David M. Gershenson, MD Rationale No prospective clinical trials in - PowerPoint PPT Presentation

A randomized, three-arm phase III trial of paclitaxel/carboplatin followed by placebo compared with paclitaxel/carboplatin followed by maintenance letrozole versus letrozole monotherapy in patients with stage II-IV, primary low-grade serous carcinoma of the ovary or peritoneum David M. Gershenson, MD

Rationale • No prospective clinical trials in front-line setting • Data from MD Anderson Low-Grade Serous Tumor Database has suggested relative chemoresistance in multiple settings: – Front-line chemotherapy setting: > 40% frequency of persistent disease Gershenson et al. Gynecol Oncol 2006 Gershenson et al. J Clin Oncol 2015 – NACT setting: < 5% ORR Schmeler et al. Gynecol Oncol 2008 – Platinum-sensitive and platinum-resistant salvage chemotherapy settings: < 5% ORR Gershenson et al. Gynecol Oncol 2009

Rationale • AGO database of 5114 pts • 39/145 (2.8%) LGSC pts had suboptimal (> 1 cm) debulking ORR = 23.1% • 80/218 (36.7%) HGSC pts had suboptimal (> 1 cm) debulking ORR = 90.1% • Conclusion: LGSC not as responsive to platinum/taxane chemotherapy as HGSC Grabowski et al. Gynecol Oncol 2016

Rationale • High frequency of ER and PR expression in LGSC Wong et al. Int J Gynecol Pathol 2007 • Hormonal therapy for recurrent LGSC associated with ORR = 9%, SD = 66%, median PFS = 7.4 mo Gershenson et al. Gynecol Oncol 2012 • LGSC similar to luminal breast cancer: Worse prognosis for women age < 35 y Gershenson et al. J Clin Oncol 2015

GCIG Ovarian Cancer Consensus Conference, Tokyo 2015 “…platinum -based chemotherapy is a standard for high-risk early or advanced stage rare epithelial ovarian cancers and should remain the control arm.”

Results: Patient Characteristics Characteristic HMT (N = 70) SURV (N = 134) P-Value Median Age (range) 47.6 (25.0, 77.6) 47.6 (21.3, 73.1) .88 Median BMI (range) 28.4 (17.9, 54.9) 26.7 (15.6, 58.1) .35 Median Cycles of Chemo 6 (3, 12) 6 (3, 14) .90 (range) N (%) N (%) Race .29 White 57 (81.4) 113 (84.3) Black 5 (7.1) 3 (2.2) Hispanic 6 (8.6) 16 (11.9) Other 2 (2.9) 2 (1.5) Primary site .13 Ovary 48 (68.6) 105 (78.4) Peritoneum 22 (31.4) 29 (21.6) LGSC Type .01 De Novo 58 (82.9) 126 (94.0) Recurrent LMP 12 (17.1) 8 (6.0) Presented by: David M. Gershenson, MD

Results: Patient Characteristics Characteristic HMT (N = 70) SURV (N = 134) P-Value N (%) N (%) Residual Disease .11 No gross 14 (22.2) 35 (34.0) Gross 49 (77.8) 68 (66.0) Missing 7 31 Platinum-Based Chemo .90 Taxane 53 (76.8) 113 (84.3) No Taxane 16 (23.1) 21 (15.7) Missing 1 0 Disease status at < .001 completion of chemotherapy NED 27 (39.1) 121 (91.7) Persistent disease 42 (60.9) 11 (8.3) Missing 1 2

Results: Patient Characteristics Hormonal Therapy No. Pts. Switched to (%) different HMT due to toxicity N (%) Median duration Of HMT = 33.3 mo Letrozole 38 (54.3) 5 (13.2) (1.0, 223.2) Anastrozole 2 (2.9) 0 Tamoxifen 20 (28.6) 4 (20.0) Leuprolide acetate 5 (7.1) 0 Depot medroxyprogesterone 1 (1.4) 0 acetate Leuprolide acetate + 2 (2.9) 0 Tamoxifen Leuprolide acetate + 2 (2.9) 0 Letrozole Total 70 9 (12.9) Presented by: David M. Gershenson, MD

Results: Progression-Free Survival Group Median 95% CI P- Value PFS (mo) SURV 27.3 22.7, 31.9 (n = 134) < .001 HMT 64.9 43.5, 86.3 (n = 70) ALL 32.9 28.6, 37.1 (N = 204) Pts who have not recurred: HMT: 28/70 (40%) SURV: 16/134 (12%)

Results: Overall Survival Group Median 95% CI P- OS (mo) Value SURV 72.4, (n = 98.8 p<.001 125.3 134) .36 HMT 45.3, 115.7 (n = 70) 186.0 ALL 75.5, (N = 102.7 130.0 204)

Results: PFS in Patients NED at Completion of Chemotherapy Group Median 95% CI P- PFS Value (mo) p<.001 SURV 29.9 24.5, 35.2 (n = 121) < .001 HMT 81.1 55.2, 106.9 (n = 27) ALL 33.0 28.4, 37.7 (N = 148)

Results: OS in Patients NED at Completion of Chemotherapy P- Group Median 95% CI Value OS (mo) SURV 72.8, p<.001 106.8 (n = 121) 140.7 .04 HMT 93.5, 191.3 (n = 27) 289.1 ALL 86.5, 115.7 (N = 148) 144.9

Results: Multivariable Analysis for PFS Characteristic HR 95% CI P-Value Group SURV (ref) .23 0.11, 0.51 < .001 HMT Primary site Ovary (ref) .45 0.27, 0.76 .003 Peritoneum Residual disease Gross (ref) .49 0.28, 0.87 .02 No gross Disease status at completion of chemo Persistent disease .42 0.18, 0.96 .04 (ref) NED

Hormonal Monotherapy • 27 pts treated with primary CRS followed by hormonal monotherapy

Patient Characteristics (n = 27)

Results PFS not significantly different from cohort treated with CRS + chemotherapy

Proposed Clinical Trial Paclitaxel + Carboplatin Followed by Placebo Stage II-IV Low- Paclitaxel + Primary Grade Serous Carboplatin Cytoreductive Carcinoma of Followed by Surgery Ovary/Peritoneum Letrozole Letrozole

Statistical Design • 210 pts randomized in 1:1:1 ratio • Accrual: 40 months • Primary endpoint: PFS • Secondary endpoints: – Toxicity – QoL – Response in pts with measurable disease • Translational: ER, PR, ERS1 mutations, NGS