What are first-line (1L) clinical trials?

What are first-line trials and why should colorectal cancer patients consider them?

First-line (1L) clinical trials are trials that newly diagnosed stage IV CRC patients enroll on BEFORE they have started any form of treatment.

1L trials are interesting to patients because usually, they combine standard of care **plus** a novel agent or procedure. This means patients can get what they would otherwise get from their oncologist in terms of treatment, but have the opportunity to get something additional on top of the standard of care in a 1L trial. Being on a clinical trial means patients get a higher standard of care with more frequent check-ins.

We know that we don’t have many good lines of therapy for metastatic or stage IV CRC. One way to improve outcomes in CRC is to test if novel drugs added to standard of care 1L options can extend the benefit from 1L chemo. Usually, these drugs have already been tested in later line settings (in chemo-refractory patients– patients whose cancer has progressed on multiple lines of therapy). This means the common side effects to expect from these novel drugs maybe already known from these studies, and most likely they may have shown some promise in the later line settings.

The 1L trials are testing these novel drugs (or already approved drugs in later line settings) in combination with standard of care chemo to see if they would provide improved response rates or better duration of response or both for metastatic CRC patients.

1L trials also means for the potential additional benefit patients may experience, patients may also be exposed to potential additional side effects from the novel agent or combination. For patients with more wide spread disease (as against low volume disease, which is also called oligometastatic disease, where the patient has 1 or 2 liver mets or lung mets at diagnosis, where the outcomes are excellent if these are the only mets they will ever have), we know the outcomes can be quite variable. Patients may not know at the outset if they are in the category where their tumors respond exceptionally well to 1L chemo. Our hope is that everyone’s tumors respond exceptionally well to 1L chemo, but that’s not always the case. So for such patients, getting on a 1L clinical trial can be one potential way to improve outcomes. Whether a 1L trial is a good option for you is something you need to discuss carefully with your care team. But if you didn’t know that a 1L trial is an option, you cannot have this discussion. That’s why this post about 1L trials.

The issue with 1L trials is that once you start standard of care 1L chemotherapy, even if it’s 1 cycle, you may not be eligible for 1L trials. This makes it quite challenging for patients. Immediately after their diagnosis, they will need to learn about 1L trials. Then decide if this would be a good option for them, then have the discussion with their care team and if yes, get enrolled quickly, so there is no time lost in the process.

Many 1L trials also require that the patient know their biomarker results — whether their tumor is MSS or MSI-H, whether their tumor is BRAF or KRAS mutated or have HER2 or ERBB2 amplification etc. Because the trials maybe for a specific subgroup of patients with a particular mutation. This testing may be part of the trial in many cases. Here’s some great information from CTU about biomarker testing.