New Developments in Uterine Cancer

Matthew A. Powell, MD Professor & Chief Division Gyn Oncology

Washington University School of Medicine

St. Louis, Missouri, USA

How do we improve? Targets: • Anti-Angiogenesis• EGRF• mTOR/PI3K/AKT• DNA repair• Immunotherapy• Combinations

Drug N RR SD PFS> 6 Months PFS

mTOR inhibitors Temsirolimus (Oza 2011) Chemo-naïve 29 14% 69% - 7.3 months

Chemo-treated 25 4% 48% - 3.2 months

Ridaforolimus (Tsoref 2014) 31a 8.8% 52.9% - -

Ridaforolimus vs progestin or investigator choice chemotherapy (Oza 2015)

64 vs 66 4.6% vs

3% 56.3 vs 27.7 (P = .003) -

5.6 months vs 1.9 months

(HR, 0.39; 95% CI, 0.23 to 0.66;

P<.001)

Everolimus (Slomovitz 2010) 28 0% 43% - -

PI3K inhibitors Pilasarilib (XL147) (Matulonis 2014) 67 6% 37.3% 11.9% -

BKM120 NCT01289041 71 2.8% 36% - 1.9 months

Oza AM, et al. J Clin Oncol. 2011;29(24):3278-3285. Tsoref D, et al. Gynecol Oncol. 2014;135(2):184-189. Oza AM, et al. J Clin Oncol. 2015;33(31):3576-3582. Slomovitz BM, et al. Cancer. 2010;116(23):5415-5419. Matulonis U, et al. Gynecol Oncol.

Courtesy Minig L and Romero I (In press)

Phase II Clinical Trials With mTOR and PI3K Family in Women With Endometrial Cancer

GOG 3007

Progression-Free and Overall Survival by regimen

PFS by Regimen Overall Survival by Regimen

PFS by prior treatment

No prior chemotherapy

Regimen RR PFS

Everolimus/letrozole 53% 21.6 months

Tamoxifen/MA 43% 6.1 months

Carboplatin/paclitaxel 51% 14 months

Future Directions???: GOG-189: Chemo v. Hormones

Stage III & IV, Recurrent Any histology

R A N D O M I Z E

Chemotherapy • Doxorubicin 45 mg/m2

• Cisplatin 50 mg/m2

• Paclitaxel (3 hr) 160mg/m2

Hormones • Megace 80 po BID• Tamoxifen 20 BID• Alternating 3 wks

P R O G R E S S I

O N Opened: 5-7-01

Closed: 8-9-02 Accrual: 42 (NNT = 630)

Eligibility: • Stage III or IVA EC

measurable disease• Stage IVB or recurrent EC

(whether there is measurable disease or not)

• No prior chemotherapy

GOG#0286B

Arm 1: Paclitaxel 175 mg/m2 IV over 3 hours day 1 Carboplatin AUC = 5 IV day 1 Metformin 850 mg oral QD, beginning on day 1. If tolerated for 4 weeks, the dose will be increased to metformin 850 mg BID. Maintenance regimen: Metformin 850 mg oral BID until disease progression or prohibition of further therapy.

Arm 2: Paclitaxel 175 mg/m2 IV over 3 hours day 1 Carboplatin AUC = 5 IV day 1 Placebo for Metformin 850 mg oral QD, beginning on day 1. If tolerated for 4 weeks, the dose will be increased to placebo for metformin 850 mg BID. Maintenance regimen: Matched placebo oral until disease progression or prohibition of further therapy

• Phase II/III• N = 240/300 patients

(500 patients)• 1º Endpoint: PFS/OS

GOG 286B: Metformin Study (Stopped for Futility)

6 ADDITIONAL STUDIES IN PROGRESS PtIhe: Vraicpytori. a Bae-Jump, M.D. PhDOpen: 17 March 2014 ClinicalTrials.gov Identifier: NCT02065687

How do we improve? Targets: • Anti-Angiogenesis• EGRF• mTOR/PI3K/AKT• DNA repair• Immunotherapy• Combinations

DNA Repair Pathways Endometrial Cancer & MSI+ (Ovary, Cervix)

• Microsatellite instability (oftenreferred to as MSI) is thehallmark of tumors withdefective MMR

• HRD has also been reported inendometrial cancers, with thehighest frequency in seroustype, TP53-mutated tumors

• Loss of MRE11, a proteininvolved in DSB repair, hasbeen reported in ~30% ofendometrial cancers

• Cervical Cancer. MSI occurs inabout 5+% of cervical cancers(Ercoli, Roa, Wong)

MSI in endometrial cancer

• Lynch syndrome, which is caused by inherited dMMR, accounts for 2%–5%of all cases1,8

• MSI also occurs in sporadic cases and is primarily attributed to MLH1 promoter hypermethylation & POLE mutants9;

SGO recommen ds all women with endometrial cancer undergo Lynch syndrome screening and/or molecular testing10

of endometrial cancers are classified as MSI+2

~20%

Ovary Sub-type Defective MMRt (%)

HGS 0.9

LGS 4.2

Endo 7.1

CC 2 Mucinous 0

(Xioa et al)

Email questions to Dr. Wendel Naumann at education@igcs.org for discussion during the break.

• A Randomized Phase II Study Comparing Single-Agent Olaparib, SingleAgent Cediranib, and the Combination of Cediranib/Olaparib inWomen with Recurrent, Persistent or Metastatic Endometrial Cancer(Mackay/Bender/Rimel)

• N=120 (40/arm). Stat: Filiaci

How do we improve? Targets: • Anti-Angiogenesis• EGRF• mTOR/PI3K/AKT• Immunotherapy:• DNA repair• Combinations

Endometrial Cancer (EC) – Four molecular subtypes<br />(Integrated genomic, transcriptomic and proteomic characterization)

GOG 210 Endometrioid (Cosgrove 2018)

Incidence: 49% CNS, 4% POLE mutant, 39% MMR deficient, 8% copy number altered (CNA). Cancer-specific mortality: 5%=CNS ; 2.6% =POLE tumors; 7.6%=MMR deficient tumors; 19% with CNA tumors.

questions t endel N

1. Fader AN, et al. Presented at SGO, 2016. 2. Ott PA, et al. J Clin Oncol. 2017;35(22):2535-41. 3. Fleming GF, et al.Presented at ASCO Annual Meeting, 2017. Abstract 5585. 4. Makker V, et al. Presented at ASCO Annual Meeting, 2018. Abstract 5596. 5. Oaknin A, et al. Presented at ESMO, 2018. Abstract 935PD. 6. Pembrolizumab package insert. Merck & Co, Inc; December 2018.

Fader et al. Pooled MSI-H

Endometrial Cancer: Immunotherapy

KEYNOTE-0282 NCT01375842

3NCT02501096

4 GARNET5

Phase(s) 2 1 and 2 1b 1a 1b/2 1/2

Population Previously treated dMMR-

recurrent or persistent EC

Previously treated MSI-H/dMMR ECb

Previously treated locally advanced or metastatic PD-

L1+ EC

Recurrent EC Advanced EC

Previously treated

recurrent/advanced MSI-H

EC

Patients, n 9 14 24 15 54 35

Treatment Pembrolizumab Pembrolizumab Pembrolizumab Atezolizumab Pembrolizumab + lenvatinib

Dostarlimab

ORR, % 56a 36a 13.0a 13 36.7 49 & 20DCR, % 89 — 26.0 27 — 64

DOR — 4.2+–17.3+ moa

— — NR NR

mPFS — — 1.8 mo 1.7 mo 10.1 mo —

mOS NR — NR 9.6 mo — —

Safety summary No AEs >Gr 3 Per label ≥Gr 3 TRAEs:

16.7% Any TRAE:

47% ≥Gr 3 TRAEs:

59% ≥Gr 3 TRAEs:

11.4%

Median follow-up 9.1 mo o 4.0 mo —

GYY-020

• Randomized phase III trial of radiation +/- checkpointinhibitor for high intermediate risk mismatch repairdeficient (dMMR) endometrioid endometrial cancer(Backes)

• N: 168

How do we improve? Targets: • Anti-Angiogenesis• EGRF• mTOR/PI3K/AKT• Immunotherapy• DNA repair• Combinations

Randomized phase II/III study of carboplatin + paclitaxel vs. carboplatin + paclitaxel + pembrolizumab in patients with advanced stage (stage 3 or 4) or

recurrent endometrial cancer

Stage III & IV or recurrent endometrial cancer

(Stage 3 or 4A: measurable disease; Stage 4B or recurrent whether there is

measurable disease or not)

MMR-proficient vs. MMR-deficient

R

C/T + placebo

C/T + pembrolizumab + maintenance pembrolizumab

x 12 months

Stratification factors: MMR-proficient vs. MMR-deficient, performance status, measurable disease status

N=590 pMMR patients N=185 deficient MMR (dMMR)

Patients may have received prior radiation therapy or hormonal therapy. Patients in whom both radiation and chemotherapy are planned must receive radiation prior to entry on study. C = Carboplatin; T = Paclitaxel

Stage III & IV or recurrent endometrial cancer

(Stage 3 or 4A: measurable disease; Stage 4B or recurrent whether there

is measurable disease or not) ALLOW CSRCINOSARCOMAS

MMR-proficient vs. MMR-deficient

R

C/T + placebo

C/T + Dostarlimab + maintenance

Dostarlimab x 12 months

A Phase 3, randomized, double-blind, multicenter study of Dostarlimab (TSR-042) plus Carboplatin-Paclitaxel versus Placebo plus Carboplatin-Paclitaxel in patients with reurrent or primary advanced endometrial cancer

GOG=Partners / ENGOT-EN6 / NSGO

Email questions to Dr. Wendel Naumann at education@igcs.org for discussion during the break.

Hot & Cold: AMANDA Study design

Stra?fiedby§ PriorRT§ Recurrentdisease§ MSI

PrimaryEndpoint:OSandPFS

SecondaryEndpoints:PFSinMSI,PFS2,RR,QoL,safety

Transla?onal Endpoints: PD1, PDL1, TILs, blood basedbiomarkers

StudyDura?on:accrual2years;Follow-up:2years

Atezolizumab\Placebowillbeadministered:- asI.V.infusionevery21days-  unQl progression confirmed at least 4 weeks aTer the firstevidenceofprogressionaccordingtoRECISTv1.1.

Paclitaxel 175mg/m2 carboplatin AUC 5 or 6

placebo

Maintenance placebo

Paclitaxel 175mg/m2 carboplatin AUC 5 or 6 atezolizumab 1200mg

Maintenance atezo 1200mg

Stage III/IV or recurrent

endometrial cancer

Confirmed PD

R 1:2

• Dynamic time in endometrial cancer therapeutics

• Multiple studies exploring the utility of IO in the front line andrecurrent settings

• Aside from MSI-H/dMMR (and TMB) no defined biomarkers

Conclusions

Pembrolizumab Avelumab Atezolizumab Cemiplimab Durvalumab Nivolumab

?

• AtTEnd/MaNGO

• Avelumabsingle agent

• Durvalumab single agent or+ olaparib

?

Dostarlimab

• Single agent(dMMR/pMMR)

• C/T + TSR-042• Lenvatinib +

Pembrolizumab• C/T + pembrolizumab

Key Clinical Studies in Advanced, Recurrent, or Metastatic Endometrial Cancer

Ongoing Phase 3 Trials for Systemic Therapy in Advanced, Recurrent, or Metastatic Endometria l Cancer

Merck: GY018 (1L), pembrolizumab/ chemotherapy

Merck: KEYTRUDA monotherapy tumor-

agnostic FDA approval, MSI-H

Merck/Eisai: KEYNOTE-146, pembrolizumab/

lenvatinib, MSI-H/non-MSI-H

Tesaro/GSK: GARNET,

dostarlimab monotherapy,

MSI-H/non-MSI-H

Tesaro/GSK: RUBY,

dostarlimab/ chemotherapy

Merck/Eisai: KEYNOTE-775

(Ph3), pembrolizumab/

lenvatinib

AstraZeneca: DOMEC,

durvalumab/olaparib

Genentech/Roche: ATEnd,

Atezolizumab/ chemotherapy

Merck/Eisai: LEAP-001 (1L),

pembrolizumab/ lenvatinib

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