Arun Singh, MD: Now let's turn our attention to QINLOCK, or ripretinib, which is a different kind of tyrosine kinase inhibitor for advanced GIST.
QINLOCK is a prescription medicine used to treat adults with advanced GIST who have received 3 or more prior treatments for their GIST. QINLOCK is a type of targeted medicine, NOT a chemotherapy. It’s also considered a TKI treatment, which works differently than other TKIs.
Your doctor may consider if QINLOCK is an appropriate treatment for you based on the following 3 categories:
- If you’ve taken at least 3 other treatments for advanced GIST
- If you have any type of GIST mutation
- And, even if you haven’t been tested for a GIST mutation type
Now, I’m going to talk about how QINLOCK works. The analogy I’m going to use is that of a power strip. Think of the power strip like the one you have at home and that’s shown here in the image. We’re going to pretend that the power strip is the tyrosine kinase protein like KIT or PDGFRα in a GIST patient’s cancer cells.
Each outlet is a site where a mutation might happen when a gene like KIT or PDGFRα gets mutated. When you have a mutation in one of these sites, it’s like this outlet is plugged in. The outlet powers GIST cancer cells to grow and spread.
How QINLOCK works is that it targets 2 of the outlets or 2 key sites of the tyrosine kinase that are involved in GIST. By targeting these 2 outlets, QINLOCK limits the kinase’s ability to power GIST cancer cells to grow and spread.
Another way of thinking of this could be, if you want to think about the plastic pieces that you use to keep your kids from sticking something into a power outlet. That’s what QINLOCK tries to do. Since mutations can happen in different outlets, targeting 2 outlets helps QINLOCK target a range of mutations, which helps it to have broad activity.
QINLOCK was rigorously studied in a clinical trial called the INVICTUS study. This study was done around the world at many different hospitals. This was a trial in which people were randomly assigned to receive QINLOCK or a placebo, otherwise known as a sugar pill. Eighty-five people received QINLOCK, and 44 people received a placebo.
The trial included patients with known or unknown mutations. There were 2 main goals: to study how well QINLOCK works, and how safe it is. Patients had to have received at least 3 prior cancer therapies for GIST. How do we know how well QINLOCK worked? Well, we analyzed the results of the trial.
A measure called median progression-free survival was used to determine how long the drug was effective.
Progression-free survival, or “PFS” for short, is the length of time during and after cancer treatment that a patient lives with the disease, but the disease does not get worse; that is, the tumor does not grow and the cancer does not spread to another part of the body.
Talking about the PFS, we often talk about something called a median, which is the middle number in the set of numbers.
Well, how well did QINLOCK work? QINLOCK was proven to give people significantly more time living without tumors growing or spreading. It reduced the risk of death or tumors growing or spreading by 85% compared to placebo. This means over the course of the clinical study, that people who took QINLOCK were 85% less likely to pass away or have their disease grow, compared to placebo. Of course, individual patient experiences may vary, and will vary.
People who took QINLOCK had a median progression-free survival of 6.3 months compared to 1 month for people on placebo or sugar pill.
The second term that’s important to understand in this trial is the term “objective response rate”, or “ORR” for short. This specifically refers to a measure of actual tumor size. Before and after a patient undergoes treatment, the tumor is often measured to evaluate the drug’s effectiveness.
If a tumor shrinks by 30% or more, we can say that the tumor has responded to treatment.
Some people who took QINLOCK had their tumors shrink. Nine percent of patients who took QINLOCK had their tumors shrink, versus none of the patients on the sugar pill. After these results were analyzed, they were not considered statistically conclusive.
The next metric that was used in this study was one for overall survival, or “OS” for short. Overall survival refers to the amount of time that a person keeps living while on a drug and after stopping the drug, as well.
The patients who took QINLOCK had a median overall survival of 15.1 months, versus 6.6 months for the placebo.
Because of the order in which the data were analyzed, it was not possible to draw statistical conclusions from these results.
That is, a summary of the efficacy of the INVICTUS study, which helped to get QINLOCK approved for advanced GIST. I’m going to pass the discussion back to my colleague, Sandra Brackert, to talk about some of the possible side effects associated with QINLOCK.
Sandra Brackert, NP: I learn a lot from what patients share with me, as far as what their side effects are, and also how they manage them.
The first one we have listed here is what we sometimes refer to as “hand-foot syndrome”, or PPES, which stands for palmar-plantar erythrodysesthesia syndrome. This side effect can cause pain, soreness, and sensitivity on the hands and the feet. It can also cause redness, blisters, bleeding, swelling, or rash on the palms of your hands or soles of your feet.
One thing I always tell people to do is use a nice urea-based hand cream, and sometimes to put on a cream on the feet and then cover the feet with socks at night to keep the moisture in. You might want to really look at your footwear and also make sure that you have comfortable shoes with no areas of increased pressure on toes, or rubbing anywhere on the heel.
The other thing I want to mention about the skin is possible new skin cancers. In certain rare cases, QINLOCK may cause skin cancers called “cutaneous squamous cell carcinoma”, or “melanoma”.
In our practice, we always refer patients right away to a dermatologist, so that a dermatologist can do a really good head-to-toe body check. They can make sure that you don’t have any unusual moles, or skin bumps, or any lumps of concern. Then probably, every 6 months or so, depending on what your doctor says, you should follow up with your dermatologist. But if you notice anything on your own, like a mole that changes shape or color, or a new little red bump—sometimes it looks like a little wart—don’t ignore it; make sure that you go and see your doctor right away and have them examine it.
Another possible side effect of QINLOCK is hypertension, or high blood pressure.
We want to make sure that your blood pressure is managed well, even before we start the medication. If your doctor determines you have high blood pressure, they would prescribe a medication, which is called an “antihypertensive”. There are many different kinds. Once you have managed the hypertension, then we can get you started and keep you on QINLOCK.
The other thing here is heart problems. In the clinical trial, there was 1 case, of the 85 patients treated with QINLOCK, so our best practice is to get an echocardiogram before we even start the medication—just as a baseline, just to let us know that the heart is functioning, and pumping well, and that there’s not any cardiac problems. If you do notice any heart-related symptoms, such as all of a sudden being very, very short of breath, or very, very tired, then you should call your doctor, let your care team know, and they would probably order another echocardiogram, to see if there are any changes.
QINLOCK may also affect the ability of the body to heal quickly, so you should tell your doctor if you plan to have any surgery before or during treatment with QINLOCK. We recommend stopping QINLOCK if you have a scheduled surgery of any kind for about a week before the procedure, and roughly about 2 weeks after the surgery, until everything is healed up well, and then we'll evaluate when you can go back to taking QINLOCK.
A common side effect of QINLOCK is hair loss or hair thinning. That’s something you may or may not have had on the other drugs. In my experience, patients on other TKIs have had hair loss and thinning, as well. But, I just think it’s better to be prepared that hair loss or hair thinning is a possible side effect, and sometimes just the way you can style your hair, or talk with your hairdresser, how they can cut your hair, may be helpful. Also, some people do like to wear a wig, and if they find a wig to match their hair, it looks more natural; or some other people like to just get a fun wig and have a different kind of look.
That’s another thing also that you could talk with your dermatologist about, as sometimes they have a suggestion for a special shampoo, or other tips to help prevent the thinning of the hair.
You also want to protect yourself from the sun, so use sunscreen, cover your head and your hair with a hat so that you’re not getting sun on your head or sunburn there, and of course, also protect your head from the cold.
Other possible side effects are some of the GI side effects, such as nausea, vomiting, diarrhea, decreased appetite; but overall, these were very low, as far as what we saw patients experiencing. For most of you with GIST, in my experience, your GI tract is a little affected too, because of the tumors or the previous TKIs that you’ve been on, so I think most of you may have learned how to manage diarrhea or constipation. But it’s always a good idea to talk to your health care provider and let them know what’s happening with your GI symptoms, as well.
The bottom line is to stay well hydrated and to really manage it. I’ve had so many patients that will have several loose stools a day and just be like, “Well, it’s okay, it’s all right. I can manage, I can handle it.” However, over time that really irritates the colon and the bowel, so you really want to slow it down and calm it down. Based on my experience, I encourage you to try Imodium, or ask your doctor about Lomotil, if diarrhea is a problem that is not being managed well. Talk to your physician about any symptoms you’re having, because they will be able to help you.
Don’t suffer in silence. Again, if you're talking to your doctor about QINLOCK, tell them if you have PPES, the hand-foot syndrome, in the past; if you currently have high blood pressure; or heart problems; or if you recently have plans to have a surgery.
Unfortunately, QINLOCK may be harmful to the fetus, so we do not recommend for anyone that’s pregnant or wanting to become pregnant to be on QINLOCK. It is very important, if you are in an age group that could become pregnant, that you take some birth control, so that you do not become pregnant while you’re on QINLOCK. You can talk with your gynecologist about what they recommend is best for you.
Additionally, we don’t want anyone that’s breastfeeding to take it. It could be potentially released in breast milk and might not be good for a baby. We do not recommend QINLOCK at all for anyone who is pregnant, thinking about getting pregnant, or breastfeeding.
Also, for any men taking it, you do not want to impregnate anybody while you’re on the medication, because we really don’t know how QINLOCK affects the sperm. With that said, we also are not 100% sure if it could cause infertility in men. If this is something that you’re serious about, you could always talk to a cryobank about freezing sperm, and sperm banking, and then you can have that for the future.
Also, you should always go through your medication list with your health care provider so they can make sure that there’s nothing that’s going to interact with QINLOCK.
Most people don’t eat grapefruit while taking QINLOCK, because that’s one of the things that can often interact with medications. Multivitamins and some of the supplements will be fine, but still make sure you go through the list to ensure there’s nothing there that you shouldn’t be on while taking QINLOCK.
A frequent question that we get is…
Q: What can I do if I start losing my hair?
A: I know this is a really hard thing for women and men. Like I said before, we usually do refer people to a dermatologist to see if they have any special hair solutions that may help. Sometimes just using gentle shampoos, or using water that’s not too hot, reducing the amount of tension on the hair, and being very gentle with your hair may also help. I think the most important thing is to be aware that hair loss may happen. If you want to, you could wear scarves, hats, or even a wig, if you’d like.
Q: What can I do if I get hypertension?
A: If you get hypertension, we highly recommend getting a home blood pressure monitor so that you can check your blood pressure daily, and keep a record of it in a diary. Make sure that you talk to your health care provider if your blood pressure is a concern.
A: If you get that, your health care team will help you through it. Sometimes there does need to be a short break in treatment for things to calm down.
The hand-foot syndrome can be severe, depending on each individual, but, in my experience, the patients I’ve seen that have been, they’ve actually been pleasantly surprised that, on QINLOCK, the hand-foot syndrome is either not there, or very mild. But again, using creams and proper footwear with padding, and not doing a lot of repetitive things, can help.
Most importantly, talk to your doctor if you start to develop PPES, as it can be very painful, and we may be able to help manage it.
The really nice news is that most patients, 93%, did not have to even reduce their dose because of side effects. We saw that almost all the patients in the trial were able to stay on the full dose.
Almost 92% did not have to stop taking QINLOCK due to side effects.
Now let’s talk about the dosing. The dose is 150 milligrams once a day. It comes in 50 milligram tablets, so you would take 3 tablets once a day.
You do not have to take all 3 tablets in 1 swallow, but it is very important that all 3 tablets are taken in the same sitting. That means you can swallow them separately, one after another, but make sure that you DO NOT space out each pill over the day.
It is also important to take the tablets at the same time every day. If you take them in the morning with breakfast, make sure you take them every morning. If you take them at night before you go to bed, then take them every night before you go to bed.
Lastly, QINLOCK can be taken with or without food, whichever you prefer. The pills should be swallowed whole, no crushing or breaking them up, and they should be taken exactly as your doctor tells you to. Your doctor may temporarily or permanently stop treatment, or change your dose of QINLOCK, if you develop side effects during treatment. If you develop side effects, make sure to tell your doctor.
We typically start QINLOCK with the full dose,150 milligrams—that’s 3 pills together at the same time every day, right away. In my experience with the other drugs, we started at a lower dose and titrated up to get your body used to it and build up tolerance, but we have been very consistent that we can start with the full dose right away with QINLOCK.
In summary, QINLOCK, or ripretinib, is a TKI for advanced GIST, but it works a little bit differently than the prior TKIs. It is a fourth-line treatment. After you’ve had 3 prior treatments, there is now a fourth-line approved drug for you. It’s a targeted therapy, not a chemotherapy. It can be taken no matter what type of GIST you have. No matter what type of exon mutation you have, you can also take QINLOCK.
Q: What should I do if I miss a dose of my treatment?
A: I usually tell people if you miss a dose and it’s been less than 8 hours, you can take the dose; but if it’s been more than that, then you should just skip that dose and resume your regular schedule.
For example, if you take it every morning with breakfast and at dinner time, you’re like, “Oh, I forgot my dose. Should I take it now?” I would say, just skip that dose and resume your normal schedule the following morning. Don’t double up on it, don’t take more because you missed a dose—just go back on your regular schedule.
If it looks like you’re missing a dose frequently, we don’t want you to skip doses like that. So, please work hard to come up with a plan, such as some kind of reminder on your phone, so that you don’t miss doses. You could also consider marking your doses on a calendar, or asking a loved one to help remind you.
Q: How often should I follow-up with my doctor?
A: Well, usually we see patients about 2 or 3 weeks after they start QINLOCK, just to make sure that you’re in good shape and that you’re tolerating it well and you don’t have any concerns or questions. We may check some blood work, check your hands and your feet, check your blood pressure.
So, for about the first 6 months or so, we see you a little more frequently; if everything is going well, probably once a month. And then we can start spreading that out depending on how comfortable you are and we are with how you’re tolerating things. But we really do want to keep a close eye on you and make sure that your blood pressure, your blood work, and the side effects are being managed well, and everything is going in the right direction. It is very important to follow-up with your health care provider routinely.