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 56th 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.
Refer
to:
|
Becky Polston;
becky.polston@lilly.com; 317-796-1028 (Lilly) – media
|
|
Kevin Hern;
hern_kevin_r@lilly.com; 317-277-1838 (Lilly) – investors
|
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SOURCE Eli Lilly and Company