), 6 (0.7%), 16 (1.8%), 5 (0.6%) and 9 (0.9%) patients showed an alteration in KRAS, BRAF, ALK, ROS1, NRAS, PIK3CA, MAPK1/2 and HER2 genes, respectively. Of the 657 patients for whom all markers were determined, 318 (48%) patients had at least one alteration. Eight patients showed overlapping mutations, 4 KRAS mutation/ EML4-ALK translocation, one KRAS mutation/ ROS1 rearrangement, 2 KRAS/PIK3CA mutations, and one BRAF/PIK3CA mutations. Conclusions: About 50% of our patients had a potentially targetable alteration, confirming the usefulness of a multiparametric approach for routine molecular diagnostics aimed at identifying potential therapeutic targets.

The variability in progression-free survival (PFS) and overall survival (OS) among patients with epithelial ovarian cancer (EOC) makes it difficult to reliably predict outcomes. A predictive biomarker of bevacizumab efficacy as first-line therapy in EOC is still lacking. The MITO group conducted a multicenter, retrospective study (MITO 24) to investigate the role of inflammatory indexes as prognostic factors and predictors of treatment efficacy in FIGO stage III–IV EOC patients treated with first-line chemotherapy alone or in combination with bevacizumab. Of the 375 patients recruited, 301 received chemotherapy alone and 74 received chemotherapy with bevacizumab. The pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) were evaluated to identify a potential correlation with PFS and OS in both the overall population and the two treatment arms. In the overall population, the PFS and OS were significantly longer in patients with low inflammatory indexes (p

Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non–small cell lung cancer (NSCLC). Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53-mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21–8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71–36.63), P < 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P < 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34–20.87, P < 0.001) and HR 4.75 (95% CI, 1.38–16.29, P = 0.013), respectively. Conclusions: TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions. Clin Cancer Res; 23(9); 2195–202. ©2016 AACR.

In the last few years, substantial progress has been made in the treatment of ovarian cancer, with increased knowledge about the biology of the disease. Ovarian cancer is a neoplasm strongly linked to defects in DNA repair mechanisms, where deficiency in the homologous recombination (HR) system results in a better response of ovarian cancers to therapy, whether platinum-based chemotherapy, anthracyclines, or poly (ADP-ribose) polymerase (PARP) inhibitors. More recently, it has been demonstrated that different ovarian cancer histotypes may have different immunogenicity. Interestingly, defects in HR systems are associated more frequently with higher tumor infiltrating lymphocytes, providing a rationale for developing combination therapy with immune-modulating agents and PARP inhibitors. Again, locoregional therapies combining heat shock and chemotherapy delivery have been shown to induce an anticancer immune response in vitro. Thus, the potential for locoregional therapeutic approaches that may impact the immune system, perhaps in combination with immune-modulating agents or PARP inhibitors, needs to be further explored. With this premise, we reviewed the main biological and clinical data demonstrating a strict interplay between the immune system, DNA repair mechanisms, and intraperitoneal therapies in ovarian cancer, with a focus on potential future therapeutic implications.

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency.

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.

Germ cell tumors of the testes represent a unique paradigm of diseases which can be cured even in extremely advanced phase. Unfortunately, this makes them unique among adult solid tumors. Seminoma and non seminoma are relatively rare with approximatively 25,000 patients in Europe per year, but numbers are increasing world wide. Different strategies are needed depending on stage and prognostic scores. Seminoma is extremely sensitive to radiation therapy and chemotherapy, while all germ cell tumors show a very good response to chemotherapy. Clinical stage I seminoma is currently treated with radiation, single course carboplatin or surveillance policy. Clinical stage I non seminoma can also be approached with different strategies such as retroperitoneal lymph node dissection, observation or one-two courses of standard chemotherapy. Stage II seminoma may be treated with either radiation or chemotherapy, while for all advanced stages chemotherapy is mandatory. Since the mid-eighties PEB (Cisplatin, Etoposide and Bleomycin) is the regimen of choice and no other schedule has proved superior in terms of efficacy. Surgery on the residual disease is crucial to the whole strategy and should be performed or attempted in all cases. Consequently, the correct treatment strategy for these tumors does not depend only on the ability of a single physician, but on a skilled team specialized in this particular tumor. Second line therapies (VeIP, PEI, TIP) can cure 25%–40% of patients, but improved strategies for resistant tumors are desperately needed. High-dose chemotherapy has shown very good results in some studies while being less impressive in others. In any case, it should remain an option for relapsing patients and could be used in some cases of upfront chemotherapy in patients with slow marker decline, but this should only be considered in referring centers.

We report the case of a HER2+ breast cancer patient, with early relapse, refractory to HER2-targeted therapy and treated with eribulin mesylate. The patient progressed during two different HER2 target therapies: trastuzumab as adjuvant/first-line treatment and lapatinib as second-line treatment. The patient underwent nine cycles of eribulin (1.23 mg/m2 days 1–8 every 3 weeks). The therapy was well tolerated. Restaging with computed tomography after the second cycle of treatment demonstrated stable disease. After nine cycles of eribulin therapy the patient experienced disease progression and she died 6 months later. This case report provides further insights regarding the use of eribulin mesylate as third-line treatment in a HER2+ breast cancer patient.

Tyrosine kinase inhibitors (TKIs) are very efficacious in non-small-cell lung cancer (NSCLC) patients harboring activating Epidermal Growth Factor Receptor (EGFR) mutations. However, about 10% of EGFR wild type (wt) patients respond to TKI, with unknown molecular mechanisms of sensitivity. We considered a case series of 34 EGFR wt NSCLC patients responsive to erlotinib after at least one line of therapy. Responsive patients were matched with an equal number of non-responsive EGFR wt patients. A panel of 26 genes, for a total of 214 somatic mutations, was analyzed by MassARRAY® System (Sequenom, San Diego, CA, USA). A 15% KRAS mutation was observed in both groups, with a prevalence of G12C in non-responders (80% vs. 40% in responders). NOTCH1, p53 and EGFR-resistance-related mutations were found more frequently in non-responders, whereas EGFR-sensitizing mutations and alterations in genes involved in proliferation pathways were more frequent in responders. In conclusion, our findings indicate that p53, NOTCH1 and exon 20 EGFR mutations seem to be related to TKI resistance. KRAS mutations do not appear to influence the TKI response, although G12C mutation is more frequent in non-responders. Finally, the use of highly sensitive methodologies could lead to the identification of under-represented EGFR mutations potentially associated with TKI sensitivity.

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 Although small-cell lung cancer is a chemosensitive malignancy, most patients rapidly relapse. Results of second-line treatment are generally poor. We conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy. Patients and Methods Eligible patients were refractory or relapsed small-cell lung cancer, with an Eastern Cooperative Oncology Group performance status of 0-2 and measurable disease. Paclitaxel was administered at 135 mg/m 2 days 1 and 8 immediately followed by gemcitabine at 1000 mg/m 2 every 3 weeks up to 6 courses. Restaging of disease was scheduled every 3 courses. Results Forty-one patients were enrolled. The median age was 65 years. Nineteen patients were considered refractory (progressive disease during or within 90 days from completion of first-line treatment), whereas 22 patients were chemotherapy sensitive. A total of 135 courses was administered (range, 1-6; median, 3). Nine patients achieved a partial remission (partial response, 22%), and 10 patients had stable disease (24%), with a disease control rate (partial response + stable disease) of 46%: in 12 (55%) of 22 patients who were sensitive and in 7 (37%) of 19 patients with refractory disease, respectively. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months. The most-frequent severe toxicities were neutropenia grade 3-4 and neurologic grade 3 in 24% and 7% of delivered courses, respectively. Conclusions The combination of gemcitabine and paclitaxel investigated in our study achieved a high disease control rate, but the schedule we adopted appeared to be quite toxic.

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.

6003 Background: This is the first phase III study directly comparing CRT vs CET/RT in LASCCHN. Primary endpoints of this study were to compare: 1) overall survival (OS) of induction vs. no induction arms; 2) Grade 3-4 in-field toxicity of CRT vs. CET/RT. Preliminary toxicity results of concomitant treatments (primary endpoint for this comparison) were reported at the 2012 ASCO meeting. Here we present response rate and survival data for the two concomitant treatments (CRT vs. CET/RT), irrespective of induction chemotherapy. Methods: Untreated patients with unresectable LASCCHN, stage III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1: CRT (2 cycles of cisplatin/5fluorouracil concomitant to RT); Arm A2: CET/RT; Arm B1: 3 cycles of TPF followed by the same CRT; Arm B2:3 cycles of TPF followed by CET/RT. Results: A total of421 patients were randomized: 261 received CRT (131 Arm A1+ 130 Arm B1) and 160 received CET/RT (80 Arm A2+ 80 Arm B2). 82% were male; median age was 60y; PS of 0 (79%) or 1 (21%). Stage was III (32%) or IV (68%). Sites of disease were: oral cavity 20%, oropharynx 57%, hypopharynx: 23%. No significant differences were observed in patients’ characteristics distribution. At a median follow-up of 32.9 months, a total of 174 deaths occurred (204 required for final OS analysis). Data on activity and efficacy of CRT and CET/RT are shown in the Table. Conclusions: No significant differences were observed in response rate, progression free survival and OS between CRT and CET/RT. Pts are still being followed-up to assess OS of induction vs. no induction arms. Clinical trial information: NCT01086826. [Table: see text]

5513 Background: The standard treatment options for LASCCHN are cCHT+RT or CET+RT. Strategies to improve the efficacy with the integration of induction chemotherapy are being investigated. Primary endpoints of this study were to compare: 1) the overall survival (OS) of induction vs. no induction arms; 2) the Grade(G)3-4 in-field toxicity of cCHT+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: cCHT+RT (2 cycles of ciplatin/5fluorouracil); Arm A2: CET+RTX; Arm B1: 3 cycles of TPF followed by the same cCHT+RT; Arm B2: 3 cycles of TPF followed by CET+RT. A total of 204 deaths over 420 pts ( including the 101 randomized in the phase II part of the study comparing cCHT+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: By February 2012, 387 pts over 413 pts were evaluable for toxicity. 82% of pts were male; median age was 60y; PS: 0=77.8% and 1=22.2%. Disease stage was III (31%) or IV (69%). Sites of disease were oral cavity (21.7%), oropharynx (54.8%), hypopharynx (23.5%). At a median follow-up of 21 months, 126 deaths occurred. Data on G3-4 in-field toxicity (primary endpoint) and compliance to cCHT+RT vs CET+RT are shown in the table. Conclusions: No advantage for CET+RT over cCHT+RT was observed regarding G3-4 in-field toxicities and feasibility. Pts are still being followed-up to assess OS. [Table: see text]