A clinical trial to look at the safety and activity of GDC-6036 at different doses in combination with pembrolizumab or other anti-cancer therapies in people with untreated non-small cell lung cancer that has a KRAS G12C mutation and has spread

1. Why is the BO44426 clinical trial needed?

Non−small cell lung cancer (NSCLC) is the most common type of lung cancer. New treatments are needed that improve health outcomes for people living with NSCLC that has spread to nearby tissue (also called ‘locally advanced’) or to other parts of the body (also called ‘metastatic’) and who have not previously received treatment for NSCLC. Standard first treatments for locally advanced or metastatic NSCLC includes medicines that help the body’s immune system to attack tumours (known as ‘immunotherapy’), such as pembrolizumab, given with or without chemotherapy. Pembrolizumab treatment is used when cancer cells have a protein called PD-L1 (known as a ‘biomarker’). PD-L1 positive cancer cells are more difficult for the immune system to find and destroy. Pembrolizumab blocks the activity of PD-L1 to help the immune system fight cancer cells.

Around 1 in 10 people with NSCLC have cancer cells with a change (mutation) in the KRAS gene, called a KRAS G12C mutation, that makes the cancer cells grow out of control. Recent research has shown that NSCLC cells with a KRAS G12C mutation are often PD-L1 positive as well. A drug called GDC-6036 has been designed to block the activity of the KRAS G12C mutation.

In this clinical trial, researchers will assess how safe and how well GDC-6036 works to block cancer cell growth when given with pembrolizumab in people with locally advanced or metastatic NSCLC that is PD-L1 positive with a KRAS G12C mutation.

2. How does the BO44426 clinical trial work?

This clinical trial is recruiting people with locally advanced or metastatic NSCLC that has not been treated before. In addition, the NSCLC must be positive for the PD-L1 protein and have the KRAS G12C mutation. The purpose of this clinical trial is to test the safety and activity of GDC-6036 at different doses in combination with pembrolizumab and to understand how the body processes these drugs. Participants will be given the clinical trial treatment GDC-6036 combined with pembrolizumab in 21-day treatment periods (called treatment ‘cycles’) until their trial doctor decides that they do not benefit from the treatment anymore. Participants will be seen by the clinical trial doctor every week for the first 3 treatment cycles, then every 2 weeks during cycles 4 and 5, and then every 3 weeks for all remaining treatment cycles. These hospital visits will include checks to see how the participant is responding to the treatment and any side effects they may be having. Participants’ total time in the clinical trial will depend on how their NSCLC responds to treatment. This could range from 1 day to more than 2 years. After being given the final dose of clinical trial treatment, the trial doctor will follow up with participants every 3 months for as long as they agree to it. Participants can stop trial treatment and leave the clinical trial at any time.

3. What are the main endpoints of the BO44426 clinical trial?

The main endpoints (the main results that are measured in the trial to see if the treatment has worked) of this clinical trial are the number of side effects and how well different doses of GDC-6036 in combination with pembrolizumab are tolerated.

The other endpoints include:

• How many participants have a decrease in the size of their tumours (known as ‘overall response rate’)
• How much time passes between participants’ cancer first responding to treatment and cancer getting worse (known as ‘duration of response’)
• How much time passes between the start of the trial and participants’ cancer getting worse (known as ‘progression-free survival’)
• The seriousness of side effects and how they affect participants’ daily lives
• How GDC-6036 moves around the body

4. Who can take part in this clinical trial?

People can take part in this trial if they are at least 18 years of age and have locally advanced or metastatic NSCLC that is positive for PD-L1 and has a KRAS G12C mutation.

People may not be able to take part in this trial if they have:

• Previously received any medicine for locally advanced or metastatic NSCLC unless treatment for non-metastatic cancer was last given more than one year previously
• Received certain other treatments, including other KRAS G12C inhibitors
• Cancer that has spread to the brain or spinal cord and causes symptoms, and is untreated or is currently being treated with certain medicines
• Certain other medical conditions such as heart problems or hepatitis virus infection; they are pregnant or breastfeeding or are planning to become pregnant during or soon after the trial.

5. What treatment will participants be given in this clinical trial?

Everyone who joins this clinical trial will be given GDC-6036, as a tablet (taken by mouth), once a day until their trial doctor decides that they do not benefit from the treatment anymore AND Pembrolizumab, given as an infusion (into the vein) every 3 weeks until their trial doctor decides that they do not benefit from the treatment anymore. The clinical trial is split into two treatment stages. Participants will be placed into one of the two stages, depending on when they start the trial. In the first stage, participants will be given a low dose (200mg) of GDC-6036 plus pembrolizumab for researchers to assess the safety and how well the body tolerates the treatment. If the low dose of GDC-6036 is shown to be acceptable, the second stage of the trial can begin. In the second stage, participants will be given either a low (200mg) or high dose (400mg) of GDC-6036 plus pembrolizumab. Participants will have an equal chance of being placed in either the low-dose or high-dose group. This is an open-label trial, which means everyone involved, including the participants and the doctors, will know which dose of GDC-6036 is given in combination with pembrolizumab.

6. Are there any risks or benefits in taking part in this clinical trial?

The safety or effectiveness of the experimental treatment may not be fully known at the time of the trial. The trial involves some risks to the participant, although it may not be greater than the risks related to routine medical care or the natural progression of the health condition. Potential participants will be told about any risks and benefits of taking part in the clinical trial, as well as any additional procedures, tests, or assessments they will be asked to undergo. These will all be described in an informed consent document (a document that provides people with the information they need to decide to volunteer for a clinical trial). Potential participants should also discuss these with members of the research team and with their usual healthcare provider.

Risks associated with the clinical trial drugs

Participants may have side effects (an unwanted effect of a drug or medical treatment) from the drugs used in this clinical trial. Side effects can be mild to severe and even life-threatening, and can vary from person to person. Potential participants will be told about the known side effects of GDC-6036 and pembrolizumab, and where relevant, also potential side effects based on human and laboratory studies or knowledge of similar drugs. GDC-6036 will be given as an oral tablet (given by mouth). Participants will be told about any known side effects of taking tablets. Pembrolizumab will be given as an infusion (into the vein). Participants will be told about any known side effects of infusions.

Potential benefits associated with the clinical trial
Participants' health may or may not improve from participation in the clinical trial, but the information that is collected may help other people who have a similar medical condition in the future.

For more information about this clinical trial see the For Expert tab on the specific ForPatients page or follow this link to ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT05789082