Hello. My name is Dr Mark Agulnik, and I’m a Professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope Comprehensive Cancer Center in Duarte, California. I’m excited to have the opportunity to talk to you about QINLOCK, or ripretinib, a treatment option for adult patients with advanced gastrointestinal stromal tumors, or GISTs, who have been treated with 3 or more prior tyrosine kinase inhibitors, or TKIs, including imatinib.

I have been involved in GIST clinical trials and have managed patients on QINLOCK. In this video, I will also be discussing Susan, a real‑life patient case of mine who has been prescribed QINLOCK.

Let’s begin with a case of a patient I have been treating for a number of years. I first met Susan when she was 60 years old. At that time, in early 2015, she initially presented with right upper quadrant pain, ultimately diagnosed with a 5.2‑cm GIST. A surgical resection was performed and mutational testing of her tumor revealed an exon 11 mutation.

When we first met, she was overwhelmed with her diagnosis because she had most recently lost her husband to lung cancer. We recommended 3 years of adjuvant therapy with imatinib, but due to her circumstances and new diagnosis, she decided to defer adjuvant treatment at that time.

She was compliant with her follow‑up care and had routine monitoring and scans per standard guidelines.

In March 2017, two years after her initial diagnosis, Susan, although asymptomatic at the time, was found to have a new left upper quadrant mass, biopsied and confirmed to be recurrent GIST. Several liver metastases were discovered as well.

Since her initial diagnosis, Susan’s son and daughter‑in‑law had moved back into the area with their one‑and‑a‑half year‑old twins. She became the primary caretaker of her grandchildren, and therefore, she was now willing to start imatinib, wanting to do whatever it took to fight her disease.

Susan began imatinib 400 mg per day. She did very well on this dose for 2 years, with slight periorbital edema and occasional diarrhea as her only side effects. In March 2019, disease progression was documented on positron emission tomography, or PET, scan, at which point the imatinib dose was increased to 800 mg per day. However, after a few months of stable disease on the higher imatinib dose, her disease began to progress and become widespread. It was clear that we needed to move on to other treatment options.

I started Susan on sunitinib in July 2019 at a starting dose of 50 mg daily with the standard 4 weeks on, 2 weeks off protocol. Her disease was well‑controlled; however, she did experience mild hand‑foot syndrome, which resolved over time with supportive care. Approximately 6 months later, in January of 2020, Susan once again developed documented disease progression. We discussed the option of regorafenib, the 3rd‑line approved therapy for GIST.

Susan started regorafenib therapy and her disease had stabilized. She did complain of a hoarse voice, or dysphonia, a somewhat unique and known side effect of regorafenib therapy. Unfortunately, approximately 5 months later, Susan’s disease had progressed despite regorafenib therapy.

Considering her disease progression as well as Susan’s desire to fight her disease, we discussed the question on what to do next to help treat Susan.

Before we get into Susan’s next treatment, let’s talk about the role of mutations in patients with advanced GIST. This is a highly complex disease with a myriad of mutations fueling resistance and progression. As seen in this table, GIST is often driven by primary, activating mutations in kinase genes KIT and PDGFR‑alpha.

70% to 80% of GISTs have mutations in one or more regions, or exons, of the KIT gene, as is the case in our patient, Susan. 5% to 10% of tumors have mutations in the PDGFR‑alpha gene, and 10% to 15% of tumors are wild type mutations.

The wide range of mutations that exist in GIST highlight the need for therapies that target these key mutations.

Complicating treatment even further, following failure of frontline TKI therapy, patients with GIST often have multiple tumors, each of which can be driven by different secondary mutations. There is broad inter‑ and intra‑tumor heterogeneity that exists among secondary resistance mutations—in other words, a single patient with GIST may have multiple mutations within or between tumors.

These factors can contribute to patients with resistant GIST progressing quickly through second‑ and third‑line therapies. Until recently, we have had no approved therapies for patients like Susan.

Luckily, QINLOCK had been approved in May 2020 as a fourth‑line treatment option for patients with advanced GIST who had received 3 or more prior kinase inhibitors, including imatinib. Until QINLOCK, we have historically not had an approved treatment option for a patient like Susan at this stage of her disease, so we were excited to offer her QINLOCK for her advanced unresectable GIST.

Let’s now discuss how QINLOCK works. QINLOCK is the first and only switch control kinase inhibitor engineered to block the drivers of resistance in advanced GIST. QINLOCK is the first approved treatment option for adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib.

Kinase activation requires the interaction of two critical regions: the activation switch and the switch pocket. Mutations in tyrosine kinases, such as KIT or PDGFR‑alpha, cause uncontrolled interaction of the activation switch with the switch pocket. This activates the kinase and leads to upregulation of kinase signaling, which drives cancer cell proliferation and/or survival.

QINLOCK provides broad‑spectrum inhibition of KIT and PDGFR‑alpha kinase signaling in vitro through a dual mechanism of action. In fact, QINLOCK was specifically engineered to block the drivers of resistance in advanced GIST.

Based on preclinical evidence, QINLOCK binds to both the activation switch and switch pocket and locks the kinase in the inactive state. This dual mechanism of action has been shown to potently inhibit kinase activation across the broad spectrum of mutations in KIT and PDGFR‑alpha kinases known to drive drug resistance and disease progression in advanced GIST.

QINLOCK was approved by the FDA based on the results of the Phase 3 randomized INVICTUS trial. Patients were randomized in a 2‑to‑1 ratio to QINLOCK 150 mg once daily, or to placebo. Upon disease progression, patients in the placebo arm had two options. They could either cross over to open‑label QINLOCK 150 mg once daily or they could discontinue the study treatment.

The primary endpoint was progression‑free survival, or PFS. Secondary endpoints included objective response rate, overall survival, quality of life, and safety.

The primary data analysis was conducted from a May 31, 2019 data cut‑off date. A long‑term follow‑up analysis was conducted with 19 months of additional follow‑up, with a January 15, 2021 data cut‑off date.

This trial enrolled the most heavily pre‑treated patient population in a Phase 3, fourth‑line or greater, GIST setting. Between 61 to 64% of patients had 3 prior therapies, and 36 to 39% of patients had between 4 to 7 prior therapies. INVICTUS included patients with ECOG performance statuses of 0 to 2, and enrolled patients regardless of mutation status. Patient characteristics reflect a real world, fourth‑line GIST population and were generally balanced between QINLOCK and placebo. Based on the patient characteristics, Susan would have been eligible for inclusion in INVICTUS, and is therefore representative of the participants in this clinical trial.

Let’s now take a look at the efficacy results. Primary efficacy results showed that QINLOCK demonstrated a powerful progression‑free survival, or PFS, benefit in INVICTUS, with a superior median PFS of 6.3 months versus 1 month for placebo in the primary analysis. This translated into a hazard ratio of 0.15 with a 95% confidence interval range of 0.09 to 0.25 and a p‑value of less than 0.0001. In the exploratory long‑term follow‑up analysis, as you see here in this figure, consistent results were seen with a median PFS of 6.3 months with QINLOCK versus 1 month for placebo, which translated into an 84% reduction in the risk of progression or death.

For QINLOCK‑treated patients with 19 months of additional follow up, estimated PFS at 6, 12, and 18 months was 51%, 22.2%, and 11.8%, respectively.

I should note that an updated exploratory subgroup analysis of the PFS data from INVICTUS was presented at the annual meeting of the Connective Tissue Oncology Society, or CTOS, in 2020. As shown in this figure, generally consistent PFS results were seen for QINLOCK across baseline primary mutation types.

The data presented support my belief that patients have the potential to benefit from QINLOCK regardless of their mutational status. Importantly, these data also emphasize the fact that mutational testing is not required when administering QINLOCK.

In INVICTUS, clinically meaningful improvement in objective response rate was observed as a secondary endpoint. The confirmed objective response rate by BICR was 9.4% with QINLOCK vs 0% with placebo in the primary analysis with a p‑value of 0.0504.

In the exploratory long‑term follow‑up analysis, ORR was 11.8% for QINLOCK vs 0% for placebo.

Looking at the percent change from baseline in sum of diameters of target lesions in the intent‑to‑treat population for patients receiving QINLOCK, the waterfall plot shows the best overall response from the long‑term follow‑up.

For this second graph, we can see the percent change from baseline in the sum of diameters of target lesions in confirmed QINLOCK responders. Most objective responses were observed within the first 2 to 4 months, and additional responses were observed between 6 to 8 months. It supports my belief that continuing treatment with QINLOCK in patients who are not progressing and are able to tolerate is clinically beneficial.

In addition, clinically meaningful overall survival, or OS, was observed with QINLOCK in the primary analysis, with a median overall survival of 15.1 months for QINLOCK vs 6.6 months for placebo.

In the exploratory long‑term follow‑up analysis, the median OS was 18.2 months for QINLOCK versus 6.3 months for placebo. This translates into a hazard ratio of 0.41, meaning a 59% reduction in risk of death, which is certainly encouraging for this heavily pretreated patient population with advanced disease.

Additionally, the median OS for patients in the placebo crossover was 10 months. These data support my decision to start my appropriate patients on QINLOCK as quickly as possible.

Additional estimated OS landmarks can be seen here in this table. With 19 months of additional exploratory long‑term follow‑up after the primary analysis of INVICTUS, the median OS for patients randomized to QINLOCK at 18 months and 24 months was 50.1% and 42.8%, respectively.

Based on the data from INVICTUS, QINLOCK was associated with a powerful PFS benefit and clinically meaningful OS outcomes, which I find to be reassuring when selecting a therapy for my patients like Susan, who have progressed beyond third‑line therapy for GIST or who may not be tolerating their current third‑line treatment well.

From this data, QINLOCK was granted preferred and Category 1 designation by the NCCN as the only therapy recommended for 4th line advanced GIST.

Next, let’s move on to discuss safety and tolerability for patients like Susan in more detail.

The safety of QINLOCK was established across the broad range of patients enrolled in the INVICTUS trial.

Generally, from my experience, QINLOCK is very well tolerated and, although adverse events can occur, they are manageable.

Most common serious adverse events in QINLOCK‑treated patients include abdominal pain, anemia, nausea, and vomiting.

As we saw in the trial, rates of dose modification were similar between QINLOCK and placebo. Specifically, dose reductions for QINLOCK were 7% versus 2% with placebo, and there was a smaller percentage of discontinuation due to adverse reactions with QINLOCK versus placebo.

Safety findings after 19 months of additional follow‑up were consistent with the primary analysis.

In addition, quality of life was also assessed as a prespecified secondary endpoint in INVICTUS, which showed that patients on QINLOCK had maintained their self‑reported health, physical function, and role function, versus a decline with placebo. Given this, we do expect most patients to feel well while on treatment.

Based on data from INVICTUS, we considered Susan to be an appropriate candidate for QINLOCK and prescribed it to her. Susan’s goal is to live as long as possible, and the INVICTUS study demonstrated a meaningful improvement in survival associated with QINLOCK. In addition, the safety profile and quality of life data for QINLOCK further support my decision to prescribe this therapy to Susan.

The most common adverse events that you can expect to see with QINLOCK include alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar‑plantar erythrodysesthesia syndrome, or PPES, and vomiting. The most common Grade 3 or 4 laboratory abnormalities were increased lipase and decreased phosphate.

There are some additional serious risks that were seen in QINLOCK‑treated patients that you need to watch out for and inform your patients of. These include PPES, new primary cutaneous malignancies, hypertension, cardiac dysfunction, risk of impaired wound healing, photosensitivity, and embryo‑fetal toxicity.

If you are initiating QINLOCK in a patient like Susan, you should feel confident in the safety profile, as most patients will do and stay well on therapy. In fact, over 90% of patients did not discontinue or need to dose reduce on therapy, and, as we discussed earlier, quality of life was maintained from participants in the study. This is exceptionally important as I often get questions from my patients on how they might feel, especially for those who had experienced severe side effects on second‑ and third‑line therapy.

Now, let’s take a look at how Susan has been doing on QINLOCK.

At her 6‑month follow‑up with me, Susan was found to be responding to and tolerating QINLOCK well. She did experience some thinning of her hair; however, with help of a stylist, she was able to find a cut and hairstyle that optimized her look and hair coverage. Given Susan’s response to therapy, we will continue treatment with QINLOCK until Susan experiences disease progression or unacceptable toxicity.

In summary, we are truly excited to have a treatment for advanced GIST that works differently for patients like Susan, who are in significant need for additional options like QINLOCK – the first and only switch control kinase inhibitor for fourth‑line or later advanced GIST.

QINLOCK demonstrated powerful PFS in the INVICTUS study and rates of dose modifications due to adverse reactions were similar between QINLOCK and placebo. In fact, efficacy was consistent regardless of the type of driver mutation present – KIT positive, PDGFR‑alpha positive, wild type, or unknown.

Side effects can occur, but most patients were able to start and stay on the full indicated dose of 150 mg daily, with or without food. Mutational testing is not required prior to administration of QINLOCK, and patients can be treated regardless of mutational status, sequence of prior therapies, evidence of progression, or performance status.

As in Susan’s case, if a patient is developing progression on their third‑line GIST treatment or is perhaps no longer able to tolerate third‑line treatment, you can consider QINLOCK as an appropriate treatment option for them. In fact, QINLOCK (ripretinib) was granted both preferred and category 1 designation from the NCCN as the only recommended 4th line therapy for advanced GIST.

My patient Susan was thrilled to have QINLOCK as a treatment option, and so far, she has been doing very well on therapy.

Thank you so much for joining me in this presentation about Susan, our patient with advanced GIST. Until recently, there have been no approved therapies for 4th‑line GIST. QINLOCK is therefore an exciting treatment option for patients like Susan in the 4th‑line setting and beyond.

 

Hello. My name is Kathleen Polson and I am a Nurse Practitioner at the Dana‑Farber Cancer Institute in Boston, Massachusetts. Today, I will be talking about QINLOCK, or ripretinib, a treatment option for patients with advanced gastrointestinal stromal tumors, or GISTs, who have been treated with 3 or more prior tyrosine kinase inhibitors, including imatinib. I have been involved in the early development of QINLOCK and have managed patients on QINLOCK’s clinical trials, including the INVICTUS trial that we will be talking about today.

QINLOCK was approved by the FDA for 4th‑line GIST, where previously we have not had any 4th‑line treatment options for this area of high unmet need for patients. QINLOCK is a switch‑control kinase inhibitor that has a unique mechanism of action and was specifically designed to block the drivers of resistance in advanced GIST. Next, let’s move on to reviewing the INVICTUS trial.

QINLOCK was approved by the FDA based on the results of the Phase 3, randomized INVICTUS trial. This trial enrolled the most heavily pre‑treated patient population in a Phase 3, 4th‑line or greater, GIST setting. Patients were randomized in a 2‑to‑1 ratio to QINLOCK 150 mg once daily, or to placebo. Patients in the placebo arm had two options. They could either cross over to open‑label QINLOCK 150 mg once daily, or they could discontinue the study treatment.

The primary data analysis was conducted from the May 31, 2019 data cut‑off date. An exploratory long‑term follow‑up analysis was conducted with 19 months of additional follow‑up, with a January 15, 2021 data cut‑off date.

QINLOCK demonstrated a powerful progression‑free survival, or PFS, benefit in INVICTUS, with a superior median PFS of 6.3 months versus 1 month, which was an 84% reduction in the risk of progression or death.

In the exploratory long‑term follow‑up analysis after 19 months of additional follow‑up, PFS results remained consistent. Median PFS for QINLOCK was 6.3 months vs 1 month for placebo, with a hazard ratio of 0.16.

Furthermore, I find it reassuring that QINLOCK was granted preferred and Category 1 designation by the NCCN as the only therapy recommended for 4^th line advanced GIST.

Furthermore, the objective response rate, or ORR, was 9.4% with QINLOCK vs 0% with placebo, with a P‑value of 0.0504.

In the exploratory follow‑up analysis after 19 months of additional follow‑up, the ORR was 11.8% for QINLOCK vs 0% for placebo.

Looking at the percent change from baseline in sum of diameters of target lesions in the intent‑to‑treat population for patients receiving QINLOCK, the waterfall plot shows the best overall response from the long‑term follow‑up.

For this second graph, we can see the change from baseline in the sum of diameters of target lesions in confirmed QINLOCK responders. Most objective responses were observed within the first 2 to 4 months, additional responses were observed between 6 to 8 months. It supports my belief that continuing treatment with QINLOCK in patients who are not progressing and are able to tolerate is clinically beneficial.

In addition, clinically meaningful overall survival, or OS, was observed with QINLOCK in the primary analysis, with a median OS of 15.1 months for QINLOCK vs 6.6 months for placebo.

In the exploratory long‑term follow‑up analysis, the median OS was 18.2 months for QINLOCK versus 6.3 months for placebo. This translates into a hazard ratio of 0.41, meaning a 59% reduction in risk of death, which is certainly encouraging for this heavily pretreated patient population with advanced disease.

Additionally, the median OS for patients in the placebo crossover was 10 months. These data support my decision to start my appropriate patients on QINLOCK as quickly as possible.

The safety of QINLOCK was established across the broad range of patients enrolled in the INVICTUS trial.

Generally, from my experience, QINLOCK is very well tolerated and, although adverse events can occur, they are manageable.

The most common serious adverse events in QINLOCK‑treated patients include abdominal pain, anemia, nausea, and vomiting.

As we saw in the trial, rates of dose modification were similar between QINLOCK and placebo. Specifically, dose reductions for QINLOCK were 7% versus 2% with placebo, and there was a smaller percentage of discontinuation due to adverse reactions with QINLOCK versus placebo.

The most common adverse events that you can expect to see with QINLOCK include alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar‑plantar erythrodysesthesia syndrome, or PPES, and vomiting. The most common Grade 3 or 4 laboratory abnormalities were increased lipase and decreased phosphate.

I find it to be very important to set expectations upfront with my patients regarding the more common adverse events and proactively manage symptomatic side effects, if possible. Later on in this presentation, we will dive further into alopecia and PPES management.

In addition, quality of life was also assessed as a pre‑specified secondary endpoint in INVICTUS, which showed that patients on QINLOCK had maintained their self‑reported health, physical function, and role function, versus a decline with placebo. I find these data to be encouraging, because in my experience, my patients on QINLOCK were able to maintain their quality of life as well.

If you are initiating QINLOCK in a new patient or had a patient ask about QINLOCK, you should feel confident managing as most patients will do and stay well on therapy. We saw this as over 90% of patients did not discontinue or need to dose reduce on therapy, and as we discussed earlier, quality of life was maintained with participants in the study. This is important as I often get questions from my patients on how they might feel, especially for those who had experienced severe side effects on 2^nd‑line and 3^rd‑line therapy.

Dosing is straightforward with QINLOCK – it is dosed 150 mg once daily with or without food and mutational testing is not required prior to administration or to be eligible for QINLOCK.

There are some additional serious risks that were seen in QINLOCK‑treated patients that you need to watch out for and inform your patients of. These include PPES, new primary cutaneous malignancies, hypertension, cardiac dysfunction, risk of impaired wound healing, photosensitivity, and embryo‑fetal toxicity.

There was no grade 3 PPES seen with QINLOCK in INVICTUS, and I have also found that PPES is generally mild for patients we have managed. Typically, we encourage proactive management with hand creams, soothing ointments, and supportive hand‑ and footwear.

While alopecia can occur, the majority of alopecia was mild or Grade 1; however, it can be as severe as Grade 2. I always counsel my patients that they may see potential changes to their hair volume, color, texture, thinning, or loss. If this occurs, there are many things that we can do to enhance the appearance of a patient’s hair, including alternate hairstyles, coloring, hair powders, or headpieces.

Regarding the potential for muscle and joint pain, in my experience, it is important to manage this side effect aggressively with symptomatic management, and I have seen my patients start to feel better.

I have found that patients tend to tolerate QINLOCK very well. Of note, some of the adverse events may be different than those of similar agents in this class.

QINLOCK is a treatment for advanced GIST that works differently for our patients who are in significant need for additional options, and it is also the first and only switch‑control kinase inhibitor for fourth‑line or later advanced GIST.

QINLOCK demonstrated powerful PFS in the INVICTUS study, and rates of dose modifications due to adverse reactions were similar between QINLOCK and placebo.

Side effects can occur, but most patients were able to start and stay on the full indicated dose of 150 mg daily, with or without food.

Mutational testing is not required prior to administration of QINLOCK, and patients can be treated regardless of mutational status, sequence of prior therapies, evidence of progression, or performance status.

If a patient is no longer able to tolerate or is developing progression on their 3rd‑line GIST treatment, you can consider QINLOCK as an appropriate treatment option for them.

Thank you so much for joining me in this presentation about QINLOCK – a proven treatment option for our adult patients with advanced GIST in the 4^th‑line setting and beyond.