Latest Vitrakvi® (larotrectinib) Subgroup Analyses at ASCO 2023 Showcase Long-Term Efficacy and Safety Profile in Adult and Pediatric Patients with NTRK Gene Fusion Cancer, Across Solid Tumors

• Post-hoc subgroup analyses of adult patients (n=180) with TRK fusion cancer across 24 different tumor types, including patients with central nervous system (CNS) metastases (n=22), were presented. All efficacy assessments were by IRC.¹
• Long-term follow-up of subgroup analyses of patients with advanced TRK fusion lung cancer (n=30), including those with CNS metastases (n=12), were also presented.²
• Additionally, separate subset analyses of three clinical trials evaluating patients with NTRK gene fusion thyroid cancer (n=30) were presented.³ 
  
  
  
  Abstracts: 3141, 9056, 6091

Bayer announced data from three distinct Vitrakvi^® (larotrectinib) post-hoc subgroup analyses. The data was presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting from June 2-6, 2023.

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 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.⁴

“These findings reinforce Vitrakvi’s ability to treat patients with NTRK fusion-positive cancer and the importance of targeting the oncogenic driver,” said Iain Webb, M.D., Vice President, U.S. Medical Affairs, Oncology at Bayer. “Testing patients comprehensively and early is pivotal to finding patients with NTRK fusion tumors and treating appropriate patients with Vitrakvi.”

Larotrectinib long-term efficacy and safety in adult patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer (Abstract 3141)¹

In post-hoc subgroup analyses (data cut-off July 2022) of adult patients (n=180) with TRK fusion cancer across 24 different tumor types, including patients with central nervous system (CNS) metastases (n=22), Vitrakvi demonstrated an objective response rate (ORR) of 57% (95% CI 50-65) {16% (n=29) complete responses (including one pathological complete response) and 41% (n=74) partial responses}. In evaluable patients with CNS metastases (n=22), ORR was 68% (95% CI 45-86). Among all patients, median time to response was 1.8 months and median duration of response (DoR) was 43.3 months (95% CI 29.2-not estimable [NE]) at a median follow-up of 32.3 months. Treatment-related adverse events (TRAEs) were predominantly Grade 1-2, with Grade 3-4 occurring in 14% (n=27) of patients. Responses were assessed by IRC.

Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer (Abstract 9056)²

In an expanded dataset (n=30) with longer follow-up, Vitrakvi demonstrated long-term efficacy and safety data in adult patients with advanced TRK fusion lung cancer, including those with CNS metastases (n=12). The results encourage wider adoption of next-generation sequencing (NGS) testing for identifying patients with solid tumors harboring NTRK gene fusions, including lung cancer. Among 27 adult patients eligible for IRC assessment with TRK fusion lung cancer enrolled, ORR was 74% (95% CI 54-89); 11% (n=3) complete responses and 63% (n=17) partial responses. Among the 12 patients with baseline CNS metastases, the ORR was 67% (95% CI 35-90), with 8 partial responses. Median DoR was 33.9 months (95% CI 9.5-NE); median follow-up was 22.9 months. TRAEs were predominantly for Grade 1-2. Grade 3-4 TRAEs were reported in 5 patients which included AST increase, ALT increase, myalgia, and hypersensitivity.

Larotrectinib (laro) long-term efficacy and safety in patients (pts) with tropomyosin receptor kinase (TRK) fusion thyroid carcinoma (TC) (Abstract 6091)³

Vitrakvi was evaluated in updated subgroup analyses of patients (n=30; data cut-off July 20, 2022) with TRK fusion thyroid cancer (TC). Among those eligible for efficacy assessment, 47% (n=14) had NTRK1 and 53% (n=16) had NTRK2. Fifty percent (n=15) of patients received no prior systemic therapies, 20% (n=6) received ≥2, and 77% (n=23) received prior radioiodine. ORR was 63% (95% CI 44-80); 10% (n=3) complete responses and 53% (n=16) partial responses. For patients classified as differentiated thyroid cancer (DTC; n=23), ORR was 78% (95% CI 56-93). For patients classified as anaplastic thyroid cancer (ATC; n=7), ORR was 14% (95% CI 0-58). All patients with CNS metastases (n=4) at baseline had a partial response. Median time to response was 1.9 months and median DoR was 43.3 months (95% CI 21.6-NE) at a median follow-up of 32.3 months. Grade ≥3 TRAEs, anemia and decreased lymphocycte count, were reported in 7% (n=2) patients. There were no treatment discontinuations due to TRAEs. Responses were assessed by IRC.

About Vitrakvi^® (larotrectinib)⁴

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

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: 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.

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 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 and rectal, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (including secretory carcinoma of the salivary gland) and pediatric cancers (infantile fibrosarcoma and other soft tissue sarcomas).^4,5

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 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 2022, the Group employed around 101,000 people and had sales of 50.7 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to www.bayer.com.

^© 2023 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. Hong D, et. al. Larotrectinib long-term efficacy and safety in adult patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer. ASCO Annual Meeting 2023 E-Poster. Abstract 3141.
2. Lin, J, et. al. Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer. ASCO Annual Meeting 2023 E-Poster. Abstract 9056.
3. Cabanillas M, et. al. Larotrectinib (laro) long-term efficacy and safety in patients (pts) with tropomyosin receptor kinase (TRK) fusion thyroid carcinoma (TC). ASCO Annual Meeting 2023 E-Poster. Abstract 6091.
4. Vitrakvi^® [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; December 2022.
5. 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.

PP-VIT-US-1303-1 6/23

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