GYNECOLOGICAL CANCERS

Transcription

1 SAMO FoROMe Post ESMO 17 th October 2014, Bern GYNECOLOGICAL CANCERS Cristiana Sessa Oncology Institute of Southern Switzerland Bellinzona

2 CONTENT Antiangiogenics in cervical cancer Antiangiogenics and QoL in ovarian cancer Do targeted therapies improve the outlook for gynecological cancers? ESMO News September 29, 2014

3 CIRCCa: (Cediranib In Recurrent Cervical Cancer) A randomised double blind phase II trial of carboplatinpaclitaxel plus cediranib versus carboplatin-paclitaxel plus placebo in metastatic/recurrent cervical cancer P Symonds, C Gourley, S Davidson, C West, C Dive, J Paul, K Carty, E McCartney, D Rai, S Banerjee, D Jackson, R Lord, M McCormack, E Hudson, N Reed, M Flubacher, P Jankowska, M Powell September 2014, Madrid, Spain esmo.org

4 Eligibility: Methods Histologically proven metastatic or relapsed cervix cancer unsuitable for radiotherapy or surgery No previous chemotherapy except cisplatin given along with radiotherapy as primary treatment Major Exclusions: Bowel obstruction Active bleeding Fistula Significant proteinuria Uncontrolled hypertension September 2014, Madrid, Spain esmo.org

5 Randomized phase II study of cediranib in cervical cancer Study design R A N D O M Carboplatin Paclitaxel Cediranib 20 mg/d Carboplatin Paclitaxel q4wks x 6 cediranib placebo Until PD Placebo Primary endpoints PFS Secondary endpoints: ORR, OS, Toxicity, QoL, change in plasma VEGFR2 Power 80% chance of detecting a 60 % increase in PFS (from 4 to 6.4 months)

6 Randomized phase II study of cediranib in cervical cancer Results Median (wks) PFS Cediranib (n=34) Placebo (n=35) Median (wks) OS HR Response rate (%) CR PR OVERALL Cediranib (n=34) Placebo (n=35)

7 Randomized phase II study of cediranib in cervical cancer Toxicity (Grade 2/3/4) Cediranib Toxicity (%) Placebo Diarrhoea P= Hypertension P= Neutropenia 31 9 P= Conclusions Significant increase of PFS, inhibition of VEGFR-2 and higher response rate with Cediranib Manageable increase in toxicity

8 Final Overall Survival Analysis of the Phase III Randomized Trial of Chemotherapy With and Without Bevacizumab for Advanced Cervical Cancer: A NRG Oncology Gynecologic Oncology Group Study KS Tewari, MW Sill, RT Penson, H Huang, LM Ramondetta, LM Landrum, A Oaknin, TJ Reid, MM Leitao, H Michael, BJ Monk September 2014, Madrid, Spain esmo.org

9 GOG 240: Schema Carcinoma of the cervix Primary stage IVB Recurrent/persistent Measureable disease GOG PS 0 1 No prior chemotherapy for recurrence (N=452) Stratification factors: Stage IVB vs recurrent/persistent disease Performance status Prior cisplatin Rx as radiationsensitizer Activated: 4/6/09 Closed to accrual: 1/3/12 R A N D O M I Z E 1:1:1:1 I II III IV Paclitaxel 135 or 175 mg/m 2 IV Cisplatin 50 mg/m 2 IV Paclitaxel 135 or 175 mg/m 2 IV Cisplatin 50 mg/m 2 IV Bevacizumab 15 mg/kg IV Paclitaxel 175 mg/m 2 IV Topotecan 0.75 mg/m 2 d1-3 Paclitaxel 175 mg/m 2 IV Topotecan 0.75 mg/m 2 d1-3 Bevacizumab 15 mg/kg IV Chemo alone Q21d Rx to PD, toxicity, CR Chemo + Bev KS Tewari (study chair). Identifier: NCT Presented by: Krishnansu S. Tewari, MD, FACOG, FACS 9

10 GOG 240 Study Objectives Does the addition of Bev to CT improve OS? Does a non platinum doublet improve OS? Which is the tolerability of the four regimens? Statistical considerations Phase III open label study with 2x2 factorial design HR by 30%, OS from 12 to 16 mos Preplanned interim analysis after 173 events

11 GOG 240 Demographics & Baseline Characteristics Characteristic Chemo Alone (n=225), % Chemo + Bev (n=227), % Median age, years (range) 46 (20 83) 48 (22 85) Histology, % Squamous Adenocarcinoma, unspec. Race, % White African American Asian 3 5 Pacific Islander 0 0 Stage of disease, % Recurrent Persistent Advanced Performance status, % 0 1 Prior platinum, % Pelvic disease, % Bev, bevacizumab; chemo, chemotherapy; GOG, Gynecologic Oncology Group; unspec., unspecified September 2014, Madrid, Spain esmo.org

12 GOG 240: Study Timeline, Part 2 April 9, 2009 Trial activation January 2, 2012 Target accrual reached (N=452) February 6, deaths (events), planned interim analysis March 13, 2012 Release of non-superiority of topotecan-paclitaxel backbone by NCI DMC and GOG December 12, 2012 Database lock and analysis January 2013 Bevacizumab-containing regimens declared superior by NCI DMC and GOG February 2013 Dear patient & Dear investigator letters; ASCO abstract submitted March 2013 ASCO makes rare exception to embargo and places abstract in public domain May 2013 NCCN considers listing chemorx plus bevacizumab as Category 1 June 2, 2013 ASCO 2013 press briefing and general plenary ASCO, American Society of Clinical Oncology; chemorx, chemotherapy treatment; DMC, data monitoring committee; GOG, Gynecologic Oncology Group; NCCN, National Comprehensive Cancer Network; NCI, National Cancer Institute September 2014, Madrid, Spain esmo.org

13 Proportion Sur rviving GOG 240 Second Interim Analysis GOG 240: OS for Chemo vs Chemo + Bev Chemotherapy (n=225) Events, n (%) 140 (62) Median OS, months 13.3 Chemotherapy + Bev (n=227) 131 (58) 17.0 HR=0.71 (97% CI, ) P=.0035 Median follow-up 20.8 months Months on Study September 2014, Madrid, Spain esmo.org bev, bevacizumab; CI, confidence interval; chemo, chemotherapy; GOG, Gynecologic Oncology Group; HR, hazard ratio; OS, overall survival. Tewari KS, et al. Presented at ASCO 2013, General Plenary Abstract #3

14 GOG 240: Study Timeline, Part 3 October through December 2013 Increasing uptake of bevacizumab (up to 40%) in the United States for advanced cervix cancer (HMOs, PPOs) October 1, 2013 Quality-of-life data presented at ESMO 2013 in Amsterdam, Netherlands (LBA42) July 2013 NCCN listing of cisplatin-paclitaxelbevacizumab as Category 2A recommendation March 12, 2014 Plenary presentation of GOG 240 prognostic factors validation (SGO 2014 Annual Meeting) March 7, deaths (final analysis) March 5, 2014 Approval of bevacizumab for advanced cervical cancer by the Cancer Drug Fund of the United Kingdom February 20, 2014 Publication of primary GOG 240 manuscript in New England Journal of Medicine July 14-15, 2014 Genentech press release indicating priority review by US FDA August 14, 2014 US FDA approves bevacizumab with chemotherapy for advanced cervical cancer August 15, 2014 NCCN cisplatin-paclitaxelbevacizumab Category 1, topotecanpaclitaxel-bevacizumab Category 2B September 28, 2014 Plenary presentation of final OS of GOG 240 at ESMO 2014 in Madrid, Spain (LBA26) ESMO, European Society of Medical Oncology; HMO, health maintenance organization; NCCN, National Comprehensive Cancer Network; PPO, preferred provider organization; GOG, Gynecologic Oncology Group; OS, overall survival; SGO, Society of Gynecologic Oncology; US FDA, United States Food and Drug Administration September 2014, Madrid, Spain esmo.org

15 FINAL OS chemo vs chemo plus bev Proportion Surviving Overall Survival by Bevacizumab Therapy Events Total Median (months) 1: Bevacizumab : No Bevacizumab HR=0.765 (95% CI, ); p= Months on Study bev, bevacizumab; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; OS, overall survival September 2014, Madrid, Spain esmo.org

16 FINAL OS: Cis-Tax vs Cis-Tax-Bev Proportion Surviving Overall Survival by Treatment Regimen Events Total Median (months) 1: Cis+Pac : Cis+Pac+Bev HR=0.73 (95% CI, ); p= Months on Study bev, bevacizumab; CI, confidence interval; cis, cisplatin; HR, hazard ratio; OS, overall survival; tax, taxotere September 2014, Madrid, Spain esmo.org

17 Updated Toxicity Chemo Alone Chemo + Bev Adverse Event, n (%) (n=220) (n=220) Treatment cycles, median (range) 6 7 Grade 5 AE(s) 3 (1.3) 7 (3.2) GI events, non-fistula (grade 2) 97 (44) 115 (53) GI fistula (grade 2) 1 (0.5) 11 (5) GI perforation (grade 3) 0 (0) 5 (2.3) GU fistula (grade 2) 1 (0.5) 8 (3.6) Hypertension (grade 2) 4 (1.8) 55 (25) Proteinuria (grade 3) 0 (0) 5 (2.3) Pain (grade 2) 63 (29) 72 (33) Neutropenia (grade 4) 58 (26) 80 (36) Febrile neutropenia (grade >3) 12 (5.5) 12 (5.5) Thromboembolism (grade 3) 4 (1.8) 18 (8.2) Bleeding CNS (any grade) 0 (0) 0 (0) GI (grade 3) 1 (0.5) 4 (1.8) GU (grade 3) 1 (0.5) 6 (2.7) bev, bevacizuamb; chemo, chemotherapy; CNS, central nervous system; GI, gastrointestinal; GU, genitourinary September 2014, Madrid, Spain esmo.org

18 Conclusions The benefit conferred by the incorporation of bevacizumab is sustained beyond 50 months Key points Significant improvements in OS, PFS, and response rate without significant deterioration in HRQoL Bevacizumab is active also in the irradiated field September 2014, Madrid, Spain esmo.org

19 GOG 240 Hypothesis: Mechanistics Tumor Hypoxia and Viral Oncogenes Drive Angiogenesis HPV E6 p53 degradation TSP-1 VEGF angiogenesis Anti-VEGF therapy HPV E7 Displacement of HDAC1, HDAC4, HDAC7 prb inactivation HIF1α p21-rb pathway dysregulation Bevacizumab activity in cervical cancer was demonstrated in a phase II single-agent study (GOG 227C) GOG, Gynecologic Oncology Group; HDAC, histone deacetylase; HIF1α, hypoxia-inducible factor 1-alpha; HPV, human papilloma virus; prb, retinoblastoma protein; TSP1, thrombospondin 1; VEGF, vascular endothelial growth factor. Tewari KS, et al. Gynecol Oncol 2000;77: Monk BJ, et al. J Clin Oncol 2009;27: MicrobiologyBytes. Available at: Accessed September 9, September 2014, Madrid, Spain esmo.org

20 Antiangiogenics in cervical cancer Cediranib (N=69) Randomized Phase II Bevacizumab (N=440) Randomized Phase III Recurrent (%) Advanced (%) PFS (mos) 8.7 vs vs 6 OS (mos) 14.7 vs vs 13.3 Gr 2 Diarrhea (%) 50 Hypertension (%) Neutropenia (%) Fistula (%) 8.6 Perforation (%) 2.3 Thrombo-embolism (%) 8.2 Subsequent step Phase III Real life Phase III

21 Antiangiogenics in cervical cancer Overall still poor results Conclusions Management of toxic events still an open topic Further steps of high priority Analysis of risk factors for toxicity (previous RT, site of recurrence) Analysis of response according to site of recurrence (local vs distant) Further careful evaluation of antiangiogenics in unselected patients Resources still to be directed with high priority on screening and prevention

22 Quality of life (QoL) in a randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer (ICON6) Dan Stark, Adrian Cook, Julia Brown, Galina Velikova, Michael Brundage, Andrew Embleton, Fharat Raja, Jonathan Ledermann on behalf of the ICON 6 Collaborators (NCRN, NCIC-CTG, ANZGOG, GEICO) September 2014, Madrid, Spain esmo.org An academic sponsored GCIG trial

23 Academic-led, industry-supported Gynaecologic Cancer InterGroup (GCIC) phase III trial to investigate the use of cediranib (20mg/d) Recruited 456 patients Dec 2007-Dec 2011 Relapse > 6 months after completion of first line platinum-based chemotherapy Randomise 2 : 3 : 3 6 Cycles platinum-based Chemotherapy Carboplatin/paclitaxel Carboplatin/gemcitabine Single agent platinum Arm A Arm B Arm C (Chemo only) (Concurrent) (Maintenance) Chemotherapy + placebo Chemotherapy + cediranib Chemotherapy + cediranib Maintenance phase Continue placebo Switch to placebo Maintenance cediranib Treatment continued to 18 months or until progression (>18 for patients continuing to benefit) September 2014, Madrid, Spain esmo.org

24 .. Maintenance Cediranib vs Chemotherapy only Progression-free survival (primary) PFS increased by 3.1 months with maintenance cediranib, from 9.4 to 12.5 months* Months p<0.001 Overall survival (secondary) OS increased by 2.7 months with maintenance cediranib, from 17.6 to 20.3 months* Months p= * Restricted means analysis due to non-proportional hazards September 2014, Madrid, Spain esmo.org

25 Number of grade 1 to 4 SYMPTOMATIC adverse events (grade 3 or 4 in brackets) Arm A Chemo only Arm B Concurrent Arm C Maintenance During chemotherapy phase Hypothyroidism Voice changes (1) Muscle weakness 8 10 (1) 14 (2) Haemorrhage Hand/Foot syndrome Diarrhoea 64 (1) 146 (12) 161 (21) During maintenance phase Hypothyroidism 4 5 (1) 12 Voice changes Muscle weakness (1) Haemorrhage Hand/Foot syndrome Diarrhoea 27 (1) 40 (1) 85 (11)

26 Explore other QLQ-C30 subscales Mean Score at 12 months Scale (QLQ C-30) Arm A Arm B Arm C p a Effect size 1 Role Function* Small Cognitive Function* Trivial Emotional Function* Small c p>0.05 in all other subscales Nausea and Vomiting** Small <0.00 Diarrhoea** * higher score = better function ** higher score = more symptoms Large a. prespecified boundary for statistical significance p< Cocks et al JCO 2010

27 Diarrhea

28 AGO-OVAR 16 Study Design Phase III randomized, placebo-controlled, double-blind, multicenter N=940 patients randomized (1:1) from June 2009 to August 2010 Pazopanib administered at 800 mg daily for up to 24 months* First-line surgery and chemotherapy (allowed: dosedense, IP, neoadjuvant) If not PD + tumor < 2 cm R A N D O M I Z E Pazopanib 24 months Placebo 24 months Observation (to PD) Survival follow-up (post-pd) Median 7 months from diagnosis to randomization ICF *Original design was for 12 months and later amended to 24 months

29 AGO-OVAR 16 1st Endpoint: Progression-free Survival (RECIST) Median time from 1 Diagnosis: 7 months Pazopanib: 472 pts. / 237 events median 17.9 ( ) mos Placebo: 468 pts. / 273 events median 12.3 ( ) mos Δ= 5.6 months HR = (95% CI: ) Stratified log-rank test: P = (months) Patients at risk

30 Grade 3/4 adverse events AGO-OVAR 16 Adverse Events Grade 3-4 per Patient occurring in at least 1% in the Pazopanib Arm Placebo (N=461) Pazopanib (N=477) Hypertension 26 (6%) 147 (31%) 121 (25%) Hypertension (including Grade 2) 80 (17%) 248 (52%) 168 (35%) Liver-related toxicity 3 (<1%) 45 (9%) 42 (9%) Neutropenia 7 (2%) 47 (10%) 40 (8%) Diarrhea 5 (1%) 39 (8%) 34 (7%) Asthenia / Fatigue 1 (<1%) 13 (3%) 12 (3%) Thrombocytopenia 3 (<1%) 12 (3%) 9 (2%) Palmar-plantar erythrodysesthesia 1 (<1%) 9 (2%) 8 (2%) Headache 3 (<1%) 8 (2%) 5 (1%) Abdominal pain 5 (1%) 8 (2%) 3 (<1%) Proteinuria 2 (<1%) 6 (1%) 4 (<1%) Arthralgia 3 (<1%) 5 (1%) 2 (<1%) Δ

31 Second interim overall survival analysis from the AGO-OVAR 16 Pazopanib versus placebo exposure Overall population Asian vs non-asian population Namura et al, Abstr. 880 PD, ESMO 2014

32 Second interim overall survival analysis from the AGO-OVAR 16 Pazopanib versus placebo exposure East Asian population Non-East Asian subpopulations Namura et al, Abstr. 880 PD

33 Toxicity and QOL important for approval of new biological agents Lessons from the pazopanib story Toxicity more important than PFS for further development of the drug QOL adequately investigated? September 2014, Madrid, Spain esmo.org