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Bayer Announces Results of Sub-group Analysis for Vitrakvi® (larotrectinib) in Patients with NTRK Gene Fusion-Positive Metastatic Non-small Cell Lung Cancer (NSCLC)

WHIPPANY, N.J., April 11, 2019 /PRNewswire/ -- Bayer today presented subgroup analysis data of patients with non-small cell lung cancer with neurotrophic receptor tyrosine kinase (NTRK) gene fusion treated with Vitrakvi® (larotrectinib).1 Vitrakvi is the only TRK inhibitor exclusively designed for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation that are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.2 In the U.S., Vitrakvi was 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.

The analysis assessed 11 advanced metastatic NSCLC patients from two clinical studies, of which seven were evaluable for response. This sub-set showed an overall response rate (ORR) of 71 percent, including one complete response (CR) and four partial responses (PR), based on investigator assessment using RECIST version 1.1. These data include Vitrakvi patients with and without brain metastasis, with a median time to response of 1.8 months. Median duration of response (DOR) was not reached at the time of the analysis (DOR ranged from 7.4 to 17.6 months, with responses ongoing). Adverse events (AEs) were generally consistent with previously reported safety profile of Vitrakvi.1 Treatment emergent AEs (>20%) across all grades include fatigue, dizziness, nausea, constipation, anemia, AST/ALT increase, cough, diarrhea, and vomiting.1 These data were presented at the European Lung Cancer Congress (ELCC) 2019, taking place in Geneva, Switzerland, from April 10-13, 2019.

"The efficacy and safety of larotrectinib in patients with NSCLC reinforce the importance of identifying genomic alterations early," said Alexander Drilon, M.D., clinical director of Early Drug Development Service at Memorial Sloan Kettering Cancer Center. "Lung cancer is the leading cause of cancer deaths in the United States and these data are important to progressing the treatment options available for these patients in order to provide appropriate care."

"As researchers learn more about tumor genomics, new medicines that directly address the genomic abnormalities driving tumor growth become increasingly relevant for patients," said Scott Fields, MD, Senior Vice President and Head of Oncology Development at Bayer's Pharmaceutical Division. "These latest Vitrakvi data in NSCLC underscore the importance of genomic cancer testing in all NSCLC patients."

Vitrakvi was approved in the U.S. in November 2018. Bayer has submitted a Marketing Authorization Application (MAA) in the European Union and additional filings in other regions are underway. Under a change-in-control clause in the collaboration agreement with Loxo Oncology, Bayer exercised its option to obtain the exclusive licensing rights for the global development and commercialization, including the U.S., for larotrectinib (Vitrakvi®) as well as BAY 2731954 (formerly LOXO-195).

About Vitrakvi® (larotrectinib)
Vitrakvi® is indicated for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation that are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.2

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.

Research suggests that the NTRK genes can become abnormally fused to other genes, producing a TRK fusion protein that can act as an oncogenic driver, leading to cancer cell growth and survival.2

Important Safety Information

Neurotoxicity: Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority (65%) of neurological adverse reactions occurred within the first three months of treatment (range 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%).2

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 dose when resumed.2

Hepatotoxicity: Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.2

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.2

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.2

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.2

Most Common Adverse Reactions (≥20%): The most common adverse reactions (≥20%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).2 

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.2

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.2

Please see the full Prescribing Information.

About TRK Fusion Cancer
TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing an altered TRK protein.2 The altered protein, or TRK fusion protein, becomes constitutively active and overexpressed, triggering a signaling cascade.2 These TRK fusion proteins act as oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer, regardless of where it originates in the body.2 TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body.2 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 (mammary analogue secretory carcinoma) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma).2,3

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 five 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 benefit people by supporting efforts to overcome the major challenges presented by a growing and aging global population. At the same time, the Group aims to increase its earning power and create value through innovation and growth. Bayer is committed to the principles of sustainable development, and the Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2018, the Group employed around 117,000 people and had sales of 39.6 billion euros. Capital expenditures amounted to 2.6 billion euros, R&D expenses to 5.2 billion euros. For more information, go to www.bayer.us.

© 2019 Bayer  
BAYER, the Bayer Cross and Vitrakvi are registered trademarks of Bayer.

Media Contact:
Rose Talarico, Tel. +1 862.404.5302
E-Mail: rose.talarico@bayer.com

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
1Drilon A., Kummar S., Moreno V., Patel J., Lassen U., Rosen L, Childs B., Nanda S., Cox M., Ku N., and Farago A. European Lung Cancer Congress 2019: '1110 Activity of Larotrectinib in TRK Fusion Lung Cancer' [powerpoint presentation]
2 Vitrakvi® (larotrectinib) capsules and solution for oral use [Prescribing Information]. Stamford, CT: Loxo Oncology Inc.; November 2018.
3 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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