Dr. Jeannine Villella, Chief of Gynecologic Oncology at Lenox Hill Hospital, provides a comprehensive update from the Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer. Dr. Villella breaks down what the research presented at the conference means for you and discusses new developments.
Report Back from SGO: What’s the Latest in Uterine Cancer?
1. Report Back from SGO:
What's the Latest in Uterine
Cancer?
Vice Chair, Gynecology
Chief, Gynecologic Oncology
Lenox Hill Hospital, Northwell Health
Associate Professor, Department of Obstetrics & Gynecology
Donald and Barbara Zucker School of Medicine
at Hofstra/Northwell
Jeannine Villella, DO, FACOG, FACS
2. Uterine Cancer
• Annually in USA
• 65,620 new cases
• 12,590 deaths
• 6th leading cause of cancer death for
women in US
• One of few cancers for which there is
rising incidence and decreasing survival
• Source of disparity in heath outcomes
• black women diagnosed at more advanced
age
• worse 5-year survival outcomes
• Unmet need
• due to rising incidence
• leading cause of health disparities
6. Obesity and cancer
• Known association
• Breast cancer in
postmenopausal women,
colon, endometrial, esophagus
(adenocarcinoma) and kidney
cancers
• Suspected association
• Pancreas, gallbladder, thyroid,
ovary, cervix, multiple
myeloma, Hodgkin’s lymphoma
and aggressive prostate cancers
6
Trends in Overweight Prevalence (%)
Adults 18 and Older, US, 1992-2005
Obesity causes
>280,000 deaths in
the US annually
7. Obesity and women’s cancer
• Research suggests that as fat cells
increase in size, the composition of
their lipid membrane changes in a
manner that may make these cells
more prone to triggering
inflammation.
7
8. Obesity and women’s cancer
• Increased estrogen production (aromatization of testosterone in fat cells)
increases the risk of endometrial, ovarian and breast cancers.
8
9. Weight loss and cancer risk reduction
• Weight loss reduces the incidence of
cancer
• Two large cohort studies from Sweden
and the U.S.
• Lower cancer incidence and
decreased risk of death in women
undergoing bariatric surgery
compared to BMI-matched controls
9
Sjostrom, Lancet 2009
10. Lynch Syndrome
• Only about 3-5% of uterine cancers are associated with Lynch Syndrome
• Prevalence 1:600-1:3000
• Associated with younger-onset cancers
• In over 50% of cases, endometrial cancer was the presenting cancer
36
11. Lynch Syndrome: Surveillance
recommendations
• Screening strategies for early detection of endometrial or ovarian cancer in patients with Lynch
Syndrome have not been shown to be cost-effective.
• Transvaginal ultrasound has poor sensitivity
• Endometrial biopsy at intervals of 1-2 years has been shown to reliably detect endometrial cancer, but an
effect on mortality has not been validated.
41
Age Frequency Modality
Colon Cancer 20-25* 1-2 years Colonoscopy
Uterine Cancer 30-35 1-2 years
Endometrial biopsy
(not TVS)
Ovarian Cancer --- ---- ----
*or 2-5 years before the earliest cancer diagnosis in the family
12. Lynch Syndrome: Risk Reducing Surgery
• TLH/BSO for women who have
completed child-bearing.
• Recommended at age 40-45*
• REDUCES RISK TO 0%
Moller, Gut BMJ 2017
• 40
*or 2-5 years before the earliest cancer diagnosis in the family
13. Evolution of treatment for endometrial cancer
since 2003
• Laparotomy was most common
• Hysterectomy + Lymphadenectomy
• Adjuvant radiation +/- chemotherapy
• Lap 2 Protocol
• Laparoscopy with similar oncologic outcomes
• Less complications
• Improved patient satisfaction, LOS
• Sentinel Lymph Node
• Alternative to lymphadenectomy
• Decreased lymphedema
• Similar oncologic outcomes
• Less complications
• Improved patient satisfaction
• Portec Studies
• Narrowed down indications for radiation
• Vaginal radiation utilized in most circumstances
24. Single agent immune checkpoint has activity in recurrent MMR deficient
(MSI-high) endometrial cancer
Pembrolizumab approved 2017 for any solid tumor that is MMR deficient or MSI-high
Up to 30% of endometrial cancers MMR-d/MSI-high
# of endometrial cancer
pts (MMR deficient)
RR Duration of response range
Pembrolizumab 14 36% 4.2 to 17.3 months
Avelumab 15 27% Not reported
Dostarlimab 103 46% Not reached
Durvalumab 35 40% Not reported
Pembrolizumab package insert; Konstantinopoulos et al. J Clin Oncol. 2019;
ESMO 2020, ASCO 2019
Response rates much lower in MMR proficient (microsatellite stable cancers) and not FDA approved
25. Combination pembrolizumab and lenvatinib
in MSS/MMRp endometrial cancer
• Lenvatinib
• Small molecule TKI
• Targets VEGFR1-3, FGFR1-4, PDGFR, KIT, RET
• FDA-approved for thyroid cancer, RCC, HCC
• Mechanism of synerhy with
pembrolizumab unclear
• May prevent VEGF-medicated immune
suppression
• Decrease in tumor-associated macrophages
• Common side effects
• Hypertension
• Fatigue/Asthenia
• Diarrhea
• Weight loss
Pembrolizumab + lenvatinib for recurrent MSS (stable) endometrial cancer due to
unmet need for these patients: received accelerated FDA approval in Sept 2019
based on Phase II results
Makker V et al. Lancet Oncology. 2019;20(5):711-718; Makker V et al. 2020 SGO Annual Meeting. Abstract 10.
26. Lenvatinib/pembrolizumab compared to chemotherapy in
advanced/recurrent endometrial cancer
(phase III KEYNOTE-775/ Study 309)
Makker, V. Abstract 37/ ID 11512, Society of Gynecologic Oncologists 2021 Virtual Annual Meeting, March 19, 2021
N= 827 patients
27. Lenvatinib/pembrolizumab is associated
with significant side effects
Makker V, et al. Abstract 37/ ID 11512, Society of Gynecologic Oncologists Virtual Annual Meeting, March 19, 2021
29. Takeaways on lenvatinib/pembrolizumab
• KEYNOTE-775 establishes lenvatinib/pembrolizumab as a standard
of care for women with recurrent pMMR endometrial cancer
• BUT, need to keep in mind these caveats:
• Comparator arm was doxorubicin or paclitaxel
• Platinum-based chemotherapy may be highly efficacious for a subset of endometrial
cancer
• Activity of pembrolizumab monotherapy in dMMR endometrial cancers is substantial
and remains the standard of care for these patients
• If hormone receptor positive:
• Hormonal therapies may be active in ER/PR+ endometrial cancers (everolimus/letrozole with
32% ORR, 42% in endometrioid1; Palbociclib/letrozole 63.6% disease control rate at 24
weeks2)
• Regimen is associated with significant toxicities
• 30% discontinuation rate
• Pro-actively follow and educate patients for lenvatinib-associated toxicities
• Further development of lenvatinib/pembrolizumab in LEAP-001
• Pembrolizumab/lenvatinib versus standard-of-care therapy.
(carboplatin/paclitaxel) in newly diagnosed advanced endometrial cancer
• Enrollment ongoing
30. Other immune checkpoint inhibitor and TKI combinations
also are being explored in endometrial cancer
33. Dostarlimab is associated with
clinically meaningful and durable response
• Phase I Dostarlimab for patients with recurrent or advanced MMRd endometrial cancer
• Anti-PD-1 Dostarlimab 500 mg IV Q3W for 4 cycles, then 1000 mg Q6W
• N= 104
• Median age 64 years
• Medium follow-up 11.2 months
• Single arm study
• ORR 42%
• CR 13%
• PR 30%
• Likelihood of maintaining disease response 96% (6 months) and 77% (12 months)
Oaknin, A, et al. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325.
Society of Gynecologic Oncologists Virtual Annual Meeting, March, 2020
34. GARNET Trial: Dostarlimab Delivers Durable Responses in
dMMR/MMRp Endometrial Cancer
Interim analysis of the immune-related endpoints of the mismatch repair deficient (dMMR) and
proficient (MMRp) endometrial cancer cohorts
• Recurrent and advanced with progression on platinum based on treatment
• dMMR IHC with <2 lines of therapy
• N= 110 dMMR/ MSI-High
• Median Follow up of 16.5 mos
• ORR 46% MSI-High/ dMMR
• Disease control rate (DCR 63.6%)
• N= 144 MMRp * group with poor prognosis and limited treatment options
• Median Follow up of 13.7 mos
• ORR 14% MSI-stable/ MMRp
• Disease control rate (DCR 63.6%)
• 19% had UPSC MMRp
• Also included carcinosarcoma
Oaknin A, Gilbert L, Tinker AV, et al. Interim analysis of the immune-related endpoints of the mismatch repair deficient (dMMR) and proficient (MMRp)
endometrial cancer cohorts from the GARNET study. Presented at: 2021 SGO Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021; virtual.
Abstract ID 10417, Society of Gynecologic Oncologists Virtual Annual Meeting, March, 2021
References -Oaknin, A, et al. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325.
36. Targeting HER2 in endometrial cancer
• ERBB2 encodes Her2/neu, a
member of the EGFR tyrosine
kinase receptor family
• Preferred dimerization
partners of EGFR family
members
• Activation via Her2 signaling
drives cell cycle progression,
proliferation, and metastases
• Focally amplified in ~24-45% of
uterine serous cancers (USC)
38. Trastuzumab in combination with carboplatin and paclitaxel prolongs
survival in HER2-amplified USC
Fader A et. al, J Clin Oncol 2018; Fader, A et. al., Clin Can Res 2020
Fader A et al. Society of Gynecologic Oncologists Virtual Annual meeting, March 2020
40. Trastuzumab in combination with carboplatin and paclitaxel
improved OS in patients with advanced Her2-amplified USC
Fader et. al, Clin Can Res 2020
42. Adavosertib (AZD1775) inhibits WEE1 and may be
most active in p53-mutant background
• Single arm phase II trial
• WEE-1 inhibitor
• “synthetic lethality” in P53 mutated patients
• P53 mutations cause loss of G1/S checkpoint
• So it relies on G2/ M checkpoint and this is
what Adavosertib blocks thus causing
“replication stress”
• recurrent or persistent uterine serous cancer
• 30% ORR
• PFS 6 months
• Duration of response 9 mos
• 55% needed dose reduction
Liu, Joyce. Et. al, Society of Gynecologic Oncologists Virtual Annual Meeting, March, 2021
43. Metformin in endometrial cancer does not change outcome
• GOG 238B: C/T/Metformin BID vs. C/T + Placebo
• Phase 2/3 study
• Stage ¾ recurrent disease
• Didn’t change OS or PFS
• BMI did not make a difference
• Stopped due to futility
• Racial Disparities did show that AA did worse and had more UPSC
• Subset of AA with UPSC have lower response rate to therapy
• N=91
• 43% vs 64%
• Worse OS HR 2.0
• Worse PFS and OS
44. Clinical trial disparities in endometrial cancer outcomes
• Black women 9.8 fold lower enrollment in clinical trials
• “Deep South” have multiple barriers that exist
• Program development to increase enrollment in clinical trials
• New endometrial cancer patients assigned lay navigator with clinical trial education module
mandatory for all patients
• 23 out of 277 black women (8.3%) enrolled in clinical trials
• This increased 1.15 fold higher enrollment as expected for black women
• Improved PFS was seen in black women who enrolled in clinical trials using this program
• Conclusion: clinical trial disparities can be overcome with specific interventions aimed at improving
care for black women
Jones N et al. Abstract 10966 Society of Gynecologic Oncologists Virtual Annual Meeting, March, 2021.
45. Landscape of therapy in endometrial cancer is changing
• “Start of a new era in endometrial cancer clinical trial drug
development and improved patient outcomes” (Ursula Matulonis, MD, ASCOPOST.com, 4/10/2021)
• Molecular characterization of endometrial cancers is important!
• MSI/MMR status, TMB. Next-gen sequencing highly desirable
• Immunotherapy and immunotherapy combinations
• PD1/PDL1 inhibitors are active as monotherapy in MSI-H/MMRp endometrial
cancer
• Pemrolizumab/Lenvatinib is active in MSS/MMRp endometrial cancer
• Ongoing trials exploring additional combinations
• No immunotherapy or immunotherapy combinations has been tested directly
against 1st line chemotherapy yet in endometrial cancer
• Her2-directed therapy
• Addition of trastuzumab to carboplatin/paclitaxel improves outcomes in
advanced Her2-amplified uterine serous cancer
• Novel Her2 therapies and combinations in development
47. Lenox Hill Gynecologic Oncology
110 East 59th Street
Suite 10D
New York, NY 10022
212-434-3770
gynonclx@northwell.edu
Vice Chair, Gynecology
Chief, Gynecologic Oncology
Lenox Hill Hospital, Northwell Health
Associate Professor, Department of Obstetrics & Gynecology
Donald and Barbara Zucker School of Medicine
at Hofstra/Northwell
Jeannine Villella, DO, FACOG, FACS
Editor's Notes
Endometrial cancer is the winner from SGO this year with a lot of interesting data I am excited to share with you.
This was a big focus this year the racial disparities in endometrial cancer.
Cancer is prevalent in the society.
1 out of 2 men and 1 out of 3 women will develop cancer in their lifetime.
Cancer can start almost anywhere in the human body, which is made up of trillions of cells.
Normally, human cells grow and divide to form new cells as the body needs them. When cells grow old or become damaged, they die, and new cells take their place.
When cancer develops, however, this orderly process breaks down. As cells become more and more abnormal, old or damaged cells survive when they should die, and new cells form when they are not needed. These extra cells can divide without stopping and may form growths called tumors.
Many cancers form solid tumors, which are masses of tissue. Cancers of the blood, such as leukemias, generally do not form solid tumors.
Cancerous tumors are malignant, which means they can spread into, or invade, nearby tissues. In addition, as these tumors grow, some cancer cells can break off and travel to distant places in the body through the blood or the lymph system and form new tumors far from the original tumor.
Progression of events during metastatic disease.
At the start of metastatic progression, tumor cells dissociate and locally invade tissue surrounding a primary tumor.
Invasive tumor cells can eventually intravasate across the endothelial barrier and circulate through the bloodstream or lymphnodes.
These cells will then further adapt to the new secondary site and proliferate to form new macroscopic tumor sites at other sites called metastases.
Many factors contribute to the changes in a cell that result in cancer.
These risk factors may be intrinsic to an individual, such as the gender, age, or genes. But most are external, in the individual’s general environment.
The interplay between the intrinsic and external factors is the major determinant of an individual’s cancer risk.
The most important modifiable risk factors for cancer are tobacco use, a diet high in saturated fats and with an insufficient intake of fresh fruits and vegetables, Physical Inactivity, Use of alcohol and infection with viruses or bacteria that cause cancer.
I think one of the most concerning (and modifiable) causes of cancer is obesity. Although slightly outdated, this slide highlights the obesity epidemic. In 2005, over 50% of the adults in all states, including District of Columbia, were overweight or obese, compared to just 12 states in 1992. And we know this problem is only getting worse
Although smoking is still #1, obesity should be considered #2 cause of preventative death in the United States.
Obesity should be thought of as a state of chronic low-grade inflammation, which increases cancer risk for several reasons.
Fat cells may also have direct and indirect effects on other tumor growth regulators, including mammalian target of rapamycin (mTOR) and AMP-activated protein kinase
Other possible mechanisms
Altered immune responses
Effects on the nuclear factor kappa beta system
Oxidative stress
Aromatization: testosterone is chemically converted to estrogen, predisposing patients to uterine and breast cancers.
Fig. 1 Different mechanisms of estrogen dependence for hormone related breast cancer in premenopausal and in postmenopausal women. In premenopausal women, the main site of synthesis of circulating estrogen is the ovary, whilst in postmenopausal women is the adipose tissue, which produces the enzymes aromatase that converts the androgens androstenedione and testosterone into estrone and estradiol. Moreover, obesity, being associated with metabolic
Aromatization: testosterone is chemically converted to estrogen, predisposing patients to uterine and breast cancers.
In a study published in the Lancet a few years ago, the authors demonstrated that patients who underwent bariatric surgery had a significant decrease in cancer incidence compared to those that did not.
Studies of screening strategies have included small numbers of patients, and not all included patients have had confirmed DNA mutations (some were diagnosed based on family history alone)
Progestin as a therapy in treatment of hyperplasia and endometrial cancer (56,57)
HRT following TLH/BSO has not been specifically studied in Lynch patients
Primary surgery is still the mainstay of treatment for early stage and debulkable advanced stage tumors; and for some recurrent disease patients.
Chemo response rates are pretty good, but toxicities and duration of response are not optimal
Over the past 10-20 years scientists have been looking how to use the immune system to recognize and fight cancers
As a result, a Dramatic increase in the number of immunotherapy clinical trials was seen in the past decade
In fact it was scientific breakthrough of the year.
The immune system and recognizes that cancer cells are foreign. NOT SELF. This is an important concept. How and why does this happen?
While the immune system can deactivate tumor cells, the reverse is true: tumor cells can turn off the effect of immune cells and herein lies a challenge with immunotherapy.
Most common toxicity was by far HTN > 37.9% in study arm.
89% of patients had grade # tox in study arm.
Pem/ Len showed stat sig and clinically meaningful improvement in OS and PFS and ORR vs chemo regardless of MMR status in patients who progressed after prior platinum based therapy. This is the confirmatory trial of the KEYNOTE-146/ Study 111 which supported the US FDA 2019 accelerated approval of the combination in adv endo ca that is not dMMR or MSI-H.
Dual primary endo=points met at median follow p of 11.4 months. Len/Pem decreased risk of recurrence or death by 44% (p<.0001) and the risk of death by 38%
Previous phase III trials showed higher single agent response rates with either doxorubicin or paclitaxel
Future trials should look at molecularly targeted agents that are appropriate for specific histologic and genetic features of tumor. Problem with this is that it will take a very long time to accrue to the trial.
Toxicity of this combination is significant, and we need to dose lenvatinib based on factors such as weight, PS and comorbidities. We need some objective criteria to select appropriate starting doses.
Methods: This is a multicenter, open-label, single-arm, dose-escalation and cohort-expansion study.
Here, we report on 2 independent expansion cohorts of pts with recurrent or advanced EC (dMMR EC
and MMRp EC, determined by immunohistochemistry [IHC]) that progressed on or after a platinum based chemotherapy regimen. Pts received
until disease progression, discontinuation, or withdrawal. The primary endpoints of objective response
rate (ORR) and duration of response (DOR) by blinded independent central review (BICR) using RECIST
v1.1, and safety have been reported previously.1 Immune-related endpoints (irORR and irDOR by
irRECIST) are based on IA, and are prespecified secondary endpoints.
Results: In total, 126 dMMR and 145 MMRp pts identified by IHC were enrolled and dosed. Of these,
103 dMMR and 142 MMRp pts had measurable disease at baseline by BICR, and sufficient follow-up
time (6 mo) for the primary efficacy analyses. 110 dMMR and 144 MMRp pts had measurable disease at
baseline by IA and sufficient follow-up time (6 mo) and were included for efficacy analysis of irORR and
irDOR; some additional pts were considered to have measurable disease at baseline by IA.Efficacy data
based on irRECIST are shown in the table. irORR was 45.5% in dMMR pts, and 13.9% in MMRp pts.
Conclusions: Efficacy endpoints reported by RECIST v1.1 and irRECIST show similar results. irDCR was
particularly of interest in the MMRp cohort, a group with a poorer prognosis. The potential benefit seen
in this single-arm trial awaits confirmation in ongoing randomized controlled studies.References -
Oaknin, A, et al. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325.
LBA36.Funding: GlaxoSmithKline
Randomized Phase II Stage III, IV or recurrent tumors
PFS and OS best for advanced disease not as good for recurrent disease