A Study of Immune Checkpoint Inhibitor Combinations With Axitinib in Participants with Previously Untreated Locally Advanced Unresectable or Renal Cell Carcinoma that has Spread from One Part of the Body to the Other

1. Why is this study needed?

Renal cell carcinoma (RCC) is the most common form of kidney cancer that originates in the cells lining the small tubes within the kidney, called renal tubules. In locally advanced or metastatic RCC, the cancer cells grow outside the kidneys and spread to other body parts. Sometimes RCC is ‘unresectable’ meaning it cannot be removed completely with surgery. Cancer treatment often includes a combination of drugs. However, these may not work for all patients, or at all times. Therefore, there is always a need to find new combinations of treatments.

This study is testing drugs called tobemstomig and tiragolumab, in combination with axitinib and comparing this to the combination of pembrolizumab with axitinib. The U.S. Food and Drug Administration (US FDA) have already approved the combination of pembrolizumab and axitinib as a standard of care in patients with RCC. However, in this study, tobemstomig in combination with axitinib, or tiragolumab in combination with tobemstomig and axitinib is experimental. This means health authorities (like the US FDA and European Medicines Agency) have not approved these combinations as a treatment for locally advanced unresectable or metastatic RCC.

This study aims to assess the safety of tobemstomig plus axitinib and tobemstomig plus tiragolumab plus axitinib as compared with pembrolizumab plus axitinib in people with previously untreated RCC that has spread to other parts of the body.

2. Who can take part in the study?

People who were at least 18 years old with RCC that could not be surgically removed or had spread to other parts of the body, took part in this study. People could not take part in this study if they had RCC that has spread to the brain and spinal cord, if they had certain other medical conditions, or had received any prior treatments for RCC. Women who were pregnant, or breastfeeding could not participate in the study.

3. How does this study work?

People were checked by the appropriate clinical staff to see if they were able to participate in the study. This review period took place for about 28 days before the start of treatment.

Everyone who joined this study was split into 3 groups (Groups A, B and a Control group) randomly (like flipping a coin). Participants received either tobemstomig plus axitinib (Group A) or tobemstomig plus tiragolumab plus axitinib (Group B) or pembrolizumab plus axitinib (Control group). Tobemstomig, tiragolumab and pembrolizumab were given as a drip into the vein (infusion) every 3 weeks and axitinib was given as tablets, to be taken by mouth twice a day (BID). Treatment may continue up to 24 months or until participants experience any unwanted side effects, their cancer worsens, or they withdraw from the study, whichever occurs first. Since the main results of this study showed reduced benefit and increased unwanted effects in Group A and B compared to the Control group with increased unwanted effects, all participants receiving treatment as a part of this study are recommended to stop the study treatment and take other cancer treatments outside of this study. However, the participant's study doctor, in consultation with the participant, may decide to allow the participant to continue to receive treatment as part of the study if the potential benefit of continuing treatment is greater than the potential risks.

Participants will be seen by the clinical trial doctor regularly. These visits will include checks to see how the participant is responding to the treatment and any unwanted effects they may be having. Participants will have follow-up visits up to 3 months after completion of the study treatment, during which the study doctor will check on the participant’s well-being. Total time of participation in the study will be up to 28 months, depending on how the cancer responds to treatment. Participants have the right to stop study treatment and leave the study at any time if they wish to do so.

This was an open-label study. This means everyone involved, including the participant and the study doctor, knew the study treatment the participant had been given.

4. What are the main results measured in this study?

The main result measured in the study is to determine the number of participants with unwanted effects and its severity in Group A and B as compared to the Control group.

5. Are there any risks or benefits in taking part in this study?

Taking part in the study may or may not make participants feel better. But the information collected in the study can help other people with similar health conditions in the future. The study involves some risks to the participant. People interested in taking part were informed about the risks and benefits, as well as any additional procedures or tests they had to undergo. All details of the study were described in an informed consent document. This includes information about possible effects and other options of treatment.

Risks associated with the study drugs
Participants may have unwanted side effects of the drugs used in this study. These unwanted side effects can be mild to severe, even life-threatening, and vary from person to person. During this study, participants are having regular check-ups to see if there are any unwanted side effects.

Participants were told about the known side effects and possible side effects of tobemstomig, tiragolumab, pembrolizumab, and axitinib based on human and laboratory studies or knowledge of similar medicines.

Tobemstomig
Known side effects include allergic reactions; symptoms may include itching, difficulty breathing (dyspnoea), chest pain, rash, drop in heart rate (bradycardia), drop in blood pressure (hypotension), loss of consciousness, a blush of purplish discoloration of the skin.

Tiragolumab
Known side effects include inflammation of the liver, also called hepatitis, (with symptoms of yellowing of skin, pain in the stomach area, nausea, vomiting, itching, feeling tired or weak (fatigue), bleeding or bruising under the skin, and dark urine.

Pembrolizumab
Known side effects include decrease in the number of red blood cells (anaemia), feeling less hungry, headache, cough, diarrhoea, nausea, vomiting, constipation, stomach pain, skin rash, fever, itching and high blood pressure (hypertension).

Axitinib
Known side effects include high blood pressure (hypertension), increased levels of protein in urine (proteinuria), diarrhoea, bleeding (haemorrhage), increased or decreased thyroid function (hyperthyroidism or hypothyroidism), and inflammation of kidneys (nephritis).

Tobemstomig, tiragolumab, and pembrolizumab were given as a drip into a vein. Known side effects with infusion include irritation with symptoms of fever, chills, rash, swelling, itching, redness, pain, headache, changes in blood pressure, vomiting. The study medicines may be harmful to an unborn baby. Women and men must take precautions to avoid exposing an unborn baby to the study treatment.