Brigatinib in Treating Patients With ALK and ROS1 Gene Alterations and Locally Advanced or Metastatic Solid Cancers

Abstract Background: Genetic alterations of FGFRs are known to play an important role in the proliferation, survival, and migration of cancer cells as well as tumor angiogenesis and drug resistance. E7090 is an orally available selective tyrosine kinase inhibitor for FGFR1-3. A global Phase 2 study of E7090 in subjects with unresectable advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusion is ongoing (NCT04238715). We recently reported FGFR alterations that are highly sensitive to E7090 using a high-throughput functional evaluation method called MANO method (Nakamura et al. npj Precision Oncology, 2021), narrowing down the most promising FGFR alteration targets. Here, we designed a single-arm, open-label, investigator-initiated multicenter Phase 2 basket study to evaluate the efficacy and safety of E7090 in subjects with advanced or recurrent solid tumors harboring FGFR gene alterations, focusing on alterations identified by MANO method, as a sub-study under the nationwide large registry for rare cancers in Japan (MASTER KEY Project). Methods: The key eligibility criteria are: 1) Histologically confirmed metastatic or locally advanced solid tumor; 2) Ineffective to or intolerant to first line treatment, or for which standard treatment is no longer available; and 3) Confirmed FGFR gene alterations via next-generation sequencing assays that are reimbursed by insurance. Subjects will receive E7090 140 mg orally once daily until disease progression or development of unacceptable toxicity. The primary endpoint is objective response rate (ORR) by independent central review (RECIST v1.1), and the secondary endpoints include ORR by investigator assessment, progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. For primary brain tumors, RANO criteria is also applied in assessment of response. The study enrolls approximately 45 subjects. (Clinical Trial Registry: jRCT2031210043, ClinicalTrials.gov: NCT04962867)

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SYST-01. MULTICENTER INVESTIGATOR-INITIATED PHASE 2 STUDY OF E7090 IN SUBJECTS WITH ADVANCED OR RECURRENT SOLID TUMORS WITH FIBROBLAST GROWTH FACTOR RECEPTOR (FGFR) GENE ALTERATION: FORTUNE STUDY

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab112.029 ◽

2021 ◽

Vol 3 (Supplement_4) ◽

pp. iv8-iv8

Author(s):

Masamichi Takahashi ◽

Yohei Chiba ◽

Kazuki Sudo ◽

Yuki Kojima ◽

Hitomi Okuma ◽

...

Keyword(s):

Solid Tumors ◽

Kinase Inhibitor ◽

Objective Response ◽

Locally Advanced ◽

Genetic Alterations ◽

Precision Oncology ◽

Functional Evaluation ◽

Phase 2 ◽

Phase 2 Study ◽

Gene Alterations

Abstract Background Genetic alterations of FGFRs are known to play an important role in the proliferation, survival, and migration of cancer cells as well as tumor angiogenesis and drug resistance. E7090 is an orally available selective tyrosine kinase inhibitor for FGFR1-3. A global Phase 2 study of E7090 in subjects with unresectable advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusion is ongoing (NCT04238715). We recently reported FGFR alterations that are highly sensitive to E7090 using a high-throughput functional evaluation method called MANO method (Nakamura et al. npj Precision Oncology, in press), narrowing down the most promising FGFR alteration targets. Here, we designed a single-arm, open-label, investigator-initiated multicenter Phase 2 basket study to evaluate the efficacy and safety of E7090 in subjects with advanced or recurrent solid tumors harboring FGFR gene alterations, focusing on alterations identified by MANO method, as a sub-study under the nationwide large registry for rare cancers in Japan (MASTER KEY Project). Methods The key eligibility criteria are: 1) Histologically confirmed metastatic or locally advanced solid tumor; 2) Ineffective to or intolerant to first line treatment, or for which standard treatment is no longer available; and 3) Confirmed FGFR gene alterations via next-generation sequencing assays that are reimbursed by insurance. Subjects will receive E7090 140 mg orally once daily until disease progression or development of unacceptable toxicity. The primary endpoint is objective response rate (ORR) by independent central review (RECIST v1.1), and the secondary endpoints include ORR by investigator assessment, progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. For primary brain tumors, RANO criteria is also applied in assessment of response. The study enrolls approximately 45 subjects. (Clinical Trial Registry: jRCT2031210043)

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A phase II open-label study in adult and adolescent patients (pts) with advanced solid tumors harboring fibroblast growth factor receptor (FGFR) gene alterations.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps480 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS480-TPS480

Author(s):

Shubham Pant ◽

Josep Tabernero ◽

Christophe Massard ◽

Gopa Iyer ◽

Olaf Witt ◽

...

Keyword(s):

Solid Tumors ◽

Kinase Inhibitor ◽

Locally Advanced ◽

Safety Data ◽

Genetic Alterations ◽

Advanced Solid Tumors ◽

Open Label ◽

Open Label Study ◽

Label Study ◽

Gene Alterations

TPS480 Background: The pan- FGFR tyrosine kinase inhibitor erdafitinib is approved by the US Food and Drug Administration for adults with locally advanced or metastatic urothelial carcinoma and susceptible FGFR3/2 genetic alterations who have progressed during or after ≥ 1 line of prior platinum-containing chemotherapy. FGFR gene alterations are potential oncogenic drivers that have been reported in many solid tumors in adult and pediatric pts. Because of limited response to standard of care options in pts failing systemic therapy, there is strong rationale to assess the safety and efficacy of erdafitinib in adolescent and adult pts with advanced solid tumors and FGFR alterations. Methods: This phase 2, open-label study (RAGNAR/42756493CAN2002; NCT04083976) will include pts aged ≥ 12 years with histologically confirmed unresectable, locally advanced, or metastatic solid tumors (except urothelial tumors) harboring predefined FGFR mutations or fusions. Eligibility screening includes molecular screening for FGFR alterations by central or local next-generation sequencing assays, and other clinical criteria. Pts will enroll into either a broad panel cohort (BPC) of target FGFR alterations or an exploratory cohort (EC) for FGFR alterations that do not meet criteria for BPC. Approximately 280 pts (BPC, n = 240; EC, n = 40) will be enrolled. The primary efficacy end point is overall response rate (ORR) as assessed by the independent review committee. Secondary end points include investigator-assessed ORR, duration of response, disease control rate, progression-free survival, overall survival, safety, pharmacokinetics, and health-related quality of life. Safety assessments include adverse events, vital signs, electrocardiograms, physical examinations, laboratory tests, performance status assessment, growth assessments in adolescents, and ophthalmologic examination. As of December 2019, pts are being enrolled at ~158 sites in 15 countries. Results of this study will provide efficacy and safety data for erdafitinib across multiple solid tumors with FGFR alterations and evaluate the potential benefit of targeting the underlying altered biology of FGFR irrespective of tumor histology in adult and adolescent pts. Clinical trial information: NCT04083976.

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Does escalation results from phase Ib/II Norse study of erdafitinib (ERDA) + PD-1 inhibitor JNJ-63723283 (Cetrelimab [CET]) in patients (pts) with metastatic or locally advanced urothelial carcinoma (mUC) and selected fibroblast growth factor receptor (FGFR) gene alterations.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.511 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 511-511 ◽

Cited By ~ 1

Author(s):

Victor Moreno ◽

Yohann Loriot ◽

Begona Pérez Valderrama ◽

Carmen Beato ◽

Yann-Alexandre Vano ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Locally Advanced ◽

Growth Factor Receptor ◽

Primary Endpoints ◽

The Us ◽

Metastatic Urothelial Carcinoma ◽

Prior Systemic Therapy ◽

Advanced Urothelial Carcinoma ◽

Us Fda ◽

Gene Alterations

511 Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for pts with metastatic urothelial carcinoma (mUC) with susceptible FGFR3/2 gene alterations and progressed after ≥1 line of prior platinum-containing chemotherapy (PCC).1 CET, an IgG4, binds to anti-programmed cell death proteins (PD-1) and has shown activity in solid tumors.2 ERDA+CET may demonstrate complementary mechanisms as neoantigen release by ERDA may prime the tumor microenvironment for response. NORSE is a phase 1b/2 study to evaluate ERDA+CET in pts with mUC. Methods: Adult mUC pts with specific FGFR alterations who have progressed after ≥1 prior systemic therapy and no prior FGFR or PD-1/PD(L)-1 inhibitors enrolled in 3 dose levels (DL) of ERDA (DL1: 6 mg, DL2A: 8 mg, DL2: 8 mg with uptitration [UPT] to 9 mg) + CET (IV, 240 mg). Cohorts enrolled until dose limiting toxicity (DLT) or RP2D was identified. Primary endpoints: DLT and adverse events (AEs). Results: Of 15 pts (DL1: 4, DL2A: 3, DL2: 8), 11 continued on treatment at the time of the data cut. 14/15 pts experienced AEs; 3 experienced serious unrelated AEs (urinary tract infection, urosepsis, and large intestinal obstruction) all in DL1, 2 led to death; 10 experienced Grade >3 AEs and 2 experienced AEs of special interest, considered related to ERDA (Table). No DLTs were observed in any cohorts, 8 mg with UPT + CET was established as the RP2D. At data cut-off, investigator-assessed best overall response rate (CR+PR+uCR+uPR) in pts treated with the RP2D was 71% and disease control rate was 100% for RECIST 1.1 evaluable pts (n=7). Conclusions: 8 mg ERDA with UPT+240 mg CET was well tolerated and established as the RP2D. The combination of ERDA+CET is being further explored in the ongoing randomized phase 2 study in first-line cisplatin-ineligible mUC pts (NCT03473743). Clinical trial information: 2017-001980-19. [Table: see text]

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