1. A randomized trial of gemcitabine vs. gemcitabine plus cisplatin in chemotherapy-naïve advanced pancreatic carcinoma. The GIP-1 (Gruppo Italiano Pancreas – GOIM/GISCAD/GOIRC) study. G.Colucci 1, R.Labianca 2, F.Di Costanzo 3, V.Gebbia 4, G.Cartenì 5, B.Massidda 6, L.Frontini 7, M.Falconi 8, C.Gallo 9, M.Di Maio 10 on behalf of the GIP-1 Investigators 1 National Cancer Institute, Bari; 2 Ospedali Riuniti, Bergamo; 3 Azienda Ospedaliero-Universitaria Careggi, Firenze; 4 Università di Palermo, Casa di Cura La Maddalena, Palermo; 5 Cardarelli Hospital, Napoli; 6 Policlinico Universitario, Cagliari; 7 San Gerardo Hospital, Monza; 8 University of Verona, Policlinico G.B.Rossi, Verona; 9 Seconda Università, Napoli; 10 National Cancer Institute, Napoli, Italy.

2. ASCO conflict of interest statement The presenting author, Massimo Di Maio, has no relationships to disclose

3. Introduction In 1997, single-agent gemcitabine (Gem) became standard treatment for patients with advanced pancreatic cancer 1 Several preclinical data support the combination of gemcitabine and cisplatin (GemCis) 2,3 In a randomized trial conducted by GOIM, GemCis significantly improved response rate and time to progression 4 1 Burris et al, J Clin Oncol 1997, 15: 2403-13 2 Bergman et al, Clin Cancer Res 1996, 2: 521-30 3 van Moorsel et al, Br J Cancer 1999, 80: 981-990 4 Colucci et al, Cancer 2002, 94: 902-10

4. Study objective To evaluate the efficacy of a weekly schedule of gemcitabine plus cisplatin compared to standard single-agent gemcitabine, as first-line treatment of patients with advanced pancreatic cancer

5. R an do m Strata: Center KPS (  70 vs  80) Stage (II-III vs IV) Control arm Gemcitabine 1000 mg/m 2 Cisplatin 25 mg/m 2 1815222936435764715078 Experimental arm Gemcitabine 1000 mg/m 2 1815222936435764715078 1:1 Study design Day

6. Study population Inclusion criteria Cyto/histological diagnosis of pancreatic cancer Age 18 – 75 Karnofsky PS  50 Stage II (unresectable) / III / IV (TNM 1997) No previous chemotherapy Exclusion criteria ANC  2000/  L, platelets  100000/  L, Hgb  10 g/dL Creatinine  UNL, SGOT and SGPT  2.5 x UNL and bilirubin  1.5 x UNL, unless due to liver metastases Brain metastases

7. Study endpoints Primary endpoint Overall survival Secondary endpoints Progression-free survival Objective response rate (RECIST) Clinical benefit (Burris, J Clin Oncol 1997) Quality of Life (EORTC C30 & PAN26) Toxicity (NCI – CTC)

8. Sample size 2-tailed  : 0.05 Power: 80% Hazard Ratio: 0.74 1-yr survival:18%  28% Median survival:4.8  6.5 months 2 analyses (1 interim, 1 final)  355 deaths, 400 patients needed

9. Study conduction Enrollment: –First patient: April 16, 2002 –Last patient: April 19, 2007 Total number of randomized patients: 400 Final analysis: December 2008 Median follow-up: 38 months

10. Baseline characteristics GemcitabineGemcitabine + Cisplatin (n = 199)(n=201) Age median (range) 63(37-75)63(35-75) Gender Males113(57%)125(62%) Females86(43%)76(38%) KPS  70 33(17%)36(18%)  80 166(83%)165(82%) Stage II-III33(17%)31(15%) IV165(83%)170(85%) Previous surgery47(24%)56(28%)

11. Treatment compliance GemGemCis (n = 199)(n=201) Missing information2 (1%)7 (3%) Did never start treatment5 (3%)6 (3%) Number of administrations Median78 Range1-31 Cause of treatment interruption Progression / death72%66% Toxicity / refusal12%20% Other / not specified16%14% Received 2 nd line treatment 346 pts with information available 53%41%

12. PatientsEvents Median OS (months) 1-yr OS Gemcitabine1991778.334.0% Gemcitabine + Cisplatin 2011807.230.7% Patients at risk Gem199121643219 87 GemCis201112573216149 Hazard Ratio: 1.10 (0.89 – 1.35) p = 0.38 Overall survival 61218243036 Months 0

13. 1 patient excluded because of missing information for stage Overall survival: Cox model Hazard Ratio(95% CI)p Treatment (GemCis vs Gem)1.100.89 – 1.350.39 Gender (Females vs males)1.020.82 – 1.280.86 Age (  65 vs <65) 0.890.72 – 1.120.32 Karnofsky PS (  80 vs  70) 0.710.54 – 0.930.01 Stage (IV vs II-III)1.821.34 – 2.470.0001 Previous surgery (yes vs no)0.860.67 – 1.100.22

14. Overall (n=400) Gender Male (n=238) Female (n=162) Age < 65 (n=233) > 65 (n=167) Stage II – III (n=64) IV (n=335) Karnofsky PS <= 70 (n=69) >= 80 (n=331) Previous surgery No (n=297) Yes (n=103) Favours GemCisFavours Gem Treatment effect in subgroups

15. PatientsEvents Median PFS (months) 6-mo PFS Gemcitabine 1991913.932.9% Gemcitabine + Cisplatin 2011913.831.8% Patients at risk Gem1996526126-- GemCis201632815974 Hazard Ratio: 0.97 (0.80 – 1.19) p = 0.80 Progression-free survival 61218243036 Months 0

16. Objective response* Gemcitabine (n=199) Gemcitabine + Cisplatin (n=201) Objective response 20 (10.1%)26 (12.9%) Complete response2 (1%)3 (1.5%) Partial response18 (9.0%)23 (11.4%) No response179 (89.9%)175 (87.1%) p = 0.37 (  2 ) *after cycle 1 (7 weeks)

17. Hematologic toxicity Any grade Severe (G  3) Gem Cis p*Gem Cis p* Anemia39%51%0.021%5%0.03 Neutropenia36%45%0.0714%25%0.007 Febrile neutropenia  1% -1 -1 Thrombocytopenia30%58%<0.0015%16%0.001 Gem 189 patients; GemCis 186 patients *Chi square or Fisher exact test as appropriate

18. Non-hematologic toxicity Any grade Severe (G  3) GemGemCisp*GemGemCisp* Heart, rhythm1%2%0.471% 1 Heart, general-2%0.12-1%0.50 Fatigue41%40%0.933%5%0.29 Constipation17%16%0.732% 0.72 Diarrhoea9%12%0.222%1%0.62 Nausea37%38%0.741%3%0.28 Vomiting19%23%0.331%3%0.12 Hair loss1%7%0.002 Liver toxicity23%15%0.037%5%0.53 Renal toxicity-2%0.06-- Neurotoxicity1%3%0.12-1%0.25 Toxic deaths2 (1%)3 (2%)0.68 Gem 189 patients; GemCis 186 patients *Chi square or Fisher exact test as appropriate

19. Clinical benefit response Gemcitabine (n=183) Gemcitabine + Cisplatin (n=179) p* Pain measures Pain intensity35(19.1%)26(14.5%) Analgesics consumption21(11.5%)17(9.5%) Primary measures Pain38(20.8%)26(14.5%) Karnofsky PS2(1.1%)3(1.7%) Clinical benefit Primary measures39(21.3%)26(14.5%) Weight3(1.6%)3(1.7%) Overall clinical benefit42(23.0%)27(15.1%)0.057 *Chi square test

20. Quality of life QoL questionnaires were administered baseline and every 4 weeks in both arms (up to 6 questionnaires) Changes from baseline after 4 weeks are described here Global QoL: trend favouring single-agent gemcitabine (p=0.07) Statistically significant differences: –Social functioning (worse with GemCis, p=0.01) –Hepatic symptoms (better with GemCis, p=0.01) –Limitation in planning (worse with GemCis, p=0.006)

21. GIP-1 trial: conclusions The weekly schedule of gemcitabine + cisplatin as 1 st line treatment of advanced pancreatic cancer did not prolong overall survival compared to gemcitabine alone The addition of cisplatin did not produce any improvement in terms of PFS, response rate, clinical benefit or quality of life

22. Acknowledgements All the patients and their families The Investigators and staff at each participating center: GOIM centersGISCAD centersGOIRC centers G. Colucci, BariR. Labianca, BergamoF. Di Costanzo, Firenze V. Gebbia, PalermoL.Frontini – G. Gardani, MonzaB. Massidda, Cagliari G. Cartenì, NapoliE. Piazza, MilanoL. Cavanna, Piacenza L. Manzione, PotenzaV. Zagonel, RomaR. Mattioli, Fano R.V. Iaffaioli, NapoliS. Luzzi Fedeli, PesaroP. Carlini, Roma N. Gebbia, PalermoC. Graiff, BolzanoG. Lelli, Ferrara C. Gridelli, AvellinoS. Barni, TreviglioS. Ortu, Olbia B. Daniele, BeneventoP. Marchetti, RomaF. Artioli, Carpi M. Lopez, RomaG. Colosini, ManerbioF. Pasini, Rovigo M. Caruso, CataniaE. Galligioni, TrentoOther centers G. Lucarelli, Acquaviva d.F.G. Cruciani, LugoM. Sannicolò, Rovereto F. Carrozza, CampobassoP. Astorre, RomaV. Fosser, Vicenza V. Lorusso, Lecce - BariA. Beretta, ComoP. Foa, Milano A. Febbraro, BeneventoR. Cellerino, AnconaP. Sandri, S.Vito al T. S. Iacobelli, ChietiM. Clerico, BiellaS. Frustaci, Aviano S.F. Robbiati, Arco Coordinating center:F.Perrone, M.Di Maio, E. De Maio, A. Morabito, F.Romano – Napoli Statistician center:C.Gallo, G.Signoriello, P.Chiodini, N.Lama - Napoli