Welcome to this presentation of Qinlock (ripretinib) for the treatment of Advanced Gastrointestinal Stromal Tumor. Qinlock is indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor or GIST, who have received prior treatment with three or more kinase inhibitors, including imatinib.
Well, my name is Neeta Somaiah. I'm a medical oncologist at MD Anderson Cancer Center in Houston, Texas. My current role is an Associate Professor and Deputy Chair of the Department of Sarcoma. I trained at Fox Chase Cancer Center in Philadelphia, and have over 10 years of experience in treating sarcomas. I have been involved in the early development and the clinical trial that led to the approval of Qinlock in GIST.
In this program, we're going to review the current state of GIST, the Qinlock mechanism of action, efficacy and safety of Qinlock, important safety information, the dosing and administration of Qinlock, and patient management and some other considerations. And then we will summarize the data in the end.
What's the current state of gastrointestinal stromal tumor? We will review the key epidemiology and origins of GIST, discuss how diagnosis and treatment has evolved over the past few decades, and review the key drivers of GIST, progression, and drug resistance. And we will highlight the unmet clinical needs for patients.
So GIST is the most common sarcoma of the GI tract. There are around 4000 to 6000 new cases of GIST per year. And it is most common in individuals aged 50 to 80 years with equal incidence in men and women. The most common site of origin is the stomach. And next most common is the small intestine, with jejunum and ileum, followed by the duodenum.
Here we're going to look at how the treatment of GIST has evolved over the past decades. GIST was recognized in the early 1980s where surgery was the only treatment and chemotherapy really had no role or was not effective in the treatment of GIST. In the 1990s, it was discovered that staining specific biomarkers, such as CD117 known as KIT or DOG1, was diagnostic and helped confirm the diagnosis of GIST. Soon after, it was discovered that there were specific oncogenic drivers such as in KIT and PDGFRA that were discovered in GIST. And this kind of led to the era of the 2000s where soon after TKIs or tyrosine kinase inhibitors with activity against KIT and PDGFRA was tested in GIST and led to the approval of the few tyrosine kinase inhibitors currently in use, starting with imatinib.
So KIT and PDGFRA mutations are the drivers in approximately 85% of GIST. The majority of GIST harbor in activating mutation in KIT and this most often is an Exon 11, followed by Exon 9. A minority of GIST patients have PDGFRA mutations found in around 5% to 10% of GIST, of which Exon 18 (D842V) is the most common. 10% to 15% of GIST are without known KIT or PDGFRA mutations, and often referred to as wild type, but basically wild type for KIT or PDGFRA. In these patients, the most common are mutations in SDH complex. We also find mutations in NF‑1, BRAF, KRAS, and NTRK3 fusions in rare cases.
The vast majority of patients who benefit from frontline tyrosine kinase inhibitor treatment will eventually develop resistance. So what we see is patients on frontline therapy will have a median progression free survival of around 18.9 months with around a 50% response rate. But after failure of frontline TKI, patients will progress, and progression can be in either a limited fashion where they develop nodular or focal progression or a nodule within a mass that is progressing, or the progression can be more widespread. The goal of treatment in advanced GIST is the control of disease progression. A long‑term follow‑up study did show a correlation between disease control, including stable disease, and long‑term survival.
Advanced GIST is marked by the development of secondary drug‑resistance mutations, which play a key role in disease progression. In GIST, there is extensive mutational heterogeneity that drives resistance to establish therapies. The development of these secondary drug‑resistant mutations play a key role in disease progression. As shown in the figure on the left, broad inter‑ and intratumor heterogeneity exist among secondary resistance mutations, whereby a single patient may have multiple mutations within or between tumors. These secondary mutations are most common in Exon 13 and 17 when they have a primary mutation in KIT, or in Exon 18 in the PDGFRA gene when the primary mutation is in PDGFRA. Therefore, there is a need for broad‑spectrum inhibition of the many mutations that fuel resistance and progression in GIST.
Patients with resistant GIST tend to progress quickly through second‑ and third‑line therapies. As we discussed, patients will derive the maximum benefit or at least majority patients will derive maximum benefit on imatinib, but thereafter, the median progression free survival on second‑line therapy is around 5.6 months with a response rate of 6.8% with sunitinib, and in third‑line therapy, the median progression free survival is 4.8 months with the response rate of around 4.5%. And until recently, there were no approved therapies for fourth‑line GIST. Avapritinib is approved for the treatment of unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, which we discussed, was present around 5% to 6% of patients. And this mutation tends to be resistance to the prior approved lines of tyrosine kinase inhibitor therapy. Could a novel therapeutic approach help address the challenge of drug resistance in advanced GIST?
Break through resistance with Qinlock. Qinlock is a novel, switch‑control kinase inhibitor for the treatment of patients with advanced GIST. It is indicated for the treatment of adult patients with advanced GIST who have received prior treatment with three or more kinase inhibitors, including imatinib. All through the presentation, we will review some important safety information, including the palmar‑plantar erythrodysesthesia syndrome, which we will discuss in depth later.
So we will now be talking about the mechanism of action of Qinlock. Qinlock is the first TKI designed specifically for GIST, and it was engineered to block the drivers of resistance in advanced GIST. Qinlock is a novel switch‑control kinase inhibitor that provides broad‑spectrum inhibition of KIT and PDGFRA kinase signaling in vitro through a dual mechanism of action. Now kinase activation requires interaction of two critical regions, the activation switch, and the switch pocket. As shown in preclinical studies, Qinlock binds to both the activation switch and the switch pocket, regardless of where mutations arise. And it locks the kinase in the inactive or off state, inhibiting downstream signaling and cancer cell proliferation. In preclinical studies, this dual mechanism provided broad‑spectrum inhibition of KIT and PDGFRA kinase activity, including multiple primary mutations, multiple secondary mutations, and even wild type GIST. We will now be looking at a video that nicely explains this mechanism of action.
How Qinlock works. Gastrointestinal stromal tumor or GIST is often driven by primary activating mutations in kinase genes KIT and PDGFRA. 70% to 80% of GIST have mutations in one or more regions or exons of the KIT gene. 5% to 10% of GIST have mutations in the PDGFRA gene, and 10% to 15% of GIST are without mutations in KIT or PDGFRA genes. These are often referred to as wild type. Kinase activation requires the interaction of two critical regions, the activation switch, and the switch pocket. Mutations in the tyrosine kinases, such as KIT or PDGFRA, cause uncontrolled interaction of the activation switch with the switch pocket.
This activates the kinase and leads to up regulation of kinase signaling which drives cancer cell proliferation and/or survival. As secondary drug resistance mutations emerge, some tyrosine kinase inhibitors may lose their ability to prevent kinase activation leading to cancer cell proliferation, otherwise known as drug resistance. Complicating treatment even further, following failure of frontline TKI therapy, GIST patients often have multiple tumors each of which can be driven by different secondary mutations.
The Qinlock mechanism of action. Qinlock is a novel switch‑control kinase inhibitor that provides broad‑spectrum inhibition of KIT and PDGFRA kinase signaling in vitro through a dual mechanism of action. As shown in preclinical studies, 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 PDGFRA kinases, known to drive drug resistance and disease progression in advanced GIST.
Now moving on to the efficacy and safety of Qinlock. Qinlock was studied in INVICTUS, a global, multicenter, randomized, double‑blind placebo‑controlled Phase 3 trial in 129 patients who had received more than equal to three prior anticancer therapies for advanced GIST. Patients who were randomized in a two is to one fashion to receive Qinlock 150 milligrams once daily, or placebo. It was 85 patients on Qinlock and 44 patients on placebo. And at the time of disease progression, patients on Qinlock were allowed to either continue on open‑label Qinlock at 150 milligrams once daily if the investigator thought the patient was benefiting, or escalates to 150 milligrams BID, or discontinue drug treatment. Patients on placebo were allowed to cross over at disease progression, and they cross over to open‑label Qinlock 150 milligrams once daily, or if they so chose to discontinue study treatment.
The primary endpoint was progression free survival based on disease assessment by blinded independent central review of radiology using the modified RECIST 1.1 criteria. The secondary endpoints included objective response rate based on disease assessment by the blinded independent central radiology, and also overall survival, quality of life, and safety.
A wide range of advanced GIST patients were enrolled in the INVICTUS study, and it was a heavily pretreated cohort that is representative of patients in the fourth line setting and beyond. Between 60% to 64% of patients had three prior therapies, and 36% to 39% of patients had between four to seven prior therapies. Patient characteristics reflect, as we said, a real world fourth line GIST population, and were generally well balanced between Qinlock and placebo. INVICTUS included patients with ECOG performance status of zero to two, and enrolled patients regardless of their mutational status.
Qinlock demonstrated a powerful PFS benefit in INVICTUS. The median progression free survival was superior with Qinlock, 6.3 months, versus one month for placebo. There was an 85% risk reduction of progression or death versus placebo. And the hazard ratio was 0.15. This result was highly significant and the separation of the two curves was dramatic and occurred quickly.
In addition to the median progression free survival and the hazard ratio or risk reduction, looking at the estimated landmark PFS at clinically relevant time points helps to further characterize the progression free survival data from the Kaplan‑Meier curve. The estimated landmark PFS at nine months was over 34% for Qinlock, and not estimatable for placebo. The estimated landmark PFS at 12 months or one year was 21% with Qinlock, and not estimatable for placebo. Furthermore, Qinlock PFS results were generally consistent across the assessed patient subgroups.
Qinlock was associated with clinically meaningful survival outcomes. The median overall survival was 15.1 months with Qinlock versus 6.6 months with placebo. This resulted in a 64% reduction in the risk of death versus placebo, with a hazard ratio of 0.36. This analysis includes patients originally randomized to placebo who crossed over to receive open‑label Qinlock as well. This data is clinically meaningful as one could see the early and sustained separation of the Kaplan‑Meier curves.
Overall survival was not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints of overall response rate and overall survival as prespecified in the statistical analysis. The confirmed overall response rate by blinded independent central review was 9.4% with Qinlock versus 0% with placebo. The P value was 0.0504 narrowly missing the statistical significance. The median duration of response had not been reached by the study cutoff date. However, nearly an additional two‑thirds of patients treated with Qinlock experienced stable disease lasting greater than six weeks versus 20.5% with placebo. The overall response rate is encouraging in a heavily pretreated patient population that progressed in multiple prior therapies. A confirmed objective response represents a greater than 30% reduction in tumor size.
When patients who were originally randomized to placebo and crossed over to Qinlock are separated out from the patients who did not cross over, we see that patients who were originally randomized to placebo and crossed over to receive Qinlock had a median overall survival of 11.6 months, and patients who did not cross over to receive Qinlock had a median overall survival of 1.8 months. Approximately 66% of patients originally randomized to placebo crossed over to receive open‑label Qinlock.
The safety of Qinlock, or ripretinib, was established across a broad range of patients in the INVICTUS trial. The most common serious adverse reactions were abdominal pain, anemia, nausea, and vomiting. The rates of dose modifications due to adverse reactions were similar between Qinlock and placebo. Dose interruptions were similar, 24% for Qinlock, and 21% for placebo. Dose reductions were rare, 7% for Qinlock, and 2% for placebo. There was a lower rate of discontinuation with Qinlock versus placebo.
The overall rates of Grade 3/4 adverse reactions were similar between Qinlock and placebo. The most common adverse reactions were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar‑plantar erythrodysesthesia, and vomiting. When you look at the rates, the alopecia rate was 52% in Qinlock versus 4.7% in placebo. And when you look at fatigue, the Grade 3‑4 toxicity was 3.5% with Qinlock, and 2.3% with placebo. And the abdominal pain was 7% for Grade 3‑4 toxicity with Qinlock versus 4.7% with placebo. The most common Grade 3 or 4 lab abnormalities were increased lipase and decreased phosphate. There were no Grade 4 laboratory abnormalities.
Clinically relevant differences were observed between Qinlock and placebo in prespecified quality of life assessments. PRO assessments were analyzed comparing changes from Cycle 1 Day 1 at baseline and Cycle 2 Day 1 between Qinlock and placebo. Comparisons were only made out to Cycle 2 Day 1 for Qinlock and placebo in patients with completed PRO assessments due to a low number of placebo patients after this point. The minimally important clinical difference has been defined as a greater than 10% mean score change, or a 5‑point change. The self‑reported health was assessed using EQ‑5D‑5L, the visual analog scale. In all this, the self‑reported health remains stable with Qinlock compared to a decrease with placebo. The physical function was assessed using the EORTC QLQ‑C30 physical function, and showed the physical function remains stable with Qinlock compared to a decrease with placebo. The role function was also assessed using the EORTC QLC‑C30 role function, and this showed that role function remains stable with Qinlock compared to a decrease with placebo.
Now moving on to important safety information and more details about it. So for the skin‑related toxicities... palmar‑plantar erythrodysesthesia syndrome or PPES. In the INVICTUS study, Grade 1‑2 PPES occurred in 21% of the 85 patients who received Qinlock. This led to a dose discontinuation in 1.2% of patients, dose interruption in 2.4% of patients, and a dose reduction in 1.2% of patients. And so based on this, if patients do have severe symptoms or severe PPES, you can withhold Qinlock, and then resume at the same or reduced dose based on their time to recovery.
With regards to primary cutaneous malignancies, on INVICTUS, cutaneous squamous cell carcinomas were reported in four patients, that is 4.7%, of the 85 patients who received Qinlock with a median time to event of 4.6 months ranging from 3.8 to 6 months. Melanoma was reported in two patients, which is 2.4%, who received Qinlock.
In the pooled safety population, the cutaneous squamous cell carcinoma and keratoacanthoma was reported in 7% and 1.9% of the 351 patients, respectively. Melanoma was reported in 0.9% of the 351 patients.
It's important to perform dermatologic evaluations when initiating Qinlock and routinely during treatment. And you manage suspicious skin lesions with excision and dermatopathologic evaluation, but you can continue treatment at the same dose thereafter.
With regards to hypertension in the INVICTUS study, Grade 1‑3 hypertension occurred in 14% of patients who received Qinlock, including Grade 3 hypertension in 7% of patients. Do not initiate Qinlock in patients with uncontrolled hypertension. You must monitor blood pressure as clinically indicated. And based on severity, withhold Qinlock and then resume at the same or reduced dose.
Cardiac dysfunction, including cardiac failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy, was also monitored. On the INVICTUS study, cardiac failure occurred in one, which is 1.2%, of the 85 patients who received Qinlock. Grade 3 decreased ejection fraction was reported in two patients of the 77 patients who received Qinlock and who had a baseline and post baseline echocardiogram, so that was 2.6%. Cardiac dysfunction led to dose discontinuation in 1.2% of the patients. In the pooled safety population, cardiac dysfunction was reported in 1.7% of the 351 patients, including Grade 3 adverse reactions in 1.1% of patients. Grade 3 decreased ejection fraction was reported in 3.4% of the 263 patients who had baseline and post baseline echocardiograms. The safety of Qinlock has not been assessed in patients with a baseline ejection fraction below 50%. As clinically indicated, assess ejection fraction by echocardiogram or MUGA scan prior to initiating Qinlock and during treatment. Permanently discontinue Qinlock for Grade 3 or 4 left ventricular systolic dysfunction.
With regards to risk of impaired wound healing, Qinlock has the potential to adversely affect wound healing, so you must withhold Qinlock for at least one week prior to elective surgery. Do not administer for at least two weeks following major surgery and until adequate wound healing. The safety of resumption of Qinlock after resolution of the wound healing complications has not been established.
Qinlock can cause fetal harm when administered to a pregnant woman. Advise pregnant females of the potential risk to a fetus. Advise females of reproductive potential and meals with female partners of reproductive potential to use effective contraception during treatment and for at least one week after the final dose. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for at least one week after the final dose. Qinlock may impair fertility in males of reproductive potential as well. The safety and effectiveness of Qinlock in pediatric patients has not been established. Administer strong CYP3A inhibitors with caution. Monitor patients who are administered strong CYP3A inhibitors more frequently for adverse reactions. Avoid concomitant use with strong CYP3A inducers.
Moving on to the dosing and administration of Qinlock. Qinlock 150 milligrams is administered as three 50 milligram tablets orally once daily. This can be taken with or without food. Instruct patients to swallow tablets whole, and advise patients to take Qinlock at the same time each day. If patients missed a dose in less than eight hours of their prescribed time, they can redose, otherwise, skip the dose and just take the next scheduled dose. Advise patients to not take additional doses if vomiting occurs after taking Qinlock and to just continue with their next scheduled dose.
Dose Qinlock with confidence as most Qinlock‑treated patients are able to start and stay on the full indicated dose. Over 90% of patients treated with Qinlock did not experience a dose reduction or discontinuation due to adverse reactions. 13 out of 14 patients did not dose reduce due to an adverse reaction. And 11 out of 12 patients did not discontinue due to an adverse reaction. Rates of dose interruptions were similar between Qinlock and placebo. Mutational testing is not required prior to administration of Qinlock. However, molecular profiling is recommended for good clinical practice.
It is important while managing patients on Qinlock to set expectations because this sets patients up for success. Advise patients that adverse reactions may occur while taking Qinlock, and encourage patients and care partners to tell you about any adverse reactions the patients may experience. Review the management recommendations of select adverse reactions with your patients. The full dose modification recommendations for adverse reactions, such as PPES, hypertension, left ventricular systolic dysfunction, arthralgia or myalgia, and other Grade 3 or 4 adverse reactions are contained in the full Prescribing information in Table 1 and also in the appendix of this presentation.
Now we'll talk about considerations for patients with advanced GIST. Qinlock is indicated for adult patients who have been diagnosed with advanced GIST and have received three or more prior TKIs, including imatinib. Qinlock has indicated regardless of the mutational status, the sequence of the prior TKIs, evidence of progression, or ECOG performance status.
Moving on to the summary and conclusions. Qinlock is a novel treatment that provides a powerful PFS benefit for patients with advanced GIST. The median progression free survival was 6.3 months on Qinlock versus one month on placebo, representing an 85% risk reduction of progression or death versus placebo. The hazard ratio is 0.15 with the P value of less than 0.0001. The median overall survival was 15.1 months on Qinlock versus 6.6 months with placebo, representing a 64% risk reduction of death versus placebo. The overall response rate, which was a key secondary endpoint, was 9.4% with Qinlock versus 0% with placebo. A P value of 0.0504. Most patients are able to start and stay on the full indicated dose, so dose Qinlock with confidence. 93% did not have their dose reduced due to an adverse reaction. And 92% did not discontinue Qinlock due to an adverse reaction. Mutational testing is not required to administer Qinlock.
The most common serious adverse reactions observed in Qinlock‑treated patients in more than 2% of patients were abdominal pain, anemia, nausea, and vomiting. The most common adverse reactions in more than equal to 20% of patients were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar‑plantar erythrodysesthesia, and vomiting. The most common Grade 3‑4 lab abnormalities included increased lipase and decreased phosphate.
Thank you for your attention and listening to this presentation. If you have any other questions or need more information, please contact your Deciphera representative.