supplementary table 1. Radiotherapy and Chemotherapy Treatment dose and Surgery

In the CARSKIN study (NCT02883556), first line pembrolizumab demonstrated promising activity and manageable safety in patients (pts) with advanced CSCC. Here we report BOR and survival endpoints. Eligible pts with unresectable locally advanced or metastatic CSCC received pembrolizumab. The imaging assessment per RECIST v1.1 was blinded with independent central review. Objectives were BOR, PFS, DOR, OS, and safety in the ITT population; exploratory objectives were BOR and survival endpoints by PD-L1 status in the PP population excluding 2 untreated pts, 1 early non related death and 3 pts tested only with 1 assay. PD-L1 status was centrally assessed by 2 blinded independent pathologists, one using the anti–PD-L1 E1L3N clone (TPSE1L3N), the other using the 22C3 antibody (TPS22C3 and CPS22C3) with a cutoff of 1%. With a median follow-up of 26 mo, BOR was 47% with 15 PR (26%) and 12 CR (21%); 1y-PFS and OS were 49% and 72% (Table). BOR was significantly higher in PD-L1+ pts than in PD-L1 – pts using TPSE1L3N (p=0.02) or CPS22C3 (p=0.038) but not TPS22C3 (p=0.76). The optimal cutoff of CPS22C3 for BOR using a ROC curve was estimated to be ≥ 7% (Se=0.70, Sp=0.75). Pts with PD-L1+ CSCCs have a significantly better 1y-PFS using TPSE1L3N (p=0.004) but not CPS22C3 and a better 1y-OS with both antibodies (p<0.03). Severe TRAEs occurred in 10 patients (17.5%); 1 pt died of a fatal 2nd aggressive HNSCC.Table: 1139PTPS (EILN3)CPS (22C3)Outcome [95%CI]ITT population #57PP population #51PD-L1+ pts #40PD-L1– pts #11PD-L1+ pts #41PD-L1– pts #10Best ORR Median PFS47% [34-61] 10.1 [4.8-NR]51% [34-62] 13.7 [4.6 -NR]60% [43-75] 19.6 [6.1-NR]18% [2-52] 2.1 [1.9-NR]59% [42-74] 13.8 [5.6-NR]20% |3-56] 4.3 [2.0-NR]1y-PFS49% [37-64]50% [38-66]57% [43-72]27% [10-72]53% [39-71]40% [19-86]Median OS25.3 [16.5-NR]25.3 [16.5-NR]NR10.0 [4.0-NR]NR10.0 [2.0-NR]1y-OS72% [61-85]73% [61-86]82% [70-95]42% [20-87]79% [67-93]50% [27-93]Median DORNRNRNR5.6 [5.6-NR]NRNR1y-DOR79% [65-97]80% [65-97]83 [69-100]50 [13-100]78 [62-97]100 Open table in a new tab Our data confirm promising activity of P in first line treatment of CSCC with a manageable side effect profile. CPS22C3 ≥ 7% appeared equivalent to TPSE1L3N ≥ 1% for predicting BOR and OS.

e21593 Background: In the CARSKIN study (NCT02883556), 1L pembrolizumab demonstrated promising activity with durable responses and manageable safety in patients (pts) with unresectable locally advanced or metastatic CSCC. Here we report best ORR and survival endpoints of the entire cohort by PD-L1 status. Methods: The imaging assessment per RECIST v1.1 was blinded with independent central review. Best ORR, PFS, DOR OS, in the overall sample and by PD-L1 status was centrally assessed by 2 blinded independent pathologists, one using the anti–PD-L1 E1L3N clone (TPS E1L3N ), the other using the 22C3 antibody (TPS 22C3 and CPS 22C3 ). Among 57 pts, 6 were excluded from the analysis: 2 untreated pts, 1 early unrelated death and 3 pts tested only with 1 assay). ROC curve analysis was used to compare assays. Results: With a median follow-up of 26 mo, best ORR was 51% with 14 PR (27%) and 12 CR (24%). Relapse occurred in 3 PR and 1 PD-L1 – CR pts. Respective median PFS, DOR, and OS were 13.7, NR, and 25.3 mo; respective 1-year PFS, DOR and OS were 50% [38-66], 80% [65-97] and 73% [61-86]. With a cutoff of 1%, best ORR was higher either for TPS E1L3N + pts vs TPS E1L3N – pts (60% vs 18%, p = 0.02) and for CPS 22C3 + pts (59% vs 20%, p = 0.038), but not TPS 22C3 + pts (p = 0.76). The optimal cutoff of CPS 22C3 for ORR using a ROC curve was estimated to be ≥ 7% with a sensitivity of 0.70 and a specificity of 0.75. For best ORR, area under the ROC curve was higher for CPS 22C3 (0.72) than TPS E1L3N (0.62) but the difference was not significant (P = 0.21). Pts with TPS E1L3N ≥ 1% had a higher 1-y PFS (57% vs 27%, p = 0.004) and OS (82% vs 42%, P = 0.01). Pts with CPS 22C3 ≥ 1%, had a better 1-y OS (79% vs 50%, p = 0.03), but not 1y-PFS. Conclusions: CPS 22C3 ≥ 7% appeared equivalent to TPS E1L3N ≥ 1% for predicting ORR and OS in pts receiving pembrolizumab in 1L treatment of advanced or metastatic CSCCs. Replications are warranted for validation. Pts with low scores might beneficiate from combined treatments. Clinical trial information: NCT02883556 .

supplementary table 3. Response evaluation at 2 time points

supplementary table 4. Multivariate analysis for Complete Clinical Response and Figo stage

supplementary table 2. Protocolâ€defined treatmentâ€related Adverse Events

PURPOSE To evaluate first-line pembrolizumab monotherapy efficacy and safety in patients with unresectable cutaneous squamous cell carcinomas (CSCCs). PATIENTS AND METHODS Patients, predominantly men, with their CSSCs’ immunohistochemically determined programmed cell death-ligand 1 (PD-L1) status determined (tumor proportion score threshold, 1%), received pembrolizumab (200 mg every 3 weeks). The primary endpoint was the 39-patient primary cohort’s objective response rate at week 15 (ORR W15 ). Secondary objectives were best ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), safety, ORR according to PD-L1 status and health-related quality of life using Functional Assessment of Cancer Therapy–General (FACT-G) score. An 18-patient expansion cohort, recruited to power the study to evaluate the ORR W15 difference between PD-L1+ and PD-L1– patients, was assessed for ORR, disease control rate, and safety, but not survival. RESULTS Median age of all patients was 79 years. The primary cohort’s ORR W15 was 41% (95% CI, 26% to 58%), including 13 partial and 3 complete responses. Best responses were 8 partial and 8 complete responses. At a median follow-up of 22.4 months, respective median PFS, DOR, and OS were 6.7 months, not reached, and 25.3 months, respectively. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were grade ≥ 3. One death was related to rapid CSCC progression; another resulted from a fatal second aggressive head and neck squamous cell carcinoma diagnosed 15 weeks postinclusion. ORR W15 for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1– patients (17%; P = .02). Responders’ W15 total FACT-G score had improved ( P = .025) compared with nonresponders. CONCLUSION First-line pembrolizumab monotherapy exhibited promising anti-CSCC activity, with durable responses and manageable safety. PD-L1 positivity appears to be predictive of pembrolizumab efficacy.

Le cémiplimab, un agent bloquant anti-PD-1, a été approuvé en septembre 2018 pour les CEC localement avancés ou métastatiques. Quelques cas de réponse sous pembrolizumab (PBZ) ont été rapportés. CARSKIN est un essai ouvert multicentrique de phase II, conduit dans 21 centres français du Groupe de Cancérologie Cutanée (GCC), évaluant le PBZ en 1re ligne de traitement chez 39 patients ayant un CEC inopérable. Nous présentons des résultats d'efficacité et de tolérance. Des patients (pts) naïfs de chimiothérapie et anti-EGFR, ayant un CEC inopérable, un PS ECOG < 2, étaient éligibles. L'expression de PD-L1 a été évaluée de manière centralisée à la baseline. Le PBZ, fourni gracieusement par Merck, était administré en intra-veineux (200 mg/3 semaines) pendant 24 mois au maximum. L'évaluation radiologique était réalisée à la baseline, à S9, S15, S24 puis toutes les 12 semaines et revue de manière indépendante. L'objectif principal était le taux de réponse à S15 (critères RECIST 1.1). Trente-neuf pts d'âge médian 80 ans (43–99), majoritairement des hommes (79 %) ayant des métastases locales (n = 5), régionales (n = 24) ou à distance (n = 10) étaient inclus entre mars 2017 et février 2018. Le PS était de 0 chez 38 % des pts. L'expression de PD-L1 à la baseline était > 1 % dans 30 cas (77 %). Le nombre médian de perfusions de PBZ était de 11 (0–33). Le suivi médian était de 10,4 mois (0–22 mois). En ITT, le taux de réponse à S15 était de 38,5 % (IC à 95 % : 23,8–55,3 %) correspondant à 13 RP et 2 RC confirmées. Le taux de contrôle de la maladie à S15 était de 51,3 % (20/39 dont 5 stabilisations). Cinq pts (13 %), dont 3 ayant des métastases à distance, ont développé une RC jusqu'à 14 mois de traitement. La médiane de survie globale n'est pas encore atteinte. La médiane de survie sans progression était de 14,2 mois. La durée médiane de réponse était de 12,5 mois (Q1–Q3 : 10,6–17,1) ; 14/15 répondeurs le sont toujours dont 2 pts en RC qui ont arrêté le PBZ depuis 9–12 mois. L'expression médiane de PD-L1 (Q1–Q3) était de 10 % (3–30 %) chez les répondeurs vs 10 % (0–55 %) chez les non-répondeurs à S15 (p = 0,55). Les EI liés au PBZ sont survenus chez 67 % des pts et ont entrainé un arrêt du PBZ chez 10 % des pts (n = 4) : une cholestase de grade 3, 1 colite de grade 3 et 1 de grade 2, et un décès dû à une récidive à S15 d'un cancer ORL non lié. Notre étude est la 1re étude clinique évaluant le PBZ chez des pts atteints de CEC. Dans cette série de 39 pts âgés atteints de CEC inopérable, le profil de tolérance est comparable à celui d'études précédentes sur le PBZ chez des pts ayant d'autres tumeurs. Le PBZ en 1re ligne montre une activité clinique anti-tumorale encourageante quel que soit le taux d'expression de PD-L1.

9547 Background: Cemiplimab, a PD-1-axis blocking agent, has recently been approved for unresectable cSCCs. We report results of the CARSKIN study evaluating pembrolizumab in the first-line setting. Methods: Chemotherapy naive patients (pts) with unresectable cSCCs, either locally or regionally advanced or metastatic, and ECOG PS ≤1 were accrued to this multi-institutional phase II trial to assess tumor response rate (RR) and safety of pembrolizumab administered IV (200 mg Q3W) for a period up to 24 months (mo). Baseline PD-L1 expression was centrally assessed on tumor. The primary endpoint was the RR at 15 weeks (wks) per RECIST v1.1 (independent review). A Simon two-stage design was used. Results: From 03/2017 to 01/2018, 39 pts (79% males, median age 79 years) were enrolled. Disease was local (18%), regional (62%) or metastatic (21%); 38% of pts were PS 0. The median number of infusions was 8. The median follow-up was 10.2 mo; 15 pts are still on pembrolizumab. Thirty-four pts were evaluable for tumor response, and 39 for toxicity. The RR at 15 wks was 38.5 % (95% CI: 24–55%) in the ITT population corresponding to 2 CR and 13 PR. The best responses were 3 CR and 12 PR. The DCR was 51% (20/39 including 5 SD) at 15 wks. The median PFS was 8.4 mo and the median OS was not reached. No responder has progressed to date including 2 pts who discontinued pembrolizumab for 6 to 12 mo. Treatment-related AEs (TRAEs) occurred in 67% of pts, including 8% with severe TRAEs (1 gr 3 cholestasis, 1 gr 3 colitis and 1 death due to recurrence of a non-related head and neck cancer) and 10% who discontinued because of a TRAE. Centrally assessed baseline PD-L1 expression was positive in 77% of patients (1% tumor staining threshold), but it failed to predict response at 15 wks with a median PD-L1 expression of 10% in responders and non-responders at 15 wks (P = .55). Conclusions: In this series of 39 elderly pts with unresectable cSCCs, the safety profile was consistent with previous pembrolizumab studies. First-line pembrolizumab provided robust antitumor activity regardless of PD-L1 expression levels. Clinical trial information: NCT02883556.

9534 Background: Patients (pts) with advanced squamous cell carcinoma of the skin (SCCS) have a poor prognosis. Response rate (RR) of 46% with an anti PD-1 (REGN2810) was recently shown in 25 pre-treated pts. CARSKIN is an open-label, phase II study evaluating pembrolizumab (Pembro) in unresectable SCCS. We report preliminary efficacy and safety findings. Methods: Chemotherapy naive pts who had unresectable SCCS, with an ECOG PS of < 2 were eligible. Baseline PD-L1 expression was centrally assessed on tumor. Pembro kindly provided by Merck was administered IV (200 mg Q3W) for a period up to 24 mths. CT evaluation was performed at baseline, 9, 15, 24 wks and thereafter Q12W and was independently reviewed. The primary endpoint was RR at 15 wks (RECIST criteria). Using Simon two-stage design, ≥4 responses were required out of 19 pts in stage 1 to continue accrual to 39 pts. Results of stage 1 are reported. Results: Nineteen pts (6, 7 and 6 with local, regional and distant metastasis, respectively) were recruited between March and July 2017, of which 15 (79%) were male. Median age was 80 yrs (range, 61-88); 61% of pts were PS 1. Median number of Pembro infusions was 9 (range, 0-13). Median follow-up was 7 mths. Seventeen pts were evaluable for tumor response, and 19 for toxicity. RR at 15 wks in the ITT population was 42 % (95% CI: 23–63%) corresponding to 7 PR (2 unconfirmed) and 1 CR. Disease control rate at 15 wks was 58% (11/19 including 3 SD). Only 1 responder progressed. Median PFS is 7 mths and median OS is not reached. There was no Pembro-related death or SAE. One pt discontinued Pembro due to grade 2 colitis. Pembro-related AE occurred in 63% of pts, the most frequent AEs being rash (32%), pruritus (16%), fatigue (26%), dysthyroidism (10%), and diarrhea (10%). Baseline PD-L1 expression was positive in 11 cases (58%). Median PD-L1 expression (Q1-Q3) was 28% (1-75%) in responders vs 0% (0-3%) in non-responders at 15 wks (P = .15). Conclusions: As first line treatment, pembrolizumab monotherapy provided encouraging clinical activity characterized by a high RR and durable response and was well tolerated in these elderly pts. The second stage of CARSKIN is ongoing. Clinical trial information: NCT02883556.

TPS9596 Background: Treatment options are limited for patients (pts) with locally advanced or metastatic cSCCs. Cisplatin-based combinations have some efficacy but their toxicity often prohibits their use, particularly for the elderly. New therapeutic options are needed. Tumors divert the programmed death receptor 1 (PD-1) pathway suppressing immune control. Pembrolizumab (MK-3475) is a high-affinity humanized monoclonal anti-PD-1 antibody. It leads to dual PD-1 ligand (PD-L1 and PD-L2) blockade that may reactivate the immune surveillance and elicit anti-tumor response. It has antitumor activity in several tumors including head and neck SCCs. Moreover, an efficacy of pembrolizumab in cSCCs has been reported recently in a series of 6 cases. Methods: CARSKIN (ClinicalTrials.gov, NCT02883556) is a French multicenter, open-label, nonrandomized phase 2 trial, designed to evaluate the efficacy and safety of pembrolizumab in 39 pts with unresectable and/or metastatic cSCCs, naive of chemotherapy and of EGFR inhibitors. Pembrolizumab is administered (200 mg IV Q3W) for up to 24 months or until disease progression or unacceptable toxicity. Eligible pts must undergo a baseline biopsy of the tumor prior to treatment for PD-L1 evaluation. Response is to be assessed at baseline, wk 9, 15 and 24, and thereafter Q12W by central radiology review per RECIST 1.1 and per modified RECIST v1.1. The primary objective is response rate (RR) at wk 15 per RECIST 1.1. Secondary efficacy objectives are to assess whether patients with PD-L1+ tumors have a better RR than the whole sample at wk 15 and to assess in the whole sample and in PD-L1+ pts, disease control rate (DCR) at wk15, RR at wk 24, best RR, overall survival (OS), progression free survival (PFS), duration of response / control and time to disease progression. A Simon optimal two-stage design will be used. Four responders among 19 pts will be needed in the 1st step to continue the trial. Overall 9 responses will be needed to conclude the effectiveness. Kaplan-Meier statistics will assess PFS and OS. Adverse events (AEs) will be assessed throughout the study and for 30 d thereafter (6 m for serious AEs) and graded per NCI CTCAE v4.0. Clinical trial information: NCT02883556.

Abstract Purpose: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis. Experimental Design: This randomized phase II trial enrolled 78 FIGO stage IB2–IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone (arm B, n = 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n = 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients. Results: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P = 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P = 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P = 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18). Conclusions: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups. Clin Cancer Res; 21(11); 2530–7. ©2015 AACR.

e15524 Background: Pelvic exenteration has been used as a potentially curative operation in recurrent pelvic malignancies. However, treatment-related morbidity is over 50% in radiated pelves. We evaluated the outcome and the morbidity of pelvic exenteration in women with recurrent cervical and endometrial cancer. Methods: We studied retrospectively all the patients who underwent a pelvic exenteration for recurrent cervical or endometrial cancer in our institution, from January 1999 to November 2011. All medical data were collected. Survival rates were calculated according to Kaplan-Meier method and compared using the log-rank test. Results: twenty-five patients were identified, 17 (68%) had cervical cancer and 8 (32%) endometrial cancer. All patients received a radiation therapy during their initial treatment. All patients had a central pelvic recurrence, in a median time of 30 months [4-384]. 15 patients (60%) had an urinary diversion with incontinent ileoconduit (Bricker). 22 patients (88%) had a complete tumor resection. Severe early complications needing a re-laparotomy occurred in 9 patients (36%) (insufficiencies of intestinal anastomosis, insufficiencies of the ureteral anastomosis and pelvic abscesses). One patient (4%) had a recto-vaginal fistula. Late complications included 1 (4%) vaginal fistula, 1 (4%) intestinal fistula), 2 (8%) intestinal occlusion and 1 (4%) ureteral stenosis. Disease Free and Overall survival rates are better in cervical than in endometrial cancer (median DFS in months 17 [2-145] vs 9.5 [3-21], p= 0.064, median OS in months 20 [2-145] vs 13 [4-42], p=0.019) (table 1). Conclusions: Morbidity of pelvic exenteration remains high. Endometrial cancer is associated with a poorer prognosis. In those patients, the benefit of exenteration should be discussed compared to best supportive care for palliative treatment. [Table: see text]

Introduction In most cases of cervical cancers, HPV DNA is integrated into the genome of carcinoma cells. This mutational insertion constitutes a highly specific molecular marker of tumor DNA for every patient. Circulating tumor DNA (ctDNA) is an emerging marker of tumor dynamics which detection requires specific molecular motif. To determine whether the sequence of the cell-viral junction could be used in clinical practice as a specific marker of ctDNA, we analyzed a series of cervical cancer patient serums. Methods and Findings Serum specimens of 16 patients diagnosed with HPV16/18-associated cervical cancer, and for which the viral integration locus had been previously localized, were analyzed. Sequential serum specimens, taken at different times during the course of the disease, were also available for two of these cases. ctDNA was found in 11 out of 13 patients with tumor size greater than 20 mm at diagnosis, and analysis of sequential serum specimens showed that ctDNA concentration in patients serum was related to tumor dynamics. Conclusions We report that HPV mutational insertion constitutes a highly specific molecular marker of ctDNA in HPV-associated tumor patients. Using this original approach, ctDNA was detected in most cervical cancer patients over stage I and ctDNA concentration was found to reflect tumor burden. In addition to its potential prognostic and predictive value, HPV mutation insertion is likely to constitute a new molecular surrogate of minimal residual disease and of subclinical relapse in HPV-associated tumor. This is of major importance in the perspective of specific anti-HPV therapy.

The GYN GEC-ESTRO working group issued three parts of recommendations and highlighted the pivotal role of MRI for the successful implementation of 3D image-based cervical cancer brachytherapy (BT). The main advantage of MRI as an imaging modality is its superior soft tissue depiction quality. To exploit the full potential of MRI for the better ability of the radiation oncologist to make the appropriate choice for the BT application technique and to accurately define the target volumes and the organs at risk, certain MR imaging criteria have to be fulfilled. Technical requirements, patient preparation, as well as image acquisition protocols have to be tailored to the needs of 3D image-based BT. The present recommendation is focused on the general principles of MR imaging for 3D image-based BT.Methods and parameters have been developed and progressively validated from clinical experience from different institutions (IGR, Universities of Vienna, Leuven, Aarhus and Ljubljana) and successfully applied during expert meetings, contouring workshops, as well as within clinical and interobserver studies.It is useful to perform pelvic MRI scanning prior to radiotherapy (“Pre-RT-MRI examination”) and at the time of BT (“BT MRI examination”) with one MR imager. Both low and high-field imagers, as well as both open and close magnet configurations conform to the requirements of 3D image-based cervical cancer BT. Multiplanar (transversal, sagittal, coronal and oblique image orientation) T2-weighted images obtained with pelvic surface coils are considered as the golden standard for visualisation of the tumour and the critical organs. The use of complementary MRI sequences (e.g. contrast-enhanced T1-weighted or 3D isotropic MRI sequences) is optional. Patient preparation has to be adapted to the needs of BT intervention and MR imaging. It is recommended to visualise and interpret the MR images on dedicated DICOM-viewer workstations, which should also assist the contouring procedure. Choice of imaging parameters and BT equipment is made after taking into account aspects of interaction between imaging and applicator reconstruction, as well as those between imaging, geometry and dose calculation.In a prospective clinical context, to implement 3D image-based cervical cancer brachytherapy and to take advantage of its full potential, it is essential to successfully meet the MR imaging criteria described in the present recommendations of the GYN GEC-ESTRO working group.

e15535 Background: Advanced stage cervical cancer (CC) remains a public health issue despite preventive vaccines and screening. EGFR is over-expressed in 50 to 85% of CC and activated in 20%, suggesting that EGFR blockage may be a promising treatment approach. Methods: A randomized phase 2 trial on 78 stage IB2–III patients from 11 French Cancer Centres evaluated the tolerance and early response to cetuximab, an anti EGFR antibody. 40 patients received cetuximab + standard RT and Cisplatinum based chemotherapy (arm A) and 38 patients received standard treatment (B). Primary endpoint is DFS at 2 years and presently not reached. MRI imaging revealed no difference in median (44 vs 40) tumour sizes between arms; there was no difference in age, menopausal status, PI and smoking habits. Parametrial involvement was clinically diagnosed in 19 and 20 cases respectively. Presence of lumbar or para-aortic lymph nodes was an exclusion criterion. Three patients withdrew consent in the cetuximab arm, one accepted standard treatment. Treatment schedules were incomplete in 13 (A) and 14 (B) patients for reasons of haematological or renal toxicity. Results: Surgical resection was feasible in 24 (65%) and 26 (70%) patients in arms A and B respectively.Tolerance was satisfactory in both arms, with significantly more acne form reactions in the cetuximab arm of grade 2 (n= 19) and 3 (n=4). More patients had diarrhea (n=8 vs 4: ns) associated with nausea and vomiting of grade 3 (n=4) and 4 (n=1) in the cetuximab arm (ns).Early results show a complete response at 6 weeks by MRI in 18% and 8% for arms A and B respectively. A central blinded review of the imaging and pathology slides is presently ongoing. Conclusions: The prediction of a response to EGFR targeted therapy in cervical cancer remains a matter of debate since no precise molecular studies are available. Consequently, no decisive results have been achieved in early trials of non selected patients with late stage disease (GOG 76-DD). Biopsy samples are available for the majority of our patients and analyses of EGFR expression, cellular sub-localization and main mutations in the PI3K pathway are ongoing. Molecular studies to allow hierarchical decision making are warranted in future studies.

Purpose To evaluate the efficacy and safety of cetuximab, a monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), as a first-line monotherapy in patients with unresectable squamous cell carcinoma of the skin (SCCS). Patients and Methods Thirty-six patients received cetuximab (initial dose of 400 mg/m 2 followed by subsequent weekly doses of 250 mg/m 2 ) for at least 6 weeks with a 48-week follow-up. The primary end point was the disease control rate (DCR) at 6 weeks (according to Response Evaluation Criteria in Solid Tumors [RECIST] criteria). Secondary end points included best response rate, overall survival, progression-free survival (PFS), and toxicity assessment. Association of treatment efficacy with RAS mutations or FcγR genotypes was investigated. Results Median age of the study population was 79 years. DCR at 6 weeks was obtained in 25 of 36 patients (69%; 95% CI, 52% to 84%) of the intention-to-treat population. The best responses were eight partial responses and two complete responses. There were no cetuximab-related deaths. There were three related serious adverse events: two grade 4 infusion reactions and one grade 3 interstitial pneumopathy. Grade 1 to 2 acne-like rash occurred in 78% of patients and was associated with prolonged PFS. One HRAS mutation was identified. Combined FcγRIIa-131H/H and/or FcγRIIIa-158V/V polymorphisms were not associated with the clinical outcomes. Conclusion As a first-line treatment in patients with unresectable SCCS, cetuximab achieved 69% DCR. A randomized phase III trial is warranted to confirm that cetuximab may be considered as a therapeutic option especially in elderly patients. The low frequency of RAS mutations in SCCS makes SCCS tumors attractive for EGFR inhibition.

OBJECTIVE:To report the outcome of preoperative low dose rate uterovaginal brachytherapy (LDR-UVBT) followed by radical surgery in the treatment of early cervical carcinoma. METHODS:257 patients treated at Institut Curie from 1985 to 2008 for cervical carcinoma less than 4cm (FIGO stages Ib1, IIA and IIB) were studied. Patients received preoperative LDR-UVBT followed by hysterectomy Piver II type, with pelvic lymph nodes dissection (PLND). Predictive factors for pathological response to brachytherapy were analyzed with logistic regression, as well as survival rates. RESULTS:44% of patients had residual tumor, 4.3% of patients had parametrial invasion and 17.9% of patients had lymph node involvement. Predictive factors for an incomplete pathological response were: initial clinical tumor size 20mm (OR 2.1), pN1 (OR 2.77), glandular carcinoma (OR 2.51) and lymphovascular invasion (OR 4.35). 7.4% and 2.7% of patients had respectively grade 2 and grade 3 post-therapeutic late complications. Median follow up was 122 months [1-282]. Five-year actuarial overall survival and disease free survival were respectively 83% CI [78.3-87.5] and 80.9% CI [76.3-85.7]. In multivariate analysis, factors affecting significantly the overall survival and disease free survival rates were: lymph node involvement (RR 4.53 and 8.96 respectively), parametrial involvement (RR 5.69 and 5.62 respectively), smoking (RR 3.07 and 2.63 respectively). CONCLUSIONS:Preoperative LDR-UVBT results in good disease control with a low complications rate. Its accuracy could be improved by a better selection of patients. Lymph nodes and parametrial evaluation remains a challenging issue that should be achieved with imaging and minimal invasive surgery.