Section 3 of 6

Product information and disease description

63 evidence topics · 46 sources

Product description

Phase of product development

Orphan designation and regulatory status

“Date Designated: 07/21/2021” (opens the source at this quote in a new tab)
“Not FDA Approved for Orphan Indication” (opens the source at this quote in a new tab)

Special FDA designations

“has granted Breakthrough Therapy Designation (BTD) for bezuclastinib in combination with sunitinib” (opens the source at this quote in a new tab)

Regulatory submission: NDA submitted April 2026

“April 1, 2026” (opens the source at this quote in a new tab)
“Bezuclastinib NDA submitted under the FDA’s RTOR program” (opens the source at this quote in a new tab)
“today announced the completion of the submission of its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for bezuclastinib in patients with Gastrointestinal Stromal Tumors (GIST)” (opens the source at this quote in a new tab)

Priority review and advisory committee

“has granted the application Priority Review” (opens the source at this quote in a new tab)
“there is no plan to hold an advisory committee” (opens the source at this quote in a new tab)

Anticipated FDA approval date

“Potential FDA approval of bezuclastinib in GIST” (opens the source at this quote in a new tab)
“PDUFA date of November 30, 2026” (opens the source at this quote in a new tab)

Launch: Anticipated in the second half of 2026

“pending regulatory approval, the company expects to launch bezuclastinib commercially in the United States in the second half of 2026.” (opens the source at this quote in a new tab)

“Pending FDA approval(s), launch bezuclastinib in the second half of 2026” (opens the source at this quote in a new tab)

“the NDA for GIST is also under FDA review, with a PDUFA target action date of November 30, 2026” (opens the source at this quote in a new tab)
“ready for the potential launches later this year” (opens the source at this quote in a new tab)

PEAK extension: first-line KIT exon 9-mutant GIST

“a single-arm, 40 patient extension cohort of the PEAK trial” (opens the source at this quote in a new tab)
“first-line GIST patients with KIT exon 9 primary mutations” (opens the source at this quote in a new tab)

Product information

Generic, brand name and therapeutic class of product

Manufacturer: Cogent Biosciences

“Sponsor: Cogent Biosciences, Inc.” (opens the source at this quote in a new tab)

Product names and molecular targets

“Bezuclastinib (CGT9486, formerly PLX9486) is an investigational TKI that inhibits mutations in KIT exons 9, 11, 17, and 18.” (opens the source at this quote in a new tab)

Dosage forms and strengths

Investigational tablet formulation

“600 mg dose of our new formulation of bezuclastinib, supplied as 75 mg tablets” (opens the source at this quote in a new tab)

Average sales price and wholesale acquisition cost

Not applicable.

American hospital formulary service (AHFS), or other drug classification

Pharmacologic classification

“protein tyrosine kinase inhibitor” (opens the source at this quote in a new tab)

Indication

Orphan-designated indication

“Orphan Designation: Treatment of gastrointestinal stromal tumors (GIST)” (opens the source at this quote in a new tab)

Anticipated indication after prior imatinib

“patients with Gastrointestinal Stromal Tumors (GIST) who have received prior treatment with imatinib.” (opens the source at this quote in a new tab)

Pharmacology

Mechanism of action

Drug class and mechanism

“An orally bioavailable protein tyrosine kinase inhibitor of mutated forms of the tumor-associated antigen mast/stem cell factor receptor c-Kit (SCFR), with potential antineoplastic activity.” (opens the source at this quote in a new tab)

Pharmacodynamics

Preclinical xenograft evidence

“PLX9486 showed anti-tumor efficacy in patient-derived imatinib-resistant GIST xenograft models, mainly through inhibition of KIT signaling.” (opens the source at this quote in a new tab)

KIT resistance mechanisms and preclinical inhibitor testing

“drugs in clinical development that potently inhibit most KIT AP or AL mutations exhibit poor activity against AP/AL mutations” (opens the source at this quote in a new tab)

Pharmacokinetics

Pharmacokinetics: PLX9486 phase 1b/2a study

“a mean terminal half-life of 71 hours” (opens the source at this quote in a new tab)

Contraindications/Warnings/Precautions/Adverse effects

Warnings and precautions

Not applicable.

Special populations

PEAK eligibility: adult participants

“Open to people ages 18 years and up” (opens the source at this quote in a new tab)

Organ impairment and pregnancy

No evidence found.

Drug/Drug, drug/disease interactions

Effects of other drugs on Bezuclastinib

Sunitinib combination pharmacokinetics

“Combination with sunitinib did not have an impact on PK of bezuclastinib” (opens the source at this quote in a new tab)

PEAK exclusion criterion: CYP3A4 modifiers

“Received strong CYP3A4 inhibitors or inducers” (opens the source at this quote in a new tab)

Effects of Bezuclastinib on other drugs

Drug interaction: PEAK Part 1

“Combination with bezuclastinib” (opens the source at this quote in a new tab)
“26% and 35% reduction in median and geometric mean steady state AUC (AUCss), respectively, of combined sunitinib + its active metabolite” (opens the source at this quote in a new tab)

Dosing and administration

Dosage

PEAK investigational combination regimen

“bezuclastinib 600 mg QD + sunitinib 37.5 mg QD” (opens the source at this quote in a new tab)

Administration

Oral administration

“Upon oral administration, bezuclastinib binds to and inhibits specific c-Kit mutants.” (opens the source at this quote in a new tab)

Access and distribution

Expanded access

“The patient must reside in the United States.” (opens the source at this quote in a new tab)
“Requests for expanded access must be submitted voluntarily by the patient’s treating physician.” (opens the source at this quote in a new tab)

Co-prescribed/Concomitant therapies

Sunitinib in the investigational combination

“sunitinib 37.5 mg QD” (opens the source at this quote in a new tab)

Effect of Bezuclastinib on quality measures

No evidence found.

Product comparison

PEAK comparison with sunitinib monotherapy

“mPFS, as assessed by blinded independent central review, was 16.5 months for the bezuclastinib combination vs. 9.2 months for sunitinib monotherapy.” (opens the source at this quote in a new tab)

Place of product in therapy

Disease description

Definition and etiology

Mesenchymal tumors of the digestive tract

“Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract” (opens the source at this quote in a new tab)

Epidemiology

Incidence of Gastrointestinal stromal tumor

U.S. epidemiology

“Annual age-adjusted incidence rose from 0.55/100,000 in 2001 to 0.78/100,000 in 2011 and increased with age, peaking among 70-79 year olds (3.06/100,000).” (opens the source at this quote in a new tab)

Prevalence of Gastrointestinal stromal tumor

Preimatinib prevalence in a western Sweden population-based cohort

“The prevalence of all GIST risk groups was 129 per million” (opens the source at this quote in a new tab)

Natural history, survival, and mortality

U.S. survival in the population-based incidence study

“The study period had 5-year overall and GIST-specific survival rates of 65% and 79%, respectively.” (opens the source at this quote in a new tab)

Pathophysiology

Constitutive KIT activation

“All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF).” (opens the source at this quote in a new tab)

Diagnosis

Mutational analysis before medical treatment

“It is strongly recommended to perform the mutational analysis in all GIST cases requiring medical treatment (II, A).” (opens the source at this quote in a new tab)

Clinical presentation - signs and symptoms

Bleeding and anemia

“GI bleeding (most common presentation), which may be acute (melena or hematemesis) or chronic, resulting in anemia.” (opens the source at this quote in a new tab)

Obstruction, swallowing difficulty, and early satiety

“GI obstruction.” (opens the source at this quote in a new tab)
“Dysphagia.” (opens the source at this quote in a new tab)
“Early satiety.” (opens the source at this quote in a new tab)

Pain

“Pain.” (opens the source at this quote in a new tab)

Long-term morbidity

Rectal GIST close to the anal sphincter: surgical morbidity

“abdominoperineal resection with permanent colostomy is required.” (opens the source at this quote in a new tab)

Burden of Gastrointestinal stromal tumor

Humanistic burden and health-related quality of life

Humanistic burden

“Severe fatigue occurs in 30% of GIST patients and in 33% of GIST patients on a TKI.” (opens the source at this quote in a new tab)

Quality of life, fear of recurrence, and adherence during imatinib treatment

“Approximately 3 out of 4 patients report high fear of cancer recurrence / progression” (opens the source at this quote in a new tab)
“Therapy adherence was high (96.1%).” (opens the source at this quote in a new tab)

Patient-reported symptoms

“Fatigue and muscle pain or cramps were reported most frequently.” (opens the source at this quote in a new tab)

Systematic review of quality of life and adverse events

“A total of 104 papers were included; 13 studies addressed HRQoL, and 96 studies investigated adverse events.” (opens the source at this quote in a new tab)

Health-state utilities from GRID

“Mean baseline utility was 0.767 (SD 0.221)” (opens the source at this quote in a new tab)
“The first post-progression health state was 0.647 (SD 0.343)” (opens the source at this quote in a new tab)

Economic burden and healthcare resource utilization

GIST recurrence costs

“The total healthcare cost was significantly higher for patients with GIST recurrence, with a difference of $4464 per patient per month (p < 0.01).” (opens the source at this quote in a new tab)

Hospital utilization

“The study analyzed 48,690 hospitalizations” (opens the source at this quote in a new tab)
“with a primary diagnosis of GIST between 2016 and 2020.” (opens the source at this quote in a new tab)

Mutation testing and subsequent treatment

“Dropout to/for further lines of treatment was 15% for patients with a Tested mutation vs. 47% in Untested patients.” (opens the source at this quote in a new tab)

U.S. inpatient burden

“In 2009, there were 14,562 hospitalizations among patients with GISTs at a rate of 44/100,000 admissions.” (opens the source at this quote in a new tab)

Economic impact of Gastrointestinal stromal tumor on families

Individual family account: medication costs and copay assistance

“hundreds of dollars just for a single pill” (opens the source at this quote in a new tab)
“This funding is enough to cover my mother’s drug copay liability for 2022” (opens the source at this quote in a new tab)

Economic impact of diagnostic testing

Tumor gene testing and tailored first-line therapy

“an increase of 0.10 QALYs at a cost of $9513 compared with the empirical imatinib approach” (opens the source at this quote in a new tab)
“an incremental cost-effectiveness ratio of $92 100.” (opens the source at this quote in a new tab)

Approaches to treatment

Current treatment options and standard of care

Active surveillance

Small tumors with a mitotic index of 5 or less per 50 high-power fields

“Endoscopic surveillance is an option for patients with tumors measuring 2 cm or smaller” (opens the source at this quote in a new tab)

Surgical resection

Surgery for localized disease

“Approximately 70% of patients with GIST will be cured by surgery alone” (opens the source at this quote in a new tab)

KIT and PDGFRA tyrosine kinase inhibitors

First-line treatment of advanced or metastatic GIST

“Imatinib” (opens the source at this quote in a new tab)
“a category 1 preferred first-line treatment option for patients with advanced or metastatic GIST with imatinib-sensitive mutations” (opens the source at this quote in a new tab)

PDGFRA D842V-mutant GIST: first-line therapy

“avapritinib is used as first-line therapy” (opens the source at this quote in a new tab)

Second-line treatment after imatinib failure

“After the failure of imatinib, the standard second-line treatment is sunitinib 50 mg daily 4/2 (I,A) or 37.5 mg continuously (III,C).” (opens the source at this quote in a new tab)

Third-line and fourth-line treatment

“Regorafenib is regarded as standard therapy for the third-line treatment” (opens the source at this quote in a new tab)
“Ripretinib was approved by the FDA in May 2020” (opens the source at this quote in a new tab)
“as 4th line treatment.” (opens the source at this quote in a new tab)

TRK inhibitors

NTRK fusion-positive disease

“NTRK gene-fusion positive GISTs only” (opens the source at this quote in a new tab)
“Larotrectinib” (opens the source at this quote in a new tab)
“Entrectinib” (opens the source at this quote in a new tab)

mTOR inhibitor and tyrosine kinase inhibitor combinations

Combination options in selected circumstances

“TKIs to be considered for use in combination with everolimus include imatinib, sunitinib, or regorafenib.” (opens the source at this quote in a new tab)

Ablative therapies

Local treatment of isolated progression

“Isolated progression may be amenable to surgery or other local measures, such as radiofrequency ablation” (opens the source at this quote in a new tab)

Radiotherapy

Local radiotherapy in advanced disease

“Radiotherapy may be a useful local therapy” (opens the source at this quote in a new tab)

Limitations of current therapies

Summary

The evidence documents heterogeneous resistance mutations within and between lesions in progressing GIST. Treatment-associated symptom burden also persists: severe fatigue occurred in 30% of participants with GIST and 33% of those receiving a TKI in the cited fatigue study. These findings address resistance and treatment burden rather than demonstrating comparative efficacy between individual TKIs.

Place in treatment, anticipated use, and care setting

Summary

The submitted application concerns GIST after prior imatinib treatment. The pivotal comparison evaluates bezuclastinib in combination with sunitinib rather than as monotherapy. The sponsor’s expanded-access policy requires the patient to reside in the United States and requests to be submitted by the treating physician.

Heterogeneity of treatment effect

Heterogeneity of treatment resistance

“This study demonstrates extensive intra- and inter-lesional heterogeneity of resistance mutations and gene amplification in patients with clinically progressing GIST.” (opens the source at this quote in a new tab)

Care management intervention strategies

Assessment at progression during TKI therapy

“Confirm adherence to treatment and rule out drug interactions at the time of progression to any TKI (III,B).” (opens the source at this quote in a new tab)

Ongoing post-approval monitoring

Not applicable.

Expected outcomes of therapy

Progression-free survival in the pivotal comparison

“mPFS, as assessed by blinded independent central review, was 16.5 months for the bezuclastinib combination vs. 9.2 months for sunitinib monotherapy.” (opens the source at this quote in a new tab)

Overall-survival maturity

“Data for overall survival remains immature.” (opens the source at this quote in a new tab)