Bayer to Showcase Data from Diverse Oncology Pipeline at AACR 2018

WHIPPANY, N.J., April 5, 2018 /PRNewswire/ -- Bayer will present research from its growing oncology portfolio at the American Association for Cancer Research (AACR) 2018 Annual Meeting, taking place April 14-18 in Chicago. These presentations reflect the company's diverse pipeline and strategic partnerships, with data on investigational agents as well as marketed products in a variety of hematologic and solid tumors. Among these is a late-breaking poster on the anti-tumor immune response of copanlisib in various drug-resistant animal models.

Presentations will highlight key areas of investigation for Bayer, including Oncogenic Signaling, Targeted Thorium Conjugates and Immuno-Oncology. An oral presentation during the "New Drugs on the Horizon" session will feature preclinical data on BAY 2402234, an investigational dihydroorotate dehydrogenase (DHODH) inhibitor derived from our collaboration with the Broad Institute (Cambridge, Massachusetts) that Bayer is developing under exclusive license. BAY 2402234 was recently advanced into Phase I clinical development for acute myeloid leukemia, and other areas are being researched. Another oral presentation covers new research on the MYCN gene resulting from Bayer's collaboration with the German Cancer Research Center ("DKFZ", Heidelberg, Germany). The MYCN gene is over-expressed in several types of cancer, including neuroblastoma and small cell lung cancer.

Additional research to be presented includes preclinical data on:

• The activity of darolutamide, an investigational second-generation androgen receptor antagonist, in androgen receptor–resistant models.
• The activity of rogaratinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor ready to enter Phase II/III clinical development that Bayer is developing for urothelial carcinoma and other FGFR-positive tumors.
• The ataxia telangiectasia rad3-related protein (ATR) inhibitor BAY 1895344, a DNA damage response inhibitor.
• The efficacy of anetumab ravtansine, a mesothelin targeting antibody-drug conjugate, being investigated as monotherapy in different human ovarian cancer models.
• Bayer's emerging Targeted Thorium Conjugate (TTC) platform including the PSMA-TTC targeting the prostate-specific membrane antigen (PSMA) and the mesothelin-targeting MSLN-TTC, both of which are expected to start first-in-human clinical trials later this year.
• Two immunotherapeutics expected to advance to first-in-human studies this year: BAY 1834942, an antibody believed to block the immune checkpoint regulator CEACAM6, which Bayer is developing in collaboration with the DKFZ; and BAY 1905254, an immune checkpoint inhibitory antibody for the immunoglobulin-like domain containing receptor 2 (ILDR2) that was derived from a collaboration with the Israel-based company Compugen.

The total of two oral and 30 poster presentations at AACR underscore Bayer's commitment in oncology to advancing promising projects – many with the potential to be first-in-class. This approach allows the company to explore a variety of agents with different mechanisms of action, develop new delivery platforms and drive toward the goal of offering treatment approaches for patients battling cancer. 

The following list comprises a selection of presentations on Bayer pipeline projects across different areas of research presented at AACR 2018:

Oncogenic Signaling

BAY 2402234: A dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of myeloid malignancies

• Oral presentation DDT02-04, Session: New Drugs on the Horizon 2
• Sunday, April 15, 4:12 PM – 4:36 PM (CDT), Room S103 – McCormick Place South (Level 1)

MYCN mediates cysteine addiction and sensitizes to ferroptosis in cancer cells

• Oral presentation 4973, Session: Metabolism: Emerging Concepts and Therapy
• Tuesday, April 17, 4:05 PM – 4:20 PM (CDT), Room S105 – McCormick Place South (Level 1)

Synergistic activity of the ATR inhibitor BAY 1895344 in combination with DNA damage inducing and DNA repair compromising therapies in preclinical tumor models

• Poster presentation 321, Session: Cancer Predisposition and Synthetic Lethality
• Sunday, April 15, 1:00 PM – 5:00 PM (CDT), Section 15

Synergistic in vivo activity of the ATR inhibitor BAY 1895344 in combination with alpha therapy radium-223 dichloride in a preclinical tumor model mimicking bone metastatic castration-resistant prostate cancer (mCRPC)

• Poster presentation 838, Session: Modulators of Ionizing Radiation and Other Radiotherapeutics
• Sunday, April 15, 1:00 PM – 5:00 PM (CDT), Section 39

Pulsatile inhibition of PI3K converts immune suppression by Tregs and M2-TAM to anti-tumor immune response in animal models insensitive or resistant to the monotherapies of PI3K and checkpoint inhibitors

• LB-123 / 20, Session: Late-Breaking Research: Immunology 1
• Monday, April 16, 8:00 AM – 12:00 PM (CDT), Section 45

Darolutamide demonstrates greater in vivo activity than enzalutamide in prostate cancer model with therapy-resistant androgen receptor mutation

• Poster presentation 1795, Session: Growth Factors and Nuclear Receptor Signaling
• Monday, April 16, 8:00 AM – 12:00 PM (CDT), Section 35

A detailed comparison between second-generation AR antagonists reveals differences in the overall impact on gene regulation patterns in prostate cancer cells

• Poster presentation 1798, Session: Growth Factors and Nuclear Receptor Signaling
• Monday, April 16, 8:00 AM – 12:00 PM (CDT), Section 35

Biological interpretation of circulating miRNA biomarkers predicting regorafenib clinical benefit in patients with hepatocellular carcinoma (HCC) in the RESORCE trial

• Poster presentation 2606, Session: Biomarkers of Therapeutic Response in Clinical Trials
• Monday, April 16, 1:00 PM – 5:00 PM (CDT), Section 26

Rogaratinib, a small molecule pan-FGFR inhibitor inhibits FGFR4-phosphorylation and exerts anti-tumor efficacy in vivo and in vitro

• Poster presentation 4779, Session: Canonical Targets 1
• Tuesday, April 17, 1:00 PM – 5:00 PM (CDT), Section 36

Changes in intracellular signaling following chronic FGFR inhibition in urothelial bladder cancer models

• Poster presentation 4781, Session: Canonical Targets 1
• Tuesday, April 17, 1:00 PM – 5:00 PM (CDT), Section 36

Antibody-Drug Conjugates

Anetumab ravtansine has single-agent activity in mesothelin-expressing human ovarian cancer models and potentiates the activity of chemotherapeutics and targeted agents

• Poster presentation 1780, Session: Therapeutic Antibodies, Including Engineered Antibodies 1
• Monday, April 16, 8:00 AM – 12:00 PM (CDT), Section 34

Targeted Thorium Conjugates (TTCs)

Preclinical activity of PSMA-TTC, a targeted alpha therapeutic in patient-derived prostate cancer models

• Poster presentation 844, Session: Modulators of Ionizing Radiation and Other Radiotherapeutics
• Sunday, April 15, 1:00 PM – 5:00 PM (CDT), Section 39

Synergistic effect of MSLN-TTC in combination with DNA damage response inhibitors

• Poster presentation 849, Session: Modulators of Ionizing Radiation and Other Radiotherapeutics
• Sunday, April 15, 1:00 PM – 5:00 PM (CDT), Section 39

Mesothelin targeted thorium-227 conjugate (MSLN-TTC): Preclinical evaluation of a targeted alpha therapeutic in mesothelin-positive cancers

• Poster presentation 850, Session: Modulators of Ionizing Radiation and Other Radiotherapeutics
• Sunday, April 15, 1:00 PM – 5:00 PM (CDT), Section 39

Increased in vitro potency and in vivo efficacy of FGFR2-targeted thorium-227 conjugate (FGFR2-TTC) in combination with the ATR inhibitor BAY 1895344

• Poster presentation 855, Session: Modulators of Ionizing Radiation and Other Radiotherapeutics
• Sunday, April 15, 1:00 PM – 5:00 PM (CDT), Section 39

Immuno-Oncology

BAY 1834942 is an immunotherapeutic antibody blocking the immune checkpoint regulator CEACAM6 (CD66c)

• Poster presentation 1771, Session: Therapeutic Antibodies, Including Engineered Antibodies 1
• Monday, April 16, 8:00 AM – 12:00 PM (CDT), Section 34

Discovery and preclinical characterization of BAY 1905254 a immune checkpoint inhibitor for cancer immunotherapy on the immunoglobulin-like domain containing receptor 2 (ILDR2)

• Poster presentation 2778, Session: Therapeutic Antibodies, Including Engineered Antibodies 2
• Monday, April 16, 1:00 PM – 5:00 PM (CDT), Section 34

About Aliqopa^™ (copanlisib) Injection

Aliqopa is a PI3K inhibitor with predominant activity against the PI3K-alpha and PI3K-delta isoforms expressed in malignant B-cells, developed by Bayer.¹ 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.¹

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

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 Stivarga^® (regorafenib)
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.¹

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

WARNING: HEPATOTOXICITY

• Severe and sometimes fatal hepatotoxicity has occurred in clinical trials.
• Monitor hepatic function prior to and during treatment.
• Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

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 Xofigo^® (radium Ra 223 dichloride) Injection
Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.¹

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 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 Bayer's Research Platforms
Bayer focuses its research activities across the following distinct scientific platforms: Oncogenic Signaling, Antibody-Drug Conjugates (ADCs), Targeted Thorium Conjugates (TTCs) and Immuno-Oncology. In the field of Oncogenic Signaling, the company is developing small molecules for crucial pathways of intracellular tumor signaling that are responsible for the development and survival of cancer in well-defined patient populations (biomarker strategy). In regard to ADCs, Bayer is working on antibodies to recognize tumor-specific proteins on cancer cell surfaces. With TTCs, drug candidates are being developed using the company's proprietary platform using high-energy alpha-radiation. In Immuno-Oncology, Bayer is developing next-generation agents specifically addressing the needs of patients not responding to current immunotherapies.

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 four 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 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, Aliqopa, Stivarga and Xofigo 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. Aliqopa^™ (copanlisib) for injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, September 2017.
2. STIVARGA^® (regorafenib) [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, April 2017.
3. XOFIGO^® (radium-223 dichloride) Injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, February 2018.

PP-700-US-0385

SOURCE Bayer

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http://www.bayer.us

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