Trial selection needs to change

The problem

A cancer patient—let’s call him John—reaches the end of standard of care. John’s care team suggests he enroll in a clinical trial.

Determining which trials to pursue are among the most critical decisions a patient and care team can make. Trials can represent the best and most cutting-edge science; they can also be ineffectual, relegate patients to treatment arms with poor or outdated options, or restrict the options a patient can pursue next.

So, there’s a lot riding on John’s trial selection.

In the absence of additional information, the care team decides to pursue a trial enrolling in John’s indication but lacking any further biological justification. Maybe it’s a trial running at John’s cancer center, maybe it’s one they heard about at a recent conference.

John gets on the trial. John’s disease progresses.

Unfortunately, John’s story is one we see regularly. Over the past year, we’ve worked with nearly 100 patients across more than a dozen different cancer types. Many of these patients participated in clinical trials before we came into contact with them, and in most of those cases, the patient’s unique tumor biology played only small role in determining the trial they pursued.

In fact, rarely have we seen patients receive thorough molecular analyses before selecting a trial to identify which ones are likeliest to work. In many cases, more basic considerations (e.g., trial location) win the day.

Take the example of a head and neck squamous cell carcinoma (HNSCC) patient we worked with earlier this year. This patient was guided to a trial for an antibody-drug conjugate that targets the protein ROR2. (In other words, it attaches to tumor cells that express ROR2 on the cell surface and kills them with a cytotoxic payload.)

We appreciate the reason this drug seemed attractive to the care team—it’s shown promising early results in a small cohort of HNSCC patients. Unfortunately, our patient did not have a response.

When we performed our diagnostic workup on his sample, we figured out why: his tumor cells don’t express ROR2 highly. In fact, his ROR2 expression is lower than 80% of the HNSCC samples in our database. Given this information, we likely wouldn’t have recommended that he pursue a ROR2-targeting therapeutic in the first place, and we suspect his care team wouldn’t have either.

The consequences

There can be further downstream consequences to poor trial selection.

Several of our patients have actually found themselves excluded from promising trials after pursuing trials that weren’t biologically supported. In the case of our HSNCC patient, his prior participation in the ROR2-targeting trial rendered him ineligible to pursue several trials with a much stronger biological justification, due principally to the fact that these latter trials used the same payload as the ROR2-targeting trial.

Poorly informed trial selection can, and often does, limit future opportunities for treatment.

The solution

Predicting a patient’s response to investigational therapeutics, especially for the patient population we work with, is enormously tricky. It shouldn’t surprise us that many of these patients don’t see a response to any given trial.

But it does concern us that most aren’t even evaluated for expression of the relevant targets.

At Valius, we help patients and their care teams rigorously assess the biological rationale for pursuing different trials.

We’re excited to lead the way towards a world in which patients and their physicians are empowered to make biologically-supported, evidence-based decisions about investigational therapeutics.

Every trial involves uncertainty. By taking a maximalist diagnostic approach, we can give patients the best shot at accessing an efficacious therapy.