MITO (Multicentre Italian Trials in Ovarian cancer) - CERV2 trial: a randomized phase II study of carboplatin and paclitaxel +/- cetuximab, in advanced and/or recurrent cervical cancer Sandro Pignata1, Giovanni Scambia2, Domenica Lorusso3, Ugo De Giorgi4, Maria Ornella Nicoletto5, Rossella Lauria6, Annamaria Mosconi7, Cosimo Sacco8, Claudia Omarini9, Pierosandro Tagliaferri10, Gabriella Ferrandina2, Saverio Cinieri11, Carmela Pisano1, Sabrina Chiara Cecere1, Marilena Di Napoli1, Vanda Salutari2, Maria Carmela Piccirillo1, Gennaro Daniele1, Ciro Gallo12, Francesco Perrone1. 1 Istituto Nazionale Tumori di Napoli, Fondazione Pascale, IRCCS, Napoli; 2 Catholic University of The Sacred Heart of Rome, Roma; 3 Fondazione IRCSS National Cancer Institute, Milano ; 4 IRST-IRCSS National Cancer Institute, Meldola-Cesena; 5 Istituto Oncologico Veneto IRCCS, Padova; 6 Federico II University, Napoli; 7 Medical Oncology, University Hospital of Perugia, Perugia; 8 University Hospital "S. Maria della Misericordia", Udine; 9 Medical Oncology, University Hospital of Modena, Modena; 10 Medical Oncology - Magna Grecia University, Germaneto (CZ); 11Medical Oncology & Breast Unit, “Senatore Antonio Perrino” Hospital, Brindisi; 12 Medical Statistics, Department of Medicine and Public Health, Second University of Naples, Napoli; Italy.

Background Carboplatin plus paclitaxel is a standard option for treatment of advanced or recurrent cervical cancer patients Long-term results of systemic treatment are poor in this setting

Study rationale Cervical cancer cells often express Epidermal Growth Factor receptor (EGFR) Cetuximab, an anti-EGFR monoclonal antibody, can be safely combined with carboplatin and paclitaxel

Study aim To assess the activity of a combination of cetuximab (weekly) with carboplatin + paclitaxel (every three weeks) compared to chemotherapy alone in terms of event-free survival (EFS)

Study endpoints Primary endpoint Secondary endpoints Event-free survival time from randomization to progression, death, definitive discontinuation of the whole treatment or loss to follow-up, whichever occurred first Secondary endpoints Overall survival Progression-free survival Response rate (RECIST 1.0) Toxicity (CTCAE 3.0)

Study design RANDOM Carbo AUC 5 + Paclitaxel 175 mg/mq, d1 Q21 Carbo AUC 5 + Paclitaxel 175 mg/mq, d1 Q21 + Cetuximab 400 mg/m² one week before starting chemo, then 250 mg/m² day 1, weekly Strata: Previous Chemo Distant mets Centre Chemotherapy was given for 3-6 cycles depending on clinical response Cetuximab was continued until disease progression or unacceptable toxicity

Study population Advanced and/or metastatic cervical cancer patients untreated or having failed only one previous chemotherapy (with at least 6 months of progression-free interval, with or without concomitant or sequential radiotherapy) PS 0-1 according to ECOG Age >18 Written informed consent

Sample size This is a randomized phase II trial, with relaxed statistical criteria* : one-tailed test, significance level 20% power 80% Assuming an expected median EFS 4.5 months and an auspicated median EFS 6.4 months (corresponding to a Hazard Ratio of 0.70) 89 events are required and 108 patients (54 per arm) were planned *Rubinstein, J Clin Oncol 2005

Study conduction The study was sponsored and supported by NCI Naples that has the property of data Merck Serono provided cetuximab and partial funding 14 Italian centers actively recruited the patients First patient enrolled: Feb 3, 2010 Last patient enrolled: May 8, 2013 Final analysis: May 5, 2015 Median Follow-up: 23 months

Carboplatin/Paclitaxel Carboplatin/Paclitaxel plus Cetuximab Patients’ flow Randomized 108 pts Carboplatin/Paclitaxel 53 pts Carboplatin/Paclitaxel plus Cetuximab 55 pts 1 patient: consent withdrawn immediately after random EFS analysis 52 pts EFS analysis 55 pts

Baseline characteristics Carboplatin/Paclitaxel (n =52) Carboplatin/Paclitaxel + Cetuximab (n=55) Median age (interquartile range - IQR) 52 (44-62) 47 (41-60) Previous chemotherapy No 22 (42%) 24 (44%) Yes 30 (58%) 31 (56%) Distant metastasis 9 (17%) 10 (18%) 43 (83%) 45 (81%) ECOG performance status 33 (64%) 40 (73%) 1 19 (36%) 15 (27%) Histotype Adenocarcinoma 11 (21%) 12 (22%) Squamous 41 (79%) (78%)

Compliance to chemotherapy Carboplatin/Paclitaxel Carboplatin/Paclitaxel + Cetuximab (n =52) (n=55) Number of cycles median (IQR) 6 (4-6) At least one delay 17 (33%) 21 (38%) At least one dose reduction 12 (23%) 8 (14%) Cause of treatment interruption Completion 35 (67%) 34 (62%) Progression or death 14 (27%) 14 (25%) Toxicity or refusal 2 (4%) 7 (13%) Other 1 (2%) 0 (0%) A median number of 6 (IQR 4-6) CP cycles was given in both arms.

Compliance to cetuximab Carboplatin/Paclitaxel Carboplatin/Paclitaxel + Cetuximab (n =52) (n=55) Weeks on treatment median (IQR) - 26 (14-35) At least one delay 27 (49%) At least one dose reduction 4 (7%) Cause of treatment interruption Progression or death 41 (74%) Toxicity or refusal 13 (24%) On treatment 1 (2%) Reason for discontinuation of cetuximab was progression/death in 41 (74%) cases and toxicity/refusal in 13 (24%) . A patient was on treatment at the time of the analysis.

Events After a median follow-up of 23 months (95% CI:20-26) 102 patients had an event 97 progressed 61 died

Carboplatin/Paclitaxel Carboplatin/Paclitaxel + Cetuximab Event-free survival Patients Events Median EFS months (95% CI) Carboplatin/Paclitaxel 52 48 4.7 (4.1 – 6.5) Carboplatin/Paclitaxel + Cetuximab 55 54 6.0 (4.4 – 7.6) Unadjusted HR=0.97 (95% CI 0.66-1.43) Log-rank p=0.43 Patients at risk Carboplatin/Paclitaxel 52 21 7 5 3 2 Carboplatin/Paclitaxel + Cetuximab 55 28 8 -

Progression-free survival Patients Events Median PFS months (95% CI) CP 52 45 5.2 (4.5 – 7.8) CP + CET 55 7.6 (5.6 – 9.0) Unadjusted HR=0.84 (95% CI 0.56-1.26) Log-rank p=0.20 Patients at risk CP 52 22 8 6 3 2 CP + CET 55 34 14 -

Overall survival Patients Events Median OS months (95% CI) CP 52 30 17.7 (11.0 – 31.6) CP + CET 55 31 17.0 (12.5 – NA) Unadjusted HR=0.85 (95% CI 0.52-1.42) Log-rank p=0.27 Patients at risk CP 52 39 29 16 10 4 2 CP + CET 55 48 30 19 11 -

Response Rate (RECIST 1.0) Carboplatin/Paclitaxel (n=44) Carboplatin/Paclitaxel + Cetuximab (n=42) P* Responders (CR+PR) 19 (43%) 95%CI: 30%-58% 16 (38%) 95%CI: 25%-53% 0.79 CR 4 (9%) 2 (5%) PR 15 (34%) 14 (33%) *Chi-square test Out of 86 patients eligible for RECIST

Safety One patient died for a stroke during standard treatment There was no difference in the occurrence of severe side-effects, except for diarrhoea and skin toxicity

Adverse events CP (n=52) CP + CET (n=55) Dry skin 2% 0% 9% 4% 0.03 Grade 1 2 3 4 5 p* Dry skin 2% 0% 9% 4% 0.03 Flushing 11% 5% 0.003 Nail changes 7% 0.006 Rash/ desquamation 18% 0.05 Rash/acneiform 24% 25% <0.001 Diarrhoea 6% 16% 0.02

Conclusions The addition of cetuximab to carboplatin/paclitaxel is feasible but not worthy of further investigation in unselected advanced cervical cancer patients Efforts are ongoing to retrospectively collect tumor samples for an exploratory biomarker analysis