Resistance in GIST warrants a different therapeutic approach1

Advanced GIST is a highly complex disease with a myriad of mutations fueling resistance and progression1,2

GIST is often driven by primary, activating mutations in kinase genes.3

  • These mutations keep the kinase in the active state, causing uncontrolled cell proliferation and/or cell survival4,5
Molecular Classification of GIST3,6
Gene/exon Primary
mutation
frequency
Secondary
mutation
frequency
KIT 70-80%
  Exon 9 10%
  Exon 11 60-70%
  Exon 13 1% 56%
  Exon 17 1% 41%
PDGFRα 5-10%
  Exon 12 1%
  Exon 14 <1%
  Exon 18 (D842V and other) 6% 3%
Wild Type 10-15%
 

Advanced GIST is marked by the development of secondary, drug-resistance mutations, which play a key role in disease progression2,3,7

  • A single patient with GIST may have multiple mutations within or between tumors1,8

  Primary lesion

  Secondary lesion

About GIST Mutations
For illustrative purposes

As resistance develops, treatments may lose their ability to control disease progression1,6

  • The vast majority of patients who benefit from front-line tyrosine kinase inhibitor (TKI) treatment will eventually develop resistance2,3
  • As secondary resistance mutations emerge, some TKIs may lose their ability to prevent kinase activation, leading to cancer cell proliferation6,8,9

 

Patients with resistant GIST tend to progress quickly through 2nd‑ and 3rd‑line therapies10-12

Median PFS and ORR10-13

Median PFS and ORR Median PFS and ORR


  • The FDA-approved 1st-, 2nd-, and 3rd-line therapies for GIST are imatinib, sunitinib, and regorafenib, respectively11-13
  • Avapritinib is approved for patients with unresectable or metastatic GIST harboring a PDGFRα exon 18 mutation (5–6% of patients), irrespective of line of therapy3,15

*PFS converted from weeks to months.


Additional therapeutic approaches are needed to help address the challenges of drug resistance in advanced GIST

 

Lock icon

Qinlock is engineered to block the drivers of resistance in advanced GIST9,14

Qinlock is the first and only switch-control kinase inhibitor that broadly inhibited KIT and PDGFRα kinase signaling in preclinical studies9,14

Chart icon

Powerful PFS Benefits

Qinlock significantly improved PFS vs placebo (6.3 months vs 1.0 month; P<0.0001)14

See the Data
Group icon

Robust Phase 3 Trial

The efficacy and safety of Qinlock was demonstrated in the INVICTUS trial14

Invictus Study Design
Operator icon

Patient Support

Learn about the services available to help patients start Qinlock

Access Assistance

FDA=Food and Drug Administration; GIST=gastrointestinal stromal tumor; KIT=KIT proto‑oncogene receptor tyrosine kinase; MOA=mechanism of action; mPFS=median progression‑free survival; ORR=objective response rate; PDGFRα=platelet‑derived growth factor receptor α; PFS=progression-free survival.

References: 1. Ordog T, Zörnig M, Hayashi Y. Targeting disease persistence in gastrointestinal stromal tumors. Stem Cells Transl Med. 2015;4(7):702‑707. 2. Antonescu CR, DeMatteo RP. CCR 20th Anniversary commentary: A genetic mechanism of imatinib resistance in gastrointestinal stromal tumor—Where are we a decade later? Clin Cancer Res. 2015;21(15):3363‑3365. 3. Lopes LF, Bacchi CE. Imatinib treatment for gastrointestinal stromal tumor (GIST). J Cell Mol Med. 2010;14(1‑2):42‑50. 4. Gramza AW, Corless CL, Heinrich MC. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Care Res. 2009;15(24):7510‑7518. 5. Yan W, Zhang A, Powell MJ. Genetic alteration and mutation profiling of circulating cell‑free tumor DNA (cfDNA) for diagnosis and targeted therapy of gastrointestinal stromal tumors. Chin J Cancer. 2016;35:68. 6. Hemming ML, Heinrich MC, Bauer S, George S. Translational insights into gastrointestinal stromal tumor and current clinical advances. Ann Oncol. 2018;29(10):2037‑2045. 7. Zhao X, Yue C. Gastrointestinal stromal tumor. J Gastrointest Oncol. 2012;3(3):189‑208. 8. Li K, Cheng H, Li Z, et al. Genetic progression in gastrointestinal stromal tumors: mechanisms and molecular interventions. Oncotarget. 2017;8(36):60589‑60604. 9. Smith BD, Kaufman MD, Lu WP, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRα variants. Cancer Cell. 2019;35(5):738‑751. 10. Demetri GD, Reichardt P, Kang Y‑K, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitib: an international, multicentre, prospective, randomised, placebo‑controlled phase 3 trial (GRID). Lancet. 2013;381(9863):295‑302. 11. Sutent [package insert]. New York, NY: Pfizer Inc; 2020. 12. Stivarga [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2020. 13. Gleevec [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020. 14. Qinlock [package insert]. Waltham, MA: Deciphera Pharmaceuticals, Inc; 2020. 15. Ayvakit [package insert]. Cambridge, MA: Blueprint Medicines Corp; 2020.


Important Safety Information

There are no contraindications for Qinlock.

Palmar‑plantar erythrodysesthesia syndrome (PPES): In INVICTUS, Grade 1–2 PPES occurred in 21% of the 85 patients who received Qinlock. PPES led to dose discontinuation in 1.2% of patients, dose interruption in 2.4% of patients, and dose reduction in 1.2% of patients. Based on severity, withhold Qinlock and then resume at same or reduced dose.

New Primary Cutaneous Malignancies: In INVICTUS, cutaneous squamous cell carcinoma (cuSCC) occurred in 4.7% of the 85 patients who received Qinlock with a median time to event of 4.6 months (range 3.8 to 6 months). In the pooled safety population, cuSCC and keratoacanthoma occurred in 7% and 1.9% of 351 patients, respectively. In INVICTUS, melanoma occurred in 2.4% of the 85 patients who received Qinlock. In the pooled safety population, melanoma occurred in 0.9% of 351 patients. Perform dermatologic evaluations when initiating Qinlock and routinely during treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Continue Qinlock at the same dose.

Hypertension: In INVICTUS, Grade 1–3 hypertension occurred in 14% of the 85 patients who received Qinlock, including Grade 3 hypertension in 7% of patients. Do not initiate Qinlock in patients with uncontrolled hypertension. Monitor blood pressure as clinically indicated. Based on severity, withhold Qinlock and then resume at same or reduced dose or permanently discontinue.

Cardiac Dysfunction: In INVICTUS, cardiac failure occurred in 1.2% of the 85 patients who received Qinlock. In the pooled safety population, cardiac dysfunction (including cardiac failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) occurred in 1.7% of 351 patients, including Grade 3 adverse reactions in 1.1% of patients.

In INVICTUS, Grade 3 decreased ejection fraction occurred in 2.6% of the 77 patients who received Qinlock and who had a baseline and at least one post‑baseline echocardiogram. Grade 3 decreased ejection fraction occurred in 3.4% of the 263 patients in the pooled safety population who received Qinlock and who had a baseline and at least one post‑baseline echocardiogram.

In INVICTUS, cardiac dysfunction led to dose discontinuation in 1.2% of the 85 patients who received Qinlock. The safety of Qinlock has not been assessed in patients with a baseline ejection fraction below 50%. Assess ejection fraction by echocardiogram or MUGA scan prior to initiating Qinlock and during treatment, as clinically indicated. Permanently discontinue Qinlock for Grade 3 or 4 left ventricular systolic dysfunction.

Risk of Impaired Wound Healing: Qinlock has the potential to adversely affect wound healing. Withhold Qinlock for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Qinlock after resolution of wound healing complications has not been established.

Embryo‑Fetal Toxicity: Qinlock can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 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 1 week after the final dose. Qinlock may impair fertility in males of reproductive potential.

Adverse Reactions: The most common adverse reactions (≥20%) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, PPES, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥4%) were increased lipase and decreased phosphate.

The safety and effectiveness of Qinlock in pediatric patients have 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.

To report SUSPECTED ADVERSE REACTIONS, contact Deciphera Pharmaceuticals, LLC, at 1-888-724-3274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Indication

Qinlock is a kinase inhibitor indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib.

Please see full Prescribing Information, including Patient Information.

Important Safety Information

There are no contraindications for Qinlock.

Palmar‑plantar erythrodysesthesia syndrome (PPES): In INVICTUS, Grade 1–2 PPES occurred in 21% of the 85 patients who received Qinlock. PPES led to dose discontinuation in 1.2% of patients, dose interruption in 2.4% of patients, and dose reduction in 1.2% of patients. Based on severity, withhold Qinlock and then resume at same or reduced dose.

New Primary Cutaneous Malignancies: In INVICTUS, cutaneous squamous cell carcinoma (cuSCC) occurred in 4.7% of the 85 patients who received Qinlock with a median time to event of 4.6 months (range 3.8 to 6 months). In the pooled safety population, cuSCC and keratoacanthoma occurred in 7% and 1.9% of 351 patients, respectively. In INVICTUS, melanoma occurred in 2.4% of the 85 patients who received Qinlock. In the pooled safety population, melanoma occurred in 0.9% of 351 patients. Perform dermatologic evaluations when initiating Qinlock and routinely during treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Continue Qinlock at the same dose.

Hypertension: In INVICTUS, Grade 1–3 hypertension occurred in 14% of the 85 patients who received Qinlock, including Grade 3 hypertension in 7% of patients. Do not initiate Qinlock in patients with uncontrolled hypertension. Monitor blood pressure as clinically indicated. Based on severity, withhold Qinlock and then resume at same or reduced dose or permanently discontinue.

Cardiac Dysfunction: In INVICTUS, cardiac failure occurred in 1.2% of the 85 patients who received Qinlock. In the pooled safety population, cardiac dysfunction (including cardiac failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) occurred in 1.7% of 351 patients, including Grade 3 adverse reactions in 1.1% of patients.

In INVICTUS, Grade 3 decreased ejection fraction occurred in 2.6% of the 77 patients who received Qinlock and who had a baseline and at least one post‑baseline echocardiogram. Grade 3 decreased ejection fraction occurred in 3.4% of the 263 patients in the pooled safety population who received Qinlock and who had a baseline and at least one post‑baseline echocardiogram.

In INVICTUS, cardiac dysfunction led to dose discontinuation in 1.2% of the 85 patients who received Qinlock. The safety of Qinlock has not been assessed in patients with a baseline ejection fraction below 50%. Assess ejection fraction by echocardiogram or MUGA scan prior to initiating Qinlock and during treatment, as clinically indicated. Permanently discontinue Qinlock for Grade 3 or 4 left ventricular systolic dysfunction.

Risk of Impaired Wound Healing: Qinlock has the potential to adversely affect wound healing. Withhold Qinlock for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Qinlock after resolution of wound healing complications has not been established.

Embryo‑Fetal Toxicity: Qinlock can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 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 1 week after the final dose. Qinlock may impair fertility in males of reproductive potential.

Adverse Reactions: The most common adverse reactions (≥20%) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, PPES, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥4%) were increased lipase and decreased phosphate.

The safety and effectiveness of Qinlock in pediatric patients have 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.

To report SUSPECTED ADVERSE REACTIONS, contact Deciphera Pharmaceuticals, LLC, at 1-888-724-3274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Indication

Qinlock is a kinase inhibitor indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib.

Please see full Prescribing Information, including Patient Information.