Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Entrectinib · 9 trials · 25 indications
PFS is defined as the time from randomization to the first documented disease progression (extracranial or intracranial) or death from any cause whichever occurs first determined by a blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).
Confirmed objective response indicates ≥4 weeks after initial documentation of response.
Confirmed objective response rate (cORR)=percentage of participants with best response as complete response (CR) or partial response (PR) for measurable disease \& CR for non-measurable disease. Confirmation=CR/PR on 2 consecutive visits ≥4 weeks apart for 3-week cycles \& ≥6 weeks apart for 4-week cycles. Per RECIST, CR=disappearance of all target lesions. PR= ≥30% decrease in sum of diameters of target lesions, in absence of CR. Per RANO, CR=complete disappearance of all measurable \& non-measurable disease for ≥4 weeks; no new lesions/abnormality on T2/FLAIR imaging; stable/improved non-enhancing lesions; participants must be off corticosteroids or on physiological doses; clinical status stable/improved. PR= ≥50% decrease in the sum of products of perpendicular diameters of measurable enhancing lesions on T2/FLAIR imaging for ≥4 weeks; no progression of non-measurable T1 disease; stable/improved non-enhancing lesions; corticosteroid dose ≤ baseline; clinical status stable/improved.
Assessed by blinded independent central review (BICR) using RECIST v1.1
Maximum observed plasma concentration. Observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units
First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units
Obtained by dividing the total dose of parent drug by its corresponding AUCinf
Obtained by dividing Dose by the product of AUCinf and λz
Maximum observed plasma concentration. Observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units
First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units
Area under the concentration-time curve from 0 to the last measurable concentration of midazolam and the pharmacologically active metabolite 1-hydoxymidazolam in the absence or presence of entrectinib.
Area under the concentration-time curve from 0 to infinity of midazolam and the pharmacologically active metabolite 1-hydoxymidazolam in the absence or presence of entrectinib.
Peak plasma concentration of midazolam and the pharmacologically active metabolite 1-hydoxymidazolam in the absence or presence of entrectinib.
Time of maximum concentration of midazolam and the pharmacologically active metabolite 1-hydoxymidazolam in the absence or presence of entrectinib.
Terminal half-life of midazolam and the pharmacologically active metabolite 1-hydoxymidazolam in the absence or presence of entrectinib.
Assessed by National Cancer Institute Common Terminology for Adverse Events Criteria (NCI CTCAE v4.03)
Assessed by NCI CTCAE v4.03
Assessed by NCI CTCAE v4.03
Assessed by NCI CTCAE v4.03
Assessed by NCI CTCAE v4.03
Assessed by RANO per the BICR
Assessed by RECIST v1.1 per the BICR
Determine dose-limiting toxicities of entrectinib.
Determine RP2D of entrectinib.
Per RECIST v1.1 as assessed by Investigator.
| Arm | Type | Description |
|---|---|---|
| Entrectinib | EXPERIMENTAL | Participants will be enrolled to receive 600 mg entrectinib orally once daily until progressive disease, unacceptable toxicity, death, or withdrawal from the study, whichever occurs first. |
| Crizotinib | ACTIVE_COMPARATOR | Participants will be enrolled to receive 250 mg crizotinib orally twice daily until progressive disease, unacceptable toxicity, death, or withdrawal from the study, whichever occurs first. |
| Cohort A: ROS Proto-oncogene 1 (ROS1) Fusion-positive Tumors (Excluding NSCLC) | EXPERIMENTAL | Participants with metastatic or advanced solid tumors, with the exception of non-small cell lung cancer (NSCLC), will receive entrectinib once daily (QD) in repeated 28-day cycles at a dose of 600 milligram per day (mg/day) for adults and pediatric participants with a body surface area (BSA) ≥ 1.51 square meter (m\^2). The total dose of daily entrectinib administration for pediatric participants with BSA \< 1.51 m\^2 will be lower. |
| Cohort B: Neurotrophic Tyrosine Receptor Kinase (NTRK) 1/2/3 Fusion-positive Tumors | EXPERIMENTAL | Participants with metastatic or advanced solid tumors will receive entrectinib, QD in repeated 28-day cycles at a dose of 600 mg/day for adults and pediatric participants with a BSA ≥ 1.51 m\^2. The total dose of daily entrectinib administration for pediatric participants with BSA \< 1.51 m\^2 will be lower. |
| Cohort C: Anaplastic Lymphoma Kinase (ALK) Fusion-positive Tumors (Excluding NSCLC) | EXPERIMENTAL | Participants with metastatic or advanced solid tumors, with the exception of NSCLC, will receive alectinib at a dosage of 600 mg, orally, twice a day (BID), taken with food, in repeated 28-day cycles. |
| Cohort D: TMB-high Tumors | EXPERIMENTAL | Participants with metastatic or advanced solid tumors will receive atezolizumab intravenously (IV) at a fixed dose for participants aged ≥ 18 years, and 15 milligrams per kilogram (mg/kg) (maximum 1200 mg) for participants aged \< 18 years on Day 1 of each 21-day cycle. Note: Cohort D has been closed. |
| Cohort E: Protein Kinase B (AKT) 1/2/3 Mutant-positive Tumors | EXPERIMENTAL | Participants with metastatic or advanced solid tumors will receive ipatasertib orally, QD at the starting dose of 400 mg in repeated 28-day cycles until the participant experiences disease progression, intolerable toxicity, or withdraws consent. For participants 12-17 years of age, ipatasertib will be administered at the starting dose of 200 mg for participants \< 35 kilograms (kg), 300 mg for participants ≥ 35 and \< 45 kg, 400 mg for those ≥ 45 kg orally QD in repeated 28-day cycles until the participant experiences disease progression, intolerable toxicity, or withdraws consent. Note: Cohort E has been closed. |
| Cohort F: Human Epidermal Growth Factor Receptor 2 (HER2) Mutant-positive Tumors | EXPERIMENTAL | Participants with metastatic or advanced solid tumors will receive trastuzumab emtansine IV at a dose of 3.6 mg/kg every 21 days. Note: Cohort F has been closed as of protocol version 7 because enrollment and participant follow-up have been completed. |
| Cohort H: PIK3CA Multiple Mutant-positive Tumors | EXPERIMENTAL | Participants with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) multiple mutant-positive tumors will receive inavolisib (GDC-0077) QD at a starting dose of 9 mg by mouth (PO) in repeated 28-day cycles. Note: Cohort H has been closed for enrollment. |
| Cohort I: BRAF Class II Mutant or Fusion-positive Tumors | EXPERIMENTAL | Participants with proto-oncogene B-Raf (BRAF) class II mutant/fusion-positive tumors (adults and adolescents ≥ 40 kg) will receive 400 mg belvarafenib, PO, BID with adequate water (more than 200 milliliters \[mL\]). One cycle consists of 28 days. Administration of belvarafenib should occur BID on every day of each 28-day cycle. Note: Cohort I has been closed. |
| Cohort J: BRAF Class III Mutant-positive Tumors | EXPERIMENTAL | Participants with BRAF class III mutant-positive tumors (adults and adolescents ≥ 40 kg) will receive 400 mg belvarafenib PO BID with adequate water (more than 200 mL). One cycle consists of 28 days. Administration of belvarafenib should occur BID on every day of each 28-day cycle. Note: Cohort J has been closed for enrollment. |
| Cohort K: Rearranged During Transfection (RET) Fusion-positive Tumors (Excluding NSCLC) | EXPERIMENTAL | Participants with RET fusion-positive tumors will self-administer pralsetinib orally at home (except on clinic days) on a continuous daily dosing regimen at a dose of 400 mg/day (four 100-mg capsules per day) for adult and pediatric participants ≥ 12 and \< 18 years of age. A treatment cycle consists of 4 weeks (28 days). Note: Cohort K has been closed. |
| Cohort L: KRAS G12C-positive Tumors (Excluding NSCLC and Colorectal Cancer [CRC]) | EXPERIMENTAL | Participants with kirsten rat sarcoma virus (KRAS) G12C-positive tumors will self-administer divarasib (GDC-6036) orally at home (except on clinic days). |
| Cohort M: Ataxia-telangiectasia Mutated (ATM) Loss of Function (LOF) Tumors | EXPERIMENTAL | Participants with ATM LOF tumors will self-administer camonsertib orally at home (except on clinic days). Note: Cohort M has been closed. |
| Cohort N: SETD2 LOF Tumors | EXPERIMENTAL | Participants with methyltransferase SET (Su(var) 3-9) Enhancer of zest and Trithorax) domain-containing 2 (SETD2) LOF tumors will self-administer camonsertib orally at home (except on clinic days). Note: Cohort N has been closed. |
| Arm A: Entrectinib | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for ROS1 gene fusion. |
| Arm B: Inavolisib | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for PI3KCA activating mutation. |
| Arm C: Alectinib | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for ALK rearrangement tumors. |
| Arm D: Ipatasertib | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for either AKT1/2/3 activating mutation or PTEN loss/loss of function. |
| Arm E: Atezolizumab + Investigator's Choice of Chemotherapy | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for either tumor mutational burden (TMB) high or microsatellite instability (MSI) high/deficient mismatch repair (dMMR). |
| Arm F: Trastuzumab Emtansine + Atezolizumab | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for human epidermal growth factor receptor 2 (HER2) mutations or amplification without known TMB high or MSI high/dMMR. |
| Arm G: PH FDC SC | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for HER2 mutation or amplification without known TMB high or MSI high/dMMR. |
| Arm H: PH FDC SC + Investigator's Choice of Chemotherapy | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for HER2 mutation or amplification without known TMB high or MSI high/dMMR. |
| Arm I: Trastuzumab Emtansine + Tucatinib | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for HER2 mutation or amplification without known TMB high or MSI high/dMMR. |
| Arm J: Trastuzumab Emtansine + Atezolizumab | EXPERIMENTAL | Participants in this treatment arm must have positive tumor biomarker results for HER2 mutation or amplification and TMB high or MSI high/dMMR. |
| Arm K: Ipatasertib + Atezolizumab | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for PI3KCA activating mutation. |
| Arm L: Ipatasertib + Atezolizumab | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for either AKT1/2/3 activating mutation or PTEN loss/loss of function. |
| Arm M: Ipatasertib + Paclitaxel | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker results for PI3KCA activating mutations and either AKT1/2/3 activating mutation or PTEN loss/loss of function. |
| Arm N: Atezolizumab + Tiragolumab | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for either TMB high or MSI high/dMMR. |
| Arm O: Pralsetinib | EXPERIMENTAL | Participants in this treatment arm must have a positive tumor biomarker result for RET fusion. |
| NTRK1/2/3-rearranged NSCLC | EXPERIMENTAL | Oral entrectinib (RXDX-101) |
| ROS1-rearranged NSCLC | EXPERIMENTAL | Oral entrectinib (RXDX-101) |
| ALK- or ROS1-rearranged NSCLC | EXPERIMENTAL | with CNS-only progression previously treated with crizotinib (NOTE: The ALK-rearranged portion of this arm is now closed to enrollment.) Oral entrectinib (RXDX-101) |
| NTRK/1/2/3-rearranged mCRC | EXPERIMENTAL | Oral entrectinib (RXDX-101) |
| ROS1-rearranged mCRC | EXPERIMENTAL | Oral entrectinib (RXDX-101) |
| ALK-rearranged mCRC | EXPERIMENTAL | Oral entrectinib (RXDX-101) |
| NTRK1/2/3-rearranged other solid tumor | EXPERIMENTAL | Oral entrectinib (RXDX-101) |
| ROS1-rearranged other solid tumor | EXPERIMENTAL | Oral entrectinib (RXDX-101) |
| ALK-rearranged other solid tumor | EXPERIMENTAL | Oral entrectinib (RXDX-101) |
| Mild | EXPERIMENTAL | Participants with mild hepatic impairment will receive 1x100 milligram (mg) F06 (entrectinib) capsule administered orally with approximately 240 milliliter (mL) water within 30 minutes after consumption of a standardized meal. |
| Moderate | EXPERIMENTAL | Participants with moderate hepatic impairment will receive 1x100 mg F06 (entrectinib) capsule administered orally with approximately 240 mL water within 30 minutes after consumption of a standardized meal. |
| Severe | EXPERIMENTAL | Participants with severe hepatic impairment will receive 1x100 mg F06 (entrectinib) capsule administered orally with approximately 240 mL water within 30 minutes after consumption of a standardized meal. |
| Normal | EXPERIMENTAL | Participants with normal hepatic function will receive 1x100 mg F06 (entrectinib) capsule administered orally with approximately 240 mL water within 30 minutes after consumption of a standardized meal. |
| Part 1 | EXPERIMENTAL | Participants will be randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, participants will cross-over to three periods taking different formulations of entrectinib. Entrectinib will be administered as a single 600 milligram (mg) oral dose under fed condition in three different formulations. Test formulation 1 (T1): film-coated mini-tablet; Test formulation 2 (T2): film-coated mini-tablet; Reference formulation (R): hard capsule. |
| Part 2 | EXPERIMENTAL | Participants will be randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, participants will cross-over to two periods taking different formulations of entrectinib. Entrectinib will be administered as a single 200 mg oral dose under fasted condition in two different formulations. Test formulation (T): hydroxypropyl methylcellulose (HPMC) capsule; Reference formulation (R): hard capsule. |
| Entrectinib / Midazolam | OTHER | - |
| Extracranial solid tumors harboring NTRK1/2/3, | ACTIVE_COMPARATOR | Arm closed for further enrollment ROS1, ALK non-gene fusion molecular alterations Oral entrectinib (RXDX-101) |
| CNS tumors harboring- NTRK1/2/3, ROS1, ALK | ACTIVE_COMPARATOR | Arm closed for further enrollment molecular alterations, including gene fusions Oral entrectinib (RXDX-101) |
| Neuroblastoma | ACTIVE_COMPARATOR | Arm closed for further enrollment Oral entrectinib (RXDX-101) |
| Non-neuroblastoma, extracranial solid tumors | ACTIVE_COMPARATOR | Arm closed for further enrollment harboring - NTRK1/2/3, ROS1, ALK gene fusions Oral entrectinib (RXDX-101) |
| Any participant unable to swallow capsules | ACTIVE_COMPARATOR | Arm closed for further enrollment Any participant who otherwise meet all other eligibility criteria Oral entrectinib (RXDX-101) |
| Expansion: CNS tumors harboring NTRK1/2/3, ROS1 | ACTIVE_COMPARATOR | gene fusions Oral entrectinib (RXDX-101) |
| Expansion: Extracranial solid tumors harboring NTRK1/2/3, ROS1 | ACTIVE_COMPARATOR | NTRK 1,2,3 and ROS1 fusions Oral entrectinib (RXDX-101) |
| Entrectinib (RXDX-101) | EXPERIMENTAL | Oral entrectinib (RXDX-101) |
| Name | Type | Description |
|---|---|---|
| Entrectinib | DRUG | Entrectinib will be self-administered orally at a dose of 600 mg (three 200 mg capsules per day) once daily with or without food. |
| Crizotinib | DRUG | Crizotinib will be self-administered orally at a dose of 250 mg twice daily with or without food. |
| Alectinib | DRUG | Alectinib will be administered orally BID with food at a dosage of 600 mg (four 150-mg capsules). |
| Atezolizumab | DRUG | Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg for participants aged ≥18 years, and 15 mg/kg (maximum 1200 mg) for participants aged \<18 years on Day 1 of each 21-day cycle. |
| Ipatasertib | DRUG | For participants 12-17 years of age, ipatasertib will be administered at the starting dose of 200 mg for participants \< 35 kg, 300 mg for participants ≥35 and \< 45 kg, 400 mg for those ≥ 45 kg orally QD, beginning of Cycle 1, on Days 1-21 of each 28-day cycle until the participant experiences disease progression, intolerable toxicity, or withdraws consent. |
| Trastuzumab emtansine | DRUG | Trastuzumab emtansine will be administered at 3.6 mg/kg by IV infusion every 21 days until disease progression or unacceptable toxicity. The dosage and administration method also applies for pediatric participants 12-17 years of age. |
| Inavolisib | DRUG | GDC-077 will be administered QD at a starting dose of 9 mg PO in repeated 28-day cycles. The dosage and administration method also applies for pediatric participants 12-17 years of age. |
| Belvarafenib | DRUG | Belvarafenib will be administered at a dose 400 mg, PO, BID with adequate water (more than 200 mL). One cycle consists of 28 days. Administration of belvarafenib should occur BID on every day of each 28-day cycle. |
| Pralsetinib | DRUG | Pralsetinib will be self-administered by participants orally at home (except on clinic days) on a continuous daily dosing regimen at a dose of 400 mg/day (four 100-mg capsules per day) for adult and pediatric participants ≥ 12 and \< 18 years of age. A treatment cycle consists of 4 weeks (28 days). |
| Divarasib | DRUG | Divarasib will be self-administered by participants orally at home (except on clinic days) on a continuous daily dosing regimen for both adult and pediatric participants. A treatment cycle consists of 3 weeks (21 days). |
| Camonsertib | DRUG | Camonsertib will be self-administered by participants orally at home (except on clinic days). A treatment cycle consists of 3 weeks and will be given on days 1-3 and days 8-10 of every 21-day cycle. |
| Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf | DRUG | PH FDC SC will be administered subcutaneously (SC) at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab once every 3 weeks. |
| Tucatinib | DRUG | Tucatinib 300 mg will be administered orally BID continuously starting from Cycle 1 Day 1 onwards. |
| Investigator's Choice of Chemotherapy | DRUG | Chemotherapy will consist of docetaxel, paclitaxel, or capecitabine, as determined by the investigator, and will be administered per the respective package insert and institutional guidelines. |
| Paclitaxel | DRUG | The dose of paclitaxel is 80 mg/m2 administered by IV infusion on Days 1, 8, and 15 of each 28-day cycle. The paclitaxel infusion will be delivered over at least 60 minutes for each dose per institutional guidelines and administered after the oral dose of ipatasertib. |
| Tiragolumab | DRUG | Following the administration of atezolizumab and an observation period, participants will receive 600 mg tiragolumab at a fixed dose administered by IV infusion on Day 1 of each 21-day cycle. |
| Entrectinib 600 mg (T1) | DRUG | Test formulation 1 (T1): Multi-particulate formulation 1: entrectinib film-coated mini-tablets |
| Entrectinib 600 mg (T2) | DRUG | Test formulation 2 (T2): Multi-particulate formulation 2: entrectinib film-coated mini-tablets |
| Entrectinib 200 mg (R) | DRUG | Reference formulation (R): entrectinib hard capsules |
| Entrectinib 200 mg (T) | DRUG | Test formulation (T): entrectinib HPMC capsules |
| Midazolam Hydrochloride | DRUG | 2 mg oral syrup (fasted) |
Inclusion Criteria: * Histologically or cytologically-confirmed diagnosis of advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC that harbors a documented ROS1 gene rearrangement. * No prior treatment with a ROS1 tyrosine kinase inhibitor, chemothe...
Entrectinib is an investigational small molecule being studied for the treatment of various cancers, including locally advanced solid tumors, advanced unresectable or metastatic solid malignancies, solid tumors, carcinoma, and non-small-cell lung cancer. It is also being evaluated in pediatric patients with solid or primary CNS tumors who have no satisfactory treatment options.
Entrectinib is being developed by Roche Holding AG, which trades under the ticker RHHBY. The company is conducting clinical trials to evaluate the drug's safety and efficacy in multiple oncology indications.
Entrectinib is in clinical development, with trials listed as Phase 1, Phase 2, and Phase 3. It is an investigational drug and has not been approved by the FDA. The ongoing studies include a Phase 1 trial in children and adolescents and a Phase 3 trial in non-small-cell lung cancer.
Entrectinib is being studied in several clinical trials, including NCT02650401, a Phase 1 study in children and adolescents with solid or CNS tumors; NCT03961100, a completed Phase 1 bioavailability study in healthy volunteers; NCT04589845, a Phase 2 platform study in solid tumors; and NCT04603807, a Phase 3 trial comparing Entrectinib to crizotinib in ROS1-positive NSCLC.
Entrectinib is a kinase inhibitor, belonging to the -tinib class of drugs. It works by targeting and inhibiting specific kinases involved in tumor growth. The drug is being evaluated for its ability to block these molecular targets in various solid tumors and non-small-cell lung cancer.
Yes, Entrectinib is also known as RXDX-101. The Phase 1 clinical trial NCT02650401, which studies the drug in children and adolescents with locally advanced or metastatic solid or primary CNS tumors, refers to Entrectinib as RXDX-101 in its title.