Latest Analyses of Vitrakvi® (larotrectinib) Support Consistently Meaningful Clinical Profile for Both Adult and Pediatric Patients with TRK Fusion Cancer

• An updated analysis on the adult (≥18 years; n=140) subset of non-central nervous system (CNS) TRK fusion cancer patients from three Vitrakvi clinical trials showed an overall response rate (ORR) of 67% (95% CI 58–75) with a median duration of response (DoR) of 49.3 months (95% CI 26.3–Not Estimable [NE]), as assessed by investigators
• Post hoc sub-analysis of investigator-assessed ORR and DoR of patients (n=218) stratified based on number of lines of prior systemic therapy or baseline Eastern Cooperative Oncology Group performance status (ECOG PS) or Lansky/Karnofsky performance status for children was published
• Data on the incidence of fractures from three Phase I/II trials of patients with solid and CNS tumors treated with Vitrakvi monotherapy was also published
• E-Poster published of a matching-adjusted indirect comparison (MAIC) evaluating efficacy (overall survival [OS], progression-free survival [PFS], ORR including complete responses and DoR) and safety observed in clinical trials with Vitrakvi compared to entrectinib. MAIC is an alternative method for comparative data when a head-to-head randomized control trial (RCT) is not available and/or possible, like for TRK fusion cancer which is an ultra-rare disease

Abstracts: 535P, 534P, 536P, 104P

Data from three subset analyses and one matching-adjusted indirect comparison (MAIC) model for Vitrakvi^® (larotrectinib) showcase its consistent noteworthy clinical profile and add to its existing safety data for patients with solid tumors harboring an NTRK gene fusion (also known as TRK fusion cancer). These analyses add to the body of evidence for the compound, which has the largest dataset and longest follow-up of any TRK inhibitor. These results are being presented at the ESMO Congress 2021, to be held between September 16-21, 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

“As we continue to see ongoing analyses of larotrectinib across a wide range of solid tumors and ages, its consistent results in NTRK fusion-positive cancers support its efficacy and safety in adults and children.” said Alexander Drilon, M.D., Chief of Early Drug Development Service at Memorial Sloan Kettering Cancer Center.* “These data reinforce the importance of early comprehensive genomic testing to uncover actionable oncogenic drivers, including NTRK gene fusions, to help identify patients who are most likely to benefit from a targeted treatment approach.”

“The U.S. FDA approval of Vitrakvi nearly three years ago represented a paradigm shift in how we treat cancer, by inhibiting the oncogenic driver that is causing a solid tumor to grow and spread rather than the location where it originates,” said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer's Pharmaceutical Division. “The long-term data for Vitrakvi continue to support consistent responses and similar safety profile seen with the addition of new patients and with longer follow-up. These findings reinforce the importance of precision oncology medicines as a meaningful advancement in cancer care.”

Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase (TRK) fusion cancer (Abstract 535P)²

In an updated subgroup analysis with longer follow-up (data cut-off July 20, 2020) in 130 evaluable patients out of 140 total adult patients with non-central nervous system (CNS) TRK fusion cancer across 20 different tumor types, Vitrakvi continued to show efficacy. Among evaluable patients, the overall response rate (ORR) was 67% (95% CI 58–75) per investigator assessment, including 12% complete responses and 55% partial responses. Among the evaluable patients with CNS metastases (n=15), ORR was 73% (95% CI 45–92). Among all patients, the median duration of response (DoR) was 49.3 months (95% CI 26.3–NE) at a median follow-up of 23.2 months.

Grade 3–4 treatment related adverse events (TRAEs) occurred in 17 patients (12%) and no new safety signals were identified. Data were pooled from three clinical trials (NCT02122913, NCT02637687, NCT02576431).

Larotrectinib in non-CNS TRK fusion cancer patients: outcomes by prior therapy and performance status (Abstract 534P)³

In a post-hoc subgroup analysis with adult and pediatric patients (n=218; data cut-off July 20, 2020), patients were evaluated based on treatment history and baseline performance status. A total of 218 patients were evaluated based on performance status as defined by Eastern Cooperative Oncology Group (ECOG PS) or equivalent Lansky/Karnofsky performance status for pediatric patients. Out of the 218 evaluable patients, 216 patients were assessed based on prior line of systemic therapy, as two patients were excluded from analysis due to data entry ambiguity. Investigator-assessed treatment response rates were highest in patients who had no previous systemic treatment (ORR=81%; 95% CI 69–91; n=58) or with a baseline ECOG PS of 0 (ORR=85%; 95% CI 77–91; n=114); however, while patients in each group showed responses from Vitrakvi across prior line of systemic therapy and baseline ECOG PS, there were differences. In patients who received Vitrakvi following one line of systemic therapy (n=59), the ORR was 73% (95% CI 60–84). In patients who received two lines of systemic therapy (n=42), the ORR was 69% (95% CI 53–82), and in patients who received three or more lines of systemic therapy (n=57) the ORR was 75% (95% CI 62–86). In patients with an ECOG PS of 1 (n=78), the ORR was 66% (95% CI 54–77), followed by 61% (95% CI 39–80; n=23) with an ECOG PS of 2, and 33% (95% CI 1–91; n=3) with an ECOG PS of 3. Across all patients, ORR was 75% (95% CI 68–81) and median DoR was 49.3 months (95% CI 27.3–NE). Data were pooled from three clinical trials (NCT02122913, NCT02637687, NCT02576431).

Incidence of fractures in TRK fusion cancer patients treated with larotrectinib (Abstract 536P)⁴

In a pooled analysis of 331 patients (n=214 adult, 117 pediatric) with solid and CNS tumors treated with Vitrakvi, the incidence of fractures, which can be an event of concern in oncology patients, was analyzed. Fractures were mainly Grade 1 or 2 (n=12 adult fractures, n=8 pediatric fractures) and were associated with trauma (fall) or were tumor-related. Treatment-emergent fractures of all grades were reported in 7% (n=15) of adults and 7.7% (n=9) of children. No fractures were considered to be treatment-related by Investigator. Data were pooled from three clinical trials (NCT02122913, NCT02637687, NCT02576431).

Matching-adjusted indirect comparison for treatment of NTRK fusion cancer with larotrectinib versus entrectinib (Abstract 104P)⁵

A MAIC of data from clinical trials with Vitrakvi (data cut-off July 2020) and entrectinib (data cut-off October 2018) analyzed the efficacy endpoints overall survival (OS), progression-free survival (PFS), ORRs including complete responses and DoR as well as safety observed in these trials, matching patients based on available common baseline characteristics (gender, age, race, ECOG score, select tumor types, metastatic disease, NTRK gene, CNS metastases, number of prior lines of therapy). Although cross-trial comparisons are subject to limitations, MAIC is an alternative method for comparative data when a head-to-head randomized control trial (RCT) is not available and/or possible, such as in the case of TRK fusion cancer in part due to the rarity of the disease.⁶ The analysis provides further, more granular information between the efficacy and safety outcomes between the clinical trials with these treatments. Data were pooled from three Vitrakvi clinical trials (NCT02122913, NCT02637687, NCT02576431) and three entrectinib studies (ALKA-372-001, STARTRK-1 and STARTRK-2).

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%) 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. VITRAKVI 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 (including secretory carcinoma of the salivary gland) and pediatric cancers (infantile fibrosarcoma and other soft tissue sarcomas).^1,7

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.

*Dr. Drilon has provided speaking and consulting services to Bayer.

^© 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.

PP-VIT-US-0848-1 09/21

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