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Long-term Data on Vitrakvi® (larotrectinib) Further Demonstrate Strong Clinical Profile in Patients with TRK Fusion Cancer Regardless of Tumor Type and Age

WHIPPANY, N.J.–()–Bayer to present new data across four distinct analyses showcasing the consistent, long-term clinical profile for Vitrakvi® (larotrectinib) across TRK fusion cancer patients of all ages (range: 0.1-84 years) and multiple tumor types. The analyses include updated long-term efficacy and safety data across solid tumors, including primary central nervous system (CNS) tumors and lung cancer, harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. In addition, an intra-patient pooled retrospective analysis assessing the treatment effect of Vitrakvi in patients with TRK fusion cancer previously treated with one or more line of therapy were presented. These analyses add to the existing clinical profile for Vitrakvi, which has the largest dataset and longest follow-up of any TRK inhibitor, at median follow-up of 22.3 months, for patients across all ages and tumor types with an NTRK gene fusion. These findings are being presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting being held online June 4-8, 2021.

Vitrakvi is approved for the treatment of adult and pediatric patients with solid tumors that have an 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 Food and Drug Administration (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.1

“This data adds to larotrectinib’s growing clinical profile, supporting its use as an effective treatment option for adults and children with NTRK gene fusion positive tumors,” said David S. Hong, M.D., Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. “These findings present a clear rationale for robust comprehensive genomic testing inclusive of NTRK 1/2/3 genes for patients to better understand what could be driving their cancer and appropriately match them with the right treatment approach.”

“Designed specifically to treat TRK fusion cancer, Vitrakvi represents a meaningful advancement in the treatment of both adult and pediatric patients with TRK fusion cancer, inhibiting the oncogenic driver that causes these tumors to spread and grow, regardless of where they originate in the body,” said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer. “These long-term data reinforce the use of Vitrakvi for patients with TRK fusion cancer and demonstrate our commitment to advancing the future of cancer care and providing true value for patients and physicians.”

Vitrakvi adult and pediatric integrated dataset (Abstract 3108)2

An expanded dataset with longer follow-up (cut-off July 20, 2020) with 206 evaluable adult and pediatric patients with TRK fusion cancer across 21 different tumor types showed an overall response rate (ORR) per investigator assessment of 75% (95% CI 68-81), including 22% complete responses (n=45). For evaluable patients with brain metastases (n=15), the ORR was 73% (95% CI 45-92). Among all evaluable patients, the median duration of response (DoR) was 49.3 months (95% CI 27.3-NE) at a median follow-up of 22.3 months. Data on progression-free survival (PFS) and overall survival (OS) in this expanded dataset were also presented.

No new safety signals were identified. The majority of treatment-related adverse events (TRAEs) reported were primarily Grade 1 or 2, with 18% of patients reporting Grade 3 or 4 TRAEs. Two percent of patients discontinued Vitrakvi due to TRAEs and no treatment-related deaths were reported.

Data for the integrated dataset were pooled from three Vitrakvi clinical trials (NCT02122913, NCT02576431 and NCT02637687) in adult and pediatric patients with TRK fusion cancer. This analysis did not include the primary CNS patient subset.

Vitrakvi in lung cancer with or without CNS metastases (Abstract 9109)3

Updated data (cut-off July 20, 2020) on heavily pre-treated adult TRK fusion cancer patients with lung cancer, who had received a median of three prior therapies, showed Vitrakvi demonstrated consistent response rates with longer follow-up. Among 15 evaluable patients and based on investigator assessment, the confirmed ORR was 73% (95% CI 45-92), and among evaluable patients with baseline CNS metastases (n=8), the ORR was 63% (95% CI 25-91). In all evaluable patients (n=15), the 12-month rate for DoR was 81%. Data on PFS and median OS in this data subset were also presented. TRAEs were reported in 16 patients, of which two patients experienced Grade 3 events. No patients discontinued Vitrakvi due to TRAEs. These data were investigator-assessed and from patients enrolled in two clinical trials (NCT02576431, NCT02122913).

Vitrakvi in primary CNS tumors (Abstract 2002)4

In another presentation (cut-off July 20, 2020) Vitrakvi was assessed in 33 pediatric and adult patients with primary CNS tumors with an NTRK gene fusion, pooled from two clinical trials (NCT02637687, NCT02576431).The majority of patients (82%) with measurable disease experienced tumor shrinkage with an ORR of 30% (CI 95% 16-49). The 24-week disease control rate was 73% (95% CI 54-87). Data on PFS and median OS in this data subset were also presented. Grade 3 or 4 TRAEs occurred in three patients. No patients discontinued Vitrakvi due to TRAEs.

Intra-patient comparison from Vitrakvi clinical trials in TRK fusion cancer (Abstract 3114)5

Additional Vitrakvi data presented at the congress include an updated and extended retrospective growth modulation index (GMI) analysis limited to patients enrolled in Vitrakvi trials with at least one prior line of therapy. GMI is a retrospective intra-patient comparison that uses the patient as their own control by comparing PFS on current therapy to time to progression or treatment failure (TTP) on the most recent prior therapy. A GMI ratio ≥ 1.33 has been used as a threshold for meaningful clinical activity.

About Vitrakvi® (larotrectinib)

Vitrakvi® (larotrectinib) 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 will likely 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 for Vitrakvi® (larotrectinib)

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: 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.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.

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 final dose of VITRAKVI.

Most Common Adverse Reactions (≥20%): 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.

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.

Please see the full Prescribing Information for VITRAKVI® (larotrectinib).

About TRK Fusion Cancer

TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing a chimeric TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade. These TRK fusion proteins are oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer. TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body. TRK fusion cancer occurs in various adult and pediatric solid tumors with varying frequency, including lung, thyroid, GI cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (secretory carcinoma of the salivary gland) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma).1,6

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. Its products and services are designed to help people and planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to drive sustainable development and generate 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 2020, the Group employed around 100,000 people and had sales of 41.4 billion euros. R&D expenses before special items amounted to 4.9 billion euros. For more information, go to www.bayer.com.

© 2021 Bayer

BAYER, the Bayer Cross, 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 www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

References

1. Vitrakvi® [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; March 2021.

2. Hong, et al. Long-term efficacy and safety of larotrectinib in an integrated dataset of patients with TRK fusion cancer [abstract]. In: ASCO Meeting Library: ASCO; 2021. Abstract 3108.

3. Lin, et al. Long-term efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancer [abstract]. In: ASCO Meeting Library: ASCO; 2021. Abstract 9109.

4. Perreault, et al. Efficacy and safety of larotrectinib in adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive primary central nervous system (CNS) tumors [abstract]. In: ASCO Meeting Library: ASCO; 2021. Abstract 2002.

5. Italiano, et al. Intra-patient comparison from larotrectinib clinical trials in TRK fusion cancer – an expanded dataset [abstract]. In: ASCO Meeting Library: ASCO; 2021. Abstract 3114.

6. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34.

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