ESMO SUMMIT MIDDLE EAST 2018

Transcription

1 ESMO SUMMIT MIDDLE EAST 2018 Practice changing studies in Gynecological Cancer in 2017 Dr Susana Banerjee MBBS MA PhD FRCP Consultant Medical Oncologist and Research Lead Gynaecology Unit The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London. UK ESMO Executive Board Member 6-7 April 2018, Dubai, UAE

2 CONFLICT OF INTEREST DISCLOSURE Research Funding Astrazeneca, Tesaro Advisory Boards- Astrazeneca, Tesaro, Clovis, Gamamabs, Pharmamar Travel/accommodation support- Tesaro, Pharmamar, Gamamabs

3 PRACTICE CHANGING AND LANDMARK STUDIES IN GYNAECOLOGICAL CANCERS 2017 Areas to cover OVARIAN CANCER Newly diagnosed- First Line o LION (surgery) o ICON8 (chemotherapy) o HIPEC (chemotherapy) OVARIAN CANCER Recurrent o DESKTOP III (surgery) o SOLO2 (PARP inhibitors) o ARIEL3 (PARP inhibitors) ENDOMETRIAL CANCER o PORTEC-3 CERVICAL CANCER Newly diagnosed, locally advanced o Neoadjuvant chemotherapy followed by surgery CERVICAL CANCER Advanced, recurrent o GOG240 (bevacizumab) o CHECKMATE 358 (cervical, vaginal, vulva)

4 Randomization (n=640) OVARIAN CANCER LION TRIAL Harter et al ASCO 2017 What is the role of pelvic/para-aortic lymphadenectomy in patients with advanced ovarian cancer who have clinically negative nodes and otherwise macroscopic complete resection? Pre-operative In/exclusion Criteria age 18-75, PS 0/1 No prior chemo No prior dissection Registration at least one day prior to surgery Intra-operative randomisation if: Epithelial ovarian cancer FIGO IIB-IV Macroscopic complete resection No contra-indication to LNE Absence of bulky nodes Strata: Center Age PS ECOG Primary endpoint: Overall Survival Systematic pelvic and para-aortic lymphadenectomy No lymphadenectomy

5 OVARIAN CANCER LION TRIAL Harter et al ASCO 2017 Surgery Characteristics Bilateral Salpingooophorectomy* LNE (%) No LNE (%) P- value 319 (98.8) 320 (98.8) 0.99 Hysterectomy* 321 (99.4) 322 (99.4) 0.99 Omentectomy 319 (98.8) 322 (99.4) 0.41 (Partial) peritonectomy Pelvis Paracolic Diaphragm Gastrointestinal tract resection Stoma 291 (90.1) 276 (85.5) 193 (59.8) 173 (53.6) 169 (52.3) 34 (10.5) 291 (89.8) 278 (85.8) 208 (64.2) 196 (60.5) 167 (51.5) 24 (7.4) Splenectomy 62 (19.2) 56 (17.3) 0.53 Porta hepatis/lesser omentum Partial pancreatectomy Partial hepatectomy Pleurectomy 61 (18.9) 69 (21.3) (2.1) 27 (8.4) 20 (6.2) 7 (2.1) 28 (8.6) 24 (7.4) Complete resection 321 (99.4) 322 (99.4) 0.99 Study procedure according to randomisation Resected LN total (median, IQR) Para-aortic LN Pelvic LN Lymph node metastases Duration (median, IQR) [min] Blood loss (median, IQR) [ml] Transfusions Massive transfusions (> 10 RBC/24h) LNE (%) No LNE (%) 320 (99.1) 313 (96.6) 57 (45-73) 22 (16-33) 35 (26-43) 180 (55.7) 340 ( ) 650 ( ) 205 (63.7) 7 (2.2) Fresh-frozen plasma 117 (36.3) Intermediate/Intensive Care Unit 250 (77.6) 280 ( ) 500 ( ) 181 (56.0) 2 (0.6) Differen ce p- value + 1 hour < ml < % (29.7) + 7% (69.4) + 8% 0.01

6 OVARIAN CANCER LION TRIAL Harter et al ASCO 2017 Post-surgical outcome Infections requiring antibiotics Fever > 38.0 o Celsius Sepsis LNE (%) No LNE (%) p-value 83 (25.8) 41 (12.7) 6 (1.9) 60 (18.6) 32 (9.9) 3 (0.9) Thrombosis 7 (2.2) 5 (1.6) 0.56 Pulmonary embolism 12 (3.7) 15 (4.6) 0.56 Secondary wound healing 31 (9.6) 19 (5.9) 0.12 Prolonged ileus (conservative management) 15 (4.6) 17 (5.3) 0.72 Peripheral sensoric neurologic event 7 (2.2) 7 (2.2) 0.99 Peripheral motoric neurologic event 10 (3.1) 8 (2.5) 0.63 Asymptomatic lymph cysts 14 (4.4) 1 (0.3) <0.001 Symptomatic lymph cysts 10 (3.1) Fistula 5 (1.6) 7 (2.2) 0.56 Readmission rate 40 (12.4) 27 (8.3) 0.09 Rate of re-laparotomy for complications 40 (12.4) 21 (6.5) day postoperative mortality 10 (3.1) 3 (0.9) Platinum + Taxan i.v. 257 (79.6) 274 (84.6)

7 OVARIAN CANCER LION TRIAL Harter et al ASCO 2017 Patients with complete resection during upfront surgery and treated in quality assured centres have an excellent prognosis (median OS ~ 67.2 months; median PFS ~ 25.5 months) Systematic pelvic and para-aortic LNE in patients with advanced ovarian cancer with both intraabdominal complete resection and clinically negative LN neither improve overall nor progression-free survival.despite detecting (and removing) sub-clinical retroperitoneal lymph node metastases in 56% of patients. Systematic LNE of clinical negative LN in patients with advanced ovarian cancer and complete resection should be omitted. - Does this conclusion apply to patients undergoing neoadjuvant chemotherapy?

8 OVARIAN CANCER ICON8 TRIAL Clamp et al ESMO 2017 Background: Platinum-Paclitaxel cornerstone of first-line management of epithelial ovarian cancer 6-8 cycles administered 3-weekly Dose-dense weekly paclitaxel is an intriguing treatment strategy that may enhance antitumor activity and prolong survival in the first-line treatment of ovarian cancer: Pre-clinical evidence of improved drug delivery, increased apoptosis and reduced angiogenesis Active and well-tolerated approach in platinum-resistant disease JGOG3016- dose dense paclitaxel. Japanese population. Ethnic pharmacogenomic differences. JGOG3016 Katsumata et al Lancet 2009, Lancet Onc 2013

9 ICON8 TRIAL SCHEMA Diagnosis of Stage IC-IV EOC/PPC/FTC After immediate primary surgery or planned to receive NACT plus delayed primary surgery Randomise 1:1:1 Arm 1 Carboplatin AUC 5 q3w Paclitaxel 175mg/m 2 q3w Arm 2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m 2 q1w Arm 3 Carboplatin AUC 2 q1w Paclitaxel 80mg/m 2 q1w Six cycles chemotherapy mandated DPS cohort Cytoreductive surgery strongly advised after 3 cycles of chemotherapy Cycle 3 day 15 treatment omitted in arms 2 and 3 9

10 ICON8: PROGRESSION FREE SURVIVAL (PFS) Total No. of Patients Arm 1 Arm 2 Arm 3 Cq3w/Tq3w Cq3w/Tq1w Cq1w/Tq1w N=522 N=523 N=521 Progressions 330 (63%) 335 (64%) 338 (65%) Median Survival 17.9 months 20.6 months 21.1 months Log rank (vs Arm1) p=0.45 p=0.56 HR vs Arm 1 (97.5% CI) 0.92 (0.77, 1.09) 0.94 (0.79, 1.12) Restricted means 24.4 months 24.9 months 25.3 months Incorporation of weekly dose-dense chemotherapy regimens into first-line treatment for women with epithelial ovarian cancer does not improve PFS 3-weekly carboplatin-paclitaxel remains the standard-of-care in first-line ovarian cancer treatment 10

11 OVARIAN CANCER OVIHIPEC Van Driel ASCO 2017, NEJM 2018 Combination of hyperthermia and intraperitoneal chemotherapy Cytotoxic effect of hyperthermia, synergy with chemotherapy, enhanced penetration

12 OVARIAN CANCER OVIHIPEC Van Driel ASCO 2017, NEJM 2018 IMPORTANT FIRST STEP Not standard of care universally (await ESMO/ESGO consensus April 2018) Questions: Tolerability- similar grade ¾ events Cost- effectiveness? Longer hospitalisation HIPEC post NACT and IDS What about post primary surgery? Highly technical procedure- training

13 PRACTICE CHANGING AND LANDMARK STUDIES IN GYNAECOLOGICAL CANCERS 2017 Areas to cover OVARIAN CANCER Newly diagnosed- First Line o LION (surgery) o ICON8 (chemotherapy) o HIPEC (chemotherapy) OVARIAN CANCER Recurrent o DESKTOP III (surgery) o SOLO2 (PARP inhibitors) o ARIEL3 (PARP inhibitors) ENDOMETRIAL CANCER o PORTEC-3 CERVICAL CANCER Newly diagnosed, locally advanced o Neoadjuvant chemotherapy followed by surgery CERVICAL CANCER Advanced, recurrent o GOG240 (bevacizumab) o CHECKMATE 358 (cervical, vaginal, vulva)

14 OVARIAN CANCER DESKTOP III Du Bois ASCO 2017 What is the role of cytoreductive surgery before chemotherapy in recurrent ovarian cancer? Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: the interim analysis of AGO DESKTOP III / ENGOT ov20 AGO Score consisted of (1) good PS (ECOG 0), (2) complete resection during 1st line therapy, and (3) ascites less than 500 ml

15 OVARIAN CANCER DESKTOP III Du Bois ASCO 2017 Cytoreductive surgery in OC patients with a treatment free interval (platinum) of more than 6 months and a positive AGO Score resulted in a PFS advantage 5.6 months Surgery should be considered for these patients. The advantage was exclusively seen in patients with complete resection (CR) indicating the importance of selecting both the right patients and specialist centre

16 OVARIAN CANCER SOLO2 Pujade-Lauraine SGO 2017, Lancet Onc 2017 Olaparib is the first-in-class PARP inhibitor to be approved In Study 19 (randomised phase II), olaparib maintenance therapy (capsules) provided a significant progression-free survival (PFS) improvement over placebo in all-comer patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. The PFS benefit was greatest for patients with a BRCA1/2 mutation SOLO2/ENGOT-Ov21 (NCT ) was a Phase III trial to confirm findings from Study 19 in the BRCA1/2 mutation subgroup using the olaparib tablet formulation Patients BRCA1/2 mutation Platinum-sensitive relapsed ovarian cancer At least 2 prior lines of platinum therapy CR or PR to most recent platinum therapy Randomized 2:1 Olaparib tablets 300 mg bid n=196 Placebo n=99 Primary endpoint Investigator-assessed PFS

17 OVARIAN CANCER SOLO2 Pujade-Lauraine SGO 2017, Lancet Onc 2017 Secondary endpoints: Olaparib (n=196) Placebo (n=99) Events (%) 107 (54.6) 80 (80.8) Median PFS, months HR % CI 0.22 to 0.41 P< FDA approval Awaiting EMA approval 0 0

18 SOLO2 adverse events Characteristic, n (%) Olaparib (n=195) Placebo (n=99) Any AE 192 (98.5) 94 (94.9) Any AE grade 3 72 (36.9) 18 (18.2) Any SAE 35 (17.9) 8 (8.1) Any AE leading to dose reduction 49 (25.1) 3 (3.0) Any AE leading to discontinuation of study treatment 21 (10.8) 2 (2.0) Any AE with an outcome of death 1 (0.5) 0 Event, n (%) Olaparib (n=195) Placebo (n=99) All grades Grade 3 All grades Grade 3 Anaemia* 85 (43.6) 38 (19.5) 8 (8.1) 2 (2.0) Neutropenia* 38 (19.5) 10 (5.1) 6 (6.1) 4 (4.0) Thrombocytopenia 16 (8.2) 0 3 (3.0) 1 (1.0) MDS/AML: 4 cases in olaparib group (2.1%), including one case of CMML; 4 cases in placebo group (4.0%)

19 SOLO2: Most common non-haematological adverse events Olaparib Placebo Nausea Fatigue/asthenia Vomiting Diarrhoea All grades (frequency 20%) Grade 3 (frequency 2.5%) Dysgeusia Headache Abdominal pain Decreased appetite Constipation Adverse events (%) Other AEs of interest Elevated ALT: 10 patients in olaparib group (5.1%) vs 4 patients in placebo group (4.0%) Elevated AST: 4 patients in olaparib group (2.1%) vs 4 patients in placebo group (4.0%)

20 SOLO2: Conclusions Lancet Onc 2017 SOLO2 demonstrated a statistically significant PFS improvement in patients receiving olaparib tablets compared to placebo The PFS benefit was supported by a significant delay in TFST, PFS2 and TSST in the olaparib group With the exception of anaemia, toxicity was mostly low grade SOLO2 is the first Phase III trial of olaparib tablets as maintenance treatment and showed a significant benefit in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation FDA approval olaparib tablets (Lynparza) for maintenance treatment for patients with recurrent EOC/FT/PPC with complete or partial response to platinum-based chemotherapy EMA approval pending

21 OVARIAN CANCER- ARIEL3 Ledermann ESMO 2017, Coleman et al Lancet 2017 Rucaparib is a potent inhibitor of PARP1, PARP2, and PARP3 Rucaparib has shown antitumour activity in patients with recurrent OC whose tumour harbours one of the following: A BRCA mutation High percentage of genomic LOH, a phenotypic marker of HRD Rucaparib is approved in the United States for the treatment of patients with deleterious BRCA mutation (germline or somatic) associated advanced OC who have been treated with 2 chemotherapy regimens The ARIEL3 phase 3 trial evaluated rucaparib vs placebo following a response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent platinum-sensitive OC, including fallopian tube and primary peritoneal carcinomas

22 Randomisation 2:1 ARIEL3: STUDY DESIGN Patient eligibility Stratification High-grade serous or endometrioid epithelial OC, primary peritoneal, or fallopian tube cancers Sensitive to penultimate platinum Responding to most recent platinum (CR or PR)* Excludes patients without assessable disease following second surgery CA-125 within normal range No restriction on size of residual tumour ECOG PS 1 No prior PARP inhibitors HRR status by NGS mutation analysis BRCA1 or BRCA2 Non-BRCA HRR gene None of the above Response to recent platinum CR PR Progression-free interval after penultimate platinum 6 to <12 months 12 months Rucaparib 600 mg BID n=375 Placebo BID n=189 *CR (defined by RECIST v1.1) or PR (defined by RECIST v1.1 and/or a GCIG CA-125 response [CA-125 within normal range]) maintained until entry to ARIEL3 ( 8 weeks of last dose of chemotherapy). ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RPA1. HRR, homologous recombination repair; NGS, next-generation sequencing. 22

23 ARIEL3: Primary Endpoint and Step-Down Analysis Primary endpoint: Investigator-assessed PFS (per RECIST) BRCA-mutant Germline or somatic BRCA mutation If significant* HRD Germline or somatic BRCA mutation + BRCA wild-type/loh high ( 16% genomic LOH prespecified) If significant* ITT (all comers) Germline or somatic BRCA mutation + BRCA wild-type/loh high + BRCA wild-type/loh low + BRCA wild-type/ LOH indeterminate BRCA mutation and LOH in tumour samples were measured using Foundation Medicine s T5 NGS assay *Investigator-assessed PFS at a two-sided 0.05 significance level 23

24 ARIEL3: Diagram of Analysis Cohorts 564 enrolled/randomised 196 BRCA mutant 368 BRCA wild type 130 germline BRCA mutant* 56 somatic BRCA mutant 158 BRCA wild type/ LOH high 161 BRCA wild type/ LOH low 49 BRCA wild type/ LOH indeterminate 10 undefined BRCA mutant BRCA-mutant cohort (n=196) 130 rucaparib 66 placebo HRD cohort (n=354) 130 rucaparib 66 placebo rucaparib 52 placebo ITT population (n=564) 130 rucaparib 66 placebo rucaparib 52 placebo rucaparib 71 placebo *No more than 150 patients with a known deleterious germline BRCA mutation were to be enrolled to ensure enough patients with carcinomas associated with a somatic BRCA mutation or wild-type BRCA were enrolled to determine statistical significance between rucaparib and placebo in the HRD cohort and 24 the ITT population. Deleterious BRCA mutation detected by next-generation sequencing of tumour tissue but not by central germline blood test. For LOH high, a cutoff of 16% genomic LOH was prespecified for ARIEL3.

25 ARIEL3: Investigator-Assessed Progression-Free Survival BRCA mutant HRD ITT Rucaparib (n=130) Placebo (n=66) Median (months) 95% CI HR, 0.23; 95% CI, ; P< Rucaparib (n=236) Placebo (n=118) Median (months) 95% CI HR, 0.32; 95% CI, ; P< Rucaparib (n=375) Placebo (n=189) Median (months) 95% CI HR, 0.36; 95% CI, ; P< At risk (events) Rucaparib 130 (0) 93 (23) 63 (46) 35 (58) 15 (64) 3 (67) 0 (67) Placebo 66 (0) 24 (37) 6 (53) 3 (55) 1 (56) 0 (56) Rucaparib, 48% censored Placebo, 15% censored At risk (events) Rucaparib 236 (0) 161 (55) 96 (104) 54 (122) 21 (129) 5 (134) 0 (134) Placebo 118 (0) 40 (68) 11 (95) 6 (98) 1 (101) 0 (101) Rucaparib, 43% censored Placebo, 14% censored At risk (events) Rucaparib 375 (0) 228 (111) 128 (186) 65 (217) 26 (226) 5 (234) 0 (234) Placebo 189 (0) 63 (114) 13 (160) 7 (164) 2 (167) 1 (167) 0 (167) Rucaparib, 38% censored Placebo, 12% censored 25 Visit cutoff date: 15 April 2017.

26 ARIEL3 Exploratory Analysis: Investigator-Assessed Progression-Free Survival in Patients with BRCA Wild-Type OC LOH high Rucaparib (n=106) Placebo (n=52) Median (months) 95% CI HR, 0.44; 95% CI, ; P< LOH low Rucaparib (n=107) Placebo (n=54) Median (months) 95% CI HR, 0.58; 95% CI, ; P= At risk (events) Rucaparib 106 (0) 68 (32) 33 (58) 19 (64) 6 (65) 2 (67) 0 (67) Placebo 52 (0) 16 (31) 5 (42) 3 (43) 0 (45) Visit cutoff date: 15 April Rucaparib, 37% censored Placebo, 13% censored At risk (events) Rucaparib 107 (0) 49 (47) 23 (65) 8 (77) 4 (79) 0 (81) Placebo 54 (0) 20 (32) 2 (49) 1 (50) 1 (50) 1 (50) 0 (50) Rucaparib, 24% censored Placebo, 7% censored

27 ARIEL3: Summary of Safety Rucaparib n=372, % (n)* Placebo n=189, % (n) At least 1 AE 100 (372) 96.3 (182) At least 1 AE grade (209) 14.8 (28) Treatment interruption and/or dose reduction due to AE 70.7 (263) 10.6 (20) Treatment interruption due to AE 63.7 (237) 10.1 (19) Dose reduction due to AE 54.6 (203) 4.2 (8) Discontinued due to AE 13.4 (50) 1.6 (3) Deaths due to AE 1.6 (6) 1.1 (2) Deaths due to disease progression 0.5 (2) 0.5 (1) Median (range) treatment duration was 8.3 ( ) months in the rucaparib arm and 5.5 ( ) months in the 27 placebo arm MDS/AML were reported in 3 (0.8%) patients in the rucaparib arm and no patients in the placebo arm

28 ARIEL3: Treatment-Emergent Adverse Events of Any Grade Reported in 15% of Patients in Either Arm Rucaparib (n=372) Placebo (n=189) (grade 3, 0) (grade 3, 0) (grade 3, 0) (grade 3, 0) (grade 3, 0) 12.7 (grade 3, 0) 1.6 (grade 3, 0) Any grade Grade (grade 3, 0.5) 2.6 (grade 3, 0) 4.8 (grade 3, 1.1) Incidence (%) 28

29 ARIEL3- Conclusions Ledermann ESMO 2017, Coleman et al Lancet 2017 Rucaparib maintenance treatment significantly improved PFS vs placebo in BRCA-mutant and HRD cohorts and in the overall ITT population following a complete or partial response to second-line or later platinum-based chemotherapy PFS was improved with rucaparib maintenance treatment vs placebo in patients with BRCA wild-type OC (LOH high and LOH low) The most common side effects were gastrointestinal (nausea and vomiting), asthenia, and anaemia, consistent with prior studies of rucaparib 29

30 PRACTICE CHANGING AND LANDMARK STUDIES IN GYNAECOLOGICAL CANCERS 2017 Areas to cover OVARIAN CANCER Newly diagnosed- First Line o LION (surgery) o ICON8 (chemotherapy) o HIPEC (chemotherapy) OVARIAN CANCER Recurrent o DESKTOP III (surgery) o SOLO2 (PARP inhibitors) o ARIEL3 (PARP inhibitors) ENDOMETRIAL CANCER o PORTEC-3 CERVICAL CANCER Newly diagnosed, locally advanced o Neoadjuvant chemotherapy followed by surgery CERVICAL CANCER Advanced, recurrent o GOG240 (bevacizumab) o CHECKMATE 358 (cervical, vaginal, vulva)

31 ENDOMETRIAL CANCER- PORTEC-3 De Boer ASCO 2017 What is the role of chemotherapy in combination with radiotherapy compared to radiotherapy alone in high-risk endometrial cancer? Trials of chemotherapy (CT) vs radiation therapy (RT) found no differences in PFS or OS; NSGO/EORTC phase III trial suggested PFS benefit with sequential RT and CT Different schedules and agents used and no data on toxicity and quality of life Endometrial carcinoma stage I grade 3, with deep invasion or LVSI+ stage II - III stage I-III serous or clear cell cancers (>25%) WHO PS 0-2 No residual macroscopic tumor after surgery Pathology review before randomisation 31 Primary endpoints: 5 yr overall survival (OS) 5 yr failure free survival (FFS) Failure Free Survival (FFS): relapse or endometrial cancer-related death Secondary endpoints: Vaginal, pelvic and distant recurrence, Toxicity and quality of life

32 PORTEC-3: Survival (OS and FFS) De Boer ASCO 2017 HR 0.79 [ ], p=0.18 HR 0.77 [ ], p= yr OS: 82% (CTRT) versus 77% (RT) 5 yr FFS: 76% (CTRT) versus 69% (RT)

33 PORTEC-3: Survival results per stage Patients with stage III EC: Lower 5-year FFS and OS: FFS: 64% stage III versus 79% for stage I-II (p<0.001) OS: 74% vs 83% (p=0.003) Greatest benefit of CTRT 5-year FFS 69% for CTRT vs 58% for RT [HR 0.66, 95% CI , p=0.032] 5-year OS 79% vs 70% [HR 0.69, , p=0.114] PORTEC-3 results

34 ENDOMETRIAL CANCER- PORTEC-3 De Boer ASCO 2017 Trend for improved 5-year FFS with addition of chemotherapy to RT Question if this benefit outweighs the toxicity without OS benefit (De Boer Lancet Onc 2016) Good pelvic control with RT alone This schedule cannot be recommended as standard for stage I-II OS analysis- needs longer follow-up TransPORTEC studies will hopefully identify those who benefit Significant 11% FFS benefit for stage III Combined CT/RT schedule recommended to maximize Failure- Free Survival PORTEC-3 results

35 PRACTICE CHANGING AND LANDMARK STUDIES IN GYNAECOLOGICAL CANCERS 2017 Areas to cover OVARIAN CANCER Newly diagnosed- First Line o LION (surgery) o ICON8 (chemotherapy) o HIPEC (chemotherapy) OVARIAN CANCER Recurrent o DESKTOP III (surgery) o SOLO2 (PARP inhibitors) o ARIEL3 (PARP inhibitors) ENDOMETRIAL CANCER o PORTEC-3 CERVICAL CANCER Newly diagnosed, locally advanced o Neoadjuvant chemotherapy followed by surgery CERVICAL CANCER Advanced, recurrent o GOG240 (bevacizumab) o CHECKMATE 358 (cervical, vaginal, vulva)

36 NEOADJUVANT CHEMOTHERAPY FOLLOWED BY SURGERY VERSUS CONCOMITANT CISPLATIN AND RADIATION THERAPY IN PATIENTS WITH STAGE IB2, IIA OR IIB SQUAMOUS CARCINOMA OF CERVIX: A RANDOMIZED CONTROLLED TRIAL Gupta et al ESMO 2017, JCO 2018 Concomitant platinum-based chemotherapy and radiotherapy( CCRT) has been the standard treatment for locally advanced cervical cancer since Cervical cancer has a moderately high response rate to modern chemotherapy including taxanes and platinum. Neoadjuvant chemotherapy(nact) followed by radical surgery(s) has insufficient evidence to be an standard approach, it is nevertheless practiced in many parts of the word. EORTC trial evaluates NACT+S to CCRT in stage IB2 IIB cervical cancer. Data are not yet reported.

37 Neoadjuvant chemotherapy followed by surgery versus concomitant cisplatin and radiation therapy in patients with stage IB2, IIA or IIB squamous carcinoma of cervix: A randomized controlled trial : Study Design Squamous carcinoma Stage IB2,IIA, or IIB ECOG 0-1 No prior treatment Adequate hematological & renal function Primary endpoint: 5 yr DFS Stratify by stage 1:1 N=633 N = 317 N = 318 Experimental NACT X 3 cycles followed by surgery Control Concurrent chemoradiation. Planned cross-over from NACT-Surgery to CTRT Unresectable disease after 2 nd or 3 rd cycle NACT Intraoperative unresectability Lymph node positive on frozen section intraoperative Postoperative adjuvant RT T > 4 cm, LVI +, deep cervical stromal invasion, (any two) Postoperative adjuvant CTRT LN +, parametrium +, surgical margin +, (any one) Sudeep Gupta, MD, presented at ESMO 2017 Congress, Madrid Spian) Neoadjuvant chemotherapy Paclitaxel (175 mg/m2) + Carboplatin: (AUC 5-6) every 3 weeks X 3 cycles Concomitant chemotherapy Cisplatin (40/m2/week) X 5 weeks Radiation therapy EBRT: 40 Gy/20 fr/5 weeks + HDR: 7Gy/5 application

38 Cervical Cancer: NACT+Surgery vs CTRT DFS and OS DFS OS Concomitant chemoradiation should continue to be the standard of care in locally advanced cervical cancer

39 CERVICAL CANCER: GOG240 OVERALL SURVIVAL FINAL RESULTS Tewari et al Lancet 2017 Overall survival imporvement 16.8 vs 13.3 months with bevacizumab After progression while receiving bevacizumab, no negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) observed Fistula (any grade) occurred in 15%) in the chemotherapyplus bevacizumab groups (all previously irradiated) versus 1%) in the chemotherapy-alone Grade 3 fistula developed in 6%)versus <1% Lancet Commentary S Banerjee 2017 Bevacizumab with platinum/taxane chemotherapy is standard of care for advanced cervical cancer patients - how to identify patients who are most likely to derive the greatest survival advantage from antiangiogenic therapy and with least risk?

40 CERVICAL CANCER, VAGINAL, VULVAR- CHECKMATE 358 Hollebecque ASCO 2017 Recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers have a high unmet need and poor prognosis Second-line treatment options for R/M cervical cancer result in median progression-free survival (PFS) of ~2 4 months and objective response rates (ORR) of 0 14% 1 Human papillomavirus (HPV) infection is causative in over 90% of cervical, 75% of vaginal, and 69% of vulvar cancers 2 HPV can evade host immune surveillance, through increased expression of programmed death ligand 1 (PD-L1), enabling viral persistence and the development of malignant lesions 3 6 PD-L1 has been shown to be a biomarker of HPV infection of the cervix and is significantly upregulated in cervical cancer 7 Nivolumab, a PD-1 inhibitor, has demonstrated antitumor activity in several tumor types, and the role of immunotherapy is evolving in gynecologic malignancies 1. Yu S, Garcia AA. Am J Hemat Oncol 2015;11: Viens LJ, et al. MMWR Morb Mortal Wkly Rep 2016;65: Westrich JA, et al. Virus Res 2017;231: Song D, et al. Oncol Lett 2015;10: Xie Z, et al. Immunol Invest 2009;38: Liu C, et al. Mol Med Rep 2017;15: Mezache L, et al. Mod Pathol 2015;28:

41 CERVICAL CANCER, VAGINAL, VULVAR- CHECKMATE 358 Hollebecque ASCO 2017 Nivolumab demonstrated encouraging clinical activity in patients with R/M cervical, vaginal, and vulvar cancers Median OS was not reached; 6-month OS rate was 87.1% Await further trials of immunotherapy

42 PRACTICE CHANGING AND LANDMARK STUDIES IN GYNAECOLOGICAL CANCERS 2017 Areas to cover Look forward to Advances in Gynaecological Cancers 2018 OVARIAN CANCER Newly diagnosed- First Line o LION (surgery) o ICON8 (chemotherapy) o HIPEC (chemotherapy) OVARIAN CANCER Recurrent o DESKTOP III (surgery) o SOLO2 (PARP inhibitors) o ARIEL3 (PARP inhibitors) Welcome you to ESMO congress 2018, Munich Gynaecological Cancers Track chair Susana Banerjee ENDOMETRIAL CANCER o PORTEC-3 CERVICAL CANCER Newly diagnosed, locally advanced o Neoadjuvant chemotherapy followed by surgery CERVICAL CANCER Advanced, recurrent o GOG240 (bevacizumab) o CHECKMATE 358 (cervical, vaginal, vulva)