Exploring the DUO-E Indication and Clinical Data With Principal Investigator Dr Shannon Westin

Introduction

 

Hello! Thank you for joining me today. I’m Dr Shannon Westin, Professor and Clinical Medical Director in the Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, and today we will discuss the US indication for IMFINZI in combination with carboplatin and paclitaxel in primary advanced or recurrent dMMR endometrial cancer and the data from the DUO-E trial that supported the FDA approval.

 

Before we proceed, I need to note that the opinions expressed in this video are solely my own and do not reflect those of AstraZeneca.

 

IMFINZI Endometrial Cancer Indication and Clinical Data

 

In June 2024, AstraZeneca received FDA approval for IMFINZI in combination with carboplatin and paclitaxel, known as CP, followed by IMFINZI as a single agent for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient, also known as dMMR.^1,2

 

This approval was based on the prespecified exploratory analysis of progression-free survival in the dMMR subgroup that included 95 patients from the DUO-E trial. IMFINZI plus CP led to a 58% reduction in the risk of progression or death, with a hazard ratio of 0.42. The median progression-free survival was not reached in the IMFINZI plus CP arm and was 7 months in the CP arm.^1,3

 

The IMFINZI-based regimen offers an additional treatment option to address a significant need for patients with advanced or recurrent endometrial cancer who have a five-year survival rate below 20%.^1,4,5

 

The DUO-E data add to the body of evidence that support the use of immunotherapy plus CP for patients with endometrial cancer that is mismatch repair deficient. This underscores the importance of determining the mismatch repair status of the patient at diagnosis to offer a precision medicine approach to their treatment.^1,4,6

 

DUO-E Study Design

 

The DUO-E study was a global, randomized, double-blind, placebo-controlled, Phase III study of 718 patients with advanced or recurrent endometrial cancer.³

 

Patients with recurrent disease were required to have at least a 12-month chemotherapy-free interval to the date of their subsequent relapse with chemotherapy being delivered in the adjuvant setting. All histologies were eligible including carcinosarcomas, except sarcomas.³

 

Within the dMMR subgroup, 95 patients received first-line treatment with CP plus IMFINZI (or placebo) at 1120 mg once every three weeks for 6 cycles, followed by maintenance IMFINZI (or placebo) at 1500 mg once every four weeks. All treatments were given until disease progression or unacceptable toxicity.³

 

For more details on the DUO-E trial design and how certain aspects may impact interpretations, consider watching the video called “The DUO-E Study Design: Physician Perspectives on Key Features.”

 

Patient Characteristics in the dMMR Subgroup

 

As for the patient baseline characteristics, these were generally balanced across treatment arms and representative of patients with newly diagnosed advanced or recurrent endometrial cancer.³

 

The DUO-E study was designed to enroll a patient group that is representative of the global real-world population. It included trial sites in North America, Europe and Asia, and included patients with advanced and/or aggressive disease.^3,7

 

In the IMFINZI arm within the dMMR subgroup, 30% of patients enrolled were from Asia, while 70% of patients were from other areas around the world, labeled as non-Asia. This highlights the environmental and genetic diversity of the patients enrolled within the DUO-E study.^3,8

 

Patients in both arms had characteristics associated with aggressive disease⁷:

• 37% had newly diagnosed Stage IV endometrial cancer

• 54% of patients had recurrent endometrial cancer

• 89% of patients had measurable disease at baseline, and

• 22% of patients had serous carcinoma, carcinosarcoma, mixed carcinoma, clear cell adenocarcinoma, or other histologies

 

Prespecified Exploratory Analysis of PFS in the dMMR Subgroup

 

As noted previously, FDA approval was based on the prespecified dMMR subgroup analysis of the DUO-E Phase III trial.^1,3

 

In the dMMR subgroup, IMFINZI in combination with CP followed by IMFINZI as a single agent reduced the risk of disease progression or death by 58%, with the hazard ratio of 0.42.³

 

At the 18-month timepoint, the Kaplan-Meier estimates of progression-free survival were approximately 68% in the IMFINZI plus CP arm and approximately 32% in the CP alone arm. This analysis was exploratory and not designed to assess statistical significance. Another way to think of these data are that approximately 2 of 3 patients were estimated to be alive and progression free in the IMFINZI and CP arm at 18 months and approximately 1 of 3 patients in the CP alone arm.³

 

Post-hoc Exploratory Analysis of OS in the dMMR Subgroup

 

At the interim overall survival analysis, the median OS for the IMFINZI plus CP arm was not reached and was 23.7 months for the CP alone arm. At 18 months, about 86% of patients were estimated to be alive in the IMFINZI plus CP arm and about 66% in the CP alone arm. This post-hoc analysis was not designed to determine significance between the treatment arms. At this analysis, the OS data were immature, at 26%. Therefore, further follow up is needed.⁸

 

Post-hoc Exploratory Analysis of ORR in the dMMR Subgroup

 

In a post-hoc subgroup analysis of ORR in the dMMR subgroup, the objective response rate was approximately 71% in the IMFINZI plus CP arm and approximately 41% in the CP alone arm. Additionally, about 29% of patients achieved a complete response in the IMFINZI plus CP arm and around 10% achieved a complete response in the CP alone arm.⁹

 

Post-hoc Exploratory Analysis of DoR in the dMMR Subgroup

 

For those patients that responded, the median duration of response was not reached in the IMFINZI plus CP arm and was 10.5 months in the CP alone arm. At the 18-month timepoint, the percentage of patients remaining in response was about 75% in the IMFINZI plus CP arm and about 48% in the CP alone arm. Said differently, approximately 3 out of 4 patients that responded were still in response at 18 months in the IMFINZI plus CP arm.⁹

 

Overall, the addition of IMFINZI to CP led to a clinically meaningful improvement in PFS and an ORR around 71%. About 75% of patients treated with IMFINZI and CP who responded were estimated to remain in response at 18 months.^3,9

 

Altogether, the DUO-E data add to the body of evidence that supports the use of immunotherapy plus CP followed by single agent immunotherapy for the treatment of primary advanced and recurrent dMMR endometrial cancer.^1,6

 

Safety and Tolerability Profile for IMFINZI + CP in the dMMR Subgroup

 

While efficacy data are important to emphasize, it is also imperative to review safety and tolerability data of a treatment regimen.¹

 

Safety data are available for a total of 44 patients with advanced or recurrent dMMR endometrial cancer who received IMFINZI with CP followed by IMFINZI as a single agent until disease progression or unacceptable toxicity.¹

 

The median duration of exposure to IMFINZI with CP was 14.8 months, with a range of 0.7 to 31.7 in the dMMR subgroup.¹

 

Serious adverse reactions occurred in 30% of patients who received IMFINZI with CP.¹

 

The most common adverse reactions that occurred in more than 20% of patients (including laboratory abnormalities) were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, decreased magnesium, increased ALT, increased AST, diarrhea, vomiting, cough, decreased potassium, dyspnea, headache, increased alkaline phosphatase, and decreased appetite.¹

 

Clinically relevant adverse reactions in less than 10% of patients who received IMFINZI with CP included autoimmune hemolytic anemia, colitis, immune-mediated thyroiditis, infusion-related reaction, interstitial lung disease, myositis, pneumonitis, pulmonary embolism, and sepsis.¹

 

Permanent discontinuation of IMFINZI due to adverse reactions occurred in 11% of patients.¹

 

Dosage interruptions of IMFINZI due to adverse reactions occurred in 52% of patients.¹

 

DUO-E Clinical Trial Key Points

 

Now that I’ve described the key DUO-E data supporting the FDA approval, I would like to leave you with a few key summary points.

 

The combination of IMFINZI and CP reduced the risk of progression or death by more than a half.³

 

Serious ARs occurred in 30% of patients receiving IMFINZI and CP. The five most common adverse reactions occurring in greater than 40% of patients were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, and fatigue.¹

 

Importantly, the FDA approval of IMFINZI in combination with CP, followed by IMFINZI as a single agent, based on the DUO-E study, provides another option for patients in the treatment of primary advanced or recurrent dMMR endometrial cancer.^1,6

 

Notably, it is important to test for mismatch repair status at diagnosis to ensure patients are eligible to receive precision medicine treatments.⁴

IMPORTANT SAFETY INFORMATION

 

There are no contraindications for IMFINZI^® (durvalumab).

 

Immune-Mediated Adverse Reactions

Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI depending on severity. See USPI Dosing and Administration for specific details. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

 

Immune-Mediated Pneumonitis

IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

 

Immune-Mediated Colitis

IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

 

Immune-Mediated Hepatitis

IMFINZI can cause immune-mediated hepatitis.

 

Immune-Mediated Endocrinopathies

• Adrenal Insufficiency: IMFINZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated.

• Hypophysitis: IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated.

• Thyroid Disorders (Thyroiditis, Hyperthyroidism, and Hypothyroidism): IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated.

  • IMFINZI with Carboplatin and Paclitaxel

    • Immune-mediated hypothyroidism occurred in 14% (34/235) of patients receiving IMFINZI in combination with carboplatin and paclitaxel.

• Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated.

 

Immune-Mediated Nephritis with Renal Dysfunction

IMFINZI can cause immune-mediated nephritis.

 

Immune-Mediated Dermatology Reactions

IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.

 

Other Immune-Mediated Adverse Reactions

The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or were reported with the use of other PD-1/PD-L1 blocking antibodies.

• Cardiac/vascular: Myocarditis, pericarditis, vasculitis.

• Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

• Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

• Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.

• Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.

• Endocrine: Hypoparathyroidism.

• Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection.

 

Infusion-Related Reactions

IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity. See USPI Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.

 

Complications of Allogeneic HSCT after IMFINZI

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT.

 

Embryo-Fetal Toxicity

Based on their mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. In females of reproductive potential, verify pregnancy status prior to initiating IMFINZI and advise them to use effective contraception during treatment with IMFINZI and for 3 months after the last dose of IMFINZI.

 

Lactation

There is no information regarding the presence of IMFINZI in human milk; however, because of the potential for serious adverse reactions in breastfed infants from IMFINZI, advise women not to breastfeed during treatment and for 3 months after the last dose.

 

Adverse Reactions

• In patients with advanced or recurrent dMMR endometrial cancer in the DUO-E study receiving IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent (n=44), the most common adverse reactions, including laboratory abnormalities (occurring in >20% of patients) were peripheral neuropathy (61%), musculoskeletal pain (59%), nausea (59%), alopecia (52%), fatigue (41%), abdominal pain (39%), constipation (39%), rash (39%), decreased magnesium (36%), increased ALT (32%), increased AST (30%), diarrhea (27%), vomiting (27%), cough (27%), decreased potassium (25%), dyspnea (25%), headache (23%), increased alkaline phosphatase (20%), and decreased appetite (18%). The most common Grade 3 or 4 adverse reactions (≥3%) were constipation (4.5%) and fatigue (4.5%).

• In patients with advanced or recurrent dMMR endometrial cancer in the DUO-E study receiving IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent (n=44), permanent discontinuation of IMFINZI due to adverse reactions occurred in 11% of patients. Serious adverse reactions occurred in 30% of patients who received IMFINZI with carboplatin and paclitaxel; the most common serious adverse reactions (≥4%) were constipation (4.5%) and rash (4.5%).

 

The safety and effectiveness of IMFINZI has not been established in pediatric patients.

 

Indication:

IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent is indicated for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) as determined by an FDA-approved test.

 

Please see Full Prescribing Information including Medication Guide for IMFINZI at IMFINZIhcp.com.

 

You are encouraged to report side effects related to AstraZeneca products by calling 1-800-236-9933. If you prefer to report these to the FDA, please call 1-800-FDA-1088.

 

©2025 AstraZeneca. All rights reserved.

US-94253 Last Updated 5/25

1. IMFINZI^® (durvalumab) [Prescribing Information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2025.

2. AstraZeneca. IMFINZI plus chemotherapy approved in the US for mismatch repair deficient advanced or recurrent endometrial cancer. Accessed March 2025. https://www.astrazeneca.com/media-centre/press-releases/2024/imfinzi-approved-in-the-us-for-endometrial-cancer.html

3. Westin SN, Moore K, Chon HS, et al; DUO-E Investigators. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: The Phase III DUO-E Trial. J Clin Oncol. 2024;42(3):283-299.

4. Hamoud BH, Sima RM, Vacaroiu IA, et al. The evolving landscape of immunotherapy in uterine cancer: A comprehensive review. Life (Basel). 2023;13(7):1502.

5. Cao SY, Fan Y, Zhang YF, Ruan JY, Mu Y, Li JK. Recurrence and survival of patients with stage III endometrial cancer after radical surgery followed by adjuvant chemo- or chemoradiotherapy: a systematic review and meta-analysis. BMC Cancer. 2023;23(1):31.