2021 Master Class Course Molecular Advances and Emerging

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2021 Master Class CourseMolecular Advances and Emerging Treatment Strategies in Ovarian CancerUrsula Matulonis, MDChief, Division of Gynecologic OncologyBrock-Wilson Family Chair Dana-Farber Cancer InstituteProfessor of MedicineHarvard Medical School

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Faculty Disclosure• Consulting: NextCure, Astrazeneca• Advisory Boards: Novartis, Blueprint Medicines, Trillium• Scientific Advisory Board Member: Clearity Foundation, Rivkin Foundation

and Ovarian Cancer Research Alliance• Data Safety Monitoring Boards: Symphogen, Advaxis

Faculty of this CE activity may include discussions of products or devices that are not currently labeled for use by the FDA.The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off label or investigational uses (any uses not approved by the FDA) of products or devices.

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Incidence and prevalence in U.S. women

• 21,410 new cases estimated for 2021;incidence is dropping

• Remains the second most common gyn tumor in the U.S.

• ~235,000 women living w/ ovarian cancer in U.S.

Mortality in U.S. women• 13,770 estimated deaths in

2021; survival is improving• 5th most common cause of

cancer death in women

Ovarian Cancer 2021

Siegal et al, 2021SEER.gov (accessed 9/24/21)

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Newly diagnosed ovarian cancer management: 2021• Basic principles

• Surgery by a gynecologic oncologist is associated with improved survival1• Extent of cytoreduction (debulking) is classified by residual disease following surgery

• Suboptimal: >1 cm of residual tumor• Optimal: ≤1 cm of residual tumor• NED (R0): No gross residual disease

• Considerations in the approach to initial disease treatment• Upfront surgery versus neoadjuvant treatment decision should be made by a gyn onc surgeon• Multiple randomized trials show equivalency of upfront surgery versus neoadjuvant, but ability

to do upfront surgery is associated with a better outcome • Optimal schedule of carboplatin and paclitaxel: q3 week = weekly• Addition of bevacizumab to carbo/paclitaxel + maintenance prolongs PFS but not OS• Histology specific treatment• HIPEC: only used at high volume centers; median overall survival was 33.9 months in the

surgery group and 45.7 months in the surgery-plus-HIPEC

1Cliby WA, Gynecol Oncol. 2015, Wright et al Gyn Onc 20162Moore et al, NEJM 2018, Van Driel et al, NEJM 2018, Coleridge 2021

5NCCN guidelines 2020; adapted from FIGO Staging System for Ovarian, Fallopian Tube, and Primary Peritoneal Cancer (8th ed., 2017)

Ovarian Cancer Staging

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Classification of ovarian cancer includes molecular data

High grade serous or endometrioid

Low grade endometrioid

Low gradeserous

Clear Cell Mucinous

Genetic characteristics

Up to 50% have HRDAssociated with TP53 and BRCA mutations

PTEN, ARID1A, PIK3CAalterations

May have Microsatellite instability

KRAS, BRAF mutations

PIK3CA, ARID1A, PTEN

KRAS; may have microsatellite instability

Clinicalcharacteristics

Platinum and PARP inhibitor sensitivity

Carcinosarcomas are treated like high grade serous cancers

Potentially more responsive to hormonal therapy, although not established

Hormonaltherapies

MEK inhibitors

May be more sensitive to immumotherapy

Are more resistant to chemotherapy

TCGA, 2011; Ilenkovan/Gourley 2018; Ryland et al, 2015; Stany et al, 2011; Hunter et al, 2015

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2020 Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guidelines

• All women diagnosed with epithelial ovarian cancer should have germline Panel testing at diagnosis.

• Somatic tumor testing for BRCA 1 and 2 should be performed in women who do not carry a germline abnormal BRCA1/2 gene mutations-- 11 recognized hereditary mutations: BRCA1, BRCA2, MSH2, MLH1, PMS2,

PALB2, BARD1, RAD51C, RAD51D, and BRIP1-- 15% of women with high grade serous ovarian cancer have germline BRCA

mutations-- 6% of patients with high grade serous histology have somatic BRCA mutations

• Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR).

Konstantinopoulos et al JCO 2020SGO guidelines, NCCN genetics guidelinesNorquist et al, JAMA Oncology 2016;2:484-490

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ICON8: Carboplatin and paclitaxel chemotherapy: All schedules are equivalent (A); Pts receiving neoadjuvant treatment had worse outcomes (B)

Carboplatin/paclitaxel every 21 days (Standard) 17.7

Carboplatin every 21 days/paclitaxel weekly 20.8

Weekly carboplatin and weekly paclitaxel 21.0

PFS in monthsPFS for All patients (A)

Clamp et al, Lancet 2019Bladgen et al, Lancet Onc 2020

Patients undergoing upfront cytoreductive surgery had better outcomes (PFS)

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Addition of bevacizumab to chemotherapy and used as maintenance extends PFS in newly diagnosed advanced ovarian cancer; no OS benefit

14.1 vs. 11.2 vs. 10.3 mos

FDA approval in June 2018; PFS improvement based on censoring patients with CA125-based progression;~6 month improvement in PFS with addition of bev to chemotherapy and as maintenance

GOG218Stages eligible:III (macroscopic, ≤1 cm)III (> 1cm)IVBev dose is 15 mg/kg; started at cycle 2 and continued for 22 cycles

Burger et al., NEJM 2011, Avastin FDA PI, Tewari et al, JCO 2019

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Does longer bevacizumab duration impact outcomes? No

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Mechanisms of Action• Inhibit the function of PARP• Formation of PARP-DNA complexes through PARP

trapping

Cannot be combined easily; doses/schedules need to be adjusted because of observed myelosuppression

PARP Inhibitors

Thomas A, et al. J Clin Invest. 2018; Matulonis UA, Monk BJ. Ann Oncol. 2017.

Can be more easily combined with chemotherapy

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First-Line Maintenance: SOLO-1 Trial

Moore K, et al. N Engl J Med. 2018;379:2495-2505.

• Newly diagnosed stage III/IV, high-grade serous or endometroid ovarian, primary peritoneal, or fallopian tube cancer

• Germline or somatic BRCAm• Cytoreductive surgery or

attempt either before chemo or interval

• Cancer showed a response to platinum-based chemotherapy

Olaparib 300 mg bd(N=260)

Placebo(N=131)

2:1 randomization

Primary Endpoint

• Investigator-assessed progression free survival or how well and long the cancer stays in remission for

Two years’ treatment if no evidence of disease

• Study treatment continued until disease progression

• Patients with no evidence of disease at 2 years stopped treatment

• Patients with PRat 2 years could continue treatment

Study Design

14Gonzalez-Martin et al., N Engl J Med 2019, ESMO 2019

15Ray-Coquard et al., ESMO 2019, N Engl J Med 2019; 381:2416-2428

PAOLA-1

Primary Endpoint

• Investigator-assessed progression free survival or how well and long the cancer stays in remission for

161Moore et al, NEJM 2019, 2Gonzalez-Martin NEJM 2019, 3Ray-Coquard NEJM 2019

Upfront PARP inhibitor studies in advanced ovarian cancer

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Newly Diagnosed ovarian cancer: BRCA mutated

Moore et al, NEJM 2019, Gonzalez-Martin NEJM 2019, Ray-Coquard NEJM 2019

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ESMO 2020 update: No additional cases of MDS/AML reported.Incidence <1.5% (3/260), no cases in placebo arm

5 year follow-up: Improvement in PFS with Olaparib compared to placebopersists in women with advanced BRCA mutated ovarian cancer

NEJM 2018, ESMO 2020, SGO 2021

Olaparib(N=260)

Placebo(N=131)

Events (%) [50.6% maturity] 102 (39.2) 96 (73.3)

Median PFS, months NR 13.8

HR 0.3095% CI 0.23, 0.41;

P<0.0001

Initial results ESMO 2018

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Newly diagnosed ovarian cancer: BRCAwt/HR deficient (HRD)

Gonzalez-Martin NEJM 2019, Ray-Coquard NEJM 2019

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Newly diagnosed ovarian cancer: BRCAwt/HR proficient (HRP)

Gonzalez-Martin NEJM 2019, Ray-Coquard NEJM 2019

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Histology specific treatment: Low grade Serous Cancer

• High proportion of LGSC’s have estrogen and progesterone receptor expression• Hormonal therapy has efficacy in recurrent LGSC• Gershenson et al: retrospective study of 203 patients (stage II to IV) LGSC

treated with surgery followed by platinum-based chemotherapy• Retrospective analysis 2 groups: no maintenance therapy versus hormonal

therapy• Results: PFS higher for women receiving hormonal therapy (most rec’d an AI)

than patients receiving no maintenance:

Hormonal therapy: 64.9 monthsObservation: 26.4 months

Gershenson et al, JCO 2017

NRG-GY019 (NCT04095364) is open currently: Letrozole versus Paclitaxel/Carboplatin/Letrozole in Treating Patients With Stage II-IV Ovarian or Primary Peritoneal Cancer

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Recurrent Ovarian Cancer• The majority of patients with advanced stage ovarian cancer will recur• Recurrences (in US) most often detected by rising CA125

• Follow-up typically every 3 months for first 2 years, every 6 months for next 3 years following initial treatment

• Recurrences defined by time since initial platinum-based therapy• Platinum-refractory: failed to achieve at least a partial response to therapy/growth on

platinum or growth within 4 weeks of platinum completion• Platinum-resistant: recurrence within 6 months of last platinum-based therapy• Platinum-sensitive: recurrence more than 6 months after last platinum-based therapy

• Can also treat per “platinum appropriate” or “not appropriate”• FDA approved treatments

• Chemotherapy +/- bevacizumab• PARP inhibitors

Salani R, Am J Obstet Gynecol. 2011;204:466-78

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Addition of Bevacizumab to non-platinum chemotherapy in recurrent platinum-resistant ovarian cancer increases PFS: the AURELIA trial

Chemotherapy options: Paclitaxel 80 mg/m2 on Days 1,8,15, 22 every 28 days Topotecan 4 mg/m2 on Days 1, 8 ,15 every 28 days or Topotecan 1.25 mg/m2 on Days 1-5 every 21 days Pegylated liposomal doxorubicin (PLD) 40 mg/m2 on Day 1 every 28 days

Pts with measurable OC that progressed < 6 mos

from platinum-based chemotherapy;

≤ 2 prior therapies;no bowel involvement

(N = 361)

Disease progression

Nonplatinum Chemotherapy

Nonplatinum Chemotherapy + Bevacizumab

Stratified by chemotherapy, PFI (< 3 mos vs 3-6 mos),

prior anti-angiogenesis

Pujade-Lauraine et al., J Clin Oncol 2014 and 2015

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Bevacizumab + chemo improved PFS in platinum-resistant ovarian cancer: still represents the standard of care for plat resistant ovarian ca

Pujade-Lauraine et al. JCO 2014Poveda et al, JCO 2015

Weekly Pac

Weekly Pac + Bev

PLD PLD + Bev Topo Topo + Bev

ORR 30.2% 53.3% 7.8% 13.7% 0% 17.0%

PFS 3.9 mo 10.4 mo

HR 0.46 (CI 0.3-0.71)

3.5 mo 5.4 mo

0.57 (CI 0.39-0.83)

2.1 mo 5.8 mo

0.32 (0.21-0.49)

No overall survival benefit with adding bevacizumab to non-platinum chemotherapy

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Platinum sensitive recurrent ovarian cancer: Key studies of platinum doublets and triplets

Study Regimen(s) PFS OSCALYPSO1 (A) Carboplatin/paclitaxel

(B) Carboplatin/pegylated liposomal doxorubicin (PLD)

9.4 months11.3 monthsHR = 0.821 (95% CI 0.72–0.94; P = 0.005)

33 months30.7 monthsHR 0.99 (95% CI 0.85-1.16, p=0.94)

OCEANS2,3 (A) Carboplatin/gemcitabine (CG)(B) CG/bevacizumab + bevacizumab maintenance

8.4 mos12.4 mosHR 0.484 (95% CI 0.388 to 0.605; log-rank P < .0001)

32.9 months33.6 monthsHR 0.95 (95% CI: 0.77–1.18; log-rank p value = 0.65)

GOG2134 (A) Carboplatin/paclitaxel (CP)(B) CP/bevacizumab + bevacizumab maintenance

10.4 mos13.8 mosHR 0.628 (95% CI 0.534–0.739; p<0·0001)

37.3 mos42.2 mosHR 0.829 (95% CI 0.683-1.005; p=0.056)

AGO-OVAR2.21/ENGOT-OV184,5

(A) Carboplatin/PLD/bev + bevacizumab maintenance

(B) Carboplatin/gemcitabine/bevacizumab + bevmaintenance

13.3 mos11.7 months HR 0.807 (95% CI 0.681-0.956; p=0.0128)

33.5 months28.2 months HR 0.810 (95% CI 0.668-0.983, p=0.0319)

1Pujard Lauraine et al, JCO 2010, 2Aghajanian et al, JCO 2012 and 3Gyn Onc 2015, 4Coleman et al., Lancet Oncology 2017,5 Pfisterer et al, ESMO 2018/SGO 2019

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Strategies for platinum sensitive ovarian cancer

• Decision making needs to occur at the start of the platinum doubletand should include risks/benefits of these approaches

1Study 19, NEJM 2012, 2NOVA NEJM 20163SOLO2 Lancet Oncology 2017, 4ARIEL3, Lancet 2017, 5OCEANS, JCO 2015

Platinum chemotherapy

Bevacizumab maintenance4,5:

Platinum chemotherapy + bevacizumab Bevacizumab maintenance

PARP inhibitor maintenance

Platinum doublet chemotherapy

Platinum chemotherapy

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SOLO2/ENGOT-OV21 Study Schema

Pujade-Lauraine, Lancet Oncology, 2017

Placebon=99

Olaparib 300 mg bid

n=196Primary endpoint

Investigator-assessedPFS

Patients• BRCA1/2 mutation• Platinum-sensitive relapsed

ovarian cancer • At least 2 prior lines of

platinum therapy• CR or PR to most recent

platinum therapy

Random

ized2:1

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ENGOT-OV16/NOVA Trial Schema

gBRCAmut (N = 203)

Treat until Progression of Disease

Niraparib 300 mg once daily Placebo

Non-gBRCAmut (N = 350)

Treat until Progression of Disease

Niraparib 300 mg once daily Placebo

2:1 Randomization 2:1 Randomization

Platinum-Sensitive Recurrent High-Grade Serous Ovarian Cancer

Response to Platinum Treatment

Treatment with at least 4 Cycles of Platinum-based Therapy

Primary Endpoint: PFS by central, blinded review: results for both gBRCA and non-gBRCA groups analyzed simultaneously

Mirza, N Engl J Med 2016

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ARIEL3: STUDY DESIGN

• HRR status by NGS mutation analysis BRCA1 or BRCA2 Non-BRCA HRR gene†

None of the above• Response to recent platinum

CR PR

• Progression-free interval after penultimate platinum 6 to <12 months ≥12 months

Patient eligibility Stratification

• High-grade serous or endometrioid epithelial OC, primary peritoneal, or fallopian tube cancers

• Sensitive to penultimate platinum• Responding to most recent platinum

(CR or PR)* Excludes patients without assessable

disease following second surgery• CA-125 within normal range• No restriction on size of residual tumour• ECOG PS ≤1• No prior PARP inhibitors

PlaceboBID

n=189

Rucaparib 600 mg BID

n=375

Ran

dom

isat

ion

2:1

Lancet 2017

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Phase III PARP inhibitor maintenance studies show:1. Strikingly similar PFS results regardless of PARP inhibitor2. Decreasing benefits with “less” HRD: most benefit for women with BRCA mutated

ovarian cancer and the least for BRCA wild-type and HRD negative (i.e. HR proficient)

Trial ITT BRCAm HRD Positive BRCAwt and HRD Negative

PFS OS PFS OS PFS OS PFS OS

NOVA (BICR)Niraparib Pts were separated into

gBRCA and non-BRCAgroups

21 NR 12.9 NR 6.9 NRPlacebo 5.5 NR 3.8 NR 3.8 NR

Hazard ratio 0.27 0.38 0.58SOLO2 (Investigator-assessed)

Olaparib Only patients with BRCAm cancers

eligible

19.1 NRNA NAPlacebo 5.5 NR

Hazard ratio 0.30ARIEL3 (Investigator-assessed)

Rucaparib 10.8 NR 16.6 NR 13.6 NR 6.7 NRPlacebo 5.4 NR 5.4 NR 5.4 NR 5.4 NR

Hazard ratio 0.36 0.23 0.32 0.58

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Overall Survival results from SOLO2: 13 month improvement in overall survival

OS benefit was 16.3 months for Olaparib after adjusting for subsequent PARPinhibitor use:

Poveda, ASCO 2020

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Toxicities of PARP inhibitorsMyelosuppression Fatigue Gastrointestinal toxicities: i.e. Nausea, vomiting, diarrhea, constipation, reduced appetiteRisk of secondary AML or MDSup to 1.5% for women with newly diagnosed ovarian cancer2 to 8% for women with recurrent cancer

Examples of drug-specific side effects:Niraparib: hypertension, tachycardia, headachesOlaparib: pneumonitis, increase in creatinineRucaparib: transient increase in liver enzymes, increase in creatinine,

increase in cholesterol and risk of rash

FDA PI’s for Olaparib, niraparib, rucaparib

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Risk of AML/MDS w/ PARP inhibitors increases in women with ovarian cancer with BRCAm and recurrence

Study Clinical Setting AML/MDS risk in BRCA mutation carriers

AML/MDS risk in non-BRCA carriers

SOLO1 1st line upfront treatment

<1.5% n/a

SOLO2 Recurrent maintenance

8% n/a

NOVA Recurrent maintenance

6.6% 1.7%

Poveda et al, ASCO 2020, Lancet Onc 2021Matulonis et al, SGO 2021

SOLO2 8% 4%

NOVA

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Risk of AML/MDS w/ PARP inhibitors increases in women with ovarian cancer with BRCAm and recurrence

Study Clinical Setting AML/MDS risk in BRCA mutation carriers

AML/MDS risk in non-BRCA carriers

SOLO1 1st line upfront treatment

<1.5% n/a

SOLO2 Recurrent maintenance

8% n/a

NOVA Recurrent maintenance

6.6% 1.7%

Poveda et al, ASCO 2020, Lancet Onc 2021Matulonis et al, SGO 2021

SOLO2 8% 4%

NOVA

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Dose modifications for each PARP inhibitor

Initial Dose: 300 mg once daily

First Dose Reduction: 200 mg once daily

Second Dose Reduction: 100 mg once daily

Niraparib Olaparib RucaparibUse weight and platelet-based dosing (in FDA PI for PRIMA-approval; monitor blood counts weekly x 4 weeks, then monthly

Initial Dose: 600 mg twice daily

First Dose Reduction: 500 mg twice daily

Second Dose Reduction: 400 mg twice daily

Third Dose Reduction: 300 mg once daily

Initial Dose: 300 mg twice daily

First Dose Reduction: 250 mg twice daily

Second Dose Reduction: 200 mg twice daily

Monitor complete blood countat baseline and monthly thereafter

Monitor complete blood countat baseline and monthly thereafter

Berek et al, 2019

100 mgcapsules

100 and150 mg tabs

200, 250 mg, 300 mg tabs

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How PARP inhibitor approvals started in ovarian cancer:PARP Inhibitors Are Active as Single Agents in BRCAm recurrent Ovarian Cancer

Olaparib1 Rucaparib1 Niraparib1,2

BRCA status Mutated Mutated Mutated

# of lines of prior therapy At least 3 prior lines At least 2 prior lines (43% had 3 or more) at least 3 prior lines

Response rate 34% 54%(IRR 42%) 24%

Median duration of response 7.9 months 9.2 months(IRR 6.7 months) 8.3 months

1FDA Prescribing Information2Niraparib is also approved for platinum sensitive HRD ovarian cancer (3 or more prior lines)

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Special FDA package insert warnings and precautionsDrugNiraparib Test complete blood counts weekly for the first month, monthly for the next 11 months and periodically

thereafter for clinically significant changesCardiovascular Effects: Monitor blood pressure and heart rate at least weekly for the first two months, then monthly for the first year, and periodically thereafter during treatment with niraparib Manage with antihypertensive medications as well as adjustment of the niraparib dose, if necessary.

Olaparib Monitor patients for hematological toxicity at baseline and monthly thereafter

Pneumonitis: Occurred in <1% of patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed. Venous thromboembolic events including pulmonary embolism occurred in 7% of patients with mCRPC. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.

Rucaparib Monitor patients for hematological toxicity at baseline and monthly thereafter. Interrupt or reduce the dose based on severity of reaction.

All Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed

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thereafter for clinically significant changes Cardiovascular Effects: Monitor blood pressure and heart rate at least weekly for the first two months, then monthly for the first year, and periodically thereafter during treatment with niraparib Manage with antihypertensive medications as well as adjustment of the niraparib dose, if necessary.


Pneumonitis: Occurred in <1% of patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed.Venous thromboembolic events including pulmonary embolism occurred in 7% of patients with mCRPC. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.



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thereafter for clinically significant changes Cardiovascular Effects: Monitor blood pressure and heart rate at least weekly for the first two months, then monthly for the first year, and periodically thereafter during treatment with niraparib Manage with antihypertensive medications as well as adjustment of the niraparib dose, if necessary.


Pneumonitis: Occurred in <1% of patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed. Venous thromboembolic events including pulmonary embolism occurred in 7% of patients with mCRPC. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.



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Immune checkpoint inhibitors have only modest activity in Recurrent Ovarian Cancer

Agent Patients, n RR Median PFS Prior therapyNivolumab (JCO 2015)

20 patients 15% 3.5 months 55% had >3 lines of prior treatment

Avelumab (JAMA Onc2019)

125 patients 9.6% 2.6 months Median number of prior therapies was 4

Pembrolizumab(Annals of Oncology 2019)

376 patients 8%

Higher RR’s in PD-L1 +(CPS 10 or higher) compared to CPS<117.1% vs 5%;

2.1 months Pts grouped into cohort A (1-3 prior lines) and B (4-6 prior lines)

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Addition of Immunotherapy to chemotherapy shows no benefit in ovarian cancer

Newly diagnosed advanced cancerJavelin 100: Avelumab/carboplatin/paclitaxel Avelumab maintenance versus Avelumab/carboplatin/paclitaxel versus carboplatin/paclitaxel IMagyn50: atezolizumab/carboplatin/paclitaxel/bevacizumab vs carbo/pac/bev, both with bev maintenance

Recurrent platinum resistant:Javelin 200: PLD versus PLD/avelumab versus avelumab

SGO 2020, ESMO 2020, JCO 2021, Lancet Oncology 2021

Results: No PFS nor OS benefit for the addition of avelumab or atezolizumab to chemotherapy

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FDA-approved indications for immunotherapy in ovarian cancer

• Pembrolizumab:

2017 FDA approval for MSI-high/MMR deficient cancers

2020 FDA approval for Tumor Mutational Burden high

(≥10 mutations/megabase)

• MMR deficiency is quite rare in high grade serous ovarian cancer but more

common in non-serous ovarian cancer

Xiao et al, Gyn Onc 2014, Morice et al, NEJM 2019Konstantinopoulos et al, JCO 2020

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• Recurrent ovarian cancer• No prior gem or PLD• Up to one prior regimen

for platinum resistant cancer

• N=316• Primary: OS• Secondary: PFS, safety, ORR

Nivolumab 240 mg IV every 2 weeks

Gemcitabine 1000 mg/m2, days 1, 8, 15

OR

PLD 50 mg/m2

ESMO 2020; Abstract 807O; JCO 2021

NINJA trial (phase 3): ICI versus single agent chemotherapy for platinum resistant ovarian cancer:No improvement in OS with nivolumab compared with either gem or PLD

Results:

Median OS 10.12 months with nivolumab 12.09 months with GEM/PLD (NS HR 1.03, 95% CI, 0.80-1.32; P=0.808).

Median PFS2.04 months nivo3.84 months with GEM or PLD (HR 1.46; 95% CI, 1.15-1.85; P=0.002).

ORR:Was non-significantly lower in the nivolumab group (7.6% vs 13.2%; p=0.191).

JapicCTI-153004

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Mirvetuximab = folate receptor alpha, DM4

Annals of Oncology 2021

45Moore et al, ESMO 2019 Annals of Oncology 2021

46Moore et al, ESMO 2019

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Trials focused on platinum resistant high grade serous ovarian cancer with high FRα expression

MIRASOLNCT04209855 Phase III study1:1 to either mirvetuximab or investigator’s choice of single-agent chemotherapy Can have received up to 3 prior regimensPrimary endpoint is PFS

SORAYANCT04296890Single-arm trial with mirvetuximabCan have received up to 3 prior regimens (at least one of which included bevacizumab)Primary endpoint is ORR, and key secondary endpoint is duration of response.

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Arm ORR (95% CI)

SD PFS OS HR PFS(95% CI)

P-value

GOG239 Selumetinib

• KRAS mutant• KRAS WT

15%

14.3%25%

65% 11 mos NR NA NA

GOG281 TrametinibControl

26.2% 6.2%

59.2%70.8%

13.0 mo7.2 mo

37 mo29.2 mo

0.48 (0.36-0.64)

<0.0001

MILO BinimetinibControl

• KRAS mutant• KRAS WT

16%13%

9.1 mo10.6 mo

17.7 mo / 14.610.8 mo / 11.5(p=0.05 in bini)

28.0 mo25.0

1.21(0.79-1.86)

0.748

Farley Lancet Oncol 2013, Monk/Grisham IGCS 2019, JCO 2020, Gershenson ESMO 2019

• MEKi is an effective treatment modality in Low grade serous ovarian cancer• Relationship of RAS mutation status and response is not clearly defined.

Low grade serous ovarian cancer: single agent MEK inhibitors are active

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Thank you!

Documents

2021 Master Class Course Molecular Advances and Emerging