Bayer to Present Key Data Across Oncology Portfolio Showcasing Significant Advances in Cancer Care at 2022 ASCO Annual Meeting

WHIPPANY, N.J.--(BUSINESS WIRE)-- Bayer will present new data across its oncology portfolio at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting from June 3-7, 2022. These presentations continue to reinforce Bayer’s position as an innovator in oncology and ongoing dedication to advancing oncology treatments for patients on a global scale.

NUBEQA^® (darolutamide) data presented will include overall survival (OS) and prostate-specific antigen (PSA) results from the investigational Phase III ARASENS trial in metastatic hormone-sensitive prostate cancer (mHSPC) and results of a post-hoc analysis from the Phase III ARAMIS trial in non-metastatic castration-resistant prostate cancer (nmCRPC). NUBEQA is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. NUBEQA is indicated in the U.S. for the treatment of men with nmCRPC.¹ The U.S. Food and Drug Administration (FDA) has recently accepted a supplemental New Drug Application (sNDA) and granted Priority Review for NUBEQA in combination with docetaxel for the treatment of mHSPC.

Research on Xofigo^® (radium Ra 223 dichloride) will also be highlighted, including results from an interim analysis of the RALU study, which evaluated safety and survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with lutetium-177-prostate-specific membrane antigen (¹⁷⁷Lu-PSMA) after Xofigo. Additionally, alkaline phosphatase (ALP) decline and OS data in mCRPC patients treated with Xofigo in the REASSURE study will be presented. Xofigo is indicated for the treatment of patients with mCRPC, symptomatic bone metastases, and no known visceral metastatic disease.²

Efficacy and safety findings of Vitrakvi^® (larotrectinib) for patients with TRK fusion cancer from an integrated pooled analysis per an independent review committee (IRC) assessment, efficacy and safety data from an expanded dataset, updated health-related quality of life (QoL) of adult and pediatric patients with TRK fusion cancer, and sub-analyses for TRK fusion cancer patients with primary central nervous system (CNS) tumors and lung cancer, respectively, will be shared. Additional data for Vitrakvi include an analysis in adult and pediatric patients evaluating Vitrakvi compared to standard of care using a matching-adjusted indirect comparison (MAIC). MAIC is an alternative method for comparative data when a randomized control trial (RCT) is not available and/or possible, as for a rare condition like TRK fusion cancer.³ Results from these studies further support Vitrakvi’s existing clinical profile in TRK fusion cancer across a variety of tumor types and ages. 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 (ORR) and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.⁴

Other research includes investigator-initiated research (IIR) for Stivarga^® (regorafenib) and Nexavar^® (sorafenib) in several areas of oncology.

Presentations from Bayer projects for the 2022 ASCO Annual Meeting are listed below:

Darolutamide

• Abstract title: Association of prostate-specific antigen (PSA) response and overall survival (OS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase 3 ARASENS trial
  • Abstract 5078; June 6, 2:15pm EDT
• Abstract title: Progression patterns by types of metastatic spread, prostate-specific antigen (PSA), and clinical symptoms: Post-hoc analyses of ARAMIS
  • Abstract 5044; June 6, 2:15pm EDT
• Abstract title: Open-label study of androgen receptor inhibition with darolutamide plus androgen-deprivation therapy (ADT) versus ADT in men with metastatic hormone-sensitive prostate cancer using an external control arm (ARASEC) – Trial in Progress (TiP)
  • Abstract TPS5111; June 6, 2:15pm EDT
• Abstract title: Influence of darolutamide on cabazitaxel systemic exposure – Investigator-Initiated Research (IIR)
  • Abstract 5038; June 6, 2:15pm EDT

Radium-223 dichloride (Ra-223)

• Abstract title: Safety and survival outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with lutetium-177-prostate-specific membrane antigen (¹⁷⁷Lu-PSMA) after radium-223 (²²³Ra): Interim analysis of the RALU study
  • Abstract 5040; June 6, 2:15pm EDT
• Abstract title: Alkaline phosphatase (ALP) decline and overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (Ra-223) in the REASSURE Study
  • Abstract 5041; June 6, 2:15pm EDT

Larotrectinib

• Abstract title: Efficacy and safety of larotrectinib in pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive cancer: An expanded dataset
  • Abstract 10030; June 6, 9:00am EDT
• Abstract title: Long-term efficacy and safety of larotrectinib in a pooled analysis of patients with tropomyosin receptor kinase (TRK) fusion cancer
  • Abstract 3100; June 5, 9:00am EDT
• Abstract title: Updated efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer
  • Abstract 9024; June 6, 2:15pm EDT
• Abstract title: Long-term control and safety of larotrectinib in a cohort of adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion primary central nervous system (CNS) tumors
  • Abstract 2010; June 5, 12:30pm EDT
• Abstract title: Updated health-related quality of life of patients with TRK-fusion cancer treated with larotrectinib in clinical trials
  • Abstract 6563; June 6, 2:15pm EDT
• Abstract title: Overall survival (OS) of patients with TRK fusion-positive cancer receiving larotrectinib versus standard of care (SoC): A matching-adjusted indirect comparison (MAIC) using real-world data (RWD)
  • Abstract 6597; June 6, 2:15pm EDT
• Abstract title: Securing access to innovative anticancer therapies for children, adolescents and young adults outside clinical trials: The SACHA study of the French Society of Pediatric Oncology (SFCE) – Investigator-Initiated Research (IIR)
  • Abstract 10006; June 6, 5:36pm EDT

Regorafenib

• Abstract title: REGOMUNE: A phase II study of regorafenib plus avelumab in solid tumors—Results of the oesophageal or gastric carcinoma (OGC) cohort – Investigator-Initiated Research (IIR)
  • Abstract 4060; June 4, 9:00am EDT
• Abstract title: Regorafenib (REGO) plus FOLFIRINOX as frontline treatment in patients (pts) with RAS-mutated metastatic colorectal cancer (mCRC): A phase I/II, dose-escalation and dose-expansion study – Investigator-Initiated Research (IIR)
  • Abstract 3561; June 4, 9:00am EDT
• Abstract title: REGOMAIN: A randomized, placebo-controlled, double-blinded, multicenter, comparative phase II study of the efficacy of regorafenib as maintenance treatment in patients (pts) with high-grade bone sarcomas (HGBS) at diagnosis or relapse and without complete remission after standard treatment – Investigator-Initiated Research (IIR); Trial in Progress (TiP)
  • Abstract TPS11585; June 5, 9:00am EDT
• Abstract title: REGOMUNE: Phase II study of regorafenib plus avelumab in solid tumors—Results of the gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) cohort – Investigator-Initiated Research (IIR)
  • Abstract 4125; June 4, 9:00am EDT
• Abstract title: Activity of regorafenib in patients with non-adipocytic soft tissue sarcoma (NASTS): Evaluation of heterogeneity of treatment effect on the updated analysis of pooled cohorts – Investigator-Initiated Research (IIR)
  • Abstract 11555; June 5, 9:00am EDT

Sorafenib

• Abstract title: Deficit Accumulation Frailty Index (DAFI) scores and acute myeloid leukemia outcomes – Investigator-Initiated Research (IIR)
  • Abstract 12040; June 4, 2:15pm EDT

About NUBEQA^® (darolutamide)¹

NUBEQA is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription.¹

On July 30, 2019, the FDA approved NUBEQA^® (darolutamide) based on the ARAMIS trial, a randomized, double-blind, placebo-controlled, multi-center Phase III study, which evaluated the safety and efficacy of oral NUBEQA in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) who were receiving a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. In the clinical study, 1,509 patients were randomized in a 2:1 ratio to receive 600 mg of NUBEQA orally twice daily in combination with androgen deprivation therapy (ADT) or ADT alone. The primary efficacy endpoint was metastasis-free survival (MFS). NUBEQA is also being investigated in further studies across various stages of prostate cancer, including in the ARANOTE Phase III trial evaluating NUBEQA plus ADT versus ADT alone for metastatic hormone-sensitive prostate cancer (mHSPC), as well as in the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) led international Phase III co-operative group DASL-HiCaP (ANZUP1801) trial evaluating NUBEQA as an adjuvant treatment for localized prostate cancer with very high risk of recurrence. Information about these trials can be found at www.clinicaltrials.gov.

Developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company, NUBEQA is indicated for the treatment of men with nmCRPC.¹ The approvals of NUBEQA for nmCRPC in the U.S., European Union (EU), and other global markets have been based on the pivotal Phase III ARAMIS trial data evaluating the efficacy and safety of NUBEQA plus ADT compared to ADT alone.¹ Filings in other regions are underway or planned.

INDICATION FOR NUBEQA^® (darolutamide)

NUBEQA^® (darolutamide) is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer.

IMPORTANT SAFETY INFORMATION FOR NUBEQA^® (darolutamide)

Embryo-Fetal Toxicity: Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose.

Adverse Reactions

Serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA were urinary retention, pneumonia, and hematuria. Overall, 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo died from adverse reactions, which included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%) for NUBEQA.

Adverse reactions occurring more frequently in the NUBEQA arm (≥2% over placebo) were fatigue (16% vs 11%), pain in extremity (6% vs 3%) and rash (3% vs 1%).

Clinically significant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease (4.0% vs 3.4% on placebo) and heart failure (2.1% vs 0.9% on placebo).

Drug Interactions

Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use.

Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed.

Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate.

NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates.

Review the prescribing information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA.

For important risk and use information about NUBEQA, please see the accompanying full Prescribing Information.

About Xofigo^® (radium Ra 223 dichloride) Injection²

Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

Important Safety Information for Xofigo^® (radium Ra 223 dichloride) Injection

Warnings and Precautions:

• Bone Marrow Suppression: In the phase 3 ALSYMPCA trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression–notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia–has been reported in patients treated with Xofigo.

  Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure
  

• Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 10⁹/L, the platelet count ≥100 × 10⁹/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 10⁹/L and the platelet count ≥50 × 10⁹/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care

• Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

• Increased Fractures and Mortality in Combination With Abiraterone Plus Prednisone/Prednisolone: Xofigo is not recommended for use in combination with abiraterone acetate plus prednisone/prednisolone outside of clinical trials. At the primary analysis of the Phase 3 ERA-223 study that evaluated concurrent initiation of Xofigo in combination with abiraterone acetate plus prednisone/prednisolone in 806 asymptomatic or mildly symptomatic mCRPC patients, an increased incidence of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received Xofigo in combination with abiraterone acetate plus prednisone/prednisolone compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone. Safety and efficacy with the combination of Xofigo and agents other than gonadotropin-releasing hormone analogues have not been established

• Embryo-Fetal Toxicity: The safety and efficacy of Xofigo have not been established in females. Xofigo can cause fetal harm when administered to a pregnant female. Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise male patients to use condoms and their female partners of reproductive potential to use effective contraception during and for 6 months after completing treatment with Xofigo

Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations

Fluid Status: Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia

Injection Site Reactions: Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo

Secondary Malignant Neoplasms: Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients on the trial

Subsequent Treatment With Cytotoxic Chemotherapy: In the randomized clinical trial, 16% of patients in the Xofigo group and 18% of patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy

Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)

Please see the full Prescribing Information for Xofigo (radium Ra 223 dichloride).

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 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 Stivarga^® (regorafenib)⁵

In April 2017, Stivarga was approved for use in patients with hepatocellular carcinoma who have been previously treated with Nexavar^® (sorafenib). In the United States, Stivarga is also indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. It is also indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate and for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Regorafenib is a compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx, now an Amgen subsidiary, under which Onyx receives a royalty on all global net sales of regorafenib in oncology.

Indication

Stivarga is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild- type, an anti-EGFR therapy.

Stivarga is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.

Stivarga is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Important Safety Information for STIVARGA^® (regorafenib)

Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients across all clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury. In metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and in 0.4% of patients in the placebo arm. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the STIVARGA arm. In hepatocellular carcinoma (HCC), there was no increase in the incidence of fatal hepatic failure as compared to placebo.

Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.

Infections: STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo-controlled trials. The incidence of grade 3 or greater infections in STIVARGA treated patients was 9%. The most common infections were urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with STIVARGA (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% vs 0.2%). Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection.

Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA vs 9.5% with placebo in randomized, placebo-controlled trials. The incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA was 3.0%. The incidence of fatal hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin.

Gastrointestinal Perforation or Fistula: Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of STIVARGA administered as a single agent; this included eight fatal events. Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and in 0.2% of patients in the placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula.

Dermatological Toxicity: In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients with STIVARGA arm and 25.5% of patients in the placebo arm including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia syndrome (PPES) and severe rash, requiring dose modification. In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated patients (53% vs 8%) than in the placebo-treated patients. Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% vs <1%), Grade 3 rash (3% vs <1%), serious adverse reactions of erythema multiforme (<0.1% vs 0%), and Stevens-Johnson syndrome (<0.1% vs 0%) were higher in STIVARGA-treated patients. Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3:18%). Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of STIVARGA administered as a single agent. Withhold STIVARGA, reduce the dose, or permanently discontinue depending on the severity and persistence of dermatologic toxicity.

Hypertension: Hypertensive crisis occurred in 0.2% in STIVARGA-treated patients and in none of the patients in placebo arm across all randomized, placebo-controlled trials. STIVARGA caused an increased incidence of hypertension (30% vs 8% in mCRC, 59% vs 27% in GIST, and 31% vs 6% in HCC). The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in randomized, placebo-controlled trials). Do not initiate STIVARGA until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension.

Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% with STIVARGA vs 0.2% with placebo) in randomized placebo-controlled trials. Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortial vasogenic edema diagnosed by characteristic finding on MRI occurred in one of 4800 STIVARGA-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion, or altered mental function. Discontinue STIVARGA in patients who develop RPLS.

Wound Healing Complications: Impaired wound healing complications can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, STIVARGA has the potential to adversely affect wound healing. Withhold STIVARGA for at least 2 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of STIVARGA after resolution of wound healing complications has not been established.

Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose.

Nursing Mothers: Because of the potential for serious adverse reactions in breastfed infants from STIVARGA, do not breastfeed during treatment with STIVARGA and for 2 weeks after the final dose.

Most Frequently Observed Adverse Drug Reactions in mCRC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), pain (59% vs 48%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).

Most Frequently Observed Adverse Drug Reactions in GIST (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo treated patients in GIST, respectively, were: HFSR/PPE (67% vs 12%), pain (60% vs 55%), hypertension (59% vs 27%), asthenia/fatigue (52% vs 39%), diarrhea (47% vs 9%), mucositis (40% vs 8%), dysphonia (39% vs 9%), infection (32% vs 5%), decreased appetite and food intake (31% vs 21%), and rash (30% vs 3%).

Most Frequently Observed Adverse Drug Reactions in HCC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in HCC, respectively, were: pain (55% vs 44%), HFSR/PPE (51% vs 7%), asthenia/fatigue (42% vs 33%), diarrhea (41% vs 15%), hypertension (31% vs 6%), infection (31% vs 18%), decreased appetite and food intake (31% vs 15%).

Please see full Prescribing Information, including Boxed Warning for Stivarga (regorafenib).

About NEXAVAR^® (sorafenib) Tablets⁶

NEXAVAR is approved in the U.S. for the treatment of patients with unresectable hepatocellular carcinoma, patients with advanced renal cell carcinoma and patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment.⁶

Indication

NEXAVAR^® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

NEXAVAR is indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment.

Important Safety Information for NEXAVAR^® (sorafenib)

Contraindications: NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR.

NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer.

Cardiovascular Events: In the SHARP (HCC) study, the incidence of cardiac ischemia/infarction was 2.7% in NEXAVAR-treated patients compared with 1.3% for placebo-treated group. In the TARGET (RCC) study, the incidence of cardiac ischemia/infarction was higher in the NEXAVAR-treated group (2.9%) compared with the placebo-treated group (0.4%). In the DECISION (DTC) study, the incidence of cardiac ischemia/infarction was 1.9% in the NEXAVAR-treated group compared with 0% in the placebo-treated group. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. Consider temporary or permanent discontinuation of NEXAVAR in patients who develop cardiovascular events.

Hemorrhage: An increased risk of bleeding may occur following NEXAVAR administration. In the SHARP (HCC) study, the rates of bleeding from esophageal varices (2.4% and 4%) and of bleeding with a fatal outcome from any site (2.4% and 4%) were similar in NEXAVAR-treated patients and those receiving placebo, respectively. In the TARGET (RCC) study, bleeding was reported in 15.3% of patients in the NEXAVAR-treated group and 8.2% of patients receiving placebo. The incidence of Grade 3 and 4 bleeding was 2% and 0%, respectively, in NEXAVAR-treated patients, and 1.3% and 0.2%, respectively, in those receiving placebo. There was one fatal hemorrhage in each treatment group in the TARGET (RCC) study. In the DECISION (DTC) study, bleeding was reported in 17.4% of NEXAVAR-treated patients and 9.6% of those receiving placebo; however, the incidence of Grade 3 bleeding was similar (1% and 1.4%) in NEXAVAR-treated patients and in those receiving placebo. If any bleeding necessitates medical intervention, consider permanent discontinuation of NEXAVAR.

Hypertension: In the SHARP (HCC) study, hypertension was reported in 9.4% of NEXAVAR-treated patients and 4.3% of patients in the placebo-treated group. In the TARGET (RCC) study, hypertension was reported in 16.9% of NEXAVAR-treated patients and 1.8% of patients in the placebo-treated group. In the DECISION (DTC) study, hypertension was reported in 40.6% of NEXAVAR-treated patients and 12.4% of placebo-treated patients. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. Monitor blood pressure weekly during the first 6 weeks of NEXAVAR. Thereafter, monitor blood pressure and treat hypertension, if required, in accordance with standard medical practice. In cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of NEXAVAR.

Dermatologic Toxicities: Hand-foot skin reaction and rash are the most common adverse reactions attributed to NEXAVAR. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of NEXAVAR, or in severe or persistent cases, permanent discontinuation of NEXAVAR. There have been reports of severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These cases may be life-threatening. Discontinue NEXAVAR if SJS or TEN are suspected

Gastrointestinal Perforation: Gastrointestinal perforation has been reported in less than 1% of patients taking NEXAVAR. In the event of a gastrointestinal perforation, permanently discontinue NEXAVAR.

Increased Risk of Bleeding with Concomitant Use of Warfarin: Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on NEXAVAR. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR, or clinical bleeding episodes.

Risk of Impaired Wound Healing: Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, NEXAVAR has the potential to adversely affect wound healing. Withhold NEXAVAR for at least 10 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of NEXAVAR after resolution of wound healing complications has not been established.

Increased Mortality, Concomitant Administration with Carboplatin/Paclitaxel & Gemcitabine/Cisplatin in Squamous Cell Lung Cancer: In a subset analysis of two randomized controlled trials in chemo-naïve patients with Stage IIIB-IV non-small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of NEXAVAR compared to those treated with carboplatin/paclitaxel alone (HR 1.81, 95% CI 1.19 – 2.74) and gemcitabine/cisplatin alone (HR 1.22, 95% CI 0.82-1.80). NEXAVAR, in combination with gemcitabine/cisplatin, is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of NEXAVAR has not been established in patients with non-small cell lung cancer.

QT Interval Prolongation: NEXAVAR can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias. Avoid use in patients with congenital long QT syndrome. Monitor electrolytes and electrocardiograms in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Correct electrolyte abnormalities (magnesium, potassium, calcium). Interrupt NEXAVAR if QTc interval is greater than 500 milliseconds or for an increase from baseline of 60 milliseconds or greater.

Drug-Induced Liver Injury: Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and INR may also occur. Liver function tests should be monitored regularly and in cases of increased transaminases without alternative explanation NEXAVAR should be discontinued.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, NEXAVAR may cause fetal harm when administered to a pregnant woman. Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiation of NEXAVAR. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of NEXAVAR. Advise male patients with female partners of reproductive potential and pregnant partners to use effective contraception during treatment and for 3 months following the last dose of NEXAVAR.

Impairment of Thyroid Stimulating Hormone Suppression in Differentiated Thyroid Carcinoma: NEXAVAR impairs exogenous thyroid suppression. In the DECISION (DTC) study, 99% of patients had a baseline thyroid stimulating hormone (TSH) level less than 0.5 mU/L. Elevation of TSH level above 0.5 mU/L was observed in 41% of NEXAVAR-treated patients as compared with 16% of placebo-treated patients. For patients with impaired TSH suppression while receiving NEXAVAR, the median maximal TSH was 1.6 mU/L and 25% had TSH levels greater than 4.4mU/L. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC.

Laboratory Abnormalities: In the HCC study, the most common laboratory abnormalities observed in the NEXAVAR arm versus the placebo arm, respectively, were hypoalbuminemia (59% vs. 47%), lymphopenia (47% vs. 42%), thrombocytopenia (46% vs. 41%), elevation in INR (42% vs. 34%), elevated lipase (40% vs. 37%), hypophosphatemia (35% vs. 11%), elevated amylase (34% vs. 29%), hypocalcemia (27% vs. 15%), and hypokalemia (10% vs. 6%).

In the RCC study, the most common laboratory abnormalities observed in the NEXAVAR arm versus the placebo arm, respectively, were hypophosphatemia (45% vs. 11%), anemia (44% vs. 49%), elevated lipase (41% vs. 30%), elevated amylase (30% vs. 23%), lymphopenia (23% vs. 13%), neutropenia (18% vs. 10%), thrombocytopenia (12% vs. 5%), hypocalcemia (12% vs. 8%), and hypokalemia (5% vs. <1%).

In the DTC study, the most common laboratory abnormalities observed in the NEXAVAR arm versus the placebo arm, respectively, were elevated ALT (59% vs. 24%), elevated AST (54% vs. 15%), and hypocalcemia (36% vs. 11%).The relative increase for the following laboratory abnormalities observed in NEXAVAR-treated DTC patients as compared to placebo-treated patients is similar to that observed in the RCC and HCC studies: lipase, amylase, hypokalemia, hypophosphatemia, neutropenia, lymphopenia, anemia, and thrombocytopenia.

Most Frequently Observed Adverse Drug Reactions (≥20%): The most common adverse reactions reported in ≥20% of patients and at a higher rate in the NEXAVAR arm versus the placebo arm, respectively, in the SHARP (HCC) study included: diarrhea (55% vs. 25%), fatigue (46% vs. 45%), abdominal pain (31% vs. 26%), weight loss (30% vs. 10%), anorexia (29% vs. 18%), nausea (24% vs. 20%), and hand-foot skin reaction (21% vs. 3%). Grade 3/4 adverse reactions were 45% vs. 32%.

The most common adverse reactions reported in ≥20% of patients and at a higher rate in the NEXAVAR arm versus the placebo arm, respectively, in the TARGET (RCC) study included: diarrhea (43% vs. 14%), rash/desquamation (40% vs. 16%), fatigue (37% vs. 28%), hand-foot skin reaction (30% vs. 7%), alopecia (27% vs. 3%), and nausea (23% vs. 19%), anorexia (29% vs. 18%), nausea (23% vs. 19%). Grade 3/4 adverse reactions were 38% vs. 28%.

The most common adverse reactions reported in ≥20% of patients and at a higher rate in the NEXAVAR arm versus the placebo arm, respectively, in the DECISION (DTC) study included: palmar-plantar erythrodysesthesia syndrome (PPES) (69% vs. 8%), diarrhea (68% vs. 15%), alopecia (67% vs. 8%), weight loss (49% vs. 14%), fatigue (41% vs. 20%), hypertension (41% vs. 12%), rash (35% vs. 7%), decreased appetite (30% vs. 5%), stomatitis (24% vs. 3%), nausea (21% vs. 12%), pruritus (20% vs. 11%), and abdominal pain (20% vs. 7%). Grade 3/4 adverse reactions were 65% vs 30%.

Drug Interactions: Avoid concomitant use of NEXAVAR with strong CYP3A4 inducers, when possible, because these drugs can decrease the systemic exposure to sorafenib. Avoid concomitant use of NEXAVAR with neomycin. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied. The concomitant use of NEXAVAR and warfarin may increase the risk of bleeding or increased the INR. Monitor INR and for clinical bleeding episodes in patients taking warfarin while receiving NEXAVAR. NEXAVAR is associated with QTc interval prolongation. Avoid coadministration of NEXAVAR with medicinal products with a known potential to prolong QT/QTc interval.

Lactation: Because of the potential for serious adverse reactions in a breastfed child from NEXAVAR, advise lactating women not to breastfeed during treatment with NEXAVAR and for 2 weeks after the last dose.

Please see the full Prescribing Information for NEXAVAR^® (sorafenib).

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 2021, the Group employed around 100,000 people and had sales of 44.1 billion euros. R&D expenses before special items amounted to 5.3 billion euros. For more information, go to www.bayer.com

^© 2022 Bayer

BAYER, the Bayer Cross, NUBEQA, Xofigo, Vitrakvi, Stivarga and Nexavar 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. NUBEQA^® (darolutamide) tablets [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, January 2021.
2. XOFIGO^® (radium-223 dichloride) Injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, December 2019.
3. Forsythe A, Zhang W, Phillip Strauss U, Fellous M, Korei M, Keating K. A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors. Ther Adv Med Oncol. 2020;12:1758835920975613. Published 2020 Dec 21. doi:10.1177/1758835920975613
4. Vitrakvi^® [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; March 2021.
5. Stivarga^® (regorafenib) tablets [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, December 2020.
6. NEXAVAR^® (sorafenib) [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, July 2020.

PP-PF-ONC-US-2463-1 05/22

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