Report Back from SGO: What’s the Latest in Uterine Cancer?
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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.
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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
- 4. Metastases
- 5. Genetic Mutations: Modifiable and Non-Modifiable Risks
- 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
- 14. Chemotherapy for advanced/recurrent endometrial cancer
- 15. New advances in endometrial cancer therapy • Immunotherapy • Immunotherapy combinations • Targeted therapy • HER2 – directed therapy • WEE1 - targeted therapy (adavosertib) • Improving hormonal therapy • Systemic • Local
- 17. Precision Therapy Patient Factors Drug Factors Tumor Factors Optimized Interaction
- 18. Classification of uterine cancers Murali et al., Lancet Oncol 2014
- 20. The Nobel Prize for 2018: Cancer Immunotherapy
- 21. Immune system recognizes cancers
- 22. Immunotherapy No cancer cell death Cancer cell death
- 23. Doukas S. et al. September 2019
- 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
- 28. Lenvatinib/pembrolizumab improves PFS and OS compared to chemotherapy
- 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
- 31. Immune checkpoint inhibitors are active in MSI-H/MMR deficient endometrial cancer
- 32. POLE-mutated tumors may have high sensitivity to immune checkpoint therapy
- 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.
- 35. Hormonal therapy is active in some endometrial cancers
- 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)
- 37. HER2-directed monotherapy in endometrial cancer has had limited activity
- 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
- 39. Trastuzumab in combination with carboplatin and paclitaxel prolonged PFS in HER2-amplified USC
- 40. Trastuzumab in combination with carboplatin and paclitaxel improved OS in patients with advanced Her2-amplified USC Fader et. al, Clin Can Res 2020
- 41. Building on hormonal therapy in endometrial cancer
- 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
- 46. Endometrial cancer: not one size fits all!
- 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