Current Medical Oncology Approaches to Gynecologic Cancers Mihaela Cristea, MD Associate Professor Medical Oncology
Nothing to disclose DISCLOSURE
Ovarian Cancer Objectives: a. To discuss new FDA approved agents/indications 1. Bevacizumab + adjuvant carboplatin/paclitaxel Bevacizumab + carboplatin/gemcitabine or carboplatin/paclitaxel in platinum sensitive ovarian CA (Dec 2016) Bevacizumab + single agent chemotherapy in platinum refractory ovarian cancer, FDA approved 2014 2. Maintenance PARP inhibition in platinum sensitive ovarian CA (niraparib, olaparib,rucaparib) Rucaparib (gbrca, sbrca 2 lines chemo), FDA approved 2016 Olaparib (gbrca; 3 lines of chemo), FDA approved 2014 b. To summarize available treatment options c. To outline new directions
GCIG Consensus Ovarian Cancer Primary Treatment Surgery remains a key component of first-line intervention. The goal of PDS is R0 resection. Consider NACT if R0 is not felt to be feasible Patients receiving NACT should be considered for trials of novel combinations and/or window studies IV 3-weekly carbo/paclitaxel remains SOC. Alternatives: conventional IV chemotherapy: weekly paclitaxel plus 3-weekly carboplatin addition of bevacizumab to 3-weekly carbo/paclitaxel intraperitoneal therapy Trial Endpoints: OS is the preferred primary endpoint +/- maintenance component
JGOG 3016 GOG 218 GOG 172 (IP Armstrong) Conventional IV Carbo AUC 6 + Paclitaxel 175mg/m2 IV Carbo AUC 6 Q 3wks/weekly Paclitaxel 80mg/m2 Conventional IV Carbo AUC 6 + Paclitaxel 175mg/m2 Chemo + Bev 15mg/m2 during and following chemo x 22 cycles IV paclitaxel 135 mg/m2 over 24h Day 1+ IV Cisplatin 75mg/m2 day 2 IV paclitaxel 135 mg/m2 over 24h Day 1+ IP Cisplatin 100mg/m2 day 2 + Paclitaxel 60mg/m2 day 8 Stage II-IV III (optimal/suboptimal) stage IV II-IV (optimal) PFS 17.5 mo 28.2 mo (p=0.0037) 10.3 mo 14.1 mo (p<.001) 18.3 mo 23.8 mo (P=0.05) OS 62.2 mo 100.5 mo (p=0.039) 39.3 mo 39.7 (p=0.45) 49.7 mo 65.6 mo (P=0.03) Toxicity Hematologic Neuropathy same Bev side effects Increase toxicity! (hematologic, N/V)
Phase III GOG 252: IV vs IP Chemotherapy + Bevacizumab in Stage II/III Ovarian Cancer Cycles 1-6 Cycles 7-22 Pts with stage II/III epithelial ovarian, fallopian tube, or primary peritoneal carcinoma and no prior therapy; R0 (N = 1560) Carboplatin AUC 6 IV Paclitaxel 80 mg/m 2 IV (1 hr) D1, 8, 15 Bevacizumab 15 mg/kg IV D1, C2-6 Carboplatin AUC 6 IP Paclitaxel 80 mg/m 2 IV (1 hr) D1, 8, 15 Bevacizumab 15 mg/kg IV D1, C2-6 Paclitaxel 135 mg/m 2 IV (3 hrs) D1 Cisplatin 75 mg/m 2 IP D2 Paclitaxel 60 mg/m 2 IP D8 Bevacizumab 15 mg/kg IV D1, C2-6 Bevacizumab D1, C7-22 Bevacizumab D1, C7-22 Bevacizumab D1, C7-22
PFS (%) PFS (%) GOG 252: PFS by Treatment Group PFS in Stage II or Stage III Optimally Debulked (< 1 cm) PFS in Stage III With No Gross Residual Disease (R0) 100 80 60 Treatment Median, Mos 1: IV Carbo (n = 461) 26.8 2: IP Carbo (n = 464) 28.7 3: IP Cis (n = 456) 27.8 100 80 60 Treatment Median, Mos 1: IV Carbo (n = 239) 31.3 2: IP Carbo (n = 239) 31.8 3: IP Cis (n = 239) 33.8 40 40 20 0 HR IV Carbo vs IP Carbo: 0.95 (95% CI: 0.808-1.11; P =.416) HR IV Carbo vs IP Cis: 1.01 (95% CI: 0.858-1.18; P =.727) 0 12 24 36 48 60 72 Mos on Study 1 461 387 244 169 111 37 0 2 464 391 262 177 125 39 0 3 456 372 255 168 120 34 0 Estimated HR, log-rank tests adjusted for stage of disease and size of residual disease (micro vs < 1 cm) CT required every 6 mos for surveillance (not required in GOG 114/172) 20 0 0 12 24 36 48 60 72 Mos on Study 1 239 203 141 97 66 21 0 2 238 209 152 103 72 21 0 3 239 204 150 104 76 24 0
Newly Diagnosed Ovarian Cancer Improvements in OS achieved with: 1. Addition of paclitaxel to platinum 2. Use of IP chemotherapy in optimally cytoreduced pts (< 1 cm residual) 3. Use of weekly paclitaxel compared with every-3-wk paclitaxel All of these treatments are instituted AFTER surgery Study Study Arms Median PFS, Mos Median OS, Mos GOG 111 [1] (all IV) Cisplatin/cyclophosphamide 13.0 24.0 Cisplatin/paclitaxel 18.0 38.0 GOG 172 [2] IV cisplatin/paclitaxel 18.3 49.7 IP cisplatin/paclitaxel and IV paclitaxel 23.8 65.6 JGOG 3016 [3] (all IV) Carbo/paclitaxel every 21 days 17.5 62.2 Carboplatin/paclitaxel every wk (dose dense) 28.2 100.5 1. McGuire WP, et al. N Engl J Med.1996;334:1-6. 2. Armstrong DK, et al. N Engl J Med. 2006;354:34-43. 3. Katsumata N, et al. Lancet Oncol. 2013;14:1020-1026.
Antiangiogenic Agents Improve PFS but Not OS Study Study Arms Median PFS, Mos Median OS, Mos GOG 218 [1] Carboplatin/paclitaxel/bevacizumab + bevacizumab maintenance 14.1 39.7 Carboplatin/paclitaxel/bevacizumab 11.2 38.7 Carboplatin/paclitaxel 10.3 39.3 Carboplatin/paclitaxel/bevacizumab + ICON7 [2] bevacizumab maintenance 21.8 NR Carboplatin/paclitaxel 20.3 NR 1. Burger RA, et al. N Engl J Med. 2011;365:2473-2483. 2. Perren TJ, et al. N Engl J Med. 2011;365:2484-2496. 3. du Bois A, et al. J Clin Oncol. 2014;32:3374-3382.
Adjuvant Chemotherapy My Opinion Asian patient: IV 3 weekly Carboplatin + IV weekly Paclitaxel +/-Bevacizumab (JGOG3016; GOG 252) Suboptimal debulking surgery: IV 3-weekly carbo/paclitaxel + bevacizumab (ICON-7) Non-Asian patient, good KPS: IP chemo with a modified Armstrong regimen
GCIG Consensus Ovarian Cancer Recurrent Disease There is no proven effective therapy for pts with asymptomatic CA 125 relapse Platinum sensitive: platinum combination +/- licensed antiangiogenic inhibitor; platinum combination +/- licensed PARP inhibitor PFS is an acceptable end point if expected median OS > 12 mo; if < 12 mo OS is preferable PROs or time to second subsequent therapy (TSST) can complement PFS
Bevacizumab for Recurrent Platinum Sensitive Ovarian Cancer: Clinical Data Summary Trial Treatment ORR, % PFS, Mos PFS HR P Value Platinum-sensitive recurrent ovarian cancer OS, Mos OS HR 0.628 P <.0001 OCEANS [2,3] (N = 484) Gem/carboplatin 57 8.4 32.9 Gem/carboplatin + bevacizumab Platinum-resistant recurrent ovarian cancer GOG 213 [4] (N =674 ) 79 12.4 33.6 0.952 P =.65 Paclitaxel/Carboplatin 59 10 4 37.3 0 823 0 628 Paclitaxel/Carboplatin p=0 0447 78 13 8 p<0 0001 42 2 + bevacizumab (audited ) 1. Coleman RL, et al. Lancet Oncol. 2017;18:779-791. 2. Aghajanian C, et al. J Clin Oncol. 2012;30:2039-2045. 3. Aghajanian C, et al. Gynecol Oncol. 2015;139:10-16. 4. Coleman et al, Lancet Oncol 2017
PARP Inhibitor Summary: Current Indications Olaparib [1] Niraparib [2] Rucaparib [3] Approval date December 2014, August 2017 March 2017 December 2016, April 2018 Current indication Dose and schedule Safety Maintenance tx for recurrent disease in CR or PR to platinum tx gbrca+ pts with 3 lines of tx 300 mg (two 150-mg tablets) PO BID MDS/AML confirmed in 2% Pneumonitis, including fatal cases, occurred in < 1% Maintenance tx for recurrent disease in CR or PR to platinum tx 300 mg (three 100-mg capsules) PO QD Thrombocytopenia (61%; 29% grade 3) Neutropenia (30%; 20% grade 3) Maintenance tx for recurrent disease in CR or PR to platinum tx Somatic or gbrca+ pts with 2 lines of tx 600 mg (two 300-mg tablets) PO BID Elevated AST/ALT (75%; 5%-13% grade 3) Dysgeusia (39%) Hypertension (20%; 9% grade 3) Most common tx-related AEs include fatigue (60% to 80%); GI symptoms: nausea (65% to 75%), vomiting (35% to 45%), diarrhea (20% to 35%), pain (30% to 40%); and anemia (35% to 50%) 1. Olaparib [package insert]. 2017. 2. Niraparib [package insert]. 2017. 3. Rucaparib [package insert]. 2017.
PFS (%) PFS (%) PFS (%) PFS (%) NOVA: Niraparib Maintenance: PFS Results in Pt Subgroups 100 75 50 gbrca mut (n = 203) 100 Median PFS, Mos Non-gBRCA mut Overall (n = 350) Median PFS, Mos Pbo 5.5 75 Nira 21.0 Pbo 3.9 50 Nira 9.3 25 0 100 0 HR: 0.27 (P <.001) 2 4 6 8 10 12 14 16 18 20 22 24 Mos Non-gBRCA mut, HRD+ (n = 162) 25 0 100 HR: 0.45 (P <.001) 0 2 4 6 8 10 12 14 16 18 20 22 24 Mos HRD Negative (n = 134) 75 50 Median PFS, Mos Pbo 3.8 Nira 12.9 75 50 Median PFS, Mos Pbo 3.8 Nira 6.9 25 0 0 HR: 0.38 (P <.001) 2 4 6 8 10 12 14 16 18 20 22 24 Mos 25 0 HR: 0.58 (P =.02) 0 2 4 6 8 10 12 14 16 18 20 22 24 Mos
SOLO-2: Maintenance Olaparib in BRCA +, recurrent platinum sensitive ovarian CA PFS by Investigator Assessment PFS (%) Pts at Risk, n Olaparib 100 90 80 70 60 50 40 30 20 10 Median follow-up: 22.1 mos in the olaparib group, 22.2 mos for placebo 0 0 3 6 9 12 15 18 21 24 27 30 Mos Since Randomization Median PFS, Mos Placebo 5.5 Olaparib 19.1 HR: 0.30 (95% CI: 0.22-0.41; log-rank P <.0001) 196 182 156 134 118 104 89 82 32 29 3 Placebo 99 70 37 22 18 17 14 12 7 6 0
ARIEL3: Maintenance Rucaparib in recurrent platinum sensitive ovarian CA PFS by Investigator Assessment ARIEL3 Analysis Population Primary Analyses PFS by Investigator Review (Primary Endpoint) HR Median PFS, Mos Rucaparib vs Pbo tbrca mut (n = 196) 0.23; P <.0001 16.6 vs 5.4 HRD positive (n = 354) 0.32; P <.0001 13.6 vs 5.4 Intent to treat (n = 564) 0.36; P <.0001 10.8 vs 5.4 Exploratory Analyses BRCA wt /HRD positive (n = 158) BRCA wt /HRD negative (n = 161) 0.44; P <.0001 9.7 vs 5.4 0.58; P =.0049 6.7 vs 5.4
Consensus or Controversy: Management of initial relapse of ovarian cancer - Eight investigators weigh in on their current approach based on genomic profiling My opinion: -most clinicians agree that patients with g/s BRCA mutations should receive maintenance PARP inhibition -maintenance therapy after response to platinum agents may be the only chance for patients to use PARP inhibitors (neg g/sbrca) -all PARPS have similar efficacy but different toxicity profile (olaparib/rucaparib >> GI toxicity than niraparib Niraparib>>> hematological toxicities than olaparin/rucaparib) -chemo + Bev is a good option for pts with ascites and no contraindication to Bev
Platinum resistant Ov CA Surgery only for organ protection, e.g. obstruction Standard of care - single agent PLD, topotecan or weekly paclitaxel +/- bevacizumab (Aurelia trial) - gemcitabine - docetaxel Chemo arm ORR bev/no bev PFS HR Bev/no Bev OS HR Bev/no Bev Paclitaxel 53.3 vs 30.2% 0.46 (10.4.vs 3.9 mo 0.65 (22.4 vs 13.2 mo) PLD 17 vs 0% 0.57 (5.4 vs 3.5 mo) Topotecan 13.7 vs 7.8% 0.32 (5.8 vs 2.1 mo) 0.91 (13.7 vs 14.1 mo) 1.09 (13.8 vs 13.3 mo)
Olaparib Monotherapy in BRCA-Mutated Advanced Ovarian Cancer Pts had received 3 prior lines of therapy Response N = 137 Objective response rate, % (95% CI) 34 (26-42) CR, % 2 PR, % 32 Median DOR, mos (95% CI) 7.9 (5.6-9.6)
ARIEL2 Designed To Assess Rucaparib Efficacy In Three Prospectively Defined Molecular Subgroups
Primary efficacy analysis: PFS in BRCAmut and BRCA-like versus Biomarker Negative patients
New directions: Olaparib And Cediranib Synergy Between Hypoxia And Inhibition Of DNA Repair
PHII-139, NCI#9825: A Phase 2 Study of Olaparib and Cediranib for the Treatment of Recurrent Ovarian Cancer Cediranib / olaparib until progression Recurrent Ovarian Cancer Parallel enrollment cohorts Platinumsensitive Platinumresistant Cediranib / olaparib until progression
Immunotherapy
TOPACIO: Phase 1/2, Single-Arm Trial in Triple-negative Breast Cancer or Recurrent Ovarian Cancer Phase 1 Dose 1 Niraparib 200 mg orally daily + Pembrolizumab 200 mg IV every 21 days Dose 2 Niraparib 300 mg orally daily + Pembrolizumab 200 mg IV every 21 days Endpoint assessment Primary Endpoint Key Secondary Endpoints Evaluate DLT and establish RP2D Safety & Tolerability Phase 2 Niraparib 200 mg orally daily + Pembrolizumab 200 mg IV every 21 days (RP2D) Endpoint assessment Primary Endpoint Key Secondary Endpoints ORR by RECIST v1.1 PFS Safety &Tolerability DCR DOR OS PK TNBC= triple-negative breast cancer; OC=ovarian cancer; DLT=dose-limiting toxicity; RP2D=recommended phase 2 dose; PK=pharmacokinetics; ORR=overall response rate; DOR=duration of response; PFS=progression-free survival; OS=overall survival; DCR=disease control rate; IV=intravenously
TOPACIO Phase 1: Safety for Ovarian Cancer and Triple-negative Breast Cancer Cohort Phase 1 Treatment-related Grade 3 TEAEs Occurring in 2 Patients AE, n(%) Dose Level 1 (n=7) Dose Level 2 (n=7) Overall (N=14) Anemia 2 (28.6) 3 (42.9) 5 (35.7) Thrombocytopenia 1 (14.3) 4 (57.1) 5 (35.7) Neutropenia 1 (14.3) 1 (14.3) 2 (14.3) Platelet count decreased 0 2 (28.6) 2 (14.3) Dose level 1 (n=7): one patient had DLTs (neutropenia, anemia, and thrombocytopenia) and discontinued niraparib but continued pembrolizumab Dose level 2 (n=7): one patient had a DLT and one had a DLT-equivalent (both thrombocytopenia); after interruption of niraparib, both patients resumed at 200mg niraparib and continued pembrolizumab throughout The RP2D was determined to be 200mg niraparib once daily and pembrolizumab 200mg IV on day 1 of each 21-day cycle Grade 3 AEs were reported in 6 of 7 (85.7%) in dose level 1 and all 7 patients in dose level 2. AE=adverse event; TEAE=treatment-emergent adverse event; DLT=dose-limiting toxicity; RP2D=recommended phase 2 dose; IV=intravenous;
TOPACIO TNBC: Clinical Activity in Biomarker-Selected Populations Efficacy Evaluable Patients ORR (CR+PR) DCR (CR+PR+SD) tbrcamut patients (n=15) 9 (60%) 12 (80%) HRRmut + tbrcamut (n=20) 11 (55%) 16 (80%) PD-L1 positive patients (n=25) 9 (36%) 13 (52%) Overall Response Rate in all evaluable (biomarkerunselected) patients (N=46): ORR 28%, DCR=50% tbrcamut=tumor breast cancer susceptibility gene mutant (includes germline and/or somatic mutant); HRRmut= homologous recombination repair pathway mutant; PD-L1=programmed cell death-ligand 1; ORR= objective response rate; DCR=disease control rate
Conclusions Cytotoxic chemotherapy still has a role in ovarian cancer Differences in dose and schedule may be important Role of IP therapy becoming clearer Angiogenesis is an established target Bevacizumab now FDA approved PARP inhibitors are emerging as important therapy Olaparib, rucaparib, and niraparib now FDA approved Labels are expanding based on recently reported positive trials Role of immunotherapy promising in ovarian cancer
Endometrial Cancer: Pembrolizumab Now Approved for All MSI-H/dMMR Solid Tumors A T A T A T A A T A T MSI-H and dmmr define response to pembrolizumab A T A T A T A T A T A
Relationship Between MSI and Tumor- Associated Inflammatory Response MSI-H Hypermutation (10-100x increase in mutational load vs MMRproficient tumors) Many neoantigens expressed on tumor cells High PD-L1 on tumor cells Robust tumorassociated inflammatory response High PD-1 and/or PD-L1 on tumorinfiltrating inflammatory cells
KEYNOTE-028 (NCT02054806) Pembrolizumab for PD-L1 positive Advanced Solid Tumors: Endometrial cohort 22 evaluable pts: ORR= 13% (all PR); SD= 13%; PD= 56.5%
Pembrolizumab in Pts With Metastatic MSI-High or dmmr Tumors After PD on Prior Tx Included data from KEYNOTE-016, -164, -012, -028, and -158 for total of 149 pts MMR testing using standard PCR-based assay for detection of MSI Tumor Type n ORR, % (95% CI) DoR Range, Mos CRC 90 36 (26-46) 1.6+ to 22.7+ Non-CRC 59 46 (33-59) 1.9+, 22.1+ Endometrial cancer 14 36(13-65) 4.2+ to 17.3+ Biliary cancer 11 27 (6-61) 11.6+ to 19.6+ Gastric or GEJ cancer 9 56 (21-86) 5.8+ to 22.1+ Pancreatic cancer 6 83 (36-100) 2.6+ to 9.2+ Small intestinal cancer 8 38 (9-76) 1.9+ to 9.1+) Additional pts not listed in table included 2 each of breast and prostate cancer; 1 each of bladder, esophageal, sarcoma, thyroid, retroperitoneal adenocarcinoma, SCLC, and RCC with 6 pts achieving CR or PR
2017: FDA approval for Pembrolizumab for IHC/MSI high Endometrial cancer All patients with endometrial Ca should have IHC/MSI testing (NCCN guidelines) If IHC abnormal protein expression or MSI high, the RR to Pembrolizumab is 36% Response MSS?
Cervical Cancer Beyond Chemotherapy: Targeting Angiogenesis GOG 240: Chemotherapy +/- bevacizumab Primary stage IVB or recurrent/persistent carcinoma of the cervix Measurable Disease PS 0-1 Serum Creatinine 1.5 mg/dl No prior chemotherapy (unless concurrent with radiation) R A N D O M I Z E D PACLITAXEL 135 or 175 mg/m 2 + Cisplatin 50 mg/m 2 PACLITAXEL 135 or 175 mg/m 2 + Cisplatin 50 mg/m 2 + BEVACIZUMAB 15/mg/kg PACLITAXEL 175 mg/m 2 over 3 hrs on day 1 & Topotecan 0.75 mg/m 2 over 30 min day 1-3 PACLITAXEL 175 mg/m 2 over 3 hrs on day 1 + Topotecan 0.75 mg/m 2 over 3 min day 1-3 + BEVACIZUMAB 15/mg/kg
GOG 240 Results
Strong Biologic Rationale For Immunotherapy In Cervical Cancer HPV and the immune response: - Immuno-tolerant environment: CD8 + CTL response to E6 and E7, CD4 + T cell response to HPV, IFNγsecretion decrease in persistent infection - Potential targets for cytotoxic T cell (CTL) mediated killing Chemo radiation and immune response: tumor antigen release (abscopal effect) Improved outcome associated with the presence of tumor infiltrating lymphocytes (TILs)
KEYNOTE-028 (NCT02054806) Pembrolizumab for PD-L1 positive Advanced Solid Tumors: Cervical cohort N= 23 evaluable patients PR = 17%, SD= 16%, PD= 67%
June 2018: FDA approval for Pembrolizumab for recurrent/metastatic cervical cancer with progression after chemotherapy For all patients whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test The recommended pembrolizumab dose for treatment of cervical cancer is 200 mg every 3 weeks Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Conclusions Globally cervical cancer remains a major problem Advanced and recurrent cervical cancer is still a problem and is disproportionately effecting under resourced communities Bevacizumab in combination with chemotherapy is the first targeted therapy to show an overall survival benefit in this disease Immunotherapy is emerging as a treatment option in cervical cancer (checkpoint inhibitors and cancer vaccines)
Thank you!