New data on Vitrakvi® (larotrectinib) in TRK fusion cancer patients with brain metastases or primary central nervous system (CNS) tumors

- Data show Vitrakvi efficacy in NTRK gene fusion positive solid tumors, including primary CNS tumors and cancers with brain metastases

- Analysis included first data ever presented for a TRK inhibitor in adult primary CNS TRK fusion cancer, and also included data on pediatric CNS TRK fusion cancer patients

Annual Meeting of the American Society of Clinical Oncology (ASCO) 2019

Abstract: 2006

News provided by

Bayer

Jun 03, 2019, 16:16 ET

WHIPPANY, N.J., June 3, 2019 /PRNewswire/ -- Bayer today announced results of a new analysis from clinical trials investigating Vitrakvi^® (larotrectinib) in patients with TRK fusion cancer with primary central nervous system (CNS) tumors or brain metastases. The analysis included 14 patients with primary CNS tumors evaluable for efficacy, including cases of glioma, glioblastoma, glioneural tumors, and astrocytoma. In this population, Vitrakvi demonstrated an overall response rate (ORR) of 36% (n=5; 95% CI: 13-65), including 14% complete responses (CR, n=2) and 21% partial responses (PR, n=3). The remaining 64% of patients had stable disease and no patients experienced progressive disease as best response based on investigator assessment using RANO (Response Assessment in Neuro-Oncology) and RECIST 1.1 (Response Evaluation Criteria In Solid Tumors). In five evaluable patients with NTRK gene fusion positive solid tumors with brain metastases, the ORR was 60% (n=3 PRs; 95% CI: 15-95) based on investigator assessment and RECIST 1.1. The remaining 40% of patients (n=2) had stable disease.¹

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, 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. 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.²

The analysis included 24 TRK fusion cancer patients with brain metastases or primary CNS tumors who were identified from across three different clinical studies.¹ Eighteen patients presented with primary CNS tumors (data cut-off February 19, 2019), of which 14 were evaluable, and six patients had non-primary CNS tumors and brain metastases, of which five were evaluable (data cut-off July 30, 2018).¹ The adverse events seen in the presentations were mostly grade 1-2.^3,4,5

These data were presented in an oral presentation at ASCO on June 3, 2019 (Abstract 2006, Session: Central Nervous System Tumors; Monday, June 3, 3:15PM – 3:27PM CDT, Room: S102).

"These data are important as we continue to see efficacy with Vitrakvi in TRK fusion cancer across different tumor types and ages," said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer's Pharmaceuticals Division. "The responses in these patients underscore the importance of widespread genomic cancer testing to identify patients who may be appropriate for this treatment."

Data on Vitrakvi in CNS tumors

A total of 24 patients with intracranial disease were identified from three clinical studies (adult Phase I trial, NCT02122913, 1 patient; Pediatric Phase I/II trial SCOUT, NCT02637687, 12 patients; and the adult/adolescent Phase II basket trial NAVIGATE, NCT02576431, 11 patients).¹

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, 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.² Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.²

Important Safety Information for VITRAKVI^® (larotrectinib)

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 neurologic 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 for VITRAKVI^®(larotrectinib).

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 or overexpressed, triggering a signaling cascade.² These TRK fusion proteins can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines, 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.⁶ 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).^2,6

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 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.

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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; DuBois, S; Farago, A et al. Activity of Larotrectinib in TRK Fusion Cancer Patients with Brain Metastases or Primary Central Nervous System Tumors. American Society of Clinical Oncology 2019; June 3, 2019. Chicago, Illinois. Abstract 2006.
²Vitrakvi^® (larotrectinib) capsules and solution for oral use [Prescribing Information]. Stamford, CT: Loxo Oncology Inc.; November 2018.
³ Van Tilburg, C; Dubois, S; Albert, C et al. Larotrectinib Efficacy and Safety in Pediatric TRK Fusion Cancer Patients. American Society of Clinical Oncology 2019; June 2, 2019. Chicago, Illinois. Abstract 10010.
⁴Hong, D; Kummar, S; Farago, A et al. Larotrectinib Efficacy and Safety in Adult TRK Fusion Cancer Patients. American Society of Clinical Oncology 2019; June 1, 2019. Chicago, Illinois. Abstract 3122.
⁵Drilon A, Laetsch TW, Kummar S et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children; N Engl J Med. 2018 Feb 22;378(8):731-739. doi: 10.1056/NEJMoa1714448.
⁶Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34.