A study to compare divarasib plus pembrolizumab with standard treatment (pembrolizumab plus chemotherapy) in people with untreated non-small cell lung cancer that has a change in a gene called KRAS G12C and has spread

1. Why is this study needed?

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. NSCLC usually develops in the tissues lining the lungs and can spread to nearby lymph nodes and other organs. Standard first treatment for NSCLC that has spread includes a type of medicine that helps a person’s natural defence (immune system) to attack cancer cells, called ‘immunotherapy’. Immunotherapy, such as pembrolizumab, is usually given with platinum-based chemotherapy. Around 1 in 10 people with NSCLC have a specific change (mutation) in their KRAS gene called a KRAS G12C mutation. This causes cancer cells to grow out of control. Combining immunotherapy with therapy that targets this mutation may work better than current standard treatment for NSCLC with this type of mutation.

This study is testing a combination of medicines called divarasib plus pembrolizumab. It is being developed to treat previously untreated NSCLC that has spread. Divarasib is a targeted therapy that may work well against NSCLC with a KRAS G12C mutation. Divarasib is an experimental medicine. This means health authorities (like the U.S. Food and Drug Administration and European Medicines Agency) have not approved divarasib on its own or in combination with pembrolizumab for the treatment of NSCLC. This study aims to compare the effects of divarasib plus pembrolizumab versus standard first treatment (pembrolizumab plus chemotherapy) in people with NSCLC with a KRAS G12C mutation that has spread.

2. Who can take part in the study?

People of at least 18 years of age who have not been treated previously for NSCLC that has spread can take part in the study if they cannot be treated with surgery, chemotherapy or radiotherapy with an intent to cure. The NSCLC must also have a change known as ‘G12C’ in the KRAS gene. People may not be able to take part if they have a type of NSCLC that starts in flat cells known as squamous cells, if NSCLC has spread to the brain or spinal cord and causes symptoms, or if the NSCLC has other changes in certain genes and there are specific treatments available for it. People who are pregnant, or currently breastfeeding cannot take part in the study. 

3. How does this study work?

People will be screened to check if they are able to participate in the study. The screening period will take place from 1 month before the start of treatment. Everyone who joins this study will be placed into 1 of 2 groups randomly (like flipping a coin) and given either:

• Divarasib, given as a tablet (to be swallowed) every day plus pembrolizumab, given as a drip into the vein every 3 weeks OR
• Pembrolizumab plus platinum-based chemotherapy, given as drips into the vein every 3 weeks

Participants will have an equal chance of being placed in either group. This is an open-label study. This means everyone involved, including the participant and the study doctor, will know the study treatment the participant has been given.

During this study, the study doctor will see participants every 1 to 3 weeks. They will see how well the treatment is working and any unwanted effects participants may have. Participants will receive treatment until their disease worsens or unwanted effects are not tolerable. Participants will have a follow-up visit 1 month after completing the study treatment, during which the study doctor will check on the participant’s wellbeing. The study doctor will continue to check on participants’ health by visits, telephone calls, or through their medical records every 3 months for as long as they agree to it, until the study ends. Total time of participation in the study could be more than 5 years depending when a person joins. Participants have the right to stop study treatment and leave the study at any time, if they wish to do so.

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

The main results measured in the study assess if the medicine has worked by looking at how long participants live and how long participants live without their cancer getting worse.

Other key results measured in the study include:

• How many participants have a reduction of their cancer after treatment
• How much time there is between the participant’s cancer first responding to treatment and the cancer getting worse
• Change in participants’ health and how their cancer symptoms impact their daily life and their ability to function and enjoy life
• The number of participants with scores that improve, worsen, or stay the same in questionnaires which measure how well they can function and how their lung cancer affects their daily life
• The time it takes for a person to have a significant worsening in cancer symptoms (cough, difficulty breathing and chest pain) and their ability to function and enjoy life
• The number and seriousness of unwanted effects

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. It may not be fully known at the time of the study how safe and how well the study treatment works.

The study involves some risks to the participant. But these risks are generally not greater than those related to routine medical care or the natural progression of the health condition. People interested in taking part will be informed about the risks and benefits, as well as any additional procedures or tests they may need to undergo. All details of the study will be described in an informed consent document. This includes information about possible effects and other options of treatment.

Risks associated with divarasib, pembrolizumab and chemotherapy (pemetrexed, carboplatin and cisplatin)

Participants may have unwanted effects of the medicines used in this study. These unwanted effects can be mild to severe, even life-threatening, and vary from person to person. During this study, participants will have regular check-ups to see if there are any unwanted effects. Participants will be told about the known unwanted effects of divarasib, pembrolizumab and chemotherapy and possible unwanted effects based on human and laboratory studies or knowledge of similar medicines. Known unwanted effects of these medicines include frequent watery stools and throwing up. Known unwanted effects of a drip into a vein include throwing up, low or high blood pressure, fever, pain or discomfort in the head, frequent watery stools, shortness of breath, cough, and hair loss.

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.