What side effects are associated with this type of intervention?

Common treatments for Renal Cell Carcinoma (RCC) include targeted therapies and immunotherapies. Targeted therapies like sunitinib and pazopanib often cause side effects such as hypertension, hand-foot syndrome, diarrhea, and hypothyroidism. Immunotherapies, including checkpoint inhibitors like pembrolizumab, can lead to immune-related adverse effects such as colitis, hepatitis, pneumonitis, and endocrinopathies. Belzutifan, a HIF-2α inhibitor, is being studied for its efficacy and safety, and while specific side effects are still being evaluated, it may share some adverse effects common to other targeted therapies.

What prior FDA approvals exist?

The FDA has approved several treatments for Renal Cell Carcinoma (RCC), including targeted therapies and immunotherapies. Notably, Pembrolizumab, an anti-PD-1 therapy, has shown efficacy in various RCC settings, including in combination with other agents. While specific FDA approvals for HIF-2α inhibitors like Belzutifan are not detailed in the provided context, other targeted therapies such as VEGFR inhibitors (e.g., sunitinib, pazopanib) and mTOR inhibitors (e.g., everolimus) have been approved for RCC treatment. These therapies aim to inhibit pathways critical for tumor growth and angiogenesis, similar to the mechanism of action of HIF-2α inhibitors.

What other types of research exist?

Promising novel alternatives to Belzutifan for RCC patients in 2024 include: 1) Pembrolizumab (an immune checkpoint inhibitor) either alone or in combination with other agents like lenvatinib or axitinib, 2) Cabozantinib (a VEGFR inhibitor) which has shown efficacy in various RCC subtypes, and 3) Combination therapies involving immune checkpoint inhibitors and VEGFR inhibitors, such as nivolumab plus cabozantinib. These alternatives have demonstrated significant efficacy in clinical trials and are expected to be key options in RCC treatment.

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HIF-2 Alpha Inhibitor

Belzutifan + Pembrolizumab for Kidney Cancer

Q: What is the mechanism of action of this treatment?

The most common treatments for Renal Cell Carcinoma (RCC) include tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors, and HIF-2α inhibitors like Belzutifan. TKIs, such as sunitinib, work by blocking the vascular endothelial growth factor (VEGF) pathway, which is crucial for tumor angiogenesis. Immune checkpoint inhibitors, like pembrolizumab, enhance the immune system's ability to recognize and destroy cancer cells by targeting proteins such as PD-1/PD-L1. HIF-2α inhibitors, such as Belzutifan, target the hypoxia-inducible factor pathway, which is involved in the adaptation of cancer cells to low oxygen environments, promoting their survival and growth. These mechanisms are vital for RCC patients as they directly interfere with the tumor's ability to grow, spread, and evade the immune system, thereby improving disease-free survival and overall outcomes.

Phase 3

Waitlist Available

Research Sponsored by Merck Sharp & Dohme LLC

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days before randomization

Has intermediate-high risk, high risk, or M1 no evidence of disease (NED) RCC as defined by specific pathological tumor-node metastasis and tumor grading criteria

Must not have

Has received prior systemic therapy for RCC

Has a pulse oximeter reading <92% at rest, requires intermittent supplemental oxygen, or requires chronic supplemental oxygen

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to approximately 89 months

Awards & highlights

Pivotal Trial

Summary

This trial is testing a new treatment in patients who have had kidney cancer surgery. The goal is to see if this treatment can prevent the cancer from coming back. One part of the treatment stops cancer cells from surviving in low oxygen, and the other part helps the immune system attack the cancer. This approach has shown improved survival rates in treating advanced kidney cancer.

Who is the study for?

This trial is for adults who've had kidney cancer surgery within the last 12 weeks. They should have a certain level of risk for their cancer returning but no current evidence of disease spread, and must be in good physical condition (ECOG 0-1). Participants need proper organ function and can't join if they've had major recent surgeries, severe heart issues, active infections or autoimmune diseases, other cancers within 3 years, or specific lung conditions.

What is being tested?

The study tests if taking belzutifan pills with pembrolizumab injections works better than placebo pills with pembrolizumab for preventing kidney cancer from coming back after surgery. The main goal is to see which combination leads to longer periods without the disease returning.

What are the potential side effects?

Possible side effects include immune system reactions that could affect organs like lungs or intestines, fatigue, skin problems, hormonal gland issues (like thyroid), and infusion-related reactions from the IV treatment.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am fully active or restricted in physically strenuous activity but can do light work.

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My kidney cancer is at an intermediate-high, high risk, or I have no signs of cancer after it spread.

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I have kidney cancer with limited spread that can be surgically removed.

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I had surgery to remove my primary cancer and any isolated spread.

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My kidney cancer diagnosis includes clear cell characteristics.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have received treatment for kidney cancer before.

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I need extra oxygen sometimes or all the time.

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My cancer has spread to my brain or bones.

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I have had radiation therapy for kidney cancer.

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I have an autoimmune disease treated in the last 2 years, except for hormone replacement.

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I have had serious heart problems in the last 6 months.

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I have an immune system disorder or am on long-term steroids.

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I have received an organ or tissue transplant from another person.

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I do not have serious wounds, ulcers, fractures, or need dialysis.

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I have or had lung inflammation that needed steroids.

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I am currently being treated for an infection.

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I have a history of HIV or Hepatitis B/C.

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I have not received a live vaccine within the last 30 days.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to approximately 89 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to approximately 89 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to approximately 89 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Disease-Free Survival (DFS)

Secondary study objectives

Kidney

Change From Baseline in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score

Change From Baseline in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score

+6 more

Side effects data

From 2024 Phase 3 trial • 804 Patients • NCT03040999

64%

Radiation skin injury

63%

Stomatitis

58%

Anaemia

56%

Nausea

48%

Dry mouth

45%

Constipation

45%

Weight decreased

44%

Dysphagia

42%

Neutrophil count decreased

33%

Dysgeusia

33%

Vomiting

32%

Fatigue

31%

White blood cell count decreased

28%

Hypomagnesaemia

26%

Decreased appetite

25%

Hypothyroidism

25%

Hypokalaemia

24%

Lymphocyte count decreased

24%

Platelet count decreased

23%

Oropharyngeal pain

23%

Blood creatinine increased

22%

Diarrhoea

22%

Odynophagia

20%

Hypoacusis

20%

Alanine aminotransferase increased

20%

Hyponatraemia

19%

Tinnitus

19%

Oral candidiasis

19%

Asthenia

16%

Pyrexia

16%

Cough

15%

Aspartate aminotransferase increased

15%

Rash

14%

Insomnia

13%

Acute kidney injury

13%

Pharyngeal inflammation

13%

Pruritus

12%

Dysphonia

12%

Gamma-glutamyltransferase increased

11%

Pneumonia

11%

Dehydration

10%

Hyperthyroidism

10%

Hypoalbuminaemia

10%

Hypocalcaemia

10%

Headache

10%

Productive cough

Neck pain

Peripheral sensory neuropathy

Gastrooesophageal reflux disease

Hiccups

Hyperglycaemia

Hyperuricaemia

Dizziness

Hypophosphataemia

Urinary tract infection

Ear pain

Localised oedema

Hyperkalaemia

Erythema

Oral pain

Abdominal pain upper

Arthralgia

Anxiety

Febrile neutropenia

Dyspepsia

Saliva altered

Back pain

Oedema peripheral

Hypertension

Dyspnoea

Nasopharyngitis

Alopecia

Dry skin

Sepsis

Pneumonia aspiration

Trismus

Pneumonitis

Laryngeal oedema

Malnutrition

Pharyngeal haemorrhage

Cellulitis

Septic shock

Systemic infection

Clostridium difficile colitis

Cardiac arrest

Death

Bronchitis

Hepatitis

Immune-mediated hepatitis

Oesophagitis

General physical health deterioration

Hypophagia

Tumour haemorrhage

Cerebrovascular accident

Syncope

Acute respiratory failure

Aspiration

Colitis

Mouth haemorrhage

Hypersensitivity

Acute myocardial infarction

Abscess neck

Device related infection

Stoma site infection

Vascular device infection

Wound infection

Hypercalcaemia

Pulmonary embolism

Respiratory failure

100%

80%

60%

40%

20%

Study treatment Arm

Pembrolizumab + CRT Followed by Pembrolizumab

Placebo + CRT Followed by Placebo

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Group I: Placebo + PembrolizumabExperimental Treatment2 Interventions

Participants receive placebo orally QD for up to approximately 54 weeks PLUS pembrolizumab 400 mg via IV infusion once Q6W for up to 9 administrations (up to approximately 54 weeks).

Group II: Belzutifan + PembrolizumabExperimental Treatment2 Interventions

Participants receive belzutifan 120 mg orally once daily (QD) for up to approximately 54 weeks PLUS pembrolizumab 400 mg via intravenous (IV) infusion once every 6 weeks (Q6W) for up to 9 administrations (up to approximately 54 weeks).

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Belzutifan

2018

Completed Phase 1

~50

Placebo

1995

Completed Phase 3

~2670

Pembrolizumab

2017

Completed Phase 3

~3150

0 / 18Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Renal Cell Carcinoma (RCC) include tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors, and HIF-2α inhibitors like Belzutifan. TKIs, such as sunitinib, work by blocking the vascular endothelial growth factor (VEGF) pathway, which is crucial for tumor angiogenesis. Immune checkpoint inhibitors, like pembrolizumab, enhance the immune system's ability to recognize and destroy cancer cells by targeting proteins such as PD-1/PD-L1. HIF-2α inhibitors, such as Belzutifan, target the hypoxia-inducible factor pathway, which is involved in the adaptation of cancer cells to low oxygen environments, promoting their survival and growth. These mechanisms are vital for RCC patients as they directly interfere with the tumor's ability to grow, spread, and evade the immune system, thereby improving disease-free survival and overall outcomes.

The future of tyrosine kinase inhibitors: single agent or combination?