NTRK fusion-positive Non-small Cell Lung Cancer

Relay Therapeutics最近的日子可能不太好过，美股市场最新股价11块，市值13亿美金左右，较巅峰期市值缩水了4分之3。截至2023年第一季度末, Relay Therapeutics持有9.378亿美元的现金、现金等价物，低于2022年底的10亿美元。该公司预计这些资金将支持到2025年的运营。 今年4月份，Relay Therapeutics公布了RLY2608的早期临床数据，股价随即大跌40%，RLY-2608是一种异构体选择性PI3K抑制剂，此类药物在安全性和有效性方面都存在挑战，FDA也曾给予黑框警告。RLY2608的一期试验中仅观察到一个患者的部分反应，且RLY-2608的最佳剂量也未确定，这给药物的安全性和有效性带来了不确定性。虽然到目前为止还没有剂量限制性毒性（DLT）的报告，由于仍处于临床试验的早期阶段，随着研究的继续，可能会出现意想不到的不良反应。 Relay公司还有另外两个有前景的资产。首先是RLY-4008（见图2），小分子抑制剂，可靶向晚期或转移性FGFR2改变的实体瘤患者的FGFR2。其首次人体试验的初步数据显示，对FGFR2具有明显的抑制作用，而不受脱靶毒性的限制（如高磷酸血症）。在2022年与FDA讨论后，Relay选择继续进行FGFR2融合CCA treatment-naïve患者的单臂试验设计，以加快审批速度。RLY-4008已获得FDA和EMA的CCA孤儿药指定。 在新药情报库中搜集到2023年5月26号的信息显示，二期推荐剂量为70 mg QD；在分组FGFRi-naïve CCA f/r中，ORR高达55%；在分组Prior-FGFRi CCA f/r中，ORR只有14%；说明接受过FGFRi治疗的患者中，ORR下降比较明显，在不同剂量下，最常见的TRAEs是低级别PPE(57%)、口炎(56%)、口干(38%)、脱发(28%)和眼干(22%)。 其次，GDC-1971(以前的RLY-1971)是Relay的另一个主要资产。该药物靶向晚期或转移性实体瘤患者的SHP2。Ia期试验于2022年完成入组。Relay与Genentech就GDC-1971的开发和商业化达成了合作。 随着诺华SHP2单药临床因有效性不足而失败，多数公司都在积极开展联用。如上图3，在情报库中搜集到2023年7月公开的一项Ib期研究，旨在评估 GDC-1971与奥西替尼联合治疗不可切除的局部晚期或转移性非小细胞肺癌患者，或与西妥昔单抗联合治疗转移性结直肠癌患者的安全性、药代动力学和活性。该临床招募了172名患者，预计2026年12月底结束试验。主要终点为：不良事件参与者的百分比和有剂量限制性毒性的患者人数。 Relay的上述三款抑制剂都出自D. E. Shaw（DESRES首席科学家），三款药物的差异化方向很明确，都是针对特定蛋白具体亚型做出高选择性靶向。三款药物分别是FGFR2抑制剂RLY-4008、PI3Kα变构抑制剂RLY-2608、SHP2抑制剂RLY-1971。 另外，D.E.Shaw还开发了针对自身免疫性疾病和炎症性疾病的小分子抑制剂DES-7114。2022年6月13日，D.E.Shaw Research宣布与礼来公司就Kv1.3抑制剂DES-7114的临床开发和商业化签订了一项全球独家许可协议。礼来将支付6000万美元的首付款，潜在开发和商业里程碑付款高达4.75亿美元，以及全球销售的特许权使用费。 Kv1.3阻断剂的开发难点：对多个亚型需要高度选择性 KV1.3电压门控钾离子通道在质膜和线粒体中参与许多生理过程，主要是在免疫和神经系统中。利用特异性肽和小分子抑制剂靶向KV1.3通道的治疗，在癌症和自身免疫性疾病(如多发性硬化症、I型糖尿病、牛皮癣、接触性皮炎、类风湿性关节炎和重症肌无力)方面显示出巨大的潜力。但是，迄今为止，尚无靶向KV1.3的化合物批准上市。一些具有明确SAR关系的小分子抑制剂已被优化为选择性抑制剂递送到线粒体，这些抑制剂为治疗癌症和自身免疫性疾病提供了治疗潜力。 1999年，小分子WIN17317-3、CP-339818被发现可以靶向Kv1.3通道。然而，这类分子缺乏对通道的选择性和特异性，除 Kv1.3通道外对钠离子通道以及 Kv1.4通道也存在阻断作用，从而导致了潜在的副作用。随后有多种小分子被发现，但都不能很好的解决选择性的问题。除了对钠离子通道和Kv1.4会抑制，对Kv1.1和Kv1.2也会产生阻断。 D.E. Shaw教授表示，DES-7114能够以高选择性的方式抑制离子通道蛋白Kv1.3。临床前研究证明了在几种慢性炎症和自身免疫性疾病(包括溃疡性结肠炎、克罗恩病和特应性皮炎)模型中的有效性，并于2022年初在健康志愿者中成功完成了I期临床试验。但是，时隔一年半，暂时未报道DES-7114临床试验的结果。 靶点Kv1.3的研发进展 如下表1，据智慧芽新药情报库统计，截止2023年09月04日，全球共有11个Kv1.3药物，来自17个机构，覆盖19个适应症，开展4个临床试验，其中有两个小分子和两个多肽。进展最快的公司是selectION, Inc.，他们在临床1期、临床前和非在研阶段都有1个药物在研发中。 对适应症进行分析，如图5所示，目前临床在研适应症均为自身免疫方向，分别是银屑病、银屑病关节炎和特应性皮炎。 美国、欧盟和德国是靶点 Kv1.3 药物研发阶段最高的国家/地区。国内公司中，武汉摩尔生物科技有限公司也在该靶点进行了研发，目前处于临床前阶段。 DES-7114的相关专利 如下图6，在智慧芽新药情报数据库中搜索D. E. Shaw Research和Kv1.3，共发现82组申请，11个INPADOC同族申请，集中在2022年申请了2个（申请日在3月和5月份）、2020年申请了5个，2021年申请了1个，以及2023年申请了两个；而DES-7114在2022年1月份开始进入一期临床。并且早在2013年9月，D.E. Shaw公司就公开了一种筛选电压门控蛋白的方法。目前临床分子DES-7114的结构尚未公开，只能从2021年和2020年6个INPADOC同族申请去寻找蛛丝马迹。 这6篇专利分别是：WO2022076285、WO2021071832、WO2021071812、WO2021071802、WO2021071803、WO2021071821。这几篇专利里面结构的合成难度都不大，不过多数化合物具有几个手性。有一些片段和母核还是比较新的，感兴趣的可以关注一下。 但是，这些专利中的化合物多数只公开了对Kv1.3通道抑制的IC50数据和hERG数据，且都只是一个范围，且没有对其他通道（如Kv1.1和Kv1.2）的选择性数据，想要推断具体的结构还是有难度。 总结 Relay Therapeutics是近年来一家颇有名气的以计算化学为特色的药物发现公司，而Relay管线中的三款药物都来自D.E. Shaw。虽然Relay公司目前3个临床化合物中，有两个在临床试验中磕磕绊绊，其以分子动力学为特色的药物发现平台对药物开发还是起到了巨大的推动作用。 而Kv1.3通道阻断剂的结构类型探索中，20多年来，小分子一直很难做到对Kv1.1和Kv1.2的选择性。D.E. Shaw Research公司在离子通道蛋白亚型的差异化靶向方面具有丰富的经验，除了Kv1.3通道蛋白外，TRPA1阳离子通道蛋白相关专利也有多篇公开。 根据智慧芽新药情报库搜集到的情报，目前Kv1.3阻断剂临床主要用于自身免疫疾病的治疗。为了开发更为安全的治疗药物，需重点关注化合物对Kv1X通道亚型(Kv1.1通道和 Kv1.2通道等)的选择性。 参考资料： 1.https://seekingalpha.com/article/4620984-relay-therapeutics-stock-market-may-be-prematurely-dismissing-rly-2608. 2.Špela Gubič et.al, Discovery of KV1.3 ion channel inhibitors:Medicinal chemistry approaches and challenges.Med Res Rev. 2021;41:2423–2473. 3.Antonio Felipe et.al; Fighting rheumatoid arthritis: Kv1.3 as a therapeutic target.Biochemical Pharmacology 165 (2019) 214-220. 4.智慧芽新药情报库/专利数据库.

WHIPPANY, N.J.--( BUSINESS WIRE )--Bayer announced data from three distinct Vitrakvi ® (larotrectinib) post-hoc subgroup analyses. The data was presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting from June 2-6, 2023. 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 and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 4 “ These findings reinforce Vitrakvi’s ability to treat patients with NTRK fusion-positive cancer and the importance of targeting the oncogenic driver,” said Iain Webb, M.D., Vice President, U.S. Medical Affairs, Oncology at Bayer. “ Testing patients comprehensively and early is pivotal to finding patients with NTRK fusion tumors and treating appropriate patients with Vitrakvi.” Larotrectinib long-term efficacy and safety in adult patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer (Abstract 3141) 1 In post-hoc subgroup analyses (data cut-off July 2022) of adult patients (n=180) with TRK fusion cancer across 24 different tumor types, including patients with central nervous system (CNS) metastases (n=22), Vitrakvi demonstrated an objective response rate (ORR) of 57% (95% CI 50-65) {16% (n=29) complete responses (including one pathological complete response) and 41% (n=74) partial responses}. In evaluable patients with CNS metastases (n=22), ORR was 68% (95% CI 45-86). Among all patients, median time to response was 1.8 months and median duration of response (DoR) was 43.3 months (95% CI 29.2-not estimable [NE]) at a median follow-up of 32.3 months. Treatment-related adverse events (TRAEs) were predominantly Grade 1-2, with Grade 3-4 occurring in 14% (n=27) of patients. Responses were assessed by IRC. Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer (Abstract 9056) 2 In an expanded dataset (n=30) with longer follow-up, Vitrakvi demonstrated long-term efficacy and safety data in adult patients with advanced TRK fusion lung cancer, including those with CNS metastases (n=12). The results encourage wider adoption of next-generation sequencing (NGS) testing for identifying patients with solid tumors harboring NTRK gene fusions, including lung cancer. Among 27 adult patients eligible for IRC assessment with TRK fusion lung cancer enrolled, ORR was 74% (95% CI 54-89); 11% (n=3) complete responses and 63% (n=17) partial responses. Among the 12 patients with baseline CNS metastases, the ORR was 67% (95% CI 35-90), with 8 partial responses. Median DoR was 33.9 months (95% CI 9.5-NE); median follow-up was 22.9 months. TRAEs were predominantly for Grade 1-2. Grade 3-4 TRAEs were reported in 5 patients which included AST increase, ALT increase, myalgia, and hypersensitivity. Larotrectinib (laro) long-term efficacy and safety in patients (pts) with tropomyosin receptor kinase (TRK) fusion thyroid carcinoma (TC) (Abstract 6091) 3 Vitrakvi was evaluated in updated subgroup analyses of patients (n=30; data cut-off July 20, 2022) with TRK fusion thyroid cancer (TC). Among those eligible for efficacy assessment, 47% (n=14) had NTRK1 and 53% (n=16) had NTRK2 . Fifty percent (n=15) of patients received no prior systemic therapies, 20% (n=6) received ≥2, and 77% (n=23) received prior radioiodine. ORR was 63% (95% CI 44-80); 10% (n=3) complete responses and 53% (n=16) partial responses. For patients classified as differentiated thyroid cancer (DTC; n=23), ORR was 78% (95% CI 56-93). For patients classified as anaplastic thyroid cancer (ATC; n=7), ORR was 14% (95% CI 0-58). All patients with CNS metastases (n=4) at baseline had a partial response. Median time to response was 1.9 months and median DoR was 43.3 months (95% CI 21.6-NE) at a median follow-up of 32.3 months. Grade ≥3 TRAEs, anemia and decreased lymphocycte count, were reported in 7% (n=2) patients. There were no treatment discontinuations due to TRAEs. Responses were assessed by IRC. 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 Warnings and Precautions 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%) of patients. Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed. Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI. Adverse Reactions 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. For coadministration with moderate CYP3A4 inhibitors, monitor for adverse reactions more frequently and reduce the dosage based on severity. For coadministration with moderate CYP3A4 inducers, modify dose as recommended. Use in Specific Populations Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose. Please see the full Prescribing Information for VITRAKVI ® (larotrectinib). About TRK Fusion Cancer TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing a chimeric TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade. These TRK fusion proteins are oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer. TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body. TRK fusion cancer occurs in various adult and pediatric solid tumors with varying frequency, including lung, thyroid, GI cancers (colon and rectal, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (including secretory carcinoma of the salivary gland) and pediatric cancers (infantile fibrosarcoma and other soft tissue sarcomas). 4,5 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 the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating 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 2022, the Group employed around 101,000 people and had sales of 50.7 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to www.bayer.com . © 2023 Bayer BAYER, the Bayer Cross and Vitrakvi are registered trademarks of Bayer. Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com . The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. References Hong D, et. al. Larotrectinib long-term efficacy and safety in adult patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer. ASCO Annual Meeting 2023 E-Poster. Abstract 3141. Lin, J, et. al. Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer. ASCO Annual Meeting 2023 E-Poster. Abstract 9056. Cabanillas M, et. al. Larotrectinib (laro) long-term efficacy and safety in patients (pts) with tropomyosin receptor kinase (TRK) fusion thyroid carcinoma (TC). ASCO Annual Meeting 2023 E-Poster. Abstract 6091. Vitrakvi ® [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; December 2022. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov . 2015;5(1):25-34. PP-VIT-US-1303-1 6/23

WHIPPANY, N.J.--( BUSINESS WIRE )--Bayer will highlight scientific research in oncology at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting , taking place from June 2-6, 2023. These presentations continue to underscore the company’s commitment to drive treatment approaches through science and innovation in the oncology space. Data featuring NUBEQA ® (darolutamide) and Xofigo ® (radium Ra 223 dichloride) will be showcased at ASCO. NUBEQA data includes results from the DEAR trial, a retrospective, observational study evaluating real-world evidence (RWE) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Additionally, investigational NUBEQA data includes ARASEC, an ongoing U.S.-based open-label study evaluating NUBEQA versus androgen deprivation therapy (ADT), as well as ARAMON, an ongoing, randomized open-label Phase II study on serum testosterone levels in patients with hormone-naive prostate cancer, will be featured. NUBEQA is currently indicated in the U.S. for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel and for the treatment of adult patients with nmCRPC. 1 Real-world safety and effectiveness data from the prospective, observational REASSURE study involving patients with metastatic castration-resistant prostate cancer (mCRPC) treated with Xofigo will also be presented. Xofigo is indicated for the treatment of patients with mCRPC, symptomatic bone metastases, and no known visceral metastatic disease. 2 Updated results from NAVIGATE and SCOUT studies will be presented for Vitrakvi ® (larotrectinib) in TRK fusion cancer in adult and pediatric patients across solid tumor types. Long-term efficacy and safety data of Vitrakvi in adult patients with TRK fusion lung cancer and thyroid carcinoma (TC) will also be presented. Additionally, an oral presentation of Phase II investigator-initiated research featuring pediatric patients with newly diagnosed infantile fibrosarcoma (IFS) treated with Vitrakvi will be highlighted. 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 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. 3 Additional data featuring Bayer’s oncology pipeline will include an oral presentation on the initial results from a first-in-human, Phase I study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 in patients with advanced solid tumors. The six-year safety and efficacy results from CHRONOS-1 study analyzing Aliqopa ® (copanlisib) in patients with relapsed or refractory follicular lymphoma (FL) will also be presented. Aliqopa is indicated for the treatment of adult patients with relapsed 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. 4 Bayer presentations at the 2023 ASCO Annual Meeting are listed below: Darolutamide Abstract title: Comparative real-world (RW) evidence on darolutamide (Daro), enzalutamide (Enza), and apalutamide (Apa) for patients (Pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the United States: DEAR Abstract 5097; June 3, 8:00am CDT Abstract title: Open-label study of darolutamide plus androgen-deprivation therapy (ADT) vs ADT in metastatic hormone-sensitive prostate cancer using an external control arm (ARASEC) Abstract TPS5112; June 3, 8:00am CDT Abstract title: A phase 2, randomized, open-label study comparing the effects of darolutamide versus enzalutamide monotherapy on serum testosterone levels in patients with hormone-naive prostate cancer: ARAMON study Abstract TPS5111; June 3, 8:00am CDT Radium-223 dichloride (Ra-223) Abstract title: Real-world safety and effectiveness of radium-223 ( 223 Ra) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated in the US: The non-interventional REASSURE study Abstract 5050; June 3, 8:00am CDT Larotrectinib Abstract title: Larotrectinib long-term efficacy and safety in adult patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer Abstract 3141; June 3, 8:00am CDT Abstract title: Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer Abstract 9056; June 4, 8:00am CDT Abstract title: Larotrectinib (laro) long-term efficacy and safety in patients (pts) with tropomyosin receptor kinase (TRK) fusion thyroid carcinoma (TC) Abstract 6091; June 5, 1:15pm CDT Abstract title: Phase 2 study of larotrectinib in children with newly diagnosed infantile fibrosarcoma (IFS): Children’s Oncology Group (COG) ADVL1823 cohort A Abstract 10008; June 4, 12:09pm CDT Pipeline Abstract title: Initial results from a first-in-human, phase I study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 in patients with advanced solid tumors Abstract 2502; June 4, 9:57am CDT Abstract title: Six-year safety and efficacy results from the CHRONOS-1 study of the PI3K inhibitor copanlisib in patients with relapsed or refractory follicular lymphoma Abstract 7555; June 5, 8:00am CDT Oncology RWE Non-Product Related Abstract Title: Using real-world evidence (RWE) in regulatory decision making: A study of 6 oncology approvals with RWE included in the product label Abstract 6611; June 3, 1:15pm CDT 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). NUBEQA is also being investigated in additional 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 adults with nmCRPC or with mHSPC in combination with docetaxel. 1 Filings in other regions are underway or planned. INDICATIONS NUBEQA ® (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with: Non-metastatic castration-resistant prostate cancer (nmCRPC) Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel IMPORTANT SAFETY INFORMATION Warnings & Precautions Ischemic Heart Disease – In a study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA versus 2.5% receiving placebo, including Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo. In a study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 2.9% of patients receiving NUBEQA with docetaxel vs. 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs. 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel vs. 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease. Seizure – In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA. It is unknown whether anti-epileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment. 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 In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA vs. 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia, and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA vs. 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). The most common adverse reactions (>2% with a ≥2% increase over placebo), including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity, and rash. Clinically relevant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease and heart failure. In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common adverse reactions (≥10% with a ≥2% increase over placebo with docetaxel) were constipation, decreased appetite, rash, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures, ischemic heart disease, seizures, and drug-induced liver injury. 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) Injection 2 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 × 10 9 /L, the platelet count ≥100 × 10 9 /L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 10 9 /L and the platelet count ≥50 × 10 9 /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) 3 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) Warnings and Precautions 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. Adverse Reactions 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. For coadministration with moderate CYP3A4 inhibitors, monitor for adverse reactions more frequently and reduce the dosage based on severity. For coadministration with moderate CYP3A4 inducers, modify dose as recommended. Use in Specific Populations 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 Aliqopa ® (copanlisib) Injection 4 ALIQOPA (copanlisib) is indicated 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 is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. 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 clinical development program for Aliqopa also includes the Phase III study CHRONOS-4, evaluating Aliqopa in combination with standard immunochemotherapy in relapsed iNHL. More information about this trial can be found at www.clinicaltrials.gov . IMPORTANT SAFETY INFORMATION FOR ALIQOPA ® (copanlisib) 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 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. 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 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 one month after the last dose. For important risk and use information about Aliqopa, please see the full Prescribing Information . 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 the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating 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 2022, the Group employed around 101,000 people and had sales of 50.7 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to www.bayer.com . © 2023 Bayer BAYER, the Bayer Cross, NUBEQA, Xofigo, Vitrakvi and Aliqopa 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 NUBEQA ® (darolutamide) tablets [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, August 2022. XOFIGO ® (radium-223 dichloride) Injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, December 2019. Vitrakvi ® [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; December 2022. Aliqopa (copanlisib) for injection [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; March 2023. PP-PF-ONC-US-2882-1 05/23