On August 13, 2019 Deciphera Pharmaceuticals, Inc. (NASDAQ:DCPH), a clinical-stage biopharmaceutical company focused on addressing key mechanisms of tumor drug resistance, reported positive top-line data from the INVICTUS pivotal Phase 3 clinical study of ripretinib, a broad-spectrum KIT and PDGFRα inhibitor, in patients with fourth-line and fourth-line plus gastrointestinal stromal tumors (GIST) (Press release, Deciphera Pharmaceuticals, AUG 13, 2019, View Source [SID1234538651]).

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"There is a dire unmet need for new therapies that can deliver effective disease control for patients with advanced GIST who have failed currently approved treatment options," said Margaret von Mehren, MD, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. "These top-line data from a Phase 3, randomized, placebo-controlled study are highly impressive and suggest that ripretinib’s approach of targeting the broad spectrum of KIT and PDGFRα mutations known to drive GIST can significantly improve progression free survival in the most heavily pretreated patients. Particularly notable is the magnitude of benefit observed for overall survival in this study."

The INVICTUS Phase 3 clinical study is a randomized (2:1), double-blind, placebo-controlled, international, multicenter study to evaluate the safety, tolerability, and efficacy of ripretinib compared to placebo in 129 patients with advanced GIST whose previous therapies have included at least imatinib, sunitinib, and regorafenib. The INVICTUS study achieved its primary endpoint of improved PFS as determined by blinded independent central radiologic review using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

In the INVICTUS study, ripretinib demonstrated a median PFS of 6.3 months (27.6 weeks) compared to 1.0 month (4.1 weeks) in the placebo arm and significantly reduced the risk of disease progression or death by 85% (HR of 0.15, p<0.0001) compared to placebo.

For the key secondary endpoint of objective response rate (ORR), as determined by blinded independent central radiologic review using modified RECIST version 1.1, ripretinib demonstrated an ORR of 9.4% compared with 0% for placebo (p-value=0.0504), which was not statistically significant. Ripretinib in this study also showed a clinically meaningful improvement over placebo in terms of the secondary endpoint overall survival (OS) (median OS 15.1 months vs. 6.6 months, HR = 0.36, nominal p-value=0.0004). Since statistical significance was not achieved for ORR, the hypothesis testing of OS was not formally performed. According to the pre-specified hierarchical testing procedure of the endpoints, the hypothesis testing of OS cannot be formally conducted unless the test of ORR is statistically significant. The OS data for the placebo arm includes patients taking placebo who, following progression, were crossed-over to ripretinib treatment.

Ripretinib was generally well tolerated and the adverse event results in INVICTUS were consistent with data from previously presented Phase 1 study results. Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurred in 42 (49%) patients on the ripretinib arm compared to 19 (44%) on the placebo arm. Grade 3 or 4 TEAEs >5% of patients in the ripretinib arm were anemia (9%; n=8), abdominal pain (7%; n=6) and hypertension (7%; n=6). Grade 3 or 4 TEAEs >5% of patients in the placebo arm were anemia (14%; n=6). The below table lists TEAEs >15% in the ripretinib arm compared to placebo.

INVICTUS Phase 3 Clinical Study

Treatment Emergent Adverse Event

Placebo

Ripretinib

(N=43)(1)

150mg
Daily

(N=85)(1)

Any event

42 (98

%)

84 (99

%)

Alopecia

2 (5

%)

44 (52

%)

Fatigue

10 (23

%)

36 (42

%)

Nausea

5 (12

%)

33 (39

%)

Abdominal pain

13 (30

%)

31 (36

%)

Constipation

8 (19

%)

29 (34

%)

Myalgia

5 (12

%)

27 (32

%)

Diarrhea

6 (14

%)

24 (28

%)

Decreased appetite

9 (21

%)

23 (27

%)

Palmar-plantar erythrodysaesthesia syndrome

0

18 (21

%)

Vomiting

3 (7

%)

18 (21

%)

Headache

2 (5

%)

16 (19

%)

Weight decreased

5 (12

%)

16 (19

%)

Arthralgia

2 (5

%)

15 (18

%)

Blood bilirubin increased

0

14 (16

%)

Oedema peripheral

3 (7

%)

14 (16

%)

Muscle spasms

2 (5

%)

13 (15

%)

Notes to table: (1) Safety population includes 128 patients. One patient was randomized to placebo but did not receive study drug.

"Today’s announcement represents a significant milestone in our mission to deliver important new medicines for the treatment of cancer," said Steve Hoerter, President and Chief Executive Officer of Deciphera. "On behalf of the entire Deciphera team, I would like to thank the patients, their caregivers and the healthcare professionals who participated in the INVICTUS study. The data from INVICTUS reinforce our belief that ripretinib has the potential to transform the treatment of GIST, and our focus now turns to working closely with the FDA as they evaluate ripretinib for those patients with GIST who, having failed all currently approved therapies, are in desperate need of a treatment option."

Based on the positive INVICTUS data, the Company expects to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for ripretinib for the treatment of patients with advanced GIST who have received prior treatment with imatinib, sunitinib and regorafenib in the first quarter of 2020.

Additional results from the INVICTUS Phase 3 clinical study are expected to be presented at an upcoming medical meeting.

Conference Call and Webcast

Deciphera will host a conference call and webcast to discuss the results of the INVICTUS Phase 3 clinical study today, August 13, 2019 at 8:00 AM ET. To access the live call by phone please dial 866-930-5479 (domestic) or 409-216-0603 (international); the conference ID is 8859018. A live audio webcast of the event and accompanying slides may also be accessed through the "Investors" section of Deciphera’s website at www.deciphera.com. A replay of the webcast will be available for 30 days following the event.

About the INVICTUS Phase 3 Study

The INVICTUS Phase 3 clinical study is a randomized, double-blind, placebo-controlled, international, multicenter study to evaluate the safety, tolerability, and efficacy of ripretinib compared to placebo in patients with advanced GIST whose previous therapies have included imatinib, sunitinib, and regorafenib. This study was designed to provide evidence of clinical benefit in fourth-line and fourth-line plus patients with GIST that would be required to secure a regulatory approval. Patients were randomized 2:1 to either 150 mg of ripretinib or placebo once daily. The primary efficacy endpoint is progression-free survival (PFS) as determined by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints as determined by independent radiologic review using modified RECIST include Objective Response Rate (ORR), Time to Tumor Progression (TTP) and Overall Survival (OS). See www.clinicaltrials.gov for further information (NCT03353753).

About GIST

Gastrointestinal stromal tumor (GIST) is a cancer affecting the digestive tract or nearby structures within the abdomen, most often presenting in the stomach or small intestine. GIST is the most common sarcoma of the gastrointestinal tract, with approximately 4,000 to 6,000 new GIST cases each year in the United States and a similar incidence rate in European and other countries. Most cases of GIST are driven by a spectrum of mutations. The most common primary mutations are in KIT kinase, representing approximately 75% to 80% of cases, or in PDGFRα kinase, representing approximately 5% to 10% of cases. Current therapies are unable to inhibit the full spectrum of primary and secondary mutations, which drives resistance and disease progression. Estimates for 5-year survival range from 48% to 90%, depending on the stage of the disease at diagnosis.

About Ripretinib

Ripretinib is an investigational KIT and PDGFRα kinase switch control inhibitor in clinical development for the treatment of KIT and/or PDGFRα-driven cancers, including gastrointestinal stromal tumors, or GIST, systemic mastocytosis, or SM, and other cancers. Ripretinib was specifically designed to improve the treatment of patients with GIST by inhibiting a broad spectrum of mutations in KIT and PDGFRα. Ripretinib is a KIT and PDGFRα inhibitor that inhibits initiating and secondary KIT mutations in exons 9, 11, 13, 14, 17, and 18, involved in GIST, as well as the primary D816V exon 17 mutation involved in SM. Ripretinib also inhibits primary PDGFRα mutations in exons 12, 14 and 18, including the exon 18 D842V mutation, involved in a subset of GIST. In June 2019, the U.S. FDA granted Fast Track Designation to ripretinib for the treatment of patients with advanced GIST who have received prior treatment with imatinib, sunitinib and regorafenib.

Deciphera Pharmaceuticals has an exclusive license agreement with Zai Lab (Shanghai) Co., Ltd. for the development and commercialization of ripretinib in Greater China (Mainland China, Hong Kong, Macau and Taiwan). Deciphera Pharmaceuticals retains development and commercial rights for ripretinib in the rest of the world.