Beyond The Coat

Social media – it’s a love/hate relationship for most of us I think.  There are some really good things about it and then there are all of the bad things about it.   One thing I like about social media is that sometimes things are brought to my attention that I may have otherwise missed.   Case in point – this study I’m about to try to break down for you.

At 3 am, while feeding my son, my Facebook feed showed me a sponsored ad that said “93% of pediatric patients respond to new drug.”  I’m not sure if that was the exact title but it was something click-bait worthy that grabbed my attention – and I clicked on it.  The article had all of the highlights touting this drug but none of the real details to tell me if it was legitimate or blown up results.  That’s the problem with lay media and science – it’s hard to discern what is real and what’s not, right?   Thankfully, I have access to a biomedical library and can dig up the original article and I’m here to tell you about it.  Spoiler alert – the results are encouraging in early studies, yay score one for social media!

Ok, so this drug is called larotrectinib (LARE-O-TREK-TEH-NIB) and it falls into a class of drugs called TRK (pronounced TREK) inhibitors.   Some pediatric and adult tumors (only estimated at 1%) have mutations in the TRK genes where two genes are stuck together that aren’t supposed to be.  This creates a fusion oncogene, much like the BCR-ABL oncogene discussed earlier. Just like Gleevec targets the BCR-ABL mutation, this class of drugs will target TRK mutations.   Blah blah blah, right?  You want to know what’s the real deal with this drug?

First, let’s revisit the phases of clinical trials and what they are designed to test.

• Phase 1: A clinical trial designed to find the optimal dose of the drug and to test the safety of that drug alone or in combination with other drugs. This type of trial usually only has 10-30 participants and in cancer trials, it includes multiple different types of cancers for which there is no known cure (i.e. they have ‘run out’ of standard options). These patients generally have had multiple treatments that have failed.
• Phase 2: A clinical trial designed to test the drug in a specific population of patients (specific cancer type) to determine the efficacy (how well the drug works for that cancer) and to continue to collect safety data (10-30 patients in a Phase 1 trial certainly won’t experience the whole spectrum of possible side effects). These participants generally have received at least one other type of therapy for their cancer and it has not responded or it has come back.
• Phase 3: A clinical trial designed to test whether a new treatment works better than standard therapy, most often in a ‘head to head’ comparison. This is generally tested in patients with a specific type of cancer and used in the first attempt to treat their disease.

Alright, so back to the drug in question, larotrectinib.  It was tested in a Phase 1 trial of adult and pediatric patients (but mainly adults) who had with confirmed TRK mutations,  and the overall response rate was 75%.   Overall response rate means that the tumor 1) disappeared completely (complete response) 2) shrunk (partial response).  A 75% response rate for a single drug in patients where most of them had already received chemotherapy is a really good response.  The key here is that these patients were screened for the TRK mutation and were only eligible if their tumor had a TRK mutation.  They gave the drug to the patients that they believed would respond based on scientific rationale.  This is SO IMPORTANT. If they hadn’t done this, it may have appeared that the drug didn’t work and the drug would not be developed further.

Concurrently, the Phase 1 dose finding study for pediatrics was running and this study included patients with and without TRK mutations.   Ok, why do you need this study and why didn’t they screen them for the TRK mutation for eligibility?  First, children are not just tiny adults and their bodies can respond quite differently to drugs.  For example, for very small children, the dose that was recommended based on this study, was actually 173% more than what is recommended for adults.  That’s pretty important stuff to know.  I think they didn’t require positive TRK mutation status in pediatric patients because it would have limited the number of patients that were eligible and the trial would have been slow to complete.  Although it seems a little weird to do it this way, you have to remember that Phase 1 is only meant to determine the dose and safety of the drug.  However, sometimes as clinicians we enrich the population that is enrolled on the trial.  Of the 22 patients enrolled in this trial and evaluable for efficacy, 71% actually had TRK mutations which is well above the general rate of 1% for all solid tumors.  This tells us that clinicians were screening for this mutation and then directing their patients with positive mutations to this particular trial.

OK, back to the click-bait title of 93% of pediatric patients responded…here are the results.  These graphs are called waterfall plots.   Each individual bar is a single patient.  If the bar goes up, that means the tumor grew.  If the bar goes down, it means the tumor shrunk.  The four patients on the left hand side of the graph did not have TRK mutations and they did not respond.  The 4^th patient whose tumor shrunk, did not shrink to a degree to be counted as a response (must hit that dashed line).   The patients on the right hand side of the graph all had a TRK mutation and 14 of the 15 patients (93%) met criteria for response.  The first patient in the dark blue bar was very close but didn’t quite meet criteria for a response.

Super…so patients with TRK mutations responded to a drug that targets TRK mutations, but how long did the response last?   This next graph is called a swimmer plot.  Again, each bar is an individual patient and the horizontal access is the length of time.

Again, you can see that the patients in the top portion are those that have the TRK mutation.  Most of them are still on treatment, which means their tumor has not gotten worse since starting the drug.   The ones on the bottom have stopped treatment (no little black arrow at the end of their bar) because their tumors got worse on the drug.   You may also notice that the numbers of patients don’t add up between the two graphs.  For various reasons, sometimes a patient may not be evaluable for all aspects of the study, but I won’t bore you with the details, but they are explained in the paper.

So let me summarize:

1. Was the click bait title accurate? Yes, but it’s a small number of patients (15).
2. Am I optimistic? Yes, but it’s a small study.
3. Do we need to do more studies? Yes, and a phase 2 study is ongoing in pediatrics.
4. Who could this potentially benefit from this drug? Patients with tumors that have TRK mutations. It appears that a particularly rare type of pediatric cancer called infantile fibrosarcoma harbors these mutations frequently.
5. Any other reasons I am happy? Yes, the first trial I described allowed simultaneous enrollment of adults and children because TRK mutations happen more frequently in children.  Yay!!! Progress in putting kids first!
6. Could someone develop resistance to this drug? Yes, and researchers have already discovered how this happens and are formulating a second generation of this drug to combat this problem…which will have to go through all of the same testing.
7. Why did I explain this study in detail? I believe this is where oncology is heading.  This is personalized medicine – treating patients with a medicine that is specific for their type of tumor. These TRK mutations occur in less than 1% of all solid tumors, which means that very few patients will benefit from it, but for those patients that do have the mutation, the potential benefit may be big.   We are entering the era of very specific and individualized therapy, which means we have years of work ahead of us to find such specific therapy for each tumor.   Will we find specific drugs for every type of cancer?  I don’t know.  Only time will tell, but we are working on it.   There is nothing more hurtful than hearing people say that physicians don’t want to cure cancer because we make a profit off of sick people.  There are many cancers we can cure.  There are many we cannot cure.  There are many we want to cure in a better fashion.   In the end, if you learn nothing from this project of mine, I hope you know that we, as an oncology community, are trying and we are not the enemy.   We don’t cause the cancers and we certainly don’t want anyone to be sick.  We just want to help people get better when they come to us sick.  We are on your side.