Etude JO25567 de phase III en première ligne, erlotinib et bevacizumab contre erlotinib seul : tumeurs EGFR mutées (1) n = 75 Erlotinib150 mg/j Bevacizumab15 mg/kg IV toutes les 3 sem. 154 patients japonais Mutation EGFR Stade IIIB/IV PS 0-1 Non prétraités Pas de métastase cérébrale R 1:1 Erlotinib150 mg/j n = 75 Objectif principal : la SSP Objectifs secondaires : survie globale, réponse, QDV, tolérance Objectifs exploratoires : biomarqueurs Stratification : sexe, stade, tabagisme, type de mutation EGFR Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive nonsquamous non-small cell lung cancer (NSCLC): An open-label randomized trial. Sub-category: Lung Cancer - Non-Small Cell Metastatic Category: Lung Cancer - Non-Small Cell Metastatic Meeting: 2014 ASCO Annual Meeting Abstract No: 8005 Attend this session at the 2014 ASCO Annual Meeting! Session: Lung Cancer - Non-small Cell Metastatic Type: Oral Abstract Session Time: Monday June 2, 3:00 PM to 6:00 PM Location: E Hall D2 Personalize your Meeting experience with a suggested or customized itinerary! Author(s): Terufumi Kato, Takashi Seto, Makoto Nishio, Koichi Goto, Shinji Atagi, Yukio Hosomi, Noboru Yamamoto, Toyoaki Hida, Makoto Maemondo, Kazuhiko Nakagawa, Seisuke Nagase, Isamu Okamoto, Takeharu Yamanaka, Ryosuke Harada, Masahiro Fukuoka, Nobuyuki Yamamoto; Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan; Department of Medical Oncology, National Kyushu Cancer Center, Fukuoka, Japan; Thoracic Oncology Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Japan; Department of Thoracic Oncology and Respiratory Medecine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan; Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; Department of Respiratory Medicine, Miyagi Cancer Center, Natori, Japan; Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan; Tokyo Medical University, Tokyo, Japan; Kyushu Univerisity, Fukuoka, Japan; National Cancer Center Hospital East, Kashiwa, Japan; Chugai Pharmaceutical Co., Ltd, Tokyo, Japan; Cancer Center, Izumi Municipal Hospital, Osaka, Japan; Wakayama Medical University, Wakayama, Japan Abstract Disclosures Abstract: Background: Despite the development of EGFR tyrosine kinase inhibitors, median progression-free survival (PFS) is only about 13 months in patients with EGFR mutation–positive NSCLC. However, results from the BeTa Lung study for a subgroup of patients with EGFR mutation suggest that EB may prolong PFS in these patients. Methods: Open-label randomized trial. Patients with stage 3b/4 or recurrent non-squamous EGFR mutation–positive NSCLC, ECOG performance status 0/1, and no previous chemotherapy were randomly allocated to receive EB (E, 150 mg/day; B, 15 mg/kg every 3 weeks) or E (150 mg/day) until disease progression or unacceptable toxicity. The primary endpoint was PFS determined by blinded independent review committee. Secondary endpoints included overall survival, objective response rate (ORR), safety, and quality of life. The planned sample size was 150, with an alpha error of 0.2 and a power of 80% for a target hazard ratio (HR) of 0.7. Results: From February 2011 to March 2012, 154 patients were enrolled (EB group, n = 77; E group, n = 77). There were no major differences in patient characteristics, including age, gender, stage, and EGFR mutation type, between the two groups. Median PFS was 16.0 months for EB and 9.7 months for E (HR, 0.54; 95% CI, 0.36–0.79; log-rank p = 0.0015). In the EGFR exon 19 deletion subgroup, median PFS was 18.0 months for EB and 10.3 months for E. In the L858R subgroup, median PFS was 13.9 months for EB and 7.1 months for E. ORR was 69.3% for EB and 63.6% for E. There were 3 and 1 complete responses to EB and E, respectively. Grade 3 or 4 rash was more common in the EB group (25.3% versus 19.5%). Grade 3 or 4 bleeding was more common in the EB group (2.7% versus 0.0%). However, most adverse events were manageable, and no new safety signals arose. Five patients experienced grade 1–3 interstitial lung disease, but there was no difference between the groups. One treatment-related death occurred in the E group. Conclusions: EB results in significantly longer PFS than E in patients with EGFR mutation–positive NSCLC. Clinical trial information: JapicCTI-111390. ASCO® 2014 - D’après Kato T et al., abstr. 8005 actualisé

Etude JO25567 de phase III en première ligne, erlotinib et bevacizumab contre erlotinib seul : tumeurs EGFR mutées (2) Groupe EB (n = 75) Groupe E (n = 77) Âge, n (%) Médian (années) 67,0 Sexe, n (%) Homme 30 (40) 26 (34) Tabagisme, n (%) Jamais fumeur 42 (56) 45 (59) Ancien ou petit fumeur 9 (12) 6 (8) Fumeur actif 24 (32) 26 (33) PS, n (%) 43 (57) 41 (53) 1 32 (43) 36 (47) Histologie, n (%) Adénocarcinome 74 (99) 76 (99) Autre 1 (1) Type de mutation EGFR , n (%) Deletion Exon19 40 (53) 40 (52) Exon21 L858R 35 (47) 37 (48) ASCO® 2014 - D’après Kato T et al., abstr. 8005 actualisé

Etude JO25567 de phase III en première ligne, erlotinib et bevacizumab contre erlotinib seul : tumeurs EGFR mutées (3) 1,0 0,8 0,6 EB E Probabilité de SSP 0,4 0,2 9,7 16,0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive nonsquamous non-small cell lung cancer (NSCLC): An open-label randomized trial. Sub-category: Lung Cancer - Non-Small Cell Metastatic Category: Lung Cancer - Non-Small Cell Metastatic Meeting: 2014 ASCO Annual Meeting Abstract No: 8005 Attend this session at the 2014 ASCO Annual Meeting! Session: Lung Cancer - Non-small Cell Metastatic Type: Oral Abstract Session Time: Monday June 2, 3:00 PM to 6:00 PM Location: E Hall D2 Personalize your Meeting experience with a suggested or customized itinerary! Author(s): Terufumi Kato, Takashi Seto, Makoto Nishio, Koichi Goto, Shinji Atagi, Yukio Hosomi, Noboru Yamamoto, Toyoaki Hida, Makoto Maemondo, Kazuhiko Nakagawa, Seisuke Nagase, Isamu Okamoto, Takeharu Yamanaka, Ryosuke Harada, Masahiro Fukuoka, Nobuyuki Yamamoto; Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan; Department of Medical Oncology, National Kyushu Cancer Center, Fukuoka, Japan; Thoracic Oncology Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Japan; Department of Thoracic Oncology and Respiratory Medecine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan; Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; Department of Respiratory Medicine, Miyagi Cancer Center, Natori, Japan; Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan; Tokyo Medical University, Tokyo, Japan; Kyushu Univerisity, Fukuoka, Japan; National Cancer Center Hospital East, Kashiwa, Japan; Chugai Pharmaceutical Co., Ltd, Tokyo, Japan; Cancer Center, Izumi Municipal Hospital, Osaka, Japan; Wakayama Medical University, Wakayama, Japan Abstract Disclosures Abstract: Background: Despite the development of EGFR tyrosine kinase inhibitors, median progression-free survival (PFS) is only about 13 months in patients with EGFR mutation–positive NSCLC. However, results from the BeTa Lung study for a subgroup of patients with EGFR mutation suggest that EB may prolong PFS in these patients. Methods: Open-label randomized trial. Patients with stage 3b/4 or recurrent non-squamous EGFR mutation–positive NSCLC, ECOG performance status 0/1, and no previous chemotherapy were randomly allocated to receive EB (E, 150 mg/day; B, 15 mg/kg every 3 weeks) or E (150 mg/day) until disease progression or unacceptable toxicity. The primary endpoint was PFS determined by blinded independent review committee. Secondary endpoints included overall survival, objective response rate (ORR), safety, and quality of life. The planned sample size was 150, with an alpha error of 0.2 and a power of 80% for a target hazard ratio (HR) of 0.7. Results: From February 2011 to March 2012, 154 patients were enrolled (EB group, n = 77; E group, n = 77). There were no major differences in patient characteristics, including age, gender, stage, and EGFR mutation type, between the two groups. Median PFS was 16.0 months for EB and 9.7 months for E (HR, 0.54; 95% CI, 0.36–0.79; log-rank p = 0.0015). In the EGFR exon 19 deletion subgroup, median PFS was 18.0 months for EB and 10.3 months for E. In the L858R subgroup, median PFS was 13.9 months for EB and 7.1 months for E. ORR was 69.3% for EB and 63.6% for E. There were 3 and 1 complete responses to EB and E, respectively. Grade 3 or 4 rash was more common in the EB group (25.3% versus 19.5%). Grade 3 or 4 bleeding was more common in the EB group (2.7% versus 0.0%). However, most adverse events were manageable, and no new safety signals arose. Five patients experienced grade 1–3 interstitial lung disease, but there was no difference between the groups. One treatment-related death occurred in the E group. Conclusions: EB results in significantly longer PFS than E in patients with EGFR mutation–positive NSCLC. Clinical trial information: JapicCTI-111390. Temps (mois) SSP Médiane : 16,0 mois vs 9,7 (HR = 0,54) Différences par type de mutation EGFR Exon 19 : SSP médiane 18,0 vs. 10,3 mois Exon 21 : SSP médiane 13,9 vs. 7,1 mois EB ASCO® 2014 - D’après Kato T et al., abstr. 8005 actualisé

Etude JO25567 de phase III en première ligne, erlotinib et bevacizumab contre erlotinib seul : tumeurs EGFR mutées (4) 60 Groupe EB Répondeurs (RC, RP) 40 Groupe EB (n = 75) Groupe E (n = 77) P RC, n (%) 3 (4) 1 (1) – RP, n (%) 49 (65) 48 (62) Stable, n (%) 22 (29) 19 (25) Prog, n (%) 0 (0) 6 (8) NE, n (%) Contrôle, % 99 88 0,0177 depuis le “baseline (%) Changement du volume tumoral Non répondeurs 20 –20 –30 –40 –60 –80 –100 60 Groupe E depuis le “baseline (%) Changement du volume tumoral 40 20 –20 –30 –40 –60 –80 –100 ASCO® 2014 - D’après Kato T et al., abstr. 8005 actualisé

Etude JO25567 de phase III en première ligne, erlotinib et bevacizumab contre erlotinib seul : tumeurs EGFR mutées (5) n (%) Groupe EB (n = 75) Groupe E (n = 77) EI Grade ≥3 68 (91)* 41 (53) EI sévères 18 (24) 19 (25) EI avec décès 0 (0) 1 (1) EI avec arrêt du Beva n % Protéinurie 11 15 Hémorragie 9 12 Anomalie test hépatiques 3 4 Hypertension 2 Infection Autres 6 8 * Higher incidence of grade ≥ 3 AEs in combination arm was driven by hypertension events Common Terminology Criteria for AEs (CTCAE) version 4.03 was used ASCO® 2014 - D’après Kato T et al., abstr. 8005 actualisé