On November 8, 2023, the FDA approved fruquintinib (Fruzaqla; Takeda Pharmaceuticals), an inhibitor of VEGFR-1, -2, and -3, for the treatment of metastatic colorectal cancer (mCRC) in adults who received previous fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. The FDA granted fruquintinib priority review for this indication.
The approval was based on efficacy results of 2 phase 3 clinical trials, FRESCO and FRESCO-2. The multicenter, placebo-controlled FRESCO trial was conducted in China and enrolled 416 patients with mCRC who had disease progression during or after receiving fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy. In the multicenter, randomized, double-blind, placebo-controlled FRESCO-2 trial, 691 patients with mCRC were required to have disease progression during or after receiving trifluridine/tipiracil (Lonsurf; Taiho Oncology), or regorafenib (Stivarga; Bayer HealthCare Pharmaceuticals). They were also required to have received fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy; an anti-VEGF biologic therapy; or, if RAS wild-type, an anti-VEGF therapy.
In both trials, patients were randomized to receive fruquintinib 5 mg orally once daily or placebo for the first 21 days of each 28-day cycle plus best supportive care. The patients received therapy until disease progression or until unacceptable adverse events.
The primary efficacy end point in both trials was overall survival (OS). In FRESCO-2, the median OS was 7.4 months (95% confidence interval [CI], 6.7-8.2) for patients receiving fruquintinib and 4.8 months (95% CI, 4.0-5.8) for patients receiving placebo (hazard ratio [HR], 0.66; 95% CI, 0.55-0.80; P<.001). In the FRESCO study, the median OS was 9.3 months (95% CI, 8.2-10.5) and 6.6 months (95% CI, 5.9-8.1) in the 2 treatment arms, respectively (HR, 0.65; 95% CI, 0.51-0.83; P<.001).
“Patients with metastatic [CRC] are often fragile and fatigued—due to both their condition as well as the therapies they have been exposed to. An oral chemotherapy-free option that offers a survival benefit despite treatment with prior therapies is a critical need for treating metastatic colorectal cancer,” stated Cathy Eng, MD, FACP, David H. Johnson Endowed Chair, Surgical and Medical Oncology, and Co-Leader, Gastrointestinal Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, in a press release. “Colorectal cancer is a highly heterogeneous disease, making it difficult to bring advancements to patients whose cancer has metastasized. I look forward to being able to offer a new solution to appropriate patients,” she added.
The most common (≥20%) adverse reactions with fruquintinib were hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia.
The recommended dose of fruquintinib is 5 mg orally once daily with or without food for the first 21 days of each 28-day cycle until disease progression or unacceptable adverse reactions.
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On October 27, 2023, the FDA approved toripalimab-tpzi (Loqtorzi; Coherus BioSciences), a PD-1 monoclonal antibody, in combination with cisplatin and gemcitabine chemotherapy, for the first-line treatment of adults with metastatic or recurrent, locally advanced nasopharyngeal carcinoma, and as a single agent for adults with recurrent unresectable or metastatic nasopharyngeal carcinoma that progressed during or after treatment with a platinum-containing chemotherapy. Toripalimab is a next-generation PD-1 inhibitor that blocks PD-1 ligands 1 and 2. The FDA granted toripalimab priority review and breakthrough therapy and orphan drug designation for these indications.
The FDA approved toripalimab plus cisplatin and gemcitabine chemotherapy based on results of the JUPITER-02 study, a randomized, multicenter, single-region, double-blind, placebo-controlled phase 3 clinical trial that included 289 patients with metastatic or recurrent, locally advanced nasopharyngeal carcinoma who had not received previous systemic chemotherapy for recurrent or metastatic disease. Patients were randomized (1:1) to toripalimab plus cisplatin and gemcitabine followed by toripalimab, or to placebo plus cisplatin and gemcitabine followed by placebo.
The primary efficacy measure was progression-free survival (PFS), as assessed by a blinded independent review committee according to RECIST version 1.1. Overall survival (OS) was a secondary end point. The PFS was significantly better in the toripalimab plus chemotherapy group versus the placebo plus chemotherapy group, with a median PFS of 11.7 months versus 8 months, respectively (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.36-0.74; P=.0003), leading to a 48% risk reduction for disease progression or death with toripalimab plus chemotherapy versus placebo plus chemotherapy. The OS was also significantly better in the toripalimab-containing arm versus the placebo arm, with a median OS not reached (95% CI, 38.7 months-not estimable) versus 33.7 months (95% CI, 27.0-44.2), respectively (HR, 0.63; 95% CI, 0.45-0.89; P=.0083), which translated to a 37% reduction in the risk for death with toripalimab plus chemotherapy.
“Today’s FDA approval of Loqtorzi is very encouraging for those living with NPC [nasopharyngeal carcinoma] who currently have very limited treatment options and are in need of new therapies to treat this aggressive and life-threatening form of cancer,” said Jong Chul Park, MD, Assistant Professor, Harvard Medical School, and Attending Physician, Center for Head and Neck Cancers, Massachusetts General Hospital Cancer Center, Boston, in a press release. “Loqtorzi is a new treatment option that has demonstrated the ability to significantly improve PFS and OS and should quickly emerge as the new standard of care when used in combination with chemotherapy.”
The efficacy of toripalimab as a single agent was evaluated in the POLARIS-02 study, a phase 1b/2, open-label, multicenter, single-country, multicohort trial that included 172 patients with unresectable or metastatic nasopharyngeal carcinoma who had previously received platinum-based chemotherapy or had disease progression within 6 months of completion of platinum-based chemotherapy administered as neoadjuvant, adjuvant, or definitive chemoradiation treatment for locally advanced disease. Patients received toripalimab as a single agent until disease progression per RECIST version 1.1 or until unacceptable adverse events (AEs).
The major efficacy measures in the POLARIS-02 study were overall response rate (ORR) and duration of response (DOR), as assessed by a blinded independent review committee using RECIST version 1.1. The ORR with toripalimab alone was 21% (95% CI, 15-28), and the median DOR was 14.9 months (95% CI, 10.3 months-not estimable).
The most common (≥20%) adverse reactions with toripalimab plus chemotherapy were nausea, vomiting, decreased appetite, constipation, hypothyroidism, rash, pyrexia, diarrhea, peripheral neuropathy, cough, musculoskeletal pain, upper respiratory infection, insomnia, dizziness, and malaise.
The most common (≥20%) adverse reactions for toripalimab as a single agent were fatigue, hypothyroidism, and musculoskeletal pain.
As with other PD-1 inhibitors, immune-mediated adverse reactions were reported with toripalimab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, and skin events.
The recommended dose of toripalimab, when used in combination with cisplatin and gemcitabine, is 240 mg every 3 weeks until disease progression, unacceptable AEs, or for up to 24 months. The recommended dose of toripalimab as a single agent is 3 mg/kg every 2 weeks until disease progression or until unacceptable AEs.
On November 16, 2023, the FDA approved the use of pembrolizumab (Keytruda; Merck) with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. The FDA granted pembrolizumab an orphan drug designation for this indication.
This new approval of pembrolizumab was based on the efficacy results of the multicenter, randomized, double-blind, placebo-controlled KEYNOTE-859 clinical trial, which included 1579 patients with HER2-negative, advanced gastric or GEJ adenocarcinoma who had not received systemic therapy for metastatic disease. Patients were randomized (1:1) to pembrolizumab 200 mg (n=790) or to placebo with the investigator’s choice of cisplatin 80 mg/m2 plus 5-fluorouracil 800 mg/m2 daily for 5 days or to oxaliplatin 130 mg/m2 on day 1 plus capecitabine (Xeloda; Genentech) 1000 mg/m2 (n=789) twice daily for 14 days every 3 weeks.
The primary efficacy outcome measure was overall survival (OS). The secondary efficacy outcome measures were progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) according to RECIST version 1.1, which was modified to maximums of 10 target lesions in total and 5 target lesions per organ.
Significant improvement was seen in OS, PFS, and ORR in the patients who received pembrolizumab and chemotherapy versus those who received placebo. The median OS was 12.9 months (95% confidence interval [CI], 11.9-14) in the pembrolizumab arm versus 11.5 months (95% CI, 10.6-12.1) in the patients who received placebo (hazard ratio [HR], 0.78; 95% CI, 0.7-0.87; P<.0001). The median PFS was 6.9 months (95% CI, 6.3-7.2) and 5.6 months (95% CI, 5.5-5.7), respectively (HR, 0.76; 95% CI, 0.67-0.85; P<.0001). The ORR was 51% in the pembrolizumab cohort (95% CI, 48-55) versus 42% in the placebo group (95% CI, 38-45; P<.0001), and the median DOR was 8 months (95% CI, 7-9.7) versus 5.7 months (95% CI, 5.5-6.9), respectively. In an additional exploratory subgroup analysis, significant improvements were seen in OS, PFS, and ORR in the pembrolizumab cohort versus the chemotherapy cohort based on PD-L1 combined positive score (CPS) ≥1 and CPS ≥10 tumor expression.
In all, 45% of the patients who received pembrolizumab had serious adverse reactions, including pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). A total of 15% of the patients permanently discontinued treatment with pembrolizumab because of adverse events (AEs), with ≥1% resulting from infections and diarrhea. In all, 65% of patients had dosage interruptions of pembrolizumab that resulted from AEs, the most common (≥2%) of which were neutropenia (21%), thrombocytopenia (13%), diarrhea (5.5%), fatigue (4.8%), infection (4.8%), anemia (4.5%), increased aspartate aminotransferase (AST; 4.3%), increased alanine transaminase (ALT; 3.8%), increased blood bilirubin (3.3%), decreased white blood cell count (2.2%), nausea (2%), and palmar-plantar erythrodysesthesia syndrome and vomiting (2% each).
The recommended dosage of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression or unacceptable AEs. Pembrolizumab should be administered before chemotherapy when received on the same day.
On November 7, 2023, the FDA restricted the existing indication of pembrolizumab with trastuzumab (Herceptin; Genentech), fluoropyrimidine, and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. Specifically, the update restricts treatment with pembrolizumab to patients whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. The GEJ approval remains under accelerated approval regulations.
The FDA also approved the Agilent PD-L1 IHC 22C3 pharmDx as a companion diagnostic test to select patients with gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS ≥1).
The updated indication for pembrolizumab in GEJ is based on a recent prespecified interim analysis of the fully enrolled KEYNOTE-811 trial, which enrolled 698 patients. In a subgroup analysis of 104 patients with PD-L1 CPS <1, the HR for OS and PFS was 1.41 (95% CI, 0.9-2.2) and 1.03 (95% CI, 0.65-1.64), respectively.
The primary efficacy outcomes of KEYNOTE-811 were OS and PFS. The original 2021 approval in GEJ was based on an interim analysis of ORR and DOR. At that time, ORR and DOR were assessed in the first 264 patients randomized. The ORR was 74% (95% CI, 66-82) in the pembrolizumab plus chemotherapy arm and 52% (95% CI, 43-61) in the placebo plus chemotherapy arm (P≤.0001). The median DOR was 10.6 months (range, 1.1+ to 16.5+) and 9.5 months (range, 1.4+ to 15.4+) in the 2 study arms, respectively.
The safety profile of pembrolizumab and trastuzumab plus chemotherapy in KEYNOTE-811 was generally consistent with the known AEs associated with trastuzumab plus chemotherapy or pembrolizumab monotherapy.
For patients with GEJ whose tumors express PD-L1 (CPS ≥1), as determined by an FDA-approved test, the recommended dose of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression or unacceptable AEs or for up to 24 months. Pembrolizumab should be administered before trastuzumab and chemotherapy when given on the same day.
On October 31, 2023, the FDA approved pembrolizumab, a PD-1 inhibitor, combined with gemcitabine/cisplatin, for the treatment of locally advanced unresectable or metastatic biliary tract cancer.
This approval of pembrolizumab was supported by efficacy findings in the KEYNOTE-966 clinical trial, a multicenter, randomized, double-blind, placebo-controlled study in 1069 patients with locally advanced unresectable or metastatic biliary tract cancer who had not received systemic therapy for advanced disease. Patients were randomized to receive pembrolizumab on day 1 plus gemcitabine and cisplatin on days 1 and 8 every 3 weeks, or placebo on day 1 plus gemcitabine and cisplatin. Treatment continued until unacceptable AEs or disease progression. Cisplatin was administered for up to 8 cycles, whereas treatment with gemcitabine was continued based on physician discretion. Pembrolizumab or placebo was continued until disease progression or unacceptable AEs, or for a maximum of 2 years.
The primary efficacy measure was OS. The median OS was 12.7 months in the pembrolizumab arm (95% CI, 11.5-13.6) and 10.9 months for those receiving placebo (95% CI, 9.9-11.6), for a significant difference (HR, 0.83; 95% CI, 0.72-0.95; one-sided P=.0034).
“Cancers of the biliary tract can be highly aggressive tumors, underscoring the need for additional treatment options for the growing number of patients facing this challenging disease,” said Robin Kate Kelley, MD, Professor, Clinical Medicine, Division of Hematology/Oncology, University of California, San Francisco, in a press release. “Today’s approval of pembrolizumab in combination with chemotherapy offers patients with locally advanced unresectable or metastatic biliary tract cancer a new immunotherapy regimen that has demonstrated the potential to help these patients live longer.”
Adverse reactions led to the interruption of pembrolizumab treatment in 55% of patients. The most common (≥2%) AEs or laboratory abnormalities leading to treatment interruption were decreased neutrophil count, decreased platelet count, anemia, decreased white blood cell count, pyrexia, fatigue, cholangitis, increased ALT, increased AST, and biliary obstruction.
For patients with advanced biliary tract cancer, the recommended dose of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression or unacceptable AEs. Pembrolizumab should be administered before chemotherapy when given on the same day.
On October 24, 2023, the FDA approved ivosidenib (Tibsovo; Servier Pharmaceuticals), an oral tyrosine kinase inhibitor, for the treatment of relapsed or refractory myelodysplastic syndromes (MDS) in adults with a susceptible IDH1 mutation, as detected by an FDA-approved test. Ivosidenib was granted priority review and received breakthrough therapy and orphan drug designations for this indication.
The Abbott RealTime IDH1 Assay was also approved by the FDA as a companion diagnostic device to select patients who qualify for treatment with ivosidenib.
“Today’s approval represents an important treatment advancement for rare blood cancers, and more specifically, patients with relapsed or refractory MDS who have an IDH1 mutation. Through the FDA’s Oncology Center of Excellence Rare Cancers Program, we remain committed to promoting scientific innovation and advancing the development of safe and effective novel therapies to treat patients with rare cancers,” said Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence, and Acting Director, Office of Oncologic Diseases, FDA’s Center for Drug Evaluation and Research, in a press release.
The approval of ivosidenib for MDS was based on results of AG120-C-001, an open-label, single-arm, multicenter clinical trial of 18 adults with relapsed or refractory MDS and IDH1 mutation as detected in peripheral blood or bone marrow by a local or central diagnostic test. The presence of these mutations was confirmed retrospectively by the Abbott RealTime IDH1 Assay.
In the AG120-C-001 trial, patients received 500 mg daily of oral ivosidenib until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The median duration of treatment with ivosidenib was 9.3 months. One patient underwent a stem cell transplantation after receiving ivosidenib.
The primary efficacy end point of AG120-C-001 was the rate of complete remission (CR) or partial remission (PR) as defined by 2006 International Working Group response for MDS, CR plus PR durations, and the conversion rate from transfusion dependence to independence. The response rate was 39% (95% confidence interval, 17%-64%), and all responses observed were CRs. The median time to CR was 1.9 months (range, 1.0-5.6 months), and the median CR duration was not estimable (range, 1.9-80.8+ months). Among the 9 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 6 (67%) became RBC and platelet transfusion independent during any 56-day postbaseline period. Among the 9 patients who did not require RBC and platelet transfusions at baseline, 7 (78%) remained transfusion independent during any 56-day post-baseline period.
The most common (≥20%) adverse reactions observed with ivosidenib were similar to those observed with ivosidenib monotherapy in patients with acute myeloid leukemia, for which ivosidenib is also FDA approved. These adverse reactions include diarrhea, constipation, mucositis, nausea, arthralgia, fatigue, cough, myalgia, and rash. Ivosidenib has a Boxed Warning about the risk for differentiation syndrome, which can be fatal. Ivosidenib can also cause QTc interval prolongation.
The recommended dose of ivosidenib is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity. Patients should be counseled to avoid taking ivosidenib with a high-fat meal.
On October 13, 2023, the FDA approved a new indication for nivolumab (Opdivo; Bristol-Myers Squibb), a PD-1 inhibitor, for the adjuvant treatment of completely resected stage IIB/C melanoma in patients aged ≥12 years. The FDA granted this application an orphan drug designation.
Nivolumab has been previously approved for the treatment of many cancers, including the adjuvant treatment of melanoma with lymph node involvement or metastatic melanoma in patients who underwent complete resection.
This approval of nivolumab was supported by results of the CheckMate-76K study, a randomized, placebo-controlled, double-blind clinical trial that enrolled 790 patients with stage IIB/C melanoma. Patients were randomized (2:1) to nivolumab 480 mg or to placebo dosed via intravenous infusion every 4 weeks for up to 1 year or until disease recurrence or unacceptable adverse events (AEs). The patients in this trial underwent complete resection of the primary melanoma with negative margins and a negative sentinel lymph node within 12 weeks before randomization. Randomization was stratified by T category according to the American Joint Committee on Cancer’s Cancer Staging Manual, 8th Edition (T3b vs T4a vs T4b).
The primary efficacy measure was recurrence-free survival (RFS), which was defined as the investigator-assessed time between randomization and first disease recurrence (local, regional, or distant metastasis), new primary melanoma, or death from any cause, whichever occurred first. The median RFS was not reached in the nivolumab arm (95% confidence interval [CI], 28.5-not reached) or in the placebo arm (95% CI, 21.6-not reached; hazard ratio [HR], 0.42; 95% CI, 0.30-0.59; P≤.0001). At 1 year, the RFS rate was 89% (95% CI, 86-92) for nivolumab compared with 79% (95% CI, 74-84) for placebo. In a prespecified exploratory subgroup analysis, the RFS unstratified HR was 0.34 (95% CI, 0.20-0.56) in patients with stage IIB melanoma and 0.51 (95% CI, 0.32-0.81) in patients with stage IIC melanoma.
The most common (≥20%) adverse reactions with nivolumab treatment in CheckMate-76K were fatigue, musculoskeletal pain, rash, diarrhea, and pruritus.
The recommended dose of nivolumab for patients weighing ≥40 kg is 240 mg every 2 weeks or 480 mg every 4 weeks until disease progression or unacceptable AEs for up to 1 year. The recommended dose for pediatric patients weighing <40 kg is 3 mg/kg nivolumab every 2 weeks or 6 mg/kg every 4 weeks until disease progression or unacceptable AEs for up to 1 year.
On October 11, 2023, the FDA approved a new indication for encorafenib (Braftovi; Array BioPharma) combined with binimetinib (Mektovi; Array BioPharma) for adults with metastatic non–small cell lung cancer (NSCLC) and a BRAFV600E mutation, as detected by an FDA-approved test.
The FDA also approved 2 companion diagnostic tests, FoundationOne CDx (tissue) and FoundationOne Liquid CDx (plasma), for encorafenib plus binimetinib. Tumor tissue should be tested if the BRAFV600E mutation is not detected in plasma.
The FDA granted this application an orphan drug designation.
Encorafenib plus binimetinib was previously approved for the treatment of patients with unresectable or metastatic melanoma and a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. Encorafenib plus cetuximab (Erbitux; Eli Lilly and Company) was previously approved for the treatment of metastatic colorectal cancer in adults who have a BRAFV600E mutation, as detected by an FDA-approved test, and have received previous therapy.
This approval was based on data from the phase 2 PHAROS study, an ongoing open-label, multicenter, single-arm clinical trial evaluating the efficacy of encorafenib and binimetinib in 98 patients with metastatic NSCLC and documented BRAFV600E mutations. Patients were treatment naïve or had disease progression after previous therapy that did not include BRAF or MEK inhibitors. In this trial, treatment with encorafenib and binimetinib continued until disease progression or unacceptable toxicity.
The key efficacy measures included objective response rate (ORR) per RECIST version 1.1 and duration of response (DOR) based on independent review committee assessment. Among the 59 treatment-naïve patients with NSCLC who received encorafenib plus binimetinib, the ORR was 75% (95% confidence interval [CI], 62-85). The median DOR was not estimable (95% CI, 23.1-not estimable). Among the 39 patients who received previous treatment, the ORR after receiving encorafenib plus binimetinib was 46% (95% CI, 30-63), with a median DOR of 16.7 months (95% CI, 7.4-not estimable).
The most common (≥25%) adverse events with encorafenib plus binimetinib were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.
For patients with metastatic NSCLC and BRAFV600E mutations, the recommended dose of encorafenib is 450 mg orally once daily. The recommended dose of binimetinib is 45 mg orally twice daily.
On October 20, 2023, the FDA accelerated the approval of the tyrosine kinase inhibitor entrectinib (Rozlytrek; Genentech) for the treatment of pediatric patients aged >1 month who are diagnosed with metastatic solid tumors associated with an NTRK gene fusion, as detected by an FDA-approved test, and no known acquired resistance mutation or whose disease is likely to lead to severe morbidity and has progressed after previous treatment, or patients who have no satisfactory standard therapy. In 2019, the FDA approved the same indication for older patients aged ≥12 years.
The FDA granted this approval priority review and breakthrough and orphan drug designations.
On the same day, the FDA also approved a new oral pellet formulation for entrectinib, which was previously only available as an oral capsule (see the prescribing information for instructions on making oral suspension from the capsules).
Entrectinib was previously approved by the FDA for the treatment of adults with metastatic, ROS1-positive non–small cell lung cancer, as detected by an FDA-approved test.
The FDA approved entrectinib for this indication for pediatric patients aged >1 month with NTRK-positive tumors based on the results in patients aged >1 month who received entrectinib 20 mg to 600 mg (based on the patient’s body surface area [BSA]), orally or via enteral feeding tube once daily, in 1 of 2 multicenter, single-arm clinical trials—the TAPISTRY study and the STARTRK-NG study.
Cohort B in the TAPISTRY study, a phase 2, international, multicenter, open-label, multicohort clinical trial, included adults and pediatric patients with metastatic or advanced solid tumors who received entrectinib once daily in repeated 28-day cycles, at a daily dose of 600 mg in patients with a BSA of ≥1.51 m2. The total daily dose of entrectinib administered to pediatric patients with a BSA of <1.51 m2 was lower.
The STARTRK-NG study is an open-label, multicenter, dose-escalation, phase 1/2 study of entrectinib in pediatric patients with relapsed or refractory extracranial solid tumors (phase 1), with additional expansion cohorts (phase 2) in patients with primary brain tumors harboring NTRK1, NTRK2, NTRK3, or ROS1 gene fusions, and extracranial solid tumors harboring NTRK1, NTRK2, NTRK3, or ROS1 gene fusions. The most common tumor types of patients included in these 2 studies were primary central nervous system (CNS) tumors and infantile fibrosarcoma.
The major efficacy measure in both studies was overall response rate (ORR), as assessed by blinded independent central review according to RECIST version 1.1 for extracranial tumors and response assessment in neuro-oncology for primary CNS tumors. Another efficacy measure was the duration of response (DOR). Overall, the ORR was 70% (95% confidence interval [CI], 51-84), and the median DOR was 25.4 months (95% CI, 14.3-not evaluable) in pediatric patients who received entrectinib.
In the pooled safety population (n=76) of pediatric patients who received entrectinib, the most common (≥20%) adverse reactions were pyrexia, constipation, increased weight, vomiting, diarrhea, nausea, cough, fatigue, pain in extremity, skeletal fracture, decreased appetite, headache, abdominal pain, urinary tract infection, upper respiratory tract infection, and nasal congestion.
The recommended dose of entrectinib for pediatric patients aged between >1 month and 6 months is 250 mg/m2 orally once daily. The recommended dose for patients aged >6 months is based on the patient’s BSA up to a maximum of 600 mg once daily; see entrectinib’s prescribing information for specific details.
This indication for the new population was granted under the FDA’s accelerated approval process based on ORR and DOR data. Continued approval for this indication for this population may be contingent on clinical benefit verification in ongoing and confirmatory studies.
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