INDIANAPOLIS, May 8, 2020 /PRNewswire/ -- Eli Lilly and
Company (NYSE: LLY) announced today that the U.S. Food and Drug
Administration (FDA) approved Retevmo™ (selpercatinib, 40 mg
& 80 mg capsules), the first therapy specifically indicated for
the treatment of adult patients with metastatic rearranged during
transfection (RET) fusion-positive non-small cell lung
cancer (NSCLC), and the treatment of adult and pediatric
patients 12 years of age and older with advanced or metastatic
RET-mutant medullary thyroid cancer (MTC) who require
systemic therapy, or advanced or metastatic RET
fusion-positive thyroid cancer who require systemic therapy and who
are radioactive iodine-refractory (if radioactive iodine is
appropriate). Retevmo was approved under the FDA's Accelerated
Approval regulations based on the LIBRETTO-001 Phase 1/2 trial's
endpoints of objective response rate (ORR) and duration of response
(DoR). Continued approval for these indications may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
Retevmo is a selective 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 based on weight, taken
twice daily until disease progression or unacceptable
toxicity.1
"In the clinical trial, we observed that the majority of
metastatic lung cancer patients experienced clinically meaningful
responses when treated with selpercatinib, including responses in
difficult-to-treat brain metastases," said Alexander Drilon, M.D., acting chief of early
drug development at Memorial Sloan Kettering Cancer Center and lead
investigator for LIBRETTO-001. "The approval of selpercatinib marks
an important milestone in the treatment of NSCLC, making
RET-driven cancers now specifically targetable in the same
manner as cancers with activating EGFR and ALK alterations, across
all lines of therapy. I am pleased that patients with these
RET-driven cancers have this newly approved option."
Retevmo was evaluated in the single-arm, multi-center Phase 1/2
LIBRETTO-001 trial, the largest trial (N=702) of patients with
RET-driven cancers. The trial enrolled both
treatment-naive patients and heavily pretreated patients with
a variety of advanced solid tumors including RET
fusion-positive NSCLC, RET-mutant MTC, RET
fusion-positive thyroid cancer, and certain other solid tumors with
RET alterations. Major efficacy outcomes were ORR and DoR,
assessed by a blinded independent review committee. Prespecified
secondary endpoints included central nervous system (CNS) ORR and
CNS DoR.
|
RET Fusion-Positive
NSCLC
|
RET-Mutant
MTC
|
RET Fusion-Positive Thyroid
Cancers
|
|
Systemic
Treatment
Naïve
|
Treatment
Experienced
|
Cabozantinib
/Vandetanib
Naïve
|
Cabozantinib
/Vandetanib
Experienced
|
Systemic
Treatment
Naïve
|
Treatment
Experienced
|
No. of
patients
|
39
|
105
|
88
|
55
|
8
|
19
|
ORR (95%
CI)
|
85 (70,
94)
|
64 (54,
73)
|
73 (62,
82)
|
69 (55,
81)
|
100 (63,
100)
|
79 (54,
94)
|
Median DoR,
months (95% CI)
|
NR (12,
NR)
|
17.5 (12,
NR)
|
22 (NR,
NR)
|
NR (19.1,
NR)
|
NR (NR,
NR)
|
18.4 (7.6,
NR)
|
|
NR=Not
Reached
|
Thyroid cancers
include: papillary, Hurthle cell, anaplastic, and poorly
differentiated
|
Up to 50 percent of patients with RET fusion-positive
NSCLCs can have tumors that metastasize to the brain.2
Among previously treated NSCLC patients with measurable brain
metastases, 10 out of 11 patients observed intracranial responses
(CNS ORR), with all 10 patients experiencing a CNS DoR of greater
than or equal to six months.
The labeling for Retevmo contains warnings and precautions for
hepatotoxicity (evidence of liver dysfunction), hypertension, QT
interval prolongation, hemorrhagic events, hypersensitivity, risk
of impaired wound healing, and embryo-fetal toxicity.
In the LIBRETTO-001 trial, there was a five percent
discontinuation rate due to adverse reactions (ARs). The most
common ARs, including laboratory abnormalities, (≥25 percent) 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 (swelling in the arms or legs), decreased platelets,
increased total cholesterol, rash, decreased sodium, and
constipation. In addition, the most frequent serious AR (≥ 2
percent) was pneumonia.
See Important Safety Information below and full Prescribing
Information for additional information, including dosing
modifications.
\"RET alterations account for the majority of medullary
thyroid cancers and a meaningful percentage of other thyroid
cancers. For patients living with these cancers, the approval of
selpercatinib means they now have a treatment option that
selectively and potently inhibits RET," said Lori J. Wirth, M.D., medical director of head
and neck cancers, Massachusetts General Hospital Cancer Center.
"Based on the published data for this new medicine, as well as my
personal experience treating patients, this may be a good treatment
option."
"We are extremely proud of how quickly the combined Loxo
Oncology and Lilly Oncology teams brought Retevmo to patients,
further demonstrating our commitment to delivering life-changing
medicines to people living with cancer," said Anne White, president of Lilly Oncology.
"Retevmo entered clinical trials in May of 2017 and is now approved
less than three years later, representing the most rapid timeline
in the development of an oncology medicine with multiple
indications. We applaud the FDA for their leadership and
collaboration, recognizing the importance of bringing a new therapy
to patients with advanced or metastatic RET-driven lung and
thyroid cancers."
Retevmo should only be used in advanced or metastatic patients
whose tumors have a RET fusion in NSCLC or thyroid cancer or
a RET mutation in MTC. This can be determined through
biomarker testing. Next-generation sequencing (NGS), either with
tumor tissue biopsy or liquid biopsy, can be an appropriate
biomarker test to determine actionable genomic alterations,
including RET. If NGS is not available, RET can be
detected using other biomarker testing methods. An FDA-approved
test for the detection of RET fusions and RET
mutations is not currently available. In LIBRETTO-001,
identification of a RET gene alteration was prospectively
determined in plasma or tumor tissue by local laboratories using
NGS, PCR, or FISH. Immunohistochemistry was not used in the
clinical trial.
"Increasingly, through the use of comprehensive biomarker
testing, patients with metastatic cancer have an opportunity to
receive a treatment tailored to the specific genomic nature of
their tumor," said Andrea Ferris,
president and chief executive officer at LUNGevity. "Retevmo
represents an important new advance in this growing field, as the
first therapy approved specifically for patients with
RET-driven tumors. We urge patients to ask their doctors
about broad biomarker tests that include RET
alterations."
Retevmo was granted orphan drug designation by the FDA for
the treatment of RET fusion-positive NSCLC and for the
treatment of RET fusion-positive and RET-mutant
thyroid cancers including poorly differentiated thyroid cancer,
undifferentiated or anaplastic thyroid cancer, MTC and locally
advanced or metastatic follicular or papillary thyroid cancer. The
two confirmatory Phase 3 trials (LIBRETTO-431 and
LIBRETTO-531) are currently enrolling patients.
Retevmo is expected to be available from specialty pharmacies
within one week.
Click here to view the metastatic RET fusion-positive
NSCLC fact sheet.
Click here to view the advanced RET-driven thyroid
cancers fact sheet.
Click here to view the broad panel biomarker testing fact
sheet.
Click here to view the Retevmo product fact sheet.
Click here to view the Retevmo product photo.
Click here to view the Retevmo logo.
Visit retevmo.com for more information.
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.3
About RET-Driven Cancers
Genomic
alterations in the RET kinase, which include fusions and
activating point mutations, lead to overactive RET signaling
and uncontrolled cell growth. RET fusions have been
identified in approximately 2 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. RET fusion-positive cancers and
RET-mutant MTC are primarily dependent on this single
activated kinase for their proliferation and survival. This
dependency, often referred to as "oncogene addiction," renders such
tumors highly susceptible to small molecule inhibitors targeting
RET. RET-driver alterations are predominantly
mutually exclusive from other oncogenic drivers.
About LIBRETTO-001
The LIBRETTO-001 Phase 1/2
trial was the largest clinical trial of patients
with RET-driven cancers treated with a RET
inhibitor. The trial included a dose escalation phase (Phase 1) and
a dose expansion phase (Phase 2). The Phase 2 portion of the trial
had major efficacy outcomes of ORR and DoR, and prespecified
secondary endpoints of CNS ORR and CNS DoR, as determined by an
independent review committee according to Response Evaluation
Criteria in Solid Tumors (RECIST v1.1). Results from the NSCLC
population were last presented at the 2019 IASLC World Congress on
Lung Cancer (WCLC), while results from the thyroid populations
were last presented at the European Society for Medical
Oncology (ESMO) 2019 Congress.
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.
Please see full Prescribing Information and Patient
Prescribing Information for Retevmo.
SE HCP ISI All_08MAY2020
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
health care 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
lilly.com and lilly.com/newsroom. P-LLY
Retevmo™ is a trademark owned by or licensed to Eli
Lilly and Company, its subsidiaries, or affiliates.
PP-SE-US-0220 05/2020
© Lilly USA, LLC 2020. ALL RIGHTS
RESERVED.
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
Retevmo (selpercatinib) for the treatment of metastatic RET
fusion-positive NSCLC, advanced or metastatic RET
mutation-positive MTC, and advanced or metastatic RET
fusion-positive thyroid cancer, 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 will be commercially
successful or receive additional regulatory approvals. 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.
1 Retevmo [package insert]. Indianapolis, IN: Eli Lilly and Company;
2020.
2 Drilon A, Lin JJ, Filleron T, et al. Frequency of
brain metastases and multikinase inhibitor outcomes in patients
with RET-rearranged lung cancers. J Thorac
Oncol. 2018;13(10):1595-1601.
3 RETEVMO [package insert]. Indianapolis, IN: Eli Lilly and Company;
2020.
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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