INDIANAPOLIS, April 11, 2021 /PRNewswire/ -- Eli Lilly and
Company (NYSE: LLY) today announced for the first time data from
the Phase 1/2 LIBRETTO-001 trial showing treatment with
Retevmo® (selpercatinib) demonstrated encouraging
antitumor activity and safety across RET fusion-positive
advanced solid tumors beyond lung and thyroid cancers, including
multiple treatment-refractory gastrointestinal (GI) malignancies.
The data were presented at the 2021 American Association for Cancer
Research (AACR) Annual Meeting, held virtually April 10-15, 2021.
"We are excited to broaden the body of evidence for Retevmo in
RET fusion-positive cancers beyond lung and thyroid tumors,"
said David Hyman, M.D., chief
medical officer, oncology at Lilly. "These encouraging outcomes,
including in difficult-to-treat GI malignancies, support a growing
body of evidence that RET fusions are potentially actionable
in a wide range of tumor types. These findings further demonstrate
the importance of broad tumor profiling in advanced cancers. We
look forward to discussing these new data with regulatory
authorities this year."
In the Phase 1/2 LIBRETTO-001 trial, 32 adult patients with 12
unique RET fusion-positive advanced cancer types were
enrolled by the efficacy cutoff date of September 19, 2020 (with follow-up through
March 19, 2021). Cancer types treated
included pancreatic, colon, breast, salivary, sarcoma, carcinoid,
rectal neuroendocrine, small intestine, xanthogranuloma, ovarian,
pulmonary carcinosarcoma, and unknown primary cancers. Among the 32
patients, 62.5 percent had gastrointestinal tumors (defined as
pancreatic [n=9], colon [n=9], small intestine [n=1], and rectal
neuroendocrine [n=1]). Across all 32 patients, the confirmed
objective response rate (ORR) was 47 percent (95% CI: 26-65%).
Confirmed responses were observed in nine unique RET
fusion-positive advanced cancer types. The median duration of
response (DoR) was not reached, with median follow-up of 13 months.
Responses were ongoing in 73 percent (11/15) of responding
patients.
Retevmo
Efficacy
|
Objective Response
Rate* % (95% CI)
|
47% (29-65),
n=32
|
Median Duration of
Response (range)
|
Not Reached (2 -33+
months)
|
Responses
Ongoing
|
73%
(11/15)
|
Median Duration of
Follow up
|
13 months
|
* per investigator assessment, + indicates patient
ongoing
Safety among patients in this cohort was consistent with the
known safety profile of Retevmo. In this cohort, the most common
treatment-emergent adverse events of any grade (≥20%) were
increased aspartate aminotransferase (AST)/increased alanine
aminotransferase (ALT), dry mouth, hypertension, diarrhea, fatigue,
nausea, and abdominal pain. No patients in this cohort discontinued
treatment due to treatment-related adverse events.
"While uncommon, RET fusions occur in a 'long tail' of
solid tumors beyond lung and thyroid cancers, and these patients do
not yet have an approved targeted therapy option to address the
underlying genomic driver of their cancer," said Vivek Subbiah, MD, associate professor in the
Investigational Cancer Therapeutics Department and center clinical
medical director of the Clinical Center for Targeted Therapy, of
the Cancer Medicine Division, at The University of Texas MD Anderson Cancer Center.
"These results demonstrate selpercatinib's potential for this
patient population and reiterate the importance of
broad-based genomic profiling to identify actionable oncogenic
drivers, including RET fusions."
In May 2020, Lilly's
first-in-class selective RET inhibitor Retevmo received Accelerated
Approval from the U.S. Food and Drug Administration (FDA) for the
treatment of adult patients with metastatic RET
fusion-positive non-small cell lung cancer (NSCLC), in adult and
pediatric patients 12 years of age and older with advanced or
metastatic RET-mutant medullary thyroid cancer (MTC) who
require systemic therapy, and in adult and pediatric patients 12
years of age and older with 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 based on the Phase 1/2
LIBRETTO-001 trial's endpoints of ORR and DoR. Retevmo (marketed as
Retsevmo® outside the U.S.) was approved by the European
Commission in February 2021.
About LIBRETTO-001
The Phase 1/2 LIBRETTO-001 trial is the largest clinical trial
of patients with RET-driven cancers treated with a RET
inhibitor. The trial, which spans 16 countries and 89
sites, 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 central nervous system (CNS) ORR and CNS DoR, as
determined by an independent review committee according to Response
Evaluation Criteria in Solid Tumors (RECIST) v1.1.
LIBRETTO-001 continues to enroll patients with
RET-altered tumors beyond lung cancer.
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. RET-driver alterations are
predominantly mutually exclusive from other oncogenic drivers.
Retevmo is an U.S. FDA-approved oral prescription medicine, 120 mg
or 160 mg dependent on weight (<50 kg or ≥50 kg, respectively),
taken twice daily until disease progression or unacceptable
toxicity.i Continued approval may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
IMPORTANT SAFETY INFORMATION FOR
RETEVMO® (selpercatinib)
Hepatotoxicity: Serious hepatic adverse reactions
occurred in 2.6% of patients treated with Retevmo. Increased
aspartate aminotransferase (AST) occurred in 51% of patients,
including Grade 3 or 4 events in 8% and increased alanine
aminotransferase (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 prednisone (or
equivalent). 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.
Tumor lysis syndrome (TLS) occurred in 1% of
patients with medullary thyroid carcinoma receiving Retevmo.
Patients may be at risk of TLS if they have rapidly growing tumors,
a high tumor burden, renal dysfunction, or dehydration. Closely
monitor patients at risk, consider appropriate prophylaxis
including hydration, and treat as clinically indicated.
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%).
Serious adverse reactions occurred in 33% of
patients who received Retevmo. The most frequently reported serious
adverse reaction (in ≥ 2% of patients) was pneumonia.
Fatal adverse reactions occurred in 3% of patients; fatal
adverse reactions which occurred in >1 patient included sepsis
(n=3), cardiac arrest (n=3) and respiratory failure (n=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
(35%), 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 decreases
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 increases 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 decreases 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 increases 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. Monitor open growth plates in adolescent
patients. Consider interrupting or discontinuing Retevmo if
abnormalities occur.
No dosage modification is recommended for patients with mild
to severe renal impairment (estimated Glomerular Filtration
Rate [eGFR] ≥15 to 89 mL/min, estimated by Modification of Diet in
Renal Disease [MDRD] equation). A recommended dosage has not been
established for patients with 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 for Retevmo.
SE HCP ISI All_25MAR2021
About Loxo Oncology at Lilly
Loxo Oncology at Lilly was created in December 2019, combining the Lilly Research
Laboratories oncology organization and Loxo Oncology, which was
acquired by Lilly in early 2019. Loxo Oncology at Lilly brings
together the focus and spirit of a biotech with the scale and
resources of large pharma, with the goal of rapidly delivering
impactful new medicines for people with cancer. Our approach
centers on creating new oncology medicines that unequivocally work
early in clinical development and will matter to patients.
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
© Lilly USA, LLC 2021. ALL
RIGHTS RESERVED.
Retevmo® and Retsevmo® are trademarks
owned by or licensed to Eli Lilly and Company, its subsidiaries, or
affiliates.
Lilly Cautionary Statement Regarding Forward-Looking
Statements
This press release contains forward-looking statements (as that
term is defined in the Private Securities Litigation Reform Act of
1995) about 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 as a
potential treatment for other indications, and reflects Lilly's
current beliefs and expectations. However, as with any
pharmaceutical product, there are substantial risks and
uncertainties in the process of development and commercialization.
Among other things, there is no guarantee that future study results
will be consistent with study findings to date or that Retevmo will
receive additional regulatory approvals. For further discussion of
these and other risks and uncertainties, see Lilly's 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.
i RETEVMO [package insert]. Indianapolis,
IN: Eli Lilly and Company; 2021.
Refer
to:
|
Tracy Henrikson;
tracy.henrikson@lilly.com; (609) 454-7116 (Lilly) –
media
|
|
Kevin Hern;
hern_kevin_r@lilly.com; 317-277-1838 (Lilly) – investors
|
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