News Release

INDIANAPOLIS, May 13, 2020 /PRNewswire/ -- Data from 23 studies across Eli Lilly and Company's (NYSE: LLY) oncology product portfolio will be presented at the 56^th Annual Meeting of the American Society of Clinical Oncology (ASCO), held virtually, May 29-31, 2020. The data, which include an updated analysis of Lilly's newest precision medicine Retevmo™ (selpercatinib), underscore Lilly Oncology's dedication to developing and delivering innovative new medicines that will make a meaningful difference to people living with cancer.

"We're excited to present data at this year's ASCO that highlight our commitment to developing new targeted treatments for people living with cancer. We are especially looking forward to sharing data from our LIBRETTO-001 trial examining Retevmo, which recently received FDA approval for the treatment of certain cancers that develop due to alterations of the RET gene," said Maura Dickler, M.D., vice president, late phase development, Lilly Oncology. "Even though we're not gathering in person this year, we remain committed to gathering virtually with physicians to share important new data so they may choose the best therapy for their patients who have difficult-to-treat, advanced stage cancers."

Latest Study Results for Retevmo
Last week, Lilly's first-in-class precision medicine, Retevmo—a selective oral RET kinase inhibitor—received approval from the U.S. Food and Drug Administration (FDA) for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer.

During ASCO, Lilly will share updated detailed results from the Phase 1/2 LIBRETTO-001 registrational trial of Retevmo. The updated analysis will be presented on both the NSCLC and thyroid cohorts, as well as on activity in difficult-to-treat brain metastases in patients with NSCLC. LIBRETTO-001 is the largest clinical trial in RET-altered cancers and builds on earlier research that has shown that Retevmo is a selective and potent inhibitor of RET. The most common adverse reactions, including laboratory abnormalities, (≥ 25%) were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation. In addition, the most frequent serious adverse reaction (in ≥ 2% of patients) was pneumonia.

RET fusions have been identified in approximately two percent of NSCLC and 10-20 percent of papillary, Hurthle cell, anaplastic and poorly differentiated thyroid cancers. Activating RET point mutations account for approximately 60 percent of sporadic MTC and approximately 90 percent of germline MTC. 

Lilly's Commitment to Advanced Breast Cancer Patients
New data for Verzenio^® (abemaciclib) include research on acquired genomic alterations in circulating tumor DNA (ctDNA)—an area of particular interest as oncologists seek to understand how to individualize treatment for people living with HR+, HER2- advanced breast cancer. Lilly will also present further overall survival (OS) exploratory subgroup data on women with advanced breast cancer receiving Verzenio plus fulvestrant in the first- and second-line settings in the MONARCH 2 trial.

CYRAMZA^® and ALIMTA^® Lung Cancer Data Highlights
Lilly will present new data from the positive Phase 3 RELAY study evaluating CYRAMZA (ramucirumab) plus erlotinib—specifically a biomarker analysis using circulating tumor DNA (ctDNA) in Japanese patients with untreated metastatic EGFR-mutated NSCLC, as well as an exploratory analysis of CYRAMZA plus gefitinib in patients with EGFR-mutated NSCLC. Last year, Lilly made a U.S. regulatory submission based on the RELAY intent-to-treat (ITT) patient population and FDA action is expected in the first half of 2020. In addition to a recent approval for CYRAMZA in the European Union based on the RELAY ITT results, Lilly has made a submission in Japan with regulatory action expected by the end of 2020.

Additionally, a final analysis of OS data from the KEYNOTE-189 trial, which enrolled patients with NSCLC regardless of PD-L1 expression and examined the ALIMTA (pemetrexed)-KEYTRUDA^® (pembrolizumab)-platinum chemotherapy combination in the first-line setting, will be presented. The KEYNOTE-189 trial was conducted by Merck (known as MSD outside the U.S. and Canada) in collaboration with Lilly.

A list of the data presentations, along with the viewing details are highlighted below.

Retevmo (selpercatinib)

Abstract 3584: Selpercatinib (LOXO-292) in patients with RET-fusion+ non-small cell lung cancer (Koichi Goto)
Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
Poster: 314

Abstract 9516: Intracranial activity of selpercatinib (LOXO-292) in RET fusion-positive non-small cell lung cancer (NSCLC) patients on the LIBRETTO-001 trial (Vivek Subbiah)
Session: Lung Cancer—Non-Small Cell Metastatic
Poster: 282

Abstract 3594: Selpercatinib (LOXO-292) in patients with RET-mutant medullary thyroid cancer (Manisha H. Shah)
Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
Poster: 324

Abstract e21693: Clinical outcomes between patients with and without RET fusions in advanced/metastatic non-small cell lung cancer in the United States (Anthony Sireci)
Publication Only

Verzenio (abemaciclib)

Abstract 1061: MONARCH 2: subgroup analysis of patients receiving abemaciclib + fulvestrant as first- and second-line therapy for HR+, HER2- advanced breast cancer (Patrick Neven)
Session: Breast Cancer—Metastatic
Poster: 146

Abstract 3519: Acquired genomic alterations in circulating tumor DNA from patients receiving abemaciclib alone or in combination with endocrine therapy (Matthew P. Goetz)
Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
Poster: 249

Abstract 9562: A phase Ib study of abemaciclib in combination with pembrolizumab for patients (pts) with stage IV Kirsten rat sarcoma mutant (KRAS-mut) or squamous non-small cell lung cancer (NSCLC) (NCT02779751): Interim results (Jean-Louis Pujol)
Session: Lung Cancer—Non-Small Cell Metastatic
Poster: 328

Abstract 1051: A phase Ib study of abemaciclib in combination with pembrolizumab for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer (MBC) (NCT02779751): Interim results (Hope S. Rugo)
Session: Breast Cancer—Metastatic
Poster: 136

Abstract TPS5591: CYCLONE 2: A phase II, randomized, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer (Matthew R. Smith)
Session: Genitourinary Cancer—Prostate, Testicular, and Penile
Poster: 172

Abstract e13083: Assessment for markers of poor prognosis in a real-world evidence study of treatment patterns in patients with HR+/HER2- locally advanced or metastatic breast cancer in Korea and Taiwan (Diego Novick)
Publication Only

CYRAMZA (ramucirumab)

Abstract 9564: RELAY+: Exploratory study of ramucirumab plus gefitinib in untreated patients (pts) with epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (NSCLC) (Makoto Nishio)
Session: Lung Cancer—Non-Small Cell Metastatic
Poster: 330

Abstract 9527: RELAY study of erlotinib (ERL) + ramucirumab (RAM) or placebo (PL) in EGFR-mutated metastatic non-small cell lung cancer (NSCLC): Biomarker analysis using circulating tumor DNA (ctDNA) in Japanese patients (pts) (Kazuto Nishio)
Session: Lung Cancer—Non-Small Cell Metastatic
Poster: 293

Abstract 4644: Ramucirumab in patients with advanced HCC and elevated alpha-fetoprotein (AFP): Outcomes by treatment-emergent ascites (Andrew X. Zhu)
Session: Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary
Poster: 252

Abstract 4543: Impact of frontline doublet versus triplet therapy on clinical outcomes: Exploratory analysis from the RAINBOW study (Samuel J. Klempner)
Session: Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary
Poster: 151

Abstract 3089: Immune profiling and clinical outcomes in patients treated with ramucirumab and pembrolizumab in phase I study JVDF (Roy S. Herbst)
Session: Developmental Therapeutics—Immunotherapy
Poster: 153

ALIMTA (pemetrexed)

Abstract 9521: Evaluation of blood TMB (bTMB) in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) with pemetrexed and platinum versus placebo plus chemo as first-line therapy for metastatic nonsquamous NSCLC (Marina C. Garassino)
Session: Lung Cancer—Non-Small Cell Metastatic
Poster: 287

Abstract 9582: Final analysis of KEYNOTE-189: Pemetrexed-platinum chemotherapy (chemo) with or without pembrolizumab (pembro) in patients (pts) with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC) (Delvys Rodriguez-Abreu)
Session: Lung Cancer—Non-Small Cell Metastatic
Poster: 348

Other

Abstract e16001: Early carcinoembryonic antigen (CEA) dynamics to predict fruquintinib efficacy in FRESCO, a 3+ line metastatic colorectal carcinoma (mCRC) phase III trial (Yuxian Bai)
Publication Only

Abstract 9563: Randomized phase II study of pembrolizumab (P) alone versus pegilodecakin (PEG) in combination with P as first-line (1L) therapy in patients (pts) with stage IV non-small cell lung cancer (NSCLC) with high PD-L1 expression (CYPRESS 1) (David R. Spigel)
Session: Lung Cancer—Non-Small Cell Metastatic
Poster: 329

Abstract e21744: Randomized phase II study of nivolumab (N) alone versus with pegilodecakin (PEG) in combination with N in patients (pts) with post-platinum immunotherapy-naive stage IV non-small cell lung cancer (NSCLC) and no or low PD-L1 expression (CYPRESS 2) (Robert M. Jotte)
Publication Only

Abstract TPS10561: A phase I study of Aurora kinase A inhibitor LY3295668 erbumine as a single agent and in combination in patients with relapsed/refractory neuroblastoma (Steven G. DuBois)
Session: Pediatric Oncology
Poster: 448

Abstract 3588: Correlation between overall response rate and progression-free survival/overall survival in comparative trials involving targeted therapies in molecularly enriched populations (Benjamin J. Solomon)
Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
Poster: 318

Abstract e19123: Impact of bolus versus continuous infusion of doxorubicin (DOX) on cardiotoxicity in patients with breast cancer (BC) and sarcomas: Analysis of real-world data (Lee D. Cranmer)
Publication Only

Notes to Editors

About Retevmo™ (selpercatinib)
Retevmo (selpercatinib, formerly known as LOXO-292) (pronounced reh-TEHV-moh) is a selective and potent RET kinase inhibitor. Retevmo may affect both tumor cells and healthy cells, which can result in side effects. Retevmo is an oral prescription medicine, 120 mg or 160 mg dependent on weight (-/+ 50 kg), taken twice daily until disease progression or unacceptable toxicity.

About Verzenio^®(abemaciclib)
Verzenio (abemaciclib) is an inhibitor of cyclin-dependent kinases (CDK)4 & 6, which are activated by binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4 & 6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

In vitro, continuous exposure to Verzenio inhibited Rb phosphorylation and blocked progression from G1 to S phase of the cell cycle, resulting in senescence and apoptosis (cell death). Preclinically, Verzenio dosed daily without interruption resulted in reduction of tumor size. Inhibiting CDK4 & 6 in healthy cells can result in side effects, some of which may be serious. Clinical evidence also suggests that Verzenio crosses the blood-brain barrier. In patients with advanced cancer, including breast cancer, concentrations of Verzenio and its active metabolites (M2 and M20) in cerebrospinal fluid are comparable to unbound plasma concentrations.

Verzenio is Lilly's first solid oral dosage form to be made using a faster, more efficient process known as continuous manufacturing. Continuous manufacturing is a new and advanced type of manufacturing within the pharmaceutical industry, and Lilly is one of the first companies to use this technology.

Verzenio is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer:

• in combination with an aromatase inhibitor for postmenopausal women as initial endocrine-based therapy
• in combination with fulvestrant for women with disease progression following endocrine therapy
• as a single agent for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting

About CYRAMZA^® (ramucirumab)
In the U.S., CYRAMZA (ramucirumab) has five FDA approvals to treat four different types of cancers. CYRAMZA is being investigated in a broad global development program that has enrolled more than 15,000 patients across more than 100 trials worldwide. These include several studies investigating CYRAMZA in combination with other anti-cancer therapies for the treatment of multiple tumor types.

CYRAMZA is an antiangiogenic therapy. It is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that binds specifically to VEGFR-2, thereby blocking the binding of the receptor ligands (VEGF-A, VEGF-C, and VEGF-D) – which may slow tumor growth. CYRAMZA inhibited angiogenesis in an in vivo animal model.

U.S. INDICATIONS FOR CYRAMZA

Gastric Cancer
CYRAMZA, as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

Non-Small Cell Lung Cancer
CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

Colorectal Cancer
CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Hepatocellular Carcinoma
CYRAMZA, as a single agent, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have an alpha-fetoprotein (AFP) of ≥400 ng/mL and have been treated with sorafenib.

About ALIMTA^® (pemetrexed for injection)
ALIMTA is indicated in combination with pembrolizumab and platinum chemotherapy for the initial treatment of patients with metastatic nonsquamous non-small cell lung cancer, with no EGFR or ALK genomic tumor aberrations. For all FDA-approved indications for ALIMTA, please see full Prescribing Information.

IMPORTANT SAFETY INFORMATION FOR RETEVMO™ (selpercatinib)

Hepatotoxicity: Serious hepatic adverse reactions occurred in 2.6% of patients treated with Retevmo. Increased AST occurred in 51% of patients, including Grade 3 or 4 events in 8% and increased ALT occurred in 45% of patients, including Grade 3 or 4 events in 9%. The median time to first onset for increased AST was 4.1 weeks (range: 5 days to 2 years) and increased ALT was 4.1 weeks (range: 6 days to 1.5 years). Monitor ALT and AST prior to initiating Retevmo, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue Retevmo based on the severity.

Hypertension occurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one (0.1%) patient. Overall, 4.6% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate Retevmo in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Retevmo. Monitor blood pressure after 1 week, at least monthly thereafter, and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue Retevmo based on the severity. Retevmo can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 6% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% of patients. Retevmo has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure.

Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia and hypocalcemia prior to initiating Retevmo and during treatment. Monitor the QT interval more frequently when Retevmo is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue Retevmo based on the severity.

Serious, including fatal, hemorrhagic events can occur with Retevmo. Grade ≥ 3 hemorrhagic events occurred in 2.3% of patients treated with Retevmo including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis. Permanently discontinue Retevmo in patients with severe or life-threatening hemorrhage.

Hypersensitivity occurred in 4.3% of patients receiving Retevmo, including Grade 3 hypersensitivity in 1.6%. The median time to onset was 1.7 weeks (range 6 days to 1.5 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. If hypersensitivity occurs, withhold Retevmo and begin corticosteroids at a dose of 1 mg/kg. Upon resolution of the event, resume Retevmo at a reduced dose and increase the dose of Retevmo by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. Permanently discontinue Retevmo for recurrent hypersensitivity.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Retevmo has the potential to adversely affect wound healing. Withhold Retevmo for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Retevmo after resolution of wound healing complications has not been established.

Based on data from animal reproduction studies and its mechanism of action, Retevmo can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. 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 Retevmo and for at least 1 week after the final dose. There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Retevmo and for 1 week after the final dose.

Severe adverse reactions (Grade 3-4) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were hypertension (18%), prolonged QT interval (4%), diarrhea (3.4%), dyspnea (2.3%), fatigue (2%), abdominal pain (1.9%), hemorrhage (1.9%), headache (1.4%), rash (0.7%), constipation (0.6%), nausea (0.6%), vomiting (0.3%), and edema (0.3%).

Common adverse reactions (all grades) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were dry mouth (39%), diarrhea (37%), hypertension (35%), fatigue (35%), edema (33%), rash (27%), constipation (25%), nausea (23%), abdominal pain (23%), headache (23%), cough (18%), prolonged QT interval (17%), dyspnea (16%), vomiting (15%), and hemorrhage (15%).

Laboratory abnormalities (all grades; Grade 3-4) ≥20% worsening from baseline in patients who received Retevmo in LIBRETTO-001, were AST increased (51%; 8%), ALT increased (45%; 9%), increased glucose (44%; 2.2%), decreased leukocytes (43%; 1.6%), decreased albumin (42%; 0.7%), decreased calcium (41%; 3.8%), increased creatinine (37%; 1.0%), increased alkaline phosphatase (36%; 2.3%), decreased platelets (33%; 2.7%), increased total cholesterol (31%; 0.1%), decreased sodium (27%; 7%), decreased magnesium (24%; 0.6%), increased potassium (24%; 1.2%), increased bilirubin (23%; 2.0%), and decreased glucose (22%; 0.7%).

Concomitant use of acid-reducing agents decrease selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid concomitant use of proton-pump inhibitors (PPIs), histamine-2 (H2) receptor antagonists, and locally-acting antacids with Retevmo. If coadministration cannot be avoided, take Retevmo with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid).

Concomitant use of strong and moderate CYP3A inhibitors increase selpercatinib plasma concentrations which may increase the risk of Retevmo adverse reactions including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with Retevmo. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the Retevmo dosage as recommended and monitor the QT interval with ECGs more frequently. Concomitant use of strong and moderate CYP3A inducers decrease selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid coadministration of Retevmo with strong and moderate CYP3A inducers.

Concomitant use of Retevmo with CYP2C8 and CYP3A substrates increase their plasma concentrations which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of Retevmo with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

The safety and effectiveness of Retevmo have not been established in pediatric patients less than 12 years of age. The safety and effectiveness of Retevmo have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of Retevmo for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older.

No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] ≥30 mL/Min, estimated by Cockcroft-Gault). A recommended dosage has not been established for patients with severe renal impairment or end-stage renal disease.

Reduce the dose when administering Retevmo to patients with severe hepatic impairment (total bilirubin greater than 3 to 10 times upper limit of normal [ULN] and any AST). No dosage modification is recommended for patients with mild or moderate hepatic impairment. Monitor for Retevmo-related adverse reactions in patients with hepatic impairment.

SE HCP ISI All_08MAY2020

Please see full Prescribing Information and Patient Prescribing Information for Retevmo.

IMPORTANT SAFETY INFORMATION FOR VERZENIO (abemaciclib)

Diarrhea occurred in 81% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 90% of patients receiving Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 20% of patients receiving Verzenio alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection. Diarrhea incidence was greatest during the first month of Verzenio dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1.

Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose.

Neutropenia occurred in 41% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 37% of patients receiving Verzenio alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 27% of patients receiving Verzenio alone in MONARCH 1. In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1, was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.

Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Febrile neutropenia has been reported in <1% of patients exposed to Verzenio in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.

Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with Verzenio and other CDK4/6 inhibitors. Across clinical trials (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of Verzenio-treated patients had ILD/pneumonitis of any grade, 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations.

Dose interruption or dose reduction is recommended in patients who develop persistent or recurrent Grade 2 ILD/pneumonitis. Permanently discontinue Verzenio in all patients with grade 3 or 4 ILD/pneumonitis.

Grade ≥3 increases in alanine aminotransferase (ALT) (6% versus 2%) and aspartate aminotransferase (AST) (3% versus 1%) were reported in the Verzenio and placebo arms, respectively, in MONARCH 3. Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the Verzenio and placebo arms respectively, in MONARCH 2. In MONARCH 3, for patients receiving Verzenio plus an aromatase inhibitor with Grade ≥3 increases in ALT or AST, median time to onset was 61 and 71 days, respectively, and median time to resolution to Grade <3 was 14 and 15 days, respectively. In MONARCH 2, for patients receiving Verzenio plus fulvestrant with Grade ≥3 increases in ALT or AST, median time to onset was 57 and 185 days, respectively, and median time to resolution to Grade <3 was 14 and 13 days, respectively. For assessment of potential hepatotoxicity, monitor liver function tests (LFTs) prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.

Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo in MONARCH 3. Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus fulvestrant in MONARCH 2 as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. Across the clinical development program, deaths due to venous thromboembolism have been reported. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.

Verzenio can cause fetal harm when administered to a pregnant woman based on findings from animal studies and the mechanism of action. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Verzenio and for at least 3 weeks after the last dose. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential.

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 3 for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were diarrhea (81% vs 30%), neutropenia (41% vs 2%), fatigue (40% vs 32%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increased (19% vs 4%), constipation (16% vs 12%), ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decreased (10% vs 3%), influenza-like illness (10% vs 8%), and thrombocytopenia (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 2 for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were diarrhea (86% vs 25%), neutropenia (46% vs 4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia (28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs 10%), headache (20% vs 15%), dysgeusia (18% vs 3%), thrombocytopenia (16% vs 3%), alopecia (16% vs 2%), stomatitis (15% vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough (13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%), peripheral edema (12% vs 7%), creatinine increased (12% vs <1%), rash (11% vs 4%), pyrexia (11% vs 6%), and weight decreased (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 1 with Verzenio were diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), leukopenia (17%), constipation (17%), arthralgia (15%), dry mouth (14%), weight decreased (14%), stomatitis (14%), creatinine increased (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 3 were neutropenia (22% vs 2%), diarrhea (9% vs 1%), leukopenia (8% vs <1%), ALT increased (7% vs 2%), and anemia (6% vs 1%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 2 were neutropenia (27% vs 2%), diarrhea (13% vs <1%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections (6% vs 3%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions from MONARCH 1 with Verzenio were neutropenia (24%), diarrhea (20%), fatigue (13%), infections (7%), leukopenia (6%), anemia (5%), and nausea (5%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 3 in ≥10% for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were increased serum creatinine (98% vs 84%; 2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs <1%), anemia (82% vs 28%; 2% vs 0%), decreased neutrophil count (80% vs 21%; 22% vs 3%), decreased lymphocyte count (53% vs 26%; 8% vs 2%), decreased platelet count (36% vs 12%; 2% vs <1%), increased ALT (48% vs 25%; 7% vs 2%), and increased AST (37% vs 23%; 4% vs <1%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 2 in ≥10% for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were increased serum creatinine (98% vs 74%; 1% vs 0%), decreased white blood cells (90% vs 33%; 23% vs 1%), decreased neutrophil count (87% vs 30%; 33% vs 4%), anemia (84% vs 33%; 3% vs <1%), decreased lymphocyte count (63% vs 32%; 12% vs 2%), decreased platelet count (53% vs 15%; 2% vs 0%), increased ALT (41% vs 32%; 5% vs 1%), and increased AST (37% vs 25%; 4% vs 4%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 1were increased serum creatinine (98%; <1%), decreased white blood cells (91%; 28%), decreased neutrophil count (88%; 27%), anemia (68%; 0%), decreased lymphocyte count (42%; 14%), decreased platelet count (41%; 2%), increased ALT (31%; 3%), and increased AST (30%; 4%). 

Strong and moderate CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Avoid concomitant use of the strong CYP3A inhibitor ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the Verzenio dose to 100 mg twice daily with concomitant use of  strong CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the Verzenio dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking Verzenio discontinues a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the Verzenio dose in 50 mg decrements. Patients should avoid grapefruit products.

Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents. Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity.

With severe hepatic impairment (Child-Pugh Class C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr <30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min).

AL HCP ISI 17SEP2019

Please see full Prescribing Information for Verzenio.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA (ramucirumab)

Warnings and Precautions
Hemorrhage

• CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. In 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage occurred between 13-44%. Grade 3-5 hemorrhage incidence ranged from 2-5%.
• Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in REGARD and RAINBOW; therefore, the risk of gastric hemorrhage in CYRAMZA treated patients with gastric tumors receiving NSAIDs is unknown.
• Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other anti platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from REVEL; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown.
• Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4) bleeding.

Gastrointestinal Perforations

• CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. In 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2%.
• Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing

• CYRAMZA has the potential to adversely affect wound healing. CYRAMZA has not been studied in patients with serious or non-healing wounds.
• Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established.

Arterial Thromboembolic Events (ATEs)

• Serious, sometimes fatal, ATEs, including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. In 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 2-3%. Grade 3-5 ATE incidence was 1-2%.
• Permanently discontinue CYRAMZA in patients who experience an ATE.

Hypertension

• An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. In 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension occurred between 11 26%. Grade 3-5 hypertension incidence ranged from 6 15%.
• Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Withhold CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRR)

• IRR, including severe and life threatening IRR, occurred in CYRAMZA clinical trials. Symptoms of IRR included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. In 1916 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade IRR occurred between <1-9%. Grade 3-5 IRR incidence was <1%.
• Premedicate prior to each CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Reduce the infusion rate by 50% for Grade 1-2 IRR. Permanently discontinue CYRAMZA for Grade 3-4 IRR.

Worsening of Pre-existing Hepatic Impairment

• Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.
• Based on safety data from REACH 2, in patients with Child-Pugh A liver cirrhosis, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received CYRAMZA (6%) compared to patients who received placebo (0%).

Posterior Reversible Encephalopathy Syndrome (PRES)

• PRES (also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) has been reported in <0.1% of 1916 patients with various cancers treated with CYRAMZA. Symptoms of PRES include seizure, headache, nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension.
• Permanently discontinue CYRAMZA in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome

• In 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-20%. Grade ≥3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from <1-3%.
• Monitor for proteinuria. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction

• In 1916 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism. Monitor thyroid function during treatment with CYRAMZA.

Embryo-Fetal Toxicity

• CYRAMZA can cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose.

Lactation

• Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with CYRAMZA and for 2 months after the last dose.

Adverse Reactions
REGARD:

• The most common adverse reactions (all Grades) observed in single agent CYRAMZA-treated gastric cancer patients at a rate of ≥5% and ≥2% higher than placebo were hypertension (16% vs 8%), diarrhea (14% vs 9%), headache (9% vs 3%;), and hyponatremia (6% vs 2%).
• The most common serious adverse reactions with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.
• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in REGARD were: neutropenia (4.7%), epistaxis (4.7%), rash (4.2%), intestinal obstruction (2.1%), and arterial thromboembolic events (1.7%).
• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and IRR. In REGARD, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in REGARD was 0.8% and the rate of IRR was 0.4%.

RAINBOW:

• The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA with paclitaxel at a rate of ≥5% and ≥2% higher than placebo with paclitaxel were fatigue/asthenia (57% vs 44%), neutropenia (54% vs 31%), diarrhea (32% vs 23%), epistaxis (31% vs 7%), hypertension (25% vs 6%), peripheral edema (25% vs 14%), stomatitis (20% vs 7%), proteinuria (17% vs 6%), thrombocytopenia (13% vs 6%), hypoalbuminemia (11% vs 5%), and gastrointestinal hemorrhage events (10% vs 6%).
• The most common serious adverse reactions with CYRAMZA with paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients who received CYRAMZA with paclitaxel received granulocyte colony-stimulating factors.
• Adverse reactions resulting in discontinuation of any component of the CYRAMZA with paclitaxel combination in ≥2% of patients in RAINBOW were neutropenia (4%) and thrombocytopenia (3%). Clinically relevant adverse reactions reported in ≥1% and <5% of patients receiving CYRAMZA with paclitaxel were sepsis (3.1%), including 5 fatal events, and gastrointestinal perforations (1.2%), including 1 fatal event.

REVEL:

• The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA with docetaxel at a rate of ≥5% and ≥2% higher than placebo with docetaxel were neutropenia (55% vs 46%), fatigue/asthenia (55% vs 50%), stomatitis/mucosal inflammation (37% vs 19%), epistaxis (19% vs 7%), febrile neutropenia (16% vs 10%), peripheral edema (16% vs 9%), thrombocytopenia (13% vs 5%), lacrimation increased (13% vs 5%), and hypertension (11% vs 5%).
• The most common serious adverse reactions with CYRAMZA with docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA with docetaxel-treated patients versus 37% in patients who received placebo with docetaxel.
• Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA with docetaxel-treated patients (9%) than in placebo with docetaxel-treated patients (5%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were IRR (0.5%) and epistaxis (0.3%).
• For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of Grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA with docetaxel compared to 6% overall incidence and 1% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of Grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA with docetaxel compared to 12% overall incidence and 2% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel.
• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA with docetaxel-treated patients in REVEL were hyponatremia (4.8%) and proteinuria (3.3%).

RAISE:

• The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA with FOLFIRI at a rate of ≥5% and ≥2% higher than placebo with FOLFIRI were diarrhea (60% vs 51%), neutropenia (59% vs 46%), decreased appetite (37% vs 27%), epistaxis (33% vs 15%), stomatitis (31% vs 21%), thrombocytopenia (28% vs 14%), hypertension (26% vs 9%), peripheral edema (20% vs 9%), proteinuria (17% vs 5%), palmar-plantar erythrodysesthesia syndrome (13% vs 5%), gastrointestinal hemorrhage events (12% vs 7%), and hypoalbuminemia (6% vs 2%). Twenty percent of patients treated with CYRAMZA with FOLFIRI received granulocyte colony-stimulating factors.
• The most common serious adverse reactions with CYRAMZA with FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).
• Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA with FOLFIRI-treated patients (29%) than in placebo with FOLFIRI-treated patients (13%). The most common adverse reactions leading to discontinuation of any component of CYRAMZA with FOLFIRI as compared to placebo with FOLFIRI were neutropenia (12.5% vs 5.3%) and thrombocytopenia (4.2% vs 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%).
• Clinically relevant adverse reaction reported in ≥1% and <5% of patients receiving CYRAMZA with FOLFIRI was gastrointestinal perforation (1.7%) including 4 fatal events.
• Thyroid-stimulating hormone (TSH) levels were evaluated in 224 patients (115 CYRAMZA with FOLFIRI-treated patients and 109 placebo with FOLFIRI-treated patients) with normal baseline TSH levels. Increased TSH levels were observed in 53 (46%) patients treated with CYRAMZA with FOLFIRI compared with 4 (4%) patients treated with placebo with FOLFIRI.

REACH-2:

• The most common adverse reactions (all Grades) observed in single agent CYRAMZA-treated HCC patients at a rate of ≥10% and ≥2% higher than placebo were fatigue (36% vs 20%), peripheral edema (25% vs 14%), hypertension (25% vs 13%), abdominal pain (25% vs 16%), decreased appetite (23% vs 20%), proteinuria (20% vs 4%), nausea (19% vs 12%), ascites (18% vs 7%), headache (14% vs 5%), epistaxis (14% vs 3%), insomnia (11% vs 6%), pyrexia (10% vs 3%), vomiting (10% vs 7%), and back pain (10% vs 7%).
• The most common serious adverse reactions with CYRAMZA were ascites (3%) and pneumonia (3%).
• Treatment discontinuations due to adverse reactions occurred in 18% of CYRAMZA-treated patients, with proteinuria being the most frequent (2%).
• Clinically relevant adverse reactions reported in ≥1% and <10% of CYRAMZA-treated patients in REACH-2 were IRR (9%), hepatic encephalopathy (5%) including 1 fatal event, and hepatorenal syndrome (2%) including 1 fatal event.

RB-P HCP ISI 05MAR2020

Please see full Prescribing Information for CYRAMZA.

IMPORTANT SAFETY INFORMATION FOR ALIMTA (pemetrexed for injection)

CONTRAINDICATION

• ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

WARNINGS AND PRECAUTIONS
Myelosuppression and Increased Risk of Myelosuppression Without Vitamin Supplementation

• ALIMTA can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation.
• Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued during treatment and for 21 days after the last dose of ALIMTA as they may reduce the severity of treatment-related hematologic and gastrointestinal toxicities. Obtain a complete blood count at the beginning of each cycle. Do not administer ALIMTA until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce ALIMTA in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles.
• In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the ALIMTA arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%.

Renal Failure

• ALIMTA can cause severe, and sometimes fatal, renal toxicity. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with ALIMTA.
• The incidences of renal failure in clinical studies in which patients received ALIMTA with cisplatin were 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received ALIMTA as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI).
• Withhold ALIMTA in patients with a creatinine clearance of less than 45 mL/min.

Bullous and Exfoliative Skin Toxicity

• Serious and sometimes fatal, bullous, blistering, and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/toxic epidermal necrolysis, can occur with ALIMTA. Permanently discontinue ALIMTA for severe and life-threatening bullous, blistering, or exfoliating skin toxicity.

Interstitial Pneumonitis

• Serious interstitial pneumonitis, including fatal cases, can occur with ALIMTA treatment. Withhold ALIMTA for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue ALIMTA.

Radiation Recall

• Radiation recall can occur with ALIMTA in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue ALIMTA for signs of radiation recall.

Increased Risk of Toxicity With Ibuprofen in Patients With Renal Impairment

• Exposure to ALIMTA is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of ALIMTA. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for ALIMTA adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity.

Embryo-Fetal Toxicity

• Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.

DRUG INTERACTIONS

• Ibuprofen increases exposure (AUC) of pemetrexed. In patients with creatinine clearance between 45 mL/min and 79 mL/min:
• Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA.
• Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

ADVERSE REACTIONS

• Severe adverse reactions (Grade 3-4) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were fatigue (12% vs 6%); diarrhea (5% vs 3%); dyspnea (3.7% vs 5%); vomiting (3.7% vs 3%); nausea (3.5% vs 3.5%); rash (2% vs 2.5%); decreased appetite (1.5% vs 0.5%); constipation (1% vs 0.5%); and pyrexia (0.2% vs 0%).
• Common adverse reactions (all grades) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were nausea (56% vs 52%); fatigue (56% vs 58%); constipation (35% vs 32%); diarrhea (31% vs 21%); decreased appetite (28% vs 30%); rash (25% vs 17%); vomiting (24% vs 23%); cough (21% vs 28%); dyspnea (21% vs 26%); and pyrexia (20% vs 15%).

USE IN SPECIFIC PATIENT POPULATIONS

• Lactation: There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from ALIMTA, advise women not to breastfeed during treatment with ALIMTA and for one week after the last dose.
• Males of Reproductive Potential: ALIMTA may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible.
• Pediatric Use: The safety and effectiveness of ALIMTA in pediatric patients have not been established. Adverse reactions observed in pediatric patients studied were similar to those observed in adults.
• Patients with Renal Impairment: ALIMTA is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function. No dose is recommended for patients with creatinine clearance less than 45 mL/min.
• Geriatric: The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials.

PM_HCP_ISI_NSCLC1L_Combo_30JAN2019

For safety and dosing guidelines for ALIMTA, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the full Prescribing Information and Patient Prescribing Information.

About Lilly Oncology
For more than 50 years, Lilly has been dedicated to delivering life-changing medicines and support to people living with cancer and those who care for them. Lilly is determined to build on this heritage and continue making life better for all those affected by cancer around the world. To learn more about Lilly's commitment to people with cancer, please visit www.LillyOncology.com.

About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and www.lilly.com/news. P-LLY 

© Lilly USA, LLC 2020. ALL RIGHTS RESERVED.

ALIMTA ^®, CYRAMZA ^®, Retevmo™ and Verzenio^® are trademarks owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

KEYTRUDA^® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 

Fulvestrant (Faslodex^®), MedImmune/AstraZeneca. MedImmune Limited/AstraZeneca provided fulvestrant for the MONARCH 2 trial.

Lilly Forward-Looking Statement
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Lilly's oncology portfolio and pipeline, including Retevmo, Verzenio, CYRAMZA and ALIMTA, and reflects Lilly's current belief.  However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. Among other things, there can be no guarantee that future study results will be consistent with the results to date or that Retevmo, Verzenio, CYRAMZA and ALIMTA will receive additional regulatory approvals or be (or continue to be) commercially successful.  For further discussion of these and other risks and uncertainties, see Lilly's most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

 

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