Letrozole + Abemaciclib vs Pembrolizumab for Endometrial Cancer

Recruiting at 6 trial locations

Overseen By Panagiotis Konstantinopoulos, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: CDK4/6 inhibitors, CYP3A4 inducers

Disqualifiers: Active infections, Brain metastases, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 4

Duration: Up to 2 years

76 Participants Needed

Trial Summary

What is the purpose of this trial?

A standard treatment for endometrial cancer is chemotherapy and pembrolizumab together followed by pembrolizumab maintenance for two years. This treatment regimen has shown benefit in terms of delaying cancer progression in prior clinical trials, but the benefit of the pembrolizumab maintenance treatment and whether all participants need it is unclear. This research is being done on the maintenance portion of treatment to compare the efficacy between the combination of letrozole + abemaciclib and pembrolizumab alone following chemotherapy and pembrolizumab. The names of the study drugs involved in this study are: * Abemaciclib (a type of cyclin-dependent kinase (CDK) inhibitor) * Letrozole (a type of aromatase inhibitor) * Pembrolizumab (a type of monoclonal antibody)

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that you cannot use certain medications that strongly interact with the study drugs. You may need to switch these medications before starting the trial.

What data supports the effectiveness of the drug pembrolizumab for endometrial cancer?

Pembrolizumab has been approved for treating advanced endometrial cancer, especially in cases with specific genetic features like microsatellite instability-high (MSI-H) or mismatch repair deficient (MMRd), and has shown effectiveness in combination with lenvatinib for broader endometrial cancer cases. ^{1 2 3 4 5}

What is known about the safety of Letrozole + Abemaciclib vs Pembrolizumab for Endometrial Cancer?

The safety of pembrolizumab (Keytruda) has been studied in combination with lenvatinib for endometrial cancer, showing common side effects like high blood pressure, low thyroid function, diarrhea, nausea, vomiting, loss of appetite, tiredness, and weight loss. This information may help understand the safety of pembrolizumab in other combinations, but specific safety data for Letrozole + Abemaciclib vs Pembrolizumab is not provided. ^{2 3 4 6 7}

How does Letrozole + Abemaciclib differ from Pembrolizumab for endometrial cancer?

Letrozole + Abemaciclib is a unique combination being studied for endometrial cancer, potentially offering a different mechanism of action compared to Pembrolizumab, which is an immunotherapy drug that helps the immune system attack cancer cells. Letrozole is an aromatase inhibitor (a drug that lowers estrogen levels), and Abemaciclib is a CDK4/6 inhibitor (a drug that blocks proteins involved in cell division), which may provide a novel approach compared to the immune-based action of Pembrolizumab. ^{2 3 4 5 8}

Research Team

Panagiotis Konstantinopoulos, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for individuals who have experienced a recurrence of endometrial cancer and carry the TP53 gene mutation. Participants must have completed initial chemotherapy with pembrolizumab and are now considering maintenance therapy.

Inclusion Criteria

I can swallow and keep down pills.

My cancer is estrogen receptor-positive.

I am deemed suitable for maintenance therapy with pembrolizumab alone.

Exclusion Criteria

I am not pregnant or breastfeeding.

I have no stomach or bowel problems affecting medicine absorption.

I currently have an active infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either Abemaciclib + Letrozole or Pembrolizumab following chemotherapy

Up to 2 years

Every 3 or 6 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Regular imaging and assessments

Treatment Details

Interventions

• Abemaciclib
• Letrozole
• Pembrolizumab

Trial Overview The study compares two maintenance treatments after standard chemo and pembrolizumab: one group receives Letrozole with Abemaciclib, while another continues Pembrolizumab alone. The goal is to see which method is more effective in delaying cancer progression.

Participant Groups

Group I: Arm 2B: Pembrolizumab Every 6 Weeks Experimental Treatment 1 Intervention

Participants will be stratified by Primary Stage IVb (4b) vs. Primary Measurable Stage III (3) /IVa (4a) vs. Recurrent Endometrial Cancer and will complete study procedures as follows: * Baseline visit with X-ray, CT, MRI, or PET scan. * Predetermined dose of Pembrolizumab 1x every 6 weeks for up to 2 years. * X-ray, CT, MRI, or PET scan every 9 weeks for first 9 months, then every 12 months. * End of Treatment visit with assessments and X-ray, CT, MRI, or PET scan. * Follow up for up to 3 years.

Group II: Arm 2: Pembrolizumab Every 3 Weeks Experimental Treatment 1 Intervention

Participants will be stratified by Primary Stage IVb (4b) vs. Primary Measurable Stage III (3) /IVa (4a) vs. Recurrent Endometrial Cancer and will complete study procedures as follows: * Baseline visit with X-ray, CT, MRI, or PET scan. * Predetermined dose of Pembrolizumab 1x every 3 weeks for up to 2 years. * X-ray, CT, MRI, or PET scan every 9 weeks for first 9 months, then every 12 months. * End of Treatment visit with assessments and X-ray, CT, MRI, or PET scan. * Follow up for up to 3 years.

Group III: Arm 1: Abemaciclib + Letrozole Experimental Treatment 2 Interventions

Participants will be stratified by Primary Stage IVb (4b) vs. Primary Measurable Stage III (3)/IVa (4a) vs. Recurrent Endometrial Cancer and will complete study procedures as follows: * Baseline visit with X-ray, CT, MRI, or PET scan. * Cycles 1 through 3: --Days 1 through 21 of 21 day cycle: Predetermined dose of Abemaciclib 2x per day. Predetermined dose of Letrozole 1x per day. * Cycle 4 and every 2 cycles thereafter: --Days 1 through 21 of 21 day cycle: Predetermined dose of Abemaciclib 2x per day. Predetermined dose of Letrozole 1x per day. * X-ray, CT, MRI, or PET scan every 9 weeks for first 9 months, then every 12 months. * End of Treatment visit with assessments and X-ray, CT, MRI, or PET scan. * Follow up for up to 3 years.

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

In a study of 44 women with advanced or recurrent MMRd/MSI-H endometrial adenocarcinomas treated with pembrolizumab, obesity (BMI≥30) was linked to a higher disease control rate (85.2%) compared to those with a BMI<30 (59.8%).

Patients with obesity also experienced significantly longer progression-free survival (PFS) while overall survival (OS) rates remained similar regardless of BMI, suggesting that body weight may influence treatment outcomes with pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obesity is associated with improved progression-free survival in Microsatellite-Instability-High endometrial cancer treated with pembrolizumab. Bernard, L., How, JA., Patel, S., et al.[2023]

In a study of 48 patients with recurrent endometrial cancer treated with pembrolizumab and lenvatinib, the best objective response rate was 23.8%, indicating a lower effectiveness compared to clinical trial results.

The treatment was associated with notable side effects, with 56.2% of patients requiring a dose reduction of lenvatinib and 16.7% discontinuing treatment due to adverse events, highlighting the importance of monitoring for safety in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea. Kim, J., Noh, JJ., Lee, TK., et al.[2022]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

The combination of lenvatinib and pembrolizumab is effective for treating advanced endometrial carcinoma, particularly in patients who have not responded to prior therapies, with manageable safety profiles similar to each drug used alone.

Common adverse reactions include hypothyroidism (51% incidence), fatigue, hypertension, and nausea, which typically occur within the first 10 weeks of treatment and can be effectively managed with dose adjustments and supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab. Makker, V., Taylor, MH., Oaknin, A., et al.[2022]

Checkpoint inhibitors like pembrolizumab and dostarlimab have become important treatment options for endometrial carcinoma, particularly for tumors that are mismatch repair deficient or have a high mutational load.

The review highlights the need for personalized immunotherapy approaches based on the distinct molecular subtypes of endometrial cancer, as these subtypes exhibit different characteristics that could influence treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Facts and Hopes in Immunotherapy of Endometrial Cancer. Marín-Jiménez, JA., García-Mulero, S., Matías-Guiu, X., et al.[2023]

In a study of 43 patients with recurrent endometrial cancer treated with lenvatinib and pembrolizumab, 84% experienced significant adverse events (AEs), with hypertension and weight loss being the most common.

Patients starting on a reduced dose of lenvatinib (10 mg or 14 mg) had significantly longer progression-free survival compared to those on the standard dose (20 mg), suggesting that dose optimization may improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. Zammarrelli, WA., Ma, W., Espino, K., et al.[2023]

The combination of lenvatinib and pembrolizumab shows significant clinical benefits for patients with endometrial carcinoma, with a safety profile consistent with each drug's individual use, primarily involving manageable side effects like hypertension and hypothyroidism.

Effective management of lenvatinib's common adverse events is crucial to maximize its efficacy, as most side effects can be prevented or mitigated through proactive monitoring and intervention during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. Lorusso, D., Danesi, R., Locati, LD., et al.[2023]

The combination of pembrolizumab and lenvatinib has shown promising efficacy in treating advanced endometrial cancer, with previous trials indicating improved objective response rates and survival outcomes compared to standard chemotherapy.

This ongoing phase 3 trial aims to determine if pembrolizumab plus lenvatinib is superior to the chemotherapy regimen of paclitaxel plus carboplatin in newly diagnosed patients, with a target enrollment of about 875 participants and results expected in 2022.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. Marth, C., Tarnawski, R., Tyulyandina, A., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Obesity is associated with improved progression-free survival in Microsatellite-Instability-High endometrial cancer treated with pembrolizumab. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Facts and Hopes in Immunotherapy of Endometrial Cancer. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. [2022]