Larotrectinib Sulfate

To convert Augtyro's accelerated approval into a full nod, the FDA is asking Bristol Myers Squibb for more tumor response and duration of response data. A Bristol Myers Squibb drug has got an FDA approval to treat tumors with a specific biomarker regardless of their locations in the body. The drug, Augtyro, has won the FDA’s accelerated approval in solid tumors that have an NTRK gene fusion, Bristol Myers said Thursday. The tyrosine kinase inhibitor (TKI) can be used in patients 12 years of age and older, but the tumors must have been previously treated or have no satisfactory alternative therapy. This tumor-agnostic indication is familiar to the oncology community. Back in 2018, Bayer’s Vitrakvi became the first targeted therapy to get its initial FDA go-ahead for cancers based on a genetic biomarker rather than where the tumor originated, and the indication was NTRK gene fusion. Then Roche’s Rozlytrek followed with the same label addition in 2019. BMS got Augtyro from its $4.1 billion acquisition of Turning Point Therapeutics in 2022, and then in November 2023 pushed the drug across the FDA finish line in ROS1-positive non-small cell lung cancer, where it’s also competing with Roche’s Rozlytrek. In NTRK mutation-positive solid tumors, Augtyro differentiates itself as the only option that has been studied both in patients who had not tried a TKI before and in TKI-experienced patients, Bristol Myers said. In the phase 1/2 TRIDENT-1 trial, Augtyro triggered a response in 58% of 40 TKI-naïve patients, including 15% who had complete responses. Of those who responded, 83% were still in response after one year. Among 48 TKI-pretreated patients, Augtyro’s overall response rate was 50%, which included no complete response. At one year, 41% of responding patients were still in remission. The median duration of response was 9.9 months. Across the two subgroups, the TRIDENT-1 trial enrolled patients with 15 different types of cancer, including NSCLC, thyroid cancer, salivary gland cancer, glioblastoma, colorectal cancer and others. With the accelerated approval, BMS will need to provide additional data to confirm Augtyro’s benefits. To convert the nod into a full approval, the FDA is asking for tumor response and duration of response data from “a sufficient number of patients” across tumor types, with all responding patients being followed for at least 12 months from the onset of response or until disease progression, according to the agency. The FDA’s request for Augtyro is similar to those for Vitrakvi and Rozlytrek, neither of which has converted their accelerated approvals. Although a tumor-agnostic label covers tumors at different locations, NTRK gene fusions are rare. Last year, Rozlytrek only got Roche 86 million Swiss francs ($96 million) in sales across its two indications. Bayer didn’t specify Vitrakvi’s sales in its annual report. Augtyro marked Bristol Myers Squibb’s initial expansion into targeted therapies from an immunotherapy-focused oncology portfolio. The New Jersey pharma went deeper into targeted therapies with the acquisition of Mirati Therapeutics, which brought with it the KRAS inhibitor Krazati.

Bayer will showcase latest data for growth driver NUBEQA® (darolutamide) and targeted radionuclide therapy XOFIGO® (radium Ra 223 dichloride) Bayer will also present a late-breaking abstract on the Phase I/II study of BAY 2927088 in patients with HER2-mutant non-small cell lung cancer (NSCLC), and data from VITRAKVI® in patients with tropomyosin receptor kinase (TRK) fusion lung cancer Abstracts: 5022, 5083, TPS5122, TPS5127, e17040, LBA8598, 8570, 6095, 3105 WHIPPANY, N.J.--(BUSINESS WIRE)-- Bayer will present new data across its oncology portfolio at the upcoming American Society of Clinical Oncology (ASCO) Annual Meeting, taking place in Chicago, from May 31 – June 4, 2024. The breadth of new data in different tumor types underscores Bayer’s ambition to deliver innovative and effective oncological therapies in areas with the highest unmet medical needs. Prostate cancer is a key focus for Bayer Oncology, with data to be presented on NUBEQA® (darolutamide) and XOFIGO® (radium Ra 223 dichloride) across multiple stages of the disease. NUBEQA data will include a post hoc analysis from the Phase III ARASENS trial, evaluating post-progression survival with NUBEQA and androgen-deprivation therapy (ADT) plus docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC), which will further support the established efficacy pro NUBEQA. Additionally a follow-up analysis from the Phase III ARAMIS trial, evaluating the association between prostate-specific antigen (PSA) level and risk of radiological progression with NUBEQA and ADT in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) will also be presented. An overview of the ongoing investigational Phase III ARASTEP trial in hormone sensitive prostate cancer patients with high-risk biochemical recurrence will also be presented. Additionally, new data from the ongoing Bayer sponsored ALADDIN study, conducted by the Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie, investigating the impact of NUBEQA plus ADT and radiation therapy on failure-free survival in patients with newly diagnosed prostate cancer and pelvic lymph nodes metastases will be presented. NUBEQA is currently indicated in the U.S. in combination with docetaxel for the treatment of adult patients with mHSPC and for the treatment of adult patients with non-metastatic castration-resistant prostate cancer (nmCRPC). In the field of targeted radionuclide therapies, Bayer will present data from the Phase III REASSURE study, evaluating patient profiles and treatment outcomes in patients with metastatic castration resistant prostate cancer (mCRPC) with XOFIGO in the real-world setting, will be shared. XOFIGO is indicated for the treatment of patients with mCRPC, symptomatic bone metastases, and no known visceral metastatic disease. Bayer will present a late-breaking abstract on BAY 2927088 in patients with HER2-mutant non-small cell lung cancer (NSCLC) from the Phase I/II SOHO-01 trial. BAY 2927088 is an oral, small molecule tyrosine kinase inhibitor being investigated for patients with NSCLC harboring HER2 activating mutations. Bayer will highlight long-term efficacy and safety data from the VICTORIA study for VITRAKVI®, including outcomes in patients with tropomyosin receptor kinase (TRK) fusion cancer treated with VITRAKVI in clinical trials (NCT02122913, NCT02576431, NCT02637687). Vitrakvi is approved for the treatment of adult and pediatric patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. Patients should be selected for therapy based on a FDA-approved test. This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Details on selected abstracts from Bayer at the 2024 ASCO Annual Meeting are listed below: Darolutamide Abstract title: Association between prostate-specific antigen (PSA) level <0.2 ng/mL and risk of radiological progression in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): Follow-up analysis of ARAMIS Poster: 5022; June 2, 2024. 09:00 AM – 12:00 PM CDT Abstract title: Post-progression survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC) who received darolutamide or placebo: Post hoc analysis of ARASENS Poster: 5083; June 2, 2024. 09:00 AM – 12:00 PM CDT Abstract title: Darolutamide plus androgen-deprivation therapy (ADT) in patients with high-risk biochemical recurrence (BCR) of prostate cancer: A phase 3, randomized, double-blind, placebo-controlled study (ARASTEP) Trial in Progress TiP Poster: TPS5122; June 2, 2024. 09:00 AM – 12:00 PM CDT Abstract title: ALADDIN: Evaluation of darolutamide in addition to androgen deprivation therapy and radiation therapy in newly diagnosed prostate cancer with pelvic lymph nodes metastases TiP Poster: TPS5127; June 2, 2024. 9:00AM CDT Radium-223 dichloride Abstract title: Comparing patient profiles and treatment outcomes with radium-223 (223Ra) in real-world settings: Academic vs. community practice in the US—Insights from the REASSURE study ePoster: e17040; Published J Clin Oncol 42, 2024, suppl 16 BAY 2927088 Abstract title: Safety and clinical activity of BAY 2927088 from a Phase I/II trial expansion cohort in patients with HER2-mutant non-small cell lung cancer (NSCLC) Late Breaking Abstract: LBA8598; June 3, 2024. 1:30PM CDT Larotrectinib Abstract title: Long-term efficacy and safety of larotrectinib in patients (pts) with TRK fusion lung cancer Poster: 8570; June 3, 2024. 1:30PM CDT Abstract title: Long-term efficacy and safety of larotrectinib (laro) in patients (pts) with TRK fusion thyroid carcinoma (TC) Poster: 6095; June 2, 2024. 9:00AM CDT Abstract title: Outcomes of larotrectinib compared with real-world data from non-TRK inhibitor therapies in patients with TRK fusion cancer: VICTORIA study Poster: 3105; June 1, 2024. 9:00AM CDT About NUBEQA® (darolutamide)1 NUBEQA® (darolutamide) is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. On July 30, 2019, the FDA approved NUBEQA based on the ARAMIS trial, a randomized, double-blind, placebo-controlled, multi-center Phase III study, which evaluated the safety and efficacy of oral NUBEQA in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Based on results from the ARASENS trial, a randomized, Phase III, multi-center, double-blind, placebo-controlled trial, NUBEQA plus androgen deprivation therapy (ADT) and docetaxel was approved on August 5, 2022 for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC). NUBEQA is also being investigated in additional studies across various stages of prostate cancer, including in the Phase III ARANOTE trial evaluating NUBEQA plus ADT versus ADT alone for mHSPC, the ARASTEP Phase III trial evaluating NUBEQA plus ADT versus ADT alone in HSPC patients with high-risk BCR and no evidence of metastatic disease, as well as in the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) led international Phase III co-operative group DASL-HiCaP (ANZUP1801) trial evaluating NUBEQA as an adjuvant treatment for localized prostate cancer with very high risk of recurrence. Information about these trials can be found at Developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company, NUBEQA is indicated for the treatment of adults with nmCRPC or with mHSPC in combination with docetaxel.1 Filings in other regions are underway or planned. INDICATIONS NUBEQA® (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with: Non-metastatic castration-resistant prostate cancer (nmCRPC) Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel IMPORTANT SAFETY INFORMATION NUBEQA® (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with: Non-metastatic castration-resistant prostate cancer (nmCRPC) Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel IMPORTANT SAFETY INFORMATION Warnings & Precautions Ischemic Heart Disease – In a study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA versus 2.5% receiving placebo, including Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo. In a study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA with docetaxel vs. 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs. 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel vs. 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease. Seizure – In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA. It is unknown whether antiepileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment. Embryo-Fetal Toxicity – Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose. Adverse Reactions In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA vs. 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia, and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA vs. 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). The most common adverse reactions (>2% with a ≥2% increase over placebo), including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity and rash. Clinically relevant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease and heart failure. In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common adverse reactions (≥10% with a ≥2% increase over placebo with docetaxel) were constipation, rash, decreased appetite, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures, ischemic heart disease, seizures, and drug-induced liver injury. Drug Interactions Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use. Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed. Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate. NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates. Review the Prescribing Information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA. For important risk and use information about NUBEQA, please see the accompanying full Prescribing Information. About XOFIGO (radium Ra 223 dichloride) Injection2 Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. Important Safety Information for Xofigo® (radium Ra 223 dichloride) Injection Warnings and Precautions: Bone Marrow Suppression: In the phase 3 ALSYMPCA trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression–notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia–has been reported in patients treated with Xofigo. Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued Increased Fractures and Mortality in Combination With Abiraterone Plus Prednisone/Prednisolone: Xofigo is not recommended for use in combination with abiraterone acetate plus prednisone/prednisolone outside of clinical trials. At the primary analysis of the Phase 3 ERA-223 study that evaluated concurrent initiation of Xofigo in combination with abiraterone acetate plus prednisone/prednisolone in 806 asymptomatic or mildly symptomatic mCRPC patients, an increased incidence of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received Xofigo in combination with abiraterone acetate plus prednisone/prednisolone compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone. Safety and efficacy with the combination of Xofigo and agents other than gonadotropin-releasing hormone analogues have not been established Embryo-Fetal Toxicity: The safety and efficacy of Xofigo have not been established in females. Xofigo can cause fetal harm when administered to a pregnant female. Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise male patients to use condoms and their female partners of reproductive potential to use effective contraception during and for 6 months after completing treatment with Xofigo Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations Fluid Status: Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia Injection Site Reactions: Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo Secondary Malignant Neoplasms: Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients on the trial Subsequent Treatment With Cytotoxic Chemotherapy: In the randomized clinical trial, 16% of patients in the Xofigo group and 18% of patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) Please see the full Prescribing Information for Xofigo (radium Ra 223 dichloride). About VITRAKVI® (larotrectinib)3 VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that: have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. Select patients for therapy based on an FDA-approved test. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. IMPORTANT SAFETY INFORMATION Warnings and Precautions Central Nervous System Effects: Central nervous system (CNS) adverse reactions occurred in patients receiving VITRAKVI, including dizziness, cognitive impairment, mood disorders, and sleep disturbances. In patients who received VITRAKVI, all grades CNS effects including cognitive impairment, mood disorders, dizziness and sleep disorders were observed in 42% with Grades 3-4 in 3.9% of patients. Cognitive impairment occurred in 11% of patients. The median time to onset of cognitive impairment was 5.6 months (range: 2 days to 41 months). Cognitive impairment occurring in ≥ 1% of patients included memory impairment (3.6%), confusional state (2.9%), disturbance in attention (2.9%), delirium (2.2%), cognitive disorders (1.4%), and Grade 3 cognitive adverse reactions occurred in 2.5% of patients. Among the 30 patients with cognitive impairment, 7% required a dose modification and 20% required dose interruption. Mood disorders occurred in 14% of patients. The median time to onset of mood disorders was 3.9 months (range: 1 day to 40.5 months). Mood disorders occurring in ≥1% of patients included anxiety (5%), depression (3.9%), agitation (2.9%), and irritability (2.9%). Grade 3 mood disorders occurred in 0.4% of patients. Dizziness occurred in 27% of patients, and Grade 3 dizziness occurred in 1.1% of patients. Among the 74 patients who experienced dizziness, 5% of patients required a dose modification and 5% required dose interruption. Sleep disturbances occurred in 10% of patients. Sleep disturbances included insomnia (7%), somnolence (2.5%), and sleep disorder (0.4%). There were no Grade 3-4 sleep disturbances. Among the 28 patients who experienced sleep disturbances, 1 patient each (3.6%) required a dose modification or dose interruption. Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed. Skeletal Fractures: Among 187 adult patients who received VITRAKVI across clinical trials, fractures were reported in 7% and among 92 pediatric patients, fractures were reported in 9% (N=279; 8%). Median time to fracture was 11.6 months (range 0.9 to 45.8 months) in patients followed per fracture. Fractures of the femur, hip or acetabulum were reported in 4 patients (3 adult, 1 pediatric). Most fractures were associated with minimal or moderate trauma. Some fractures were associated with radiologic abnormalities suggestive of local tumor involvement. VITRAKVI treatment was interrupted due to fracture in 1.4% patients. Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity). There are no data on the effects of VITRAKVI on healing of known fractures or risk of future fractures. Hepatotoxicity: Hepatotoxicity including drug induced liver injury (DILI) has been reported in patients taking VITRAKVI. In patients who received VITRAKVI, increased AST of any grade occurred in 52% of patients and increased ALT of any grade occurred in 45%. Grade 3-4 increased AST or ALT occurred in 3.1% and 2.5% of patients, respectively. The median time to onset of increased AST was 2.1 months (range: 1 day to 4.3 years). The median time to onset of increased ALT was 2.3 months (range: 1 day to 4.2 years). Increased AST and ALT leading to dose modifications occurred in 1.4% and 2.2% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 3 (1.1%) of patients. There have been reports in adult patients from clinical studies and post-marketing cases of Grade ≥ 2 increases in ALT and/or AST with increases in bilirubin ≥ 2 x ULN. Obtain liver function tests (ALT, AST, ALP and bilirubin) before initiation of VITRAKVI and monitor every 2 weeks during the first two months of treatment, then monthly thereafter, or more frequently following the occurrence of Grade 2 or greater AST or ALT elevation. Temporarily withhold, reduce the dose, or permanently discontinue VITRAKVI based on severity. Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the last dose of VITRAKVI. Adverse Reactions The most common adverse reactions (≥20%), including laboratory abnormalities, were: increased AST (52%), increased ALT (45%), anemia (42%), musculoskeletal pain (42%), fatigue (36%), hypoalbuminemia (36%), neutropenia (36%), increased alkaline phosphatase (34%), cough (32%), leukopenia (28%), constipation (27%), diarrhea (27%), dizziness (27%), hypocalcemia (25%), nausea (25%), vomiting (25%), pyrexia (24%), lymphopenia (22%) and abdominal pain (21%). Drug Interactions Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs. For coadministration with moderate CYP3A4 inhibitors, monitor for adverse reactions more frequently and reduce the dosage based on severity. For coadministration with moderate CYP3A4 inducers, modify dose as recommended. Use in Specific Populations Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the last dose. Please see the full Prescribing Information for VITRAKVI® (larotrectinib). About Oncology at Bayer Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. In line with its mission, “Health for all, Hunger for none,” the company’s products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2023, the Group employed around 100,000 people and had sales of 47.6 billion euros. R&D expenses before special items amounted to 5.8 billion euros. For more information, go to . © 2024 Bayer BAYER, the Bayer Cross, NUBEQA, XOFIGO and VITRAKVI are registered trademarks of Bayer. Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at . The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. References NUBEQA® (darolutamide) tablets [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, April 2024. XOFIGO® (radium-223 dichloride Injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, April 2024. VITRAKVI® (larotrectinib) [Package Insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, April 2024. PP-PF-ONC-US-3156-1 5/24