Milan - Italy. Gynecologic Oncology Unit Domenica Lorusso. AIOM post ASCO review: updates and news from the Annual Meeting in Chicago

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1 Milan - Italy AIOM post ASCO review: updates and news from the Annual Meeting in Chicago Milano Giugno 2018 Gynecologic Oncology Unit Domenica Lorusso

2 OVARIAN CANCER: FIRST LINE SURGERY

3 Comparison of survival between upfront primary debulking surgery versus neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers in phase III randomized trial: JCOG0602. Presented By Takashi ONDA at 2018 ASCO Annual Meeting

4 Results of Previous studies Presented By Takashi ONDA at 2018 ASCO Annual Meeting

5 Trial Design Presented By Takashi ONDA at 2018 ASCO Annual Meeting

6 Main Objective of the JCOG0602 Presented By Takashi ONDA at 2018 ASCO Annual Meeting

7 CONSORT Flow Diagram Presented By Takashi ONDA at 2018 ASCO Annual Meeting

8 Surgical Procedures Presented By Takashi ONDA at 2018 ASCO Annual Meeting

9 Overall Survival (N=301) Presented By Takashi ONDA at 2018 ASCO Annual Meeting

10 Progression-free Survival (N=301) Presented By Takashi ONDA at 2018 ASCO Annual Meeting

11 OS according to Debulking Results Presented By Takashi ONDA at 2018 ASCO Annual Meeting

12 Treatment Effect on OS in Major Subgroups Presented By Takashi ONDA at 2018 ASCO Annual Meeting

13 Conclusions Presented By Takashi ONDA at 2018 ASCO Annual Meeting

14 Survival analyses from a randomized trial of primary debulking surgery versus neoadjuvant chemotherapy for advanced epithelial ovarian cancer with high tumor load (SCORPION trial) (NCT ) Fagotti A, Ferrandina G, Vizzielli G, Fanfani F, Gallotta V, Chiantera V, Costantini B, Margariti PA, Gueli Alletti S, Cosentino F, Tortorella L, Scambia G. Fondazione Policlinico Universitario A. Gemelli, IRCCS Università Cattolica del Sacro Cuore, Rome, Italy Abs #

15 Study design Objective: To investigate whether NACT followed by surgery is superior to primary surgery in terms of PFS, in advanced epithelial ovarian cancer patients endowed with HTL. Methods: Assuming a drop out of 10%, a sample size of 166 patients (83 per arm) is required to provide 80% power of detecting a 0.6 HR of progression (Two-tailed = 0.05) with an improvement of median PFS from 12 to 20 months in the NACT arm. 1 5

16 CONSORT diagram and patients characteristics Variable Arm A PDS N. (%) Arm B NACT N. (%) All cases FIGO surgical stage IIIC IV LPS score at diagnosis (84.5) 13 (15.5) 46 (54.8) 28 (33.3) 10 (11.9) 79 (90.8) 8 (9.2) 34 (39.1) 43 (49.4) 10 (11.5) 1 6

17 Survival analysis on ITT population PDS NACT PDS NACT Number at risk PDS NACT Months Number at risk PDS NACT Months PDS NACT HR (95% CI) P value Recurrences 65 (77.4) 72 (82.4) Median PFS (mths) ( ) PDS NACT HR (95% CI) P value Deaths 38 (45.2) 36 (41.4) Median OS (mths) 41 NR 0.88 ( )

18 Post-operative complications for debulked patients Variable Arm A PDS N. (%) Arm B IDS N. (%) All cases p value Variable Arm A PDS N. (%) Arm B IDS N. (%) All cases p value Pts with early major post-operative complications 40 (47.6) 7 (9.5) < Pts with late major post-operative complications 10 (11.9) 1 (1.4) All events Early major Grade III Grade IV Grade V (21.4) 3 (1.7) 3 (1.7) 92 7 (7.6) All events Late major Grade III Grade IV Grade V 31 6 (19.3) 3 (9.6) 4 (12.9) 4 1 (25)

19 OVARIAN CANCER: FIRST LINE CHEMOTHERAPY

21 OVARIAN CANCER: RECURRENT PLATINUM RESISTANT DISEASE

22 Antitumor Activity and Safety of Pembrolizumab in Patients with Advanced Recurrent Ovarian Cancer: Interim Results from the Phase 2 KEYNOTE-100 Study Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

<br />KEYNOTE-100 (NCT02674061): Phase 2, Two-Cohort Study of Pembrolizumab for

23 KEYNOTE-100 (NCT ): Phase 2, Two-Cohort Study of Pembrolizumab for Recurrent Advanced Ovarian Cancer Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

24 Endpoints and Assessments Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

25 Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

26 Progression-Free Survival and Overall Survival Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

27 PD-L1 Expression Analysis Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

28 Efficacy by PD-L1 Expression: Cohort A Confirmed Response Rates Based on RECIST v1.1 per BICR Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

29 Efficacy by PD-L1 Expression: Cohorts B and A + B Confirmed Response Rates Based on RECIST v1.1 per BICR Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

30 Conclusions Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

31 QUADRA (NCT ): A phase 2, open-label, single-arm study to evaluate the safety and efficacy of niraparib in patients with advanced, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer Kathleen N. Moore, 1 Angeles A. Secord, 2 Melissa Geller, 3 David S. Miller, 4 Noelle G. Cloven, 5 Gini F. Fleming, 6 Andrea E. Wahner Hendrickson, 7 Masoud Azodi, 8 Paul DiSilvestro, 9 Amit Oza, 10 Mihaela Cristea, 11 Jonathan S. Berek, 12 John K. Chan, 13 Yong Li, 14 Katarina Luptakova, 14 Romnee Clark, 14 Ursula A. Matulonis, 15 Bradley J. Monk 16 1 University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 2 Duke University Medical Center, Raleigh, SC, USA; 3 University of Minnesota Medical School, Minneapolis, MN, USA; 4 UT Southwestern Medical Center, Dallas, TX, USA; 5 Texas Oncology - Fort Worth, Fort Worth, TX, USA; 6 The University of Chicago Medicine, Chicago, IL, USA; 7 Mayo Clinic, Rochester, MN, USA; 8 Smilow Cancer Hospital at Yale and Yale University, New Haven, CT, USA; 9 Women and Infants Hospital, Providence, RI, USA; 10 University Health Network and Princess Margaret Cancer Centre, Toronto, ON, Canada; 11 City Of Hope National Medical Center, Duarte, CA, USA; 12 Stanford Cancer Institute, Palo Alto, CA, USA; 13 Sutter Health, San Francisco, CA, USA; 14 TESARO, Inc., Waltham, MA, USA; 15 Harvard Medical School, Boston, MA, USA; 16 Division of Gynecologic Oncology, Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Phoenix Creighton University School of Medicine at St. Joseph s Hospital, Phoenix, AZ, USA. 3 1

32 Parp Inhibitor: active disease setting Potential Line of Therapy Rucaparib Pooled Analysis (103 pts) US and EMA label 3 rd line treatment (regardless platinum sensitivity) Dosing 600 mg BID 400 mg BID Potential label Populations Most common Grade 3 AEs in treatment setting Dose interruptions/ reductions due to side effects ORR (RECIST 1.1) by investigator Progression free survival (median, months) Tumour BRCA mut (includes germline and somatic mutations) Fatigue (11%) Anaemia (23%) ALT/AST (11%) 8% 44.3% Olaparib US Label (137 pts) 4 th line treatment (regardless platinum sensitivity) Germline BRCA mut Fatigue (8%) Anaemia (18%) Abdominal pain (8%) 36% 42% 54% 34%

33 QUADRA Study Design and Patient Eligibility Study purpose: Evaluate the efficacy of niraparib in a broad, late-line recurrent OC population. ORR objective response rate HRD homologous recombination deficiency 3 3

$= platinum resistant (time from last platinum until next progression between 28 days and 6 months); Plat. ref. = platinum refractory (progression on or within 28 days from last platinum); Plat.$

34 Patient Characteristics Plat. sens. = platinum sensitive (time from last platinum until next progression 6 months), including platinumineligible; Plat. res. = platinum resistant (time from last platinum until next progression between 28 days and 6 months); Plat. ref. = platinum refractory (progression on or within 28 days from last platinum); Plat. unk. = platinum status unknown 3 4

35 QUADRA Study Met Primary Endpoint Objective response rate (ORR) in 4 th and 5 th line HRDpos patients* who are considered platinum sensitive to their last platinum therapy was 29% (95% CI 16-44, p=0.0003, n=45).significant number of patients treated in 6 th line or later => all subsequent subgroup analyses included 4 th line or later. An expanded primary population was created to include 4 th line or later, HRDpos patients, sensitive to last platinum (n=51)* ORR (CR+PR) 27% (14/51) SD 41% (21/51) DCR (CR+PR+SD) 69% (35/51) Median DOR 9.2 months (95% CI ) Median OS 19.0 months (95% CI 15.5 NE) * PARPi exposed patients are not included mdor median duration of response DCR disease control rate (best overall response) mos median overall survival CR complete response PR partial response SD stable disease 3 5

36 Response Status in Biomarker-Defined Populations 4 th line or later Platinum-sensitive to last line of platinum therapy (including platinum ineligible) BRCAmut* HRDpos ORR CBR16 ORR CBR16 39% (7/18) 72% (13/18) 27% (14/51) 49% (25/51) Platinum-resistant or -refractory 27% (10/37) 43% (16/37) 10% (12/120) 33% (39/120) Total** 31% (17/55) 53% (29/55) 15% (26/171) 37% (64/171) *BRCAmut includes patients with both germline or somatic mutations. **Total includes platinum-sensitive, -resistant and -refractory patients. Additional 16 HRDpos (8 BRCAmut) patients had unknown platinum status; of these, 3 had PR and 10 had CR+PR+SD for at least 16 weeks. PARPi exposed patients are not included. ORR = objective response rate; CBR16 = clinical benefit rate (CR+PR+SD for at least 16 weeks). 3 6

37 Duration of Response in Biomarker-Defined Populations Patients with platinum-sensitive, -resistant and -refractory disease are included, excluding PARPi exposed patients. 3 7

38 Overall Survival in All Patients Treated in 4 th Line or Later Patients treated in 4 th or later line, including patients treated with PARP inhibitors 3 8

39 Summary of TEAEs Grade 3 in >5% of Patients (Safety Population, N=463) MedDRA System Preferred Term (N=463) n (%) Any CTCAE Grade 3 TEAE 338 (73.0) Anaemia 122 (26.3) Thrombocytopenia* 95 (20.5) Nausea 45 (9.7) Platelet count decreased* 42 (9.1) Neutropenia 38 (8.2) Vomiting 37 (8.0) Small intestinal obstruction 30 (6.5) Abdominal pain 29 (6.3) Treatment-emergent adverse events (TEAEs), including grade 3, were consistent with prior clinical experience. Percentage of patients who experienced a TEAE resulting in dose: interruption (62.2%) reduction (47.1%) withdrawal (21.2%) Fatigue 29 (6.3) 1 patient out of 463 (0.2%) with MDS/AML and 1 patient with related grade 5 gastric hemorrhage. *Events are not mutually exclusive. TEAE treatment emergent adverse events MDS myelodysplastic syndrome AML- acute myeloid leukemia 3 9

40 Conclusions Niraparib is the first PARP to demonstrate antitumor activity in a real world, late-line treatment setting QUADRA represented a difficult-to-treat population with a high unmet need: 27% received niraparib as the 6 th or later line of therapy. Two-thirds were platinum resistant (33%) or refractory (35%). <20% of patients were BRCAmut and 48% were HRDpos. Niraparib achieved clinical activity beyond BRCAmut in 4 th line or later OC patients. In the expanded primary population, ORR was 27%, mdor was 9.2 months, and CBR16 was 49%. In all evaluable patients, ORR was 10%, mdor was 9.4 months, and CBR16 was 35%. Responses to niraparib were durable across the entire population. Estimated 44% of responses lasting 12 months. mos in all patients treated in 4 th line or later was 17.2 months No new safety signals were identified. ORR objective response rate mdor median duration of response CBR16 clinical benefit rate (CR+PR+SD for at least 16 weeks) 4 0

41 OVARIAN CANCER: RECURRENT PLATINUM SENSITIVE DISEASE

42 Surgery in relapse: the new reality

A Phase III Randomized Controlled Trial of Secondary Surgical Cytoreduction followed by Platinum-Based Combination Chemotherapy, With or Without Bevacizumab

43 A Phase III Randomized Controlled Trial of Secondary Surgical Cytoreduction followed by Platinum-Based Combination Chemotherapy, With or Without Bevacizumab in Platinum- Sensitive, Recurrent Ovarian Cancer: A NRG Oncology/Gynecologic Oncology Group Study Presented By Robert Coleman at 2018 ASCO Annual Meeting

44 GOG 213: Schema Objective #1 Presented By Robert Coleman at 2018 ASCO Annual Meeting

45 GOG 213 Objective 1: OS Presented By Robert Coleman at 2018 ASCO Annual Meeting

46 GOG 213: Schema Modification 8/29/2011 Presented By Robert Coleman at 2018 ASCO Annual Meeting

47 Slide 11 Presented By Robert Coleman at 2018 ASCO Annual Meeting

48 Eligibility for Surgery Presented By Robert Coleman at 2018 ASCO Annual Meeting

49 CONSORT and Accrual Presented By Robert Coleman at 2018 ASCO Annual Meeting

50 Patient Characteristics Presented By Robert Coleman at 2018 ASCO Annual Meeting

51 Slide 18 Presented By Robert Coleman at 2018 ASCO Annual Meeting

52 Surgical Findings Presented By Robert Coleman at 2018 ASCO Annual Meeting

53 Primary Endpoint OS: Surgery vs. No Surgery Presented By Robert Coleman at 2018 ASCO Annual Meeting

54 Secondary Endpoint PFS: Surgery vs. Chemo Presented By Robert Coleman at 2018 ASCO Annual Meeting

55 Exploratory Endpoint: Surgery Outcome R0 vs. Non-R0 Presented By Robert Coleman at 2018 ASCO Annual Meeting

56 Exploratory Endpoint: Surgical R0 vs. No Surgery Presented By Robert Coleman at 2018 ASCO Annual Meeting

57 Conclusions Presented By Robert Coleman at 2018 ASCO Annual Meeting

58 Chemotherapy plus or minus bevacizumab for platinum-sensitive ovarian cancer patients recurring after a bevacizumab containing first line. The randomized phase 3 trial MITO16B - MaNGO OV2B - ENGOT OV17 Sandro Pignata, Domenica Lorusso, Florence Joly, Ciro Gallo, Nicoletta Colombo, Cristiana Sessa, Aristotelis Bamias, Carmela Pisano, Frédéric Selle, Eleonora Zaccarelli, Giovanni Scambia, Patricia Pautier, Maria Ornella Nicoletto, Ugo De Giorgi, Coraline Dubot, Alessandra Bologna, Michele Orditura, Isabelle Ray-Coquard, Francesco Perrone, Gennaro Daniele on the behalf of MITO, GINECO, MaNGO, SAKK and HeCOG groups Sandro Pignata

59 Study Design R A N D O M 1:1 Standard Experimental Platinum-Based Chemotherapy Platinum-Based Chemotherapy plus Bevacizumab Platinum-based Chemotherapy: Carboplatin + Paclitaxel +/- Beva 15mg/kg q 21 Carboplatin + Gemcitabine +/- Beva 15mg/kg q 21 Carboplatin + PLD q 28 +/- Beva 10mg/kg q 14 Stratification: center relapse during or after 1 line Beva performance status chemo backbone Sandro Pignata

60 Study end-points Primary: PFS (Investigator assessed RECIST 1.1) Secondary: Overall survival Safety (CTCAE v4.03) Objective response rate (RECIST 1.1) PFS centrally reviewed (not yet available) Prognostic and predictive molecular factors (not yet available) Sandro Pignata

61 Participating cooperative groups Country Group Total N Italy MITO 206 MaNGO 72 France GINECO 100 Switzerland SAKK 17 Greece HECOG 10 Total 405 Sandro Pignata

62 Probability of PFS PFS Investigator assessed (primary end-point) Kaplan-Meier survival estimates Standard Experimental Log Rank P # events Median PFS 8.8 mos 11.8 mos <0.001 HR* (95%CI) 0.51 ( ) months Number at risk Control Experimental Control Experimental *adjusted by: age, PS, centre size, bevacizumab at relapse, chemo backbone, residual disease at initial surgery Sandro Pignata

63 Overall survival Standard Experimental Log Rank P # events Median OS 27.1 mos 26.6mos 0.98 HR* (95%CI) 0.97 ( ) months Number at risk Standard Experimental Control Experimental *adjusted by: age, PS, centre size, bevacizumab at relapse, chemo backbone, residual disease at initial surgery Sandro Pignata

64 Objective Response Rate (RECIST 1.1) Standard N= 143 Experimental N= 130 P Responders (CR+PR) 94 (65.7%) [95%CI: 57.6%-73.0%] 97 (74.6%) [95%CI: 66.5%-81.4%] 0.14 CR 9 (6.3%) 20 (15.4%) PR 85 (59.4%) 77 (59.2%) Sandro Pignata

65 Severe Toxicity occurring >4% of patients STD (N=200) EXP (N=201) G3 G4 G3 G4 P* Hypertension 20 (10%) 0 58 (28.9%) 0 <0.001 Neutrophils 56 (28%) 25 (12.5%) 48 (23.9%) 32 (15.9%) 0.95 Thrombocytopenia 20 (10%) 23 (11.5%) 31 (15.4%) 30 (14.9%) 0.04 Proteinuria (3.9) Febrile Neutropenia 6 (3%) 4 (2%) 3 (1.5%) 1(0.5%) 0.17 Allergic Reaction 11 (5.5%) 0 5 (2.48%) 1 (0.5%) 0.22 Anemia 22 (11%) 1(0.5%) 22 (10.9%) 0 0,88 *Chi-square or Fisher s exact test as appropriate (severe vs non-severe) Sandro Pignata

66 Conclusions In ovarian cancer patients relapsing 6 months after last platinum, previously treated with bevacizumab in first line, rechallenge with bevacizumab in combination with a platinum-based doublet is associated with a significantly prolonged PFS, with no unexpected toxicity Rechallenge with platinum based chemotherapy and bevacizumab is a clinical option in recurrent patients already treated with bevacizumab Future translational analyses will provide a deeper insight into prognostic and predictive factors Sandro Pignata

67 EARLY STAGE CERVICAL CANCER: PRIMARY TREATMENT

68 Outcomes and costs of open, robotic, and laparoscopic radical hysterectomy for stage IB1 cervical cancer Presented By Daniel Margul at 2018 ASCO Annual Meeting

69 Objectives Presented By Daniel Margul at 2018 ASCO Annual Meeting

70 Premier Cohort ( ) Presented By Daniel Margul at 2018 ASCO Annual Meeting

71 NCDB Cohort ( ) Presented By Daniel Margul at 2018 ASCO Annual Meeting

72 Premier Cohort: Costs and Complications Presented By Daniel Margul at 2018 ASCO Annual Meeting

73 Results: NCDB Cohort Characteristics Presented By Daniel Margul at 2018 ASCO Annual Meeting

74 Overall Survival by Surgical Approach Presented By Daniel Margul at 2018 ASCO Annual Meeting

75 Slide 18 Presented By Daniel Margul at 2018 ASCO Annual Meeting

76 Conclusions: Presented By Daniel Margul at 2018 ASCO Annual Meeting

77 UTERINE CANCER: LEIOMYOSARCOMA

78 Adjuvant Gemcitabine plus Docetaxel followed by Doxorubicin versus Observation for Uterus-Limited, High Grade Leiomyosarcoma: a Phase III NRG Oncology/Gynecologic Oncology Group Study Presented By Martee Hensley at 2018 ASCO Annual Meeting

79 Study Rationale Presented By Martee Hensley at 2018 ASCO Annual Meeting

80 Study Schema Presented By Martee Hensley at 2018 ASCO Annual Meeting

81 Key study design features Presented By Martee Hensley at 2018 ASCO Annual Meeting

82 Study Accrual Presented By Martee Hensley at 2018 ASCO Annual Meeting

83 Slide 7 Presented By Martee Hensley at 2018 ASCO Annual Meeting

84 Grade 3 and 4 Adverse Events Presented By Martee Hensley at 2018 ASCO Annual Meeting

85 Sites of recurrent disease (n=16) Presented By Martee Hensley at 2018 ASCO Annual Meeting

86 Recurrence Free Survival: chemo v. observation Presented By Martee Hensley at 2018 ASCO Annual Meeting

87 Overall Survival: chemo v. observation Presented By Martee Hensley at 2018 ASCO Annual Meeting

88 Conclusions: Presented By Martee Hensley at 2018 ASCO Annual Meeting

89 Grazie per l attenzione

Lo stato dell arte nel carcinoma ovarico: Il Trattamento Medico

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