New Data Support Strong Clinical Profile of Vitrakvi® (larotrectinib) for Adult and Pediatric Patients with TRK Fusion Cancer, Including Lung and Thyroid Tumors

• 78% overall response rate (ORR) and median progression-free survival (PFS) of 36.8 months demonstrate durable response in expanded data set of 175 adults and children¹
• Majority of adverse events were grade 1 or 2; no new safety signals reported¹
• Consistently high ORRs shown in lung and thyroid data subsets (71% and 75%, respectively) as well as long durability (estimated duration of response at 12 months of 88% and 95%, respectively)^2,3
• Among lung patients with brain metastases, the ORR was 57% (no patients with complete response, n=4/7 with partial response)²
• New retrospective analysis measuring growth modulation index (GMI) will also be presented⁴

Abstracts: 1955P, 1916P, 1289P, 542P

WHIPPANY, N.J.--(BUSINESS WIRE)-- Updated clinical data for Vitrakvi^® (larotrectinib) reinforce the consistent, long-term efficacy and established safety profile in an integrated dataset of 175 adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion cancer.¹ In addition, new tumor type specific sub-analyses in lung and thyroid cancer patients further emphasize these durable responses with no new safety signals reported.^2,3 These results are being presented at the ESMO Virtual Congress 2020, to be held between September 19-21, 2020.

Vitrakvi is approved in the U.S., Canada, Brazil and the European Union (EU). In the U.S., Vitrakvi is approved 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. 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. Additional filings in other regions are underway or planned.

Adult and Pediatric Integrated Data Set

In an expanded data set with a longer follow-up (cut-off July 15, 2019) of 175 patients (116 adult and 59 pediatric) with non-primary central nervous system (CNS) TRK fusion cancer, Vitrakvi demonstrated a durable, investigator-assessed overall response rate (ORR) of 78% (95% CI 71-84; n=136/175), with 19% (n=33) complete responses (CRs), 59% (n=103) partial responses (PRs) and 13% (n=23) with stable disease. The ORR in 14 patients with CNS metastases was 71% (95% CI 42-92; n=10/14; all responses were partial responses).¹

“The consistent and durable responses as well as the safety profile from the larotrectinib data are supportive in determining the appropriate treatment option for my patients with TRK fusion cancer,” said Professor Ray McDermott, St. Vincent University Hospital and Tallaght Hospital, Ireland. “These clinically meaningful responses underscore the urgency for widespread NTRK testing.”

The median duration of response (DoR) was not estimable at a median follow-up of 13.5 months, with a 12-month DoR rate of 81% (95% CI 73-89). After a median follow-up of 13.8 months, the median progression-free survival (PFS) was 36.8 months (95% CI 25.7- NE). Median overall survival (OS) was not reached after 15.3 months of follow-up; 12-month estimated median OS rate was 90% (95% CI 85-95) and 24-month estimated OS rate was 83% (95% CI 75-90). At the time of data cut-off, 100 patients (57%) were still on treatment.¹

In the expanded safety population of 279 patients, with 34 patients being treated with Vitrakvi for more than 24 months, adverse events (AEs) were primarily grade 1 and 2, and no new safety signals were reported. Serious AEs related to Vitrakvi were reported in 5% (15/279) of patients; the most common serious grade 3 and 4 events were increased alanine aminotransferase, increased aspartate aminotransferase and nausea (n=2 each).¹

In the primary data set at the time of FDA approval, Vitrakvi demonstrated an ORR of 75% (n=55) (95% CI, 61-85), including 22% CRs and 53% PRs assessed by independent review committee and the median DoR was not yet reached (range 1.6+ to 33.2+) (n=44).

“Designed specifically to treat TRK fusion cancer, Vitrakvi is a meaningful advancement in the treatment of both adult and pediatric patients with TRK fusion cancer and represents a true paradigm shift in cancer care -- where treatment is based on the oncogenic driver and not the tumor location,” said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer‘s Pharmaceutical Division. “These data affirm Vitrakvi’s robust clinical profile with the largest dataset and longest follow-up of any TRK inhibitor and reinforce our longstanding commitment to developing innovative treatments for patients.”

Vitrakvi in Lung and Thyroid Cancers

In a sub-analysis of 14 adult heavily pre-treated patients with metastatic lung cancer harboring an NTRK gene fusion, the demonstrated ORR was 71% (95% CI 42-92; n=10/14) with an additional year of follow-up, with 7% (n=1) CRs, 64% (n=9) PRs and 21% (n=3) with stable diseases. For patients with CNS metastases, the ORR was 57% (95% CI 18-90; no patients with CR, n=4/7 with PRs). At a median follow-up of 12.9 months, median DoR was not estimable (NE) (95% CI 5.6-NE months). The estimated DoR at 12 months was 88%. At a median follow-up of 14.6 months, the median PFS had not been reached (95% CI 7.2-NE) and the estimated rate of PFS at 12 months or more was 69%. The median OS was not reached (95% CI 17.2-NE) at a median follow-up of 12.6 months and 91% of patients were alive at 12 months. Duration of treatment ranged from 2.1 to 39.6+ months with three of seven patients with CNS metastases still on treatment at the time of data cut-off. Treatment-emergent AEs were primarily grade 1 and 2, supporting Vitrakvi’s long-term safety profile.²

In a separate subset analysis of 28 adults and children with locally advanced or metastatic TRK fusion thyroid cancer, the ORR was 75% (95% CI 55-89; n=21/28), with 7% (n=2) CRs and 68% (n=19) PRs. The ORR was 29% (no CR, 29% PR [95% CI 4-71; n=2/7]) for patients with anaplastic disease, a rare, aggressive subtype of thyroid cancer. The ORR was 90% (95% CI 70-99; n=19/21) for differentiated histology. All four patients with CNS metastases at baseline had a PR, three of which are continuing treatment. While median DoR was not estimable (95% CI 14.8-NE months) at a median follow-up of 10.2 months, the estimated DoR at 12 months was 95% (95% CI 85-100). Median PFS was not estimable (95% CI 16.6-NE months) at a median follow up of 12.8 months; estimated PFS was 81% (95% CI 67–96) at 12 months and 70% (95% CI 45–94) at 18 months. The median OS was 27.8 months (95% CI 16.7-NE) with an estimated OS at 12 months of 92% (95% CI 82-100) and a median OS of 14.1 months (95% CI 2.6-NE) for patients with anaplastic thyroid cancer; not reached for differentiated thyroid cancer. The safety profile was consistent with that of the overall safety population previously reported, with AEs mostly grade 1 and 2.³

Vitrakvi Growth Modulation Index Analysis

122 patients who had been treated with Vitrakvi and followed up for at least 6 months (or discontinued early) and had at least one prior line of systemic therapy in the advanced setting were eligible for retrospective growth modulation index (GMI) analysis. GMI is calculated as a ratio of PFS with Vitrakvi to the time to progression or time to treatment failure (TTPF) on the most recent prior line of therapy. In the analysis of 122 adult and pediatric patients with metastatic and locally advanced disease treated with Vitrakvi, the median GMI was 3.35 (range 0.00-337). 69% (n=84/122) of patients had a GMI of ≥ 1.33. The median TTPF on prior line of therapy was 2.7 months (95% CI 2.0–3.1) and median PFS on Vitrakvi was 33.4 months (95% CI 13.8–[NE]; hazard ratio [HR] 0.20 [95% CI 0.14–0.29]).⁴

Data for the integrated dataset and GMI analysis were pooled from three larotrectinib clinical trials (NCT02122913, NCT02576431 and NCT02637687) in adult and pediatric patients with TRK fusion cancer.^1,4 Data from the lung and thyroid cancer subsets were pooled from two larotrectinib clinical trials (NCT02122913 and NCT02576431).^2,3

About Vitrakvi^® (larotrectinib)⁵

Vitrakvi^® (larotrectinib) 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.

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%).

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.

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.

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%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).

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 an altered TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade. These TRK fusion proteins act as oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer, regardless to where it originates in the body. 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 (mammary analogue secretory carcinoma) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma).

About Oncology at Bayer

Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. We have the passion and determination to develop innovative medicines to help extend the lives of people living with cancer. The oncology franchise at Bayer includes six marketed products across various indications and several compounds in different stages of clinical development. A key area of focus is prostate cancer, where we have several treatments on the market or in development. Another key focus at Bayer is on shifting oncology treatment, with an approved TRK inhibitor exclusively designed to treat solid tumors that have an NTRK gene fusion, a key oncogenic driver, and another TRK inhibitor advancing through the pipeline. The company’s approach to research 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 2019, the Group employed around 104,000 people and had sales of 43.5 billion euros. Capital expenditures amounted to 2.9 billion euros, R&D expenses to 5.3 billion euros. For more information, go to www.bayer.us.

^© 2020 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. McDermott R, et. al. Survival benefits of larotrectinib in an integrated dataset of patients with TRK fusion cancer. ESMO Virtual Congress 2020 E-Poster. Abstract 1955P.
2. Drilon AE, et. al. Efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer. ESMO Virtual Congress 2020 E-Poster. Abstract 1289P.
3. Cabanillas ME, et. al. Larotrectinib treatment of advanced TRK fusion thyroid cancer. ESMO Virtual Congress 2020 E-Poster. Abstract 1916P.
4. Italiano A, et. al. Growth modulation index (GMI) of larotrectinib versus prior systemic treatments for TRK fusion cancer patients. ESMO Virtual Congress 2020 E-Poster. Abstract 542P.
5. VITRAKVI [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; July 2019.

PP-VIT-US-0485-1 09/20

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