Bayer Highlights Latest Oncology Research at ASCO 2018

WHIPPANY, N.J., May 17, 2018 /PRNewswire/ -- Bayer announced today that the latest research across its growing oncology portfolio will be presented at the 54^th Annual Meeting of the American Society of Clinical Oncology (ASCO), taking place June 1-5 in Chicago. Highlights include data on approved therapies as well as new research from Bayer's early and late-stage pipeline compounds. In line with the theme of this year's meeting, "Delivering Discoveries: Expanding the Reach of Precision Medicine," the company's research includes larotrectinib, an investigational compound jointly developed by Bayer and Loxo Oncology. The New Drug Application in the U.S. was recently submitted to the U.S. Food and Drug Administration.

Results from a randomized Phase II study investigating three dosing regimens of radium Ra 223 dichloride in bone metastatic castration-resistant prostate cancer (mCRPC) and a Phase III trial of sorafenib in desmoid tumors, sponsored by the National Cancer Institute, will be highlighted in oral presentations at the meeting. Poster presentations of note include the final analysis from the global OPTIMIS study of outcomes in patients with hepatocellular carcinoma treated with transarterial chemoembolization (TACE), safety and tolerability data of radium Ra 223 dichloride in combination with enzalutamide in patients with mCRPC and a subgroup analyses of diabetic patients from the Phase II CHRONOS-1 study of copanlisib in patients with relapsed or refractory indolent B-cell lymphoma.

Notable studies from Bayer's portfolio and pipeline therapies being featured at ASCO 2018 include the following:

Radium Ra 223 Dichloride (radium-223)

• A randomized phase 2 study investigating 3 dosing regimens of radium-223 dichloride (Ra-223) in bone metastatic castration-resistant prostate cancer (mCRPC)
• Abstract 5008, Oral Abstract Session: Genitourinary (Prostate) Cancer
• Date: Monday, June 4, Time: 5:24 PM – 5:36 PM
• Location: Hall D1
• Radium-223 re-treatment in an international, open-label, phase 1/2 study in patients with castration-resistant prostate cancer and bone metastases: 2-year follow-up
• Abstract 5022, Poster Session: Genitourinary (Prostate) Cancer
• Date: Saturday, June 2, Time: 1:15 PM – 4:45 PM
• Location: Hall A
• Phase II study of Ra-223 combined with hormonal therapy and denosumab for treatment of hormone receptor-positive breast cancer with bone-dominant metastasis [investigator-initiated research; IIR]
• Abstract 1065, Poster Session: Breast Cancer - Metastatic
• Date: Saturday, June 2, Time: 8:00 AM – 11:30 AM
• Location: Hall A
• Radium-223: Disease response and fracture assessment by whole body diffusion-weighted MRI (WB-DWMRI) in metastatic castration resistant prostate cancer (mCRPC) [IIR]
• Abstract 5024, Poster Session: Genitourinary (Prostate) Cancer
• Date: Saturday, June 2, Time: 1:15 PM – 4:45 PM
• Location: Hall A
• Safety data from a phase II randomized trial of radium-223 dichloride (Ra-223) plus enzalutamide (Enza) vs. Enza alone in men with metastatic castration refractory prostate cancer (mCRPC) [IIR]
• Abstract 5057, Poster Session: Genitourinary (Prostate) Cancer
• Date: Saturday, June 2, Time: 1:15 PM – 4:45 PM
• Location: Hall A
• Phase II safety and tolerability study of Radium-223 (R223) in combination with enzalutamide (ENZA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): CTRIAL-IE (ICORG)13-21 [IIR]
• Abstract 5050, Poster Session: Genitourinary (Prostate) Cancer
• Date: Saturday, June 2, Time: 1:15 PM – 4:45 PM
• Location: Hall A
• Genomic and phenotypic evidence for prostate cancer osteomimicry in circulating tumor cells from men with metastatic castration resistant prostate cancer (mCRPC) treated with radium-223 [IIR]
• Abstract 5029, Poster Session: Genitourinary (Prostate) Cancer
• Date: Saturday, June 2, Time: 1:15 PM – 4:45 PM
• Location: Hall A

Sorafenib

• Phase III, randomized, double blind, placebo-controlled trial of sorafenib in desmoid tumors (Alliance A091105) [IIR]
• Abstract 11500, Oral Abstract Session: Sarcoma
• Date: Monday, June 4, Time: 8:00 AM – 8:12 AM
• Location: S100a
• A randomized, open label, multicenter phase 2 study, to evaluate the efficacy of sorafenib (So) in patients (pts) with metastatic renal cell carcinoma (mRCC) after a radical resection of the metastases: RESORT trial [IIR]
• Abstract 4502, Oral Abstract Session: Genitourinary (Nonprostate) Cancer
• Date: Sunday, June 3, Time: 8:12 AM – 8:24 AM
• Location: Arie Crown Theater
• Outcomes of patients (pts) with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE): Global OPTIMIS final analysis
• Abstract 4018, Poster Discussion Session: Gastrointestinal (Noncolorectal) Cancer
• Date: Sunday, June 3, Time: 4:45 PM – 6:00 PM
• Location: Hall D2
• Second interim analysis of RIFTOS MKI, a global non-interventional study assessing the use of multikinase inhibitors (MKIs) in the treatment of patients with asymptomatic radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC)
• Abstract 6081, Poster Session: Head and Neck Cancer
• Date: Saturday, June 2, Time: 1:15 PM – 4:45 PM
• Location: Hall A
• Phase II trial of sorafenib plus doxorubicin (SD) in patients (Pts) with advanced hepatocellular carcinoma (HCC) after progression of disease (PD) on sorafenib (S) [IIR]
• Abstract 4080, Poster Session: Gastrointestinal (Noncolorectal) Cancer
• Date: Sunday, June 3, Time: 8:00 AM – 11:30 AM
• Location: Hall A

Regorafenib

• Multi institutional phase II trial of single agent regorafenib in refractory advanced biliary cancers [IIR]
• Abstract 4082, Poster Session: Gastrointestinal (Noncolorectal) Cancer
• Date: Sunday, June 3, Time: 8:00 AM – 11:30 AM
• Location: Hall A
• REVERCE: Randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin, and irinotecan – Biomarker analysis [IIR]
• Abstract 3510, Poster Discussion Session: Gastrointestinal (Colorectal) Cancer
• Date: Sunday, June 3, Time: 11:30 AM – 12:45 PM
• Location: Hall D2
• High levels of cell-free DNA (cfDNA) at baseline (BL) and increase of at least one mutation at day 14 (D14) as independent prognostic biomarkers for patients (pts) with advanced colorectal cancer (aCRC) under regorafenib [IIR]
• Abstract 3532, Poster Session: Gastrointestinal (Colorectal) Cancer
• Date: Sunday, June 3, Time: 8:00 AM – 11:30 AM
• Location: Hall A
• Phase II trial of continuous dosing of regorafenib in patients with metastatic or recurrent gastrointestinal stromal tumors (GISTs) after failure of imatinib and sunitinib [IIR]
• Abstract 11537, Poster Session: Sarcoma
• Date: Saturday, June 2, Time: 8:00 AM – 11:30 AM
• Location: Hall A
• Results of randomized, placebo (PL)-controlled phase II study evaluating efficacy and safety of regorafenib (REG) in patients (pts) with metastatic osteosarcoma (metOS), on behalf of the French Sarcoma Group (FSG) and Unicancer [IIR]
• Abstract 11504, Oral Abstract Session: Sarcoma
• Date: Monday, June 4, Time: 9:12 AM – 9:24 AM
• Location: S100a
• A randomized, double-blind, placebo-controlled, phase II study of regorafenib vs placebo in advanced/metastatic, treatment-refractory liposarcoma: results from the SARC024 study [IIR]
• Abstract 11505, Oral Abstract Session: Sarcoma
• Date: Monday, June 4, Time: 9:24 AM - 9:36 AM
• Location: S100a
• Updated results of REGOMA: A randomized, multicenter, controlled open-label phase II clinical trial evaluating regorafenib in relapsed glioblastoma (GBM) patients (PTS) [IIR]
• Abstract 2047, Poster Session: Central Nervous System Tumors
• Date: Saturday, June 2, Time: 1:15 PM – 4:45 PM
• Location: Hall A
• A phase II study of regorafenib in patients with thymic epithelial tumours previously treated with chemotherapy [IIR]
• Abstract 8579, Poster Session: Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers
• Date: Sunday, June 3, Time: 8:00 AM – 11:30 AM
• Location: Hall A

Copanlisib

• Copanlisib treatment in patients with relapsed or refractory indolent B-cell lymphoma: Subgroup analyses of diabetic patients from the phase II CHRONOS-1 study
• Abstract 7570, Poster Session: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia
• Date: Monday, June 4, Time: 8:00 AM – 11:30 AM
• Location: Hall A
• A phase Ib trial of copanlisib and trastuzumab in pretreated recurrent or metastatic HER2-positive breast cancer "PantHER" [IIR]
• Abstract 1036, Poster Session: Breast Cancer - Metastatic
• Date: Saturday, June 2, Time: 8:00 AM – 11:30 AM
• Location: Hall A

Darolutamide

• ODENZA: A study of patient preference between ODM-201(darolutamide) and enzalutamide in men with metastatic castrate-resistant prostate cancer (mCRPC) [TIP] [IIR]
• Abstract TPS5093, Poster Session: Genitourinary (Prostate) Cancer
• Date: Saturday, June 2, Time: 1:15 PM – 4:45 PM
• Location: Hall A

Other Pipeline Abstracts

• Rogaratinib in patients with advanced urothelial carcinomas prescreened for tumor FGFR mRNA expression and effects of mutations in the FGFR signaling pathway
• Abstract 4513, Poster Discussion Session: Genitourinary (Nonprostate) Cancer
• Date: Saturday, June 2, Time: 1:15 PM – 2:30 PM
• Location: Hall D2
• Phase Ib study of anti-mesothelin antibody drug conjugate anetumab ravtansine in combination with pegylated liposomal doxorubicin in platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer
• Abstract 5571, Poster Session: Gynecologic Cancer
• Date: Monday, June 4, Time: 1:15 PM – 4:45 PM
• Location: Hall A
• Phase 1b multi-indication study of the antibody drug conjugate anetumab ravtansine in patients with mesothelin-expressing advanced or recurrent malignancies [TIP]
• Abstract TPS2607, Poster Session: Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
• Date: Monday, June 4, Time: 8:00 AM – 11:30 AM
• Location: Hall A
• Phase I dose escalation study of the first-in-class selective PTEFb inhibitor BAY 1251152 in patients with advanced cancer: Novel target validation and early evidence of clinical activity
• Abstract 2507, Oral Abstract Session: Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
• Date: Friday, June 1, Time: 4:57 PM – 5:09 PM
• Location: S406

About Xofigo^® (radium Ra 223 dichloride) Injection¹
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

• Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman.

• Bone Marrow Suppression: In the randomized 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 leucopenia – 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 greater than or equal to 1.5 × 10⁹/L, the platelet count greater than or equal to 100 × 10⁹/L, and hemoglobin greater than or equal to 10 g/dL. Prior to subsequent administrations, the ANC should be greater than or equal to 1 × 10⁹/L and the platelet count greater than or equal to 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.
• 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% patients in the Xofigo group and 18% 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 full Prescribing Information for Xofigo (radium Ra 223 dichloride).

About NEXAVAR^® (sorafenib) Tablets²
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.

Important Safety Information for Nexavar

• 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
• Cardiac ischemia and/or myocardial infarction may occur. The incidence of cardiac ischemia/infarction in NEXAVAR-treated vs placebo-treated patients was 2.7% vs 1.3%, 2.9% vs 0.4%, and 1.9% vs 0% in the HCC, RCC, and DTC studies, respectively. Temporary or permanent discontinuation of NEXAVAR should be considered in patients who develop cardiac ischemia and/or myocardial infarction
• An increased risk of bleeding may occur following NEXAVAR administration. The following bleeding adverse reactions were reported in the NEXAVAR-treated vs placebo-treated patients, respectively, in the HCC study: bleeding from esophageal varices (2.4% vs 4%) and bleeding with fatal outcome at any site (2.4% vs 4%); in the RCC study: bleeding regardless of causality (15.3% vs 8.2%), Grade 3 bleeding (2.0% vs 1.3%), Grade 4 bleeding (0% vs 0.2%), and one fatal hemorrhage in each treatment group; in the DTC study: bleeding (17.4% vs 9.6%) and Grade 3 bleeding (1% vs 1.4%). There was no Grade 4 bleeding reported and there was one fatal hemorrhage in a placebo-treated patient. If bleeding necessitates medical intervention, consider permanent discontinuation of NEXAVAR. Due to the potential risk of bleeding, tracheal, bronchial, and esophageal infiltration should be treated with local therapy prior to administering NEXAVAR in patients with DTC
• Monitor blood pressure weekly during the first 6 weeks and periodically thereafter, and treat, if required. In the HCC study, hypertension was reported in approximately 9.4% of NEXAVAR-treated patients and 4.3% of patients in the placebo-treated group. In the RCC study, hypertension was reported in approximately 16.9% of NEXAVAR-treated patients and 1.8% of patients in the placebo-treated group. In the DTC study, hypertension was reported in 40.6% of NEXAVAR-treated patients and 12.4% of the placebo-treated patients. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. In cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of NEXAVAR
• Hand-foot skin reaction and rash are the most common adverse reactions attributed to NEXAVAR. Management may include topical therapies for symptomatic relief. In cases of any severe or persistent adverse reactions, temporary treatment interruption, dose modification, or permanent discontinuation of NEXAVAR should be considered. 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 was an uncommon adverse reaction and has been reported in less than 1% of patients taking NEXAVAR. Discontinue NEXAVAR in the event of a gastrointestinal perforation
• 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
• Temporary interruption of NEXAVAR therapy is recommended in patients undergoing major surgical procedures
• 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
• NEXAVAR can prolong the QT/QTc interval and increase the risk for ventricular arrhythmias. Avoid use in patients with congenital long QT syndrome and monitor electrolytes and electrocardiograms in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. 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
• 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
• NEXAVAR may cause fetal harm when administered to a pregnant woman. Women of child-bearing potential should be advised to avoid becoming pregnant while on NEXAVAR
• Female patients should be advised against breastfeeding while receiving NEXAVAR
• In DTC, NEXAVAR impairs exogenous thyroid suppression. Elevation of thyroid stimulating hormone (TSH) level above 0.5 mU/L was observed in 41% of NEXAVAR-treated patients as compared with 16% of placebo-treated patients in the DTC study. 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 4.4 mU/L. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC
• 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 (9.5% vs. 5.9%)
• 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 (5.4% vs. 0.7%)
• 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
• Avoid concomitant use of strong CYP3A4 inducers, when possible, because inducers can decrease the systemic exposure of sorafenib. NEXAVAR exposure decreases when co-administered with oral neomycin. Effects of other antibiotics on NEXAVAR pharmacokinetics have not been studied
• Most common adverse reactions reported for NEXAVAR-treated patients vs placebo-treated patients in unresectable HCC, respectively, were: 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%
• Most common adverse reactions reported for NEXAVAR-treated patients vs placebo-treated patients in advanced RCC, respectively, were: diarrhea (43% vs. 13%), 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%). Grade 3/4 adverse reactions were 38% vs. 28%
• Most common adverse reactions reported for NEXAVAR-treated patients vs placebo-treated patients in DTC, respectively, were: 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%

Please see full Prescribing Information for Nexavar (sorafenib).

About Stivarga^® (regorafenib)³
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.

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.

Important Safety Information for Stivarga

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: Treatment with STIVARGA should be stopped at least 2 weeks prior to scheduled surgery. Resuming treatment after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence.

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 Aliqopa™ (copanlisib) Injection⁴
Aliqopa is a PI3K inhibitor with predominant activity against the PI3K-alpha and PI3K-delta isoforms expressed in malignant B-cells, developed by Bayer. Aliqopa is indicated in the U.S. for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Aliqopa has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Aliqopa inhibits several key cell-signaling pathways, including B-cell receptor signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.

The broad clinical development program for copanlisib also includes ongoing Phase III studies in indolent NHL (iNHL) patients who have relapsed or are refractory to prior therapies. The CHRONOS-3 Phase III study is evaluating copanlisib in combination with rituximab in relapsed iNHL and the CHRONOS-4 Phase III study is evaluating copanlisib in combination with standard immunochemotherapy in relapsed iNHL. More information about these trials can be found at www.clinicaltrials.gov.

Important Safety Information for Aliqopa

Infections: Serious, including fatal, infections occurred in 19% of 317 patients treated with ALIQOPA monotherapy. The most common serious infection was pneumonia. Monitor patients for signs and symptoms of infection and withhold ALIQOPA for Grade 3 and higher infection.

Serious pneumocystis jiroveci pneumonia (PJP) infection occurred in 0.6% of 317 patients treated with ALIQOPA monotherapy. Before initiating treatment with ALIQOPA, consider PJP prophylaxis for populations at risk.  Withhold ALIQOPA in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis.

Hyperglycemia: Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with ALIQOPA monotherapy. Serious hyperglycemic events occurred in 2.8% of patients. Treatment with ALIQOPA may result in infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours post-infusion and subsequently declined to baseline levels for a majority of patients; blood glucose levels remained elevated in 17.7% of patients one day after ALIQOPA infusion. Of 155 patients with baseline HbA1c <5.7%, 16 (10%) patients had HbA1c >6.5% at the end of treatment.

Of the twenty patients with diabetes mellitus treated in CHRONOS-1, seven developed Grade 4 hyperglycemia and two discontinued treatment. Patients with diabetes mellitus should only be treated with ALIQOPA following adequate glucose control and should be monitored closely. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hyperglycemia.

Achieve optimal blood glucose control before starting each ALIQOPA infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hyperglycemia.

Hypertension: Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with ALIQOPA monotherapy. Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with ALIQOPA may result in infusion-related hypertension. The mean change of systolic and diastolic BP from baseline to 2 hours post-infusion on Cycle 1 Day 1 was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately 2 hours post-infusion; BP remained elevated for 6 to 8 hours after the start of the ALIQOPA infusion. Optimal BP control should be achieved before starting each ALIQOPA infusion. Monitor BP pre- and post-infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hypertension.

Non-infectious Pneumonitis: Non-infectious pneumonitis occurred in 5% of 317 patients treated with ALIQOPA monotherapy. Withhold ALIQOPA and conduct a diagnostic examination of a patient who is experiencing pulmonary symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. Patients with pneumonitis thought to be caused by ALIQOPA have been managed by withholding ALIQOPA and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of non-infectious pneumonitis.

Neutropenia: Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with ALIQOPA monotherapy. Serious neutropenic events occurred in 1.3%. Monitor blood counts at least weekly during treatment with ALIQOPA. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of neutropenia.

Severe Cutaneous Reaction: Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with ALIQOPA monotherapy respectively. Serious cutaneous reaction events were reported in 0.9%. The reported events included dermatitis exfoliative, exfoliative rash, pruritus, and rash (including maculo-papular rash). Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of severe cutaneous reactions.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ALIQOPA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis caused embryo-fetal death and fetal abnormalities in rats at maternal doses as low as 0.75 mg/kg/day (4.5 mg/m2/day body surface area) corresponding to approximately 12% the recommended dose for patients. 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 and for at least one month after the last dose.

Adverse Drug Reactions: Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most frequently observed adverse drug reactions (≥20%) in ALIQOPA-treated patients were: hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%).

Drug Interactions: Avoid concomitant use with strong CYP3A inducers. Reduce the ALIQOPA dose to 45 mg when concomitantly administered with strong CYP3A inhibitors.

Lactation: Advise women not to breastfeed. Advise a lactating woman not to breastfeed during treatment with ALIQOPA and for at least 1 month after the last dose.

Please see the full Prescribing Information of Aliqopa (copanlisib).

About Darolutamide
Darolutamide is currently in Phase III clinical trials for the treatment of patients with castration-resistant prostate cancer (CRPC). It is not approved by the U.S. Food and Drug Administration, the European Medicines Agency or any other health authority.

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 now includes four oncology products and several other compounds 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 agriculture. Its products and services are designed to benefit people and improve their quality of life. At the same time, the Group aims to create value through innovation, growth and high earning power. Bayer is committed to the principles of sustainable development and to its social and ethical responsibilities as a corporate citizen. In fiscal 2017, the Group employed around 99,800 people and had sales of EUR 35.0 billion. Capital expenditures amounted to EUR 2.4 billion, R&D expenses to EUR 4.5 billion. For more information, go to www.bayer.us.

© 2018 Bayer
BAYER^®, the Bayer Cross, Xofigo, Stivarga, Nexavar and Aliqopa are registered trademarks of Bayer.

Media Contact:
Rose Talarico, Tel. +1 862.404.5302
E-Mail: [email protected]

Forward-Looking Statement
This news release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup 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. 

1. XOFIGO^® (radium-223 dichloride) Injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, February 2018.
2. NEXAVAR^® (sorafenib) [Prescribing Information]. Whippany, NJ. Bayer HeathCare Pharmacetuicals, December 2017.
3. STIVARGA^® (regorafenib) [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, April 2017.
4. Aliqopa™ (copanlisib) for injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, September 2017.

PP-700-US-0426

Intended for U.S. Media Only

SOURCE Bayer

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