Updates in Gynecologic Cancer Care

Margaret Liang, MD, MSHS

Division of Gynecologic Oncology

University of Alabama at Birmingham

ACC-MOS Joint Spring Meeting

April 13, 2019

Disclosures

• Dr. Liang has no disclosures

• Off label utilization of cancer therapeutics will be mentioned. The view(s) expressed herein are those of the speaker and do not reflect the official policy or position of University of Alabama at Birmingham

UAB Division of Gynecologic Oncology

OvarianCancer

Ovarian cancer 22,240

Siegel et al. CA Cancer J Clin, 2018.

Advanced ovarian cancer

• Cornerstone of treatment – combo of surgery and chemotherapy

• Aggressive optimal debulking surgery to <1 cm and ideally to no gross residual disease (R0)

• Platinum/taxane doublet chemotherapy

• Platinum sensitivity is a prognostic factor

Role of neoadjuvant chemotherapy

• 2 RCTs demonstrating neoadjuvant chemotherapy (NACT) approach is non-inferior to primary debulking surgery (PDS) in terms of PFS and OS for patients with advanced ovarian cancer• EORTC

• CHORUS

• NACT approach associated with less perioperative morbidity and mortality

Vergote et al. NEJM, 2010.Kehoe et al. Lancet Oncol, 2015.

RCTs evaluating neoadjuvant chemotherapyEORTC

PDSEORTCNACT

CHORUSPDS

CHORUSNACT

Number of patients 361 357 255 219

Residual ≤ 1 cm 42% 81% 41% 73%

No gross residual 18% 45% 17% 39%

PFS 12 months 12 months 11 months 12 months

OS 29 months 30 months 23 months 24 months

Postop complications24%

any grade 3/414%

any grade 3/4

7%, 8%, 3% (grade 3/4

hemorrhage, infection, venous)

4% , 2%, 0%(grade 3/4

hemorrhage, infection, venous)

Death within 30 days of surgery 6% 1% 3% 1%

Vergote et al. NEJM, 2010.Kehoe et al. Lancet Oncol, 2015.

Planned pooled analysis EORTC/CHORUS trials

OSHR 0.97 (95% CI 0.86-1.09)

PFSHR 0.98 (95% CI 0.87-1.10)

Vergote et al. Lancet Oncol, 2018.

Subgroup analysis suggests NACT for stage IV and PDS for stage IIIC without bulky disease

OS for stage IV diseaseHR 0.76 (95% CI 0.58-1.00)

PFS for stage IIIC diseasewith tumor <5 cm

HR 1.36 (95% CI 1.06-1.75)

Vergote et al. Lancet Oncol, 2018.

If cannot obtain biopsy cytologic evaluation (i.e., ascites, pleural effusion) combined with serum CA-125 to CEA ratio >25 acceptable

RCTs tested interval cytoreductive surgery following 3-4 cycles of chemotherapy

CT imaging to evaluate extent of disease and GYN ONC consult to evaluate surgical risk/resectability

Platinum/taxane doublet

Wright et al. J Clin Oncol, 2016.

Increasing Use of NACT Approach

• High perioperative risk:- Low albumin esp. if need bowel resection

- Recent VTE

- Poor ECOG performance status

• Optimal cytoreduction unlikely:• Mesenteric involvement

• Porta hepatis

• Pulmonary involvement

• Laparoscopic scoring

Melamed et al. Gynecol Oncol, 2016.

Using the National Cancer Database (NCDB)2004-2013

Laparoscopic scoring to determine resectability

Fagotti score components

2 points for each

Peritoneal carcinomatosis

Massive/unresectable + miliary distribution

Diaphragmatic disease Infiltrating/widespread, confluent nodules

Mesenteric disease Infiltrating/widespread, root of mesentary

Omental disease Up to greater curvature

Bowel infiltration Bowel resection assumed to be required

Stomach infiltration Gastric wall involved

Liver metastasis Any surface lesions

Score ≥ 8 was was associated with 0% probability of optimal resection

(113 patients in prospective cohort)

Avoided 40% of unnecessary laparotomies

Fagotti et al. Am J Obstet Gynecol, 2008.

Treatment Landscape for Ovarian Cancer Is Rapidly Changing

https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed March 29 and April 9, 2018. Kelland et al. Nat Rev Cancer, 2007.

Primary

Landmark FDA approvals in ovarian cancer therapy

Maintenance

1978 2017

Cisplatin2 Carboplatin2

(1L)

Paclitaxel

Topotecan

Liposomal Doxorubicin (Accelerated)

Liposomal Doxorubicin

(Full)

Gemcitabine

Bevacizumab (platinum-resistant)

Olaparib(BRCAmut carriers)

Bevacizumab (platinum-sensitive)

Rucaparib (somatic + germline BRCAmut)

Niraparib (platinum-sensitive)

Olaparib (platinum-sensitive)

1990 1992 1996 2005 20141991 1999 20061989

Carboplatin2

(palliative)

Altretamine

2018

Rucaparib (platinum-sensitive)

2016

Olaparib(somatic + germline BRCAmut)

Intraperitoneal (IP) chemo - GOG 172

Median PFS 18.3 vs. 23.8 months (p=0.05) Median OS 49.7 vs. 65.6 months, p=0.03

Armstrong et al. NEJM, 2006.

IP chemo in the real world

• GOG 172:• IV chemo arm: D1 IV taxol 135 mg/m2 over 24h + D2 75 mg/m2 IV cisplatin

• IP chemo arm: D1 IV taxol 135 mg/m2 over 24h + D2 100 mg/m2 IP cisplatin + D8 60 mg/m2 IP taxol

• Only 42% completed all 6 cycles

• The real world:• IV taxol usually given over 3 hours

• Drug modifications - estimated 43% of NCCN institutions use modified regimen (i.e., IV drug substitution, IP drug substitution, IP dose reduction)

• Intensive management of side effects (i.e., dehydration, IP port malfunction, abdominal distention, nausea/vomiting, renal dysfunction)

Armstrong et al. NEJM, 2006. Wright et al. J Clin Oncol, 2015.

Trends in NACT and IP chemotherapy

Stage IIIC disease Stage IV disease

Meyer et al. J Clin Oncol, 2016.

Dose-dense taxol/carbo – JGOG 3016

Katsumata et al. Lancet Oncol, 2013.

PFSHR 0.76 (95% CI 0.62-0.91)

28.2 months vs. 17.5 months

OSHR 0.79 (95% CI 0.63-0.99)

100.5 months vs. 62.2 months

Dose-dense regimen after suboptimal debulking – JGOG 3016

Katsumata et al. Lancet Oncol, 2013.

PFS OS

SuboptimalSuboptimal

Optimal

Optimal

Dose-dense taxol/carbo - GOG 262

Chan et al. NEJM, 2016.

Dose-dense taxol/carbo - GOG 262

Chan et al. NEJM, 2016.

In those who did not receive bevacizumab, weekly taxol extended PFS by 3.9 months

Dose-dense regimens

• JGOG 3016• Conventional arm: D1 carboplatin AUC 6 + taxol 180 mg/m2

• Dose-dense arm: D1 carboplatin AUC 6 + taxol 80 mg/m2 on D1, 8, 15• Included stage II-IV, gave 6 cycles (but could add 3 additional cycles if

measurable lesions with PR or CR)• Asian patients with better survival than prior trials in USA/Europe

• GOG 262 • Same arms but could add bevacizumab 15 mg/kg q21 days starting cycle 2

• 85% opted in

• Stratified based on bevacizumab use (patient/provider selection)• Included stage II-IV, gave 6 cycles

Bevacizumab in upfront setting – GOG 218

Bevacizumab in upfront setting – GOG 218

Primary endpoint: PFSHR 0.72 (95% CI 0.63-0.82)

14.1 vs. 10.3 months

No difference in OS on final analysis

BEV-throughout compared to controlHR 0.96 (95% CI 0.85-1.09)

BEV-initiation compared to controlHR 1.06 (95% CI 0.94-1.20)

Median OS for stage IV BEV-throughout (42.8 months) similar to median OS for

stage III patients in all 3 arms (44.3 months, 42.9 months, 44.2 months)

Burger et al. NEJM, 2011.Burger et al. ASCO, 2018.

Testing too many hypotheses? GOG 252

Walker et al. SGO 2016.

GOG 252 – No difference in PFS

HR Proficient

~47%

Non-BRCA

HR Deficient

~33%

Germline

BRCAmut

~14%

Somatic

BRCAmut

~6%

Beyond BRCA mutations – homologous recombination deficiency (HRD)

Konstantinopoulos et al. Cancer Discov, 2015.

~50% high grade serous ovarian cancer patients have HRD which may also determine potential benefit from

targeted therapies

PARP Inhibitors Yield Synthetic Lethality in Patients With HRD• PARP inhibitors prevent repair of single-strand breaks, which accumulate and generate double-strand breaks

• People with HRD cannot repair double-strand breaks, which triggers cell death

HRD, homologous recombination deficiency; PARP, poly ADP ribose polymerase.

Sonnenblick A, et al. Nat Rev Clin Oncol. 2015;12(1):27-41.

Single-strand break

PARP

PARP inhibitors

Double-strand breaks

Repair by homologous recombination

No homologousrecombination or repair

Cell survival Cell death DNA repaired

Normal Cell Cell with HRD

Sonnenblick et al. Nat Rev Clin Oncol, 2015.

FDA approved PARP inhibitorsOlaparib Rucaparib Niraparib

2014 Recurrence treatmentgBRCA3 or more prior linesStudy 19

2016 Recurrence treatmentgBRCA or sBRCA2 or more prior linesARIEL 2

2017 Recurrence maintenancegBRCA or sBRCAPlatinum sensitiveSOLO 2

Recurrence maintenancePlatinum sensitive2 or more prior linesNOVA

2018 Primary maintenancegBRCA or sBRCASOLO 1

Recurrence maintenancePlatinum sensitive2 or more prior linesARIEL 3

PARP inhibitor toxicities and MDS risk

Moore K. SGO Distillation, 2019.Matulonis et al. SGO, 2019.

PARP inhibitor dose reductionsOlaparib100 mg (tablet)150 mg (tablet)

Rucaparib300 mg (tablet)250 mg (tablet)200 mg (tablet)

Niraparib100 mg (capsule)

Starting dose 300 mg PO BID 600 mg PO BID 300 mg PO daily

First dose reduction 250 mg PO BID 500 mg PO BID 200 mg PO daily*(start at this dose if <77 kg or plt <150K)

Second dose reduction

200 mg PO BID 400 mg PO BID 100 mg PO daily

Third dose reduction

300 mg PO BID

SOLO 1 – PARP inhibitor maintenance in the upfront setting

Moore et al. ESMO, 2018.

Testing paradigms – timing of germline and somatic testing

Moore K. SGO Distillation, 2019.Would miss ~5% of germline BRCA if relied on somatic testing alone

Fallopian tube as the origin of ovarian cancer

• BRCA mutation carriers undergoing risk-reducing salpingo-oophorectomy (RRSO)• SEE-FIM protocol: Sectioning and Extensive Examining of the FIMbria

• Precursor lesions:• p53 signature• STIC lesions (serous tubal intraepithelial carcinoma) – present in 50-60% of

high grade serous ovarian cancers Perets et al. Cancer Res, 2016.

Prophylactic salpingectomy in women at high-risk for ovarian cancer

TUBA (Netherlands) WISP (USA)

Strategy RRSO age 35-40 for BRCA1RRSO age 40-45 for BRCA2d-RRO age 40-45 for BRCA1d-RRO age 45-50 if BRCA2

Normal pelvic US and CA-125 within 6 months

N 384 (50) 190 (270)

BRCA1/BRCA2 51%/49% 51/39%

Selected d-RRO 72% 52%

Primary outcome Menopause-related QOL Change in sexual function using FSFI (female sexual function index)

Future trials will be needed to determine efficacy (n=3000) Lu et al. SGO, 2019.Steenbeek et al. SGO, 2019Herzog. SGO Distillation, 2019.

Opportunistic salpingectomy

• Salpingectomy at time of gynecologic surgical procedure (i.e., hysterectomy) or as permanent sterilization technique

• Opportunity to decrease (but not eliminate) ovarian cancer

• Does not blood supply to the ovaries

• Should not alter the surgical approach to surgery

CervicalCancer

2007- National HPV vaccination program12/2017- Primary HPV testing q5 years (age 25-69)

Elimination threshold of cervical cancer prediction6 new cases/100,000 by 2020<4 new cases/100,000 by 2028

Hall et al. Lancet Public Health, 2019.

2009 FIGO cervical cancer staging

2018 FIGO cervical cancer staging

Stage IA – lateral extent not considered

Old stage IB1 divided into:Stage IB1 <2 cmStage IB2 2-4cm

New stage IB3 for ≥ 4 cm

New stage IIIC1 (pelvic nodes)New stage IIIC2 (para-aortic nodes)

r for radiologicp for pathologic

If in doubt… use lower stage

Surgical management of early stage cervical cancer – LACC trial

- Stage IA1 (+LVSI), IA2, or IB1 cervical cancer- Randomized to minimally invasive vs. abdominal radical hysterectomy- Primary outcome: disease-free survival at 4.5 years

MIS associated with worse DFS and OS

3-year DFS97.1% MIS vs. 91.2% openHR 3.74 (95% CI 1.63-8.58)

3-year OS99.0% MIS vs. 93.8 open

HR 6.00 (95% CI 1.77-20.30)

Unanswered questions after LACC trial

• What is the mechanism to explain worse survival?• No differences in adjuvant therapy (~30% in both arms)

• Are there a subgroup of appropriate candidates for MIS surgery?• <2 cm• Microscopic

• What about robotic-assisted laparoscopic surgery?• Only 15% were robotic (vs. laparoscopic) in LACC trial• Robotic-assisted approach to cervical cancer (RACC) RCT planned in Sweden

Immunotherapy mechanism of action

An effective antitumor immune response requires:

• Presentation of cancer antigens and activation of T cells

• Trafficking of T cells to tumors and infiltration into tumors

• Killing of tumor cells by T cells

Singh et al Gastroenterology Report, 2015.

Anti-PD1 immunotherapy for cervical cancer

Pembrolizumab – KEYNOTE 158 (basket trial)

• 98 patients with recurrent/metastatic cervical cancer

• Pembrolizumab 200 mg IV every 3 weeks until unacceptable toxicity or progression

• Approval based on 79% of cohort who had PD-L1 + (CPS ≥ 1) who had received at least one line of chemotherapy for metastatic disease

• ORR 14.3% (2.6% CR, 11.7% PR)

• 91% had response duration ≥ 6 months; median response duration not reached

• No responses if CPS <1

• Serious adverse reaction in 39%, discontinued due to adverse reactions in 8%

• Most frequent serious adverse reactions: anemia (7%), fistula (4%), hemorrhage (4%), infections not including UTIs (4%)

Managing immunotherapy toxicities

• Immune-specific toxicity profile• Thyroiditis, hypophysitis, colitis, pancreatitis, pneumonitis, myocarditis, uveitis, arthritis,

hepatitis, vasculitis, nephritis, Guillain-Barre

• Usually develop in first few weeks/months, but can even develop after cessation of therapy

• Dose adjustments are not recommended holding drug or immunosuppression• Grade 2: 0.5 mg/kg/day prednisone

• Grade 3: 1-2 mg/kg/day prednisone

• Infliximab (TNF-alpha inhibitor)

• Most grade 4 toxicities necessitate permanent discontinuation (exception: grade 4 endocrinopathy can sometimes be medically managed)

Brahmer et al. J Clin Oncol, 2018.

UterineCancer

Siegel et al. CA Cancer J Clin, 2018.

The obesity epidemic and its link to endometrial cancer

https://www.cdc.gov/obesity/data/prevalence-maps.html

Sentinel lymph node (SLN) mapping

- Usually only sentinel pelvic lymph node maps, consider para-aortic sampling for high-risk tumors (i.e., grade 3, deep myoinvasion, positive pelvic nodes) especially if would change management i.e., radiation fields

https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf

SLN algorithm

• FIRES trial• 385 patients with clinical stage I

endometrial cancer

• Indocyanine green (ICG) dye

• 86% had mapping of at least 1 sentinel node

• Sensitivity 97.2%

• NPV 99.7%

• To minimize false-negatives, perform complete dissection for unmapped sides and remove any suspicious nodes Rossi et al. Lancet Oncol, 2017.

https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf

Tumor mutational burden – increased in endometrial cancers

Immunotherapy

Pembrolizumab200 mg IV q3 weeks

(KEYNOTE 016, 164, 012, 028, 158)

MSI-H/dMMR cancern = 149

Endometrial cancern = 14

Objective response rate 39.6%95% CI 32-48%

36%95% CI 13-65%

Median duration of response (months)

NR1.6+, 22.7+ 4.2+, 17.3+

Pembrolizumab package insert

PORTEC-3De Boer et al. Lancet Oncol, 2018.

GOG 258Matei et al. ASCO, 2017

GOG 249Randall et al. ASTRO, 2017.

Population Stage I grade 3 deep invasion and/or LVSI; stage II/III;serous/clear cell

Stage III-IV, optimally debulking Stage I with high-intermediate risk factors (GOG 99) or serous/clearcell), stage II

Treatment arms

RT48.6 Gy in 1.8 Gy fractionsCTRTcisplatin 50 mg/m2 D1, D28 of RT) followed by carbo AUC 5 + taxol715 mg/m2 q21d x 4 cycles

CTcarbo AUC 6 x taxol 175 mg/m2 q21d x 6 cyclesCTRTcisplatin 50 mg/m2 D1, D28 of RT) followed by carbo AUC 5 + taxol715 mg/m2 q21d x 4 cycles

PXRTpelvic radiation 45 Gy or IMRT + boost if serous/clear cell/stage IIVCB/Cvaginal cuff brachy + carbo AUC 6 + taxol 175 mg/m2 x 3 cycles

Results 5-year OS: 77% RT vs. 82% CTRT (HR 0.79 95% CI 0.57-1.12)5-year FFS: 69% vs. 76% (HR 0.77 95% CI 0.58-1.03)

RFS 0.9 (95% 0.74-1.10) 3-year RFS 82% both arms3-year OS 91% PXRT 88% VCB/C

Conclusion Adjuvant chemo did not improve 5-year FFS and OS compared to RT aloneStage III FFS improved with CTRT by 11% at 5 years

No difference in RFS or estimated 5-year OSFewer distant metastases in CT alone group at expense of more vaginal and nodal recurrences

No difference in RFS and OSNo difference in vaginal or distant recurrences (18% distant in both groups)More nodal recurrences in VCB/C

Adjuvant therapy for uterine-limited leiomyosarcoma – GOG 277 unanswered

Chemo arm:Estimated PFS 18.1 monthsEstimated OS 34.3 months

Observation arm: Estimated PFS 14.6 monthsEstimated OS 46.4 months

Closed for accrual futility after 4 years(38/216 enrolled)

Hensley et al. J Clin Oncol, 2018.

Adding olaratumab to doxorubicin for soft tissue sarcoma treatment

• Anti-platelet derived growth factor receptor alpha monoclonal antibody (anti-PDGF) in combination with doxorubicin for unresectable or metastatic soft tissue sarcoma

• 133 patients enrolled in randomized phase II trial

• Approximately 40% study population had leiomyosarcoma

Tap et al. Lancet, 2016.

ANNOUNCE phase III trial does not support use of olaratumab

• Did not meet primary endpoints of OS in the full study population or in the leiomyosarcoma subpopulation

• No new safety signals

• Do not initiate olaratumab outside of a clinical trial

• If currently receiving olaratumab, may continue if patient is receiving benefit and after consultation with their physician

https://investor.lilly.com/node/40206/pdf

ClinicalTrials • On average, FDA drug approval takes…

• $2.6 billion dollars in R&D

• At least 10 years

• Only 1 in 10 drugs tested in phase I trials make it to FDA approval

http://phrma-docs.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf

Clinical trials Crisis in GYN Cancers

https://www.sgo.org/wp-content/uploads/2012/09/SGO-Clinical-Trial-Crisis-FINAL.pdf

Precision medicine trial designs

Sample of GYN ONC clinical trials at UABPrimaryOvarian

RecurrentOvarian

RecurrentUterine

PrimaryCervical

RecurrentCervical

NACT or PDS:IP GEN-1 with taxol/carboTaxol/carbo +/-metformin/placebo

Platinum resistant:Cedirinib vs. cedirinib/PARP vs. chemo (GY005)Imaging study with weekly taxol + bev

Prior chemo:Olaparib vs. cedirinib vs. olaparib/cedirinib(GY012)Anti-PD1 for MSI-S or MSI-H (GARNET)

Surgical candidate:Cvx SPORE vaccine after completion of primary therapy

Prior GOG 240regimen:Anti-PD1 +/- CTLA4 (GOG3028)

IP cisplatin:antiemetic study

Platinum sensitive:Weekly CDK7i + carbo

Not surgical candidate:Primary chemorads+/- triapine (GY006)Pre-tx atezolizumabprior to primary chemorads (GY017)

To refer a patient for clinical trial eligibility

GYN ONC CLINICAL TRIALS

Trey Leath, MD cleath@uabmc.edu

Rebecca Arend, MD rarend@uabmc.edu

PHASE 1 CLINICAL TRIALS