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

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Jun 29, 2023 159 likes •355 views

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

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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

f the ovary or peritoneum

David M. Gershenson, MD

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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

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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

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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

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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.”

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Results: Patient Characteristics

Presented by: David M. Gershenson, MD

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 (range) 6 (3, 12) 6 (3, 14) .90 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)

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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 Disease status at completion of chemotherapy < .001 NED 27 (39.1) 121 (91.7) Persistent disease 42 (60.9) 11 (8.3) Missing 1 2

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Results: Patient Characteristics

Presented by: David M. Gershenson, MD

Hormonal Therapy

No. Pts.

(%) Switched to different HMT due to toxicity N (%)

Letrozole 38 (54.3) 5 (13.2) Anastrozole 2 (2.9) Tamoxifen 20 (28.6) 4 (20.0) Leuprolide acetate 5 (7.1) Depot medroxyprogesterone acetate 1 (1.4) Leuprolide acetate + Tamoxifen 2 (2.9) Leuprolide acetate + Letrozole 2 (2.9) Total 70 9 (12.9)

Median duration Of HMT = 33.3 mo (1.0, 223.2)

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Results: Progression-Free Survival

Group Median PFS (mo) 95% CI

P- Value

SURV (n = 134) 27.3 22.7, 31.9

< .001

HMT (n = 70) 64.9 43.5, 86.3 ALL (N = 204) 32.9 28.6, 37.1

Pts who have not recurred: HMT: 28/70 (40%) SURV: 16/134 (12%)

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Results: Overall Survival

Group Median OS (mo) 95% CI P- Value

SURV (n = 134) 98.8 72.4, 125.3 .36 HMT (n = 70) 115.7 45.3, 186.0 ALL (N = 204) 102.7 75.5, 130.0

p<.001

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Results: PFS in Patients NED at Completion

f Chemotherapy

Group Median PFS (mo) 95% CI P- Value

SURV (n = 121) 29.9 24.5, 35.2 < .001 HMT (n = 27) 81.1 55.2, 106.9 ALL (N = 148) 33.0 28.4, 37.7

p<.001

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Results: OS in Patients NED at Completion

f Chemotherapy

Group Median OS (mo) 95% CI

P- Value

SURV (n = 121) 106.8 72.8, 140.7 .04 HMT (n = 27) 191.3 93.5, 289.1 ALL (N = 148) 115.7 86.5, 144.9

p<.001

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Results: Multivariable Analysis for PFS

Characteristic HR 95% CI P-Value

Group SURV (ref) HMT .23 0.11, 0.51 < .001 Primary site Ovary (ref) Peritoneum .45 0.27, 0.76 .003 Residual disease Gross (ref) No gross .49 0.28, 0.87 .02 Disease status at completion of chemo Persistent disease (ref) NED .42 0.18, 0.96 .04

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Hormonal Monotherapy

27 pts treated with primary CRS followed by

hormonal monotherapy

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Patient Characteristics (n = 27)

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Results

PFS not significantly different from cohort treated with CRS + chemotherapy

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Proposed Clinical Trial

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

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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