Warnings
and Precautions
Blood
pressure should be optimized prior to starting selpercatinib. Do
not initiate selpercatinib in patients with uncontrolled
hypertension.1
Monitor
blood pressure during selpercatinib treatment and treat as needed
with standard anti-hypertensive therapy.1
Dosing
Modifications
Initiate
or adjust antihypertensive therapy as appropriate. Withhold, reduce
dose, or permanently discontinue selpercatinib based on the
severity (Table 1).1
Table
1. Dose Management for Hypertension1
Grade
|
Dose
Modification
|
1
or 2
|
No
action required.
|
3
|
Patient
blood pressure should be controlled before starting treatment.
Selpercatinib
should be suspended temporarily for medically significant
hypertension until controlled with antihypertensive therapy.
Dosing
should be resumed at the next lower dose if clinically indicated.
|
4
|
Selpercatinib
should be discontinued permanently if medically significant
hypertension cannot be controlled
|
LIBRETTO-001
Clinical Trial
LIBRETTO-001
is a multicenter, open-label, phase 1/2 study of selpercatinib
administered orally to patients with RET fusion-positive solid
tumors, RET-mutant MTC, and other tumors with RET
activation.1-4
In
the study, AEs were coded using the MedDRA, Version 21 and graded
using the NCI-CTCAE, Version 4.03.5
Hypertension
was defined as
a
sustained increase in blood pressure from baseline on ≥2 readings
on ≥2 separate occasions, or
a
clinically significant elevation requiring acute treatment.5
The
NCI-CTCAE grade definitions for the AE term “hypertension”
are shown in Table 2.
Table
2. NCI-CTCAE v 4.03 Grade Definitions for Hypertension6
Grade
|
Definition
|
1
|
Prehypertension
(SBP 120-139 mmHg or DBP 80-89 mmHg)
|
2
|
Stage
I HTN (SBP 140-159 mmHg or DBP 90-99 mmHg), medical intervention
indicated; recurrent or persistent (≥24 hours), symptomatic
increase by >20 mmHg (diastolic) or to >140/90 mmHg if
previously WNL, monotherapy indicated
|
3
|
Stage
2 HTN (SBP ≥160 mmHg or DBP ≥100 mmHg); medical intervention
indicated; more than one drug or more intensive therapy than
previously used indicated
|
4
|
Life-threatening
consequences (eg, malignant HTN, transient or permanent neurologic
deficit, hypertensive crisis); urgent intervention indicated
|
5
|
Death
|
Abbreviations:
DBP = diastolic blood pressure; HTN = hypertension; NCI-CTCAE =
National Cancer Institute-Common Terminology Criteria for Adverse
Events; SBP = systolic blood pressure; WNL = within normal limits.
Hypertension
Occurrence
In
the study of 746 patients, hypertension was among the most common
adverse reactions reported in the study (Table
3).1
Table
3. Incidence of Hypertension in LIBRETTO-001 (N=746)1,5
Preferred
Term, n (%)a
|
Grade
1
|
Grade
2
|
Grade
3
|
Grade
4
|
All
Grades
|
Hypertension
|
29
(4)
|
101
(14)
|
142
(19)
|
1
(0.1)
|
273
(37)
|
a
Data cut-off March 2020.
In
the study, 7 patients (1%) experienced an SAE of hypertension,
including 5 SAEs (1%) which were considered related to study drug.5
Selpercatinib
Dose Modifications and Antihypertensive Therapy
Hypertension
led to dose interruptions in 5% of patients and dose reductions in 1%
of patients. No patients discontinued study drug due to
hypertension.1,5
Treatment-emergent
hypertension was successfully managed through the addition or
adjustment of concomitant antihypertensive medications and
selpercatinib dose modifications. Most patients tolerated continued
therapy while receiving concomitant antihypertensive therapy such as
amlodipine.5
The
decision to add antihypertensive medication(s) should be made in
accordance with institutional guidelines and incorporating clinical
judgment. Lilly does not have any recommendation regarding which
antihypertensive medications should be used to treat
hypertension while on selpercatinib.
Patients
With A History of Hypertension
Approximately
41% of the population had a documented history of hypertension.
Although the overall incidence of treatment-emergent hypertension was
similar in patients with and without a history of hypertension (42%
vs 34%), patients with a preexisting history of hypertension
displayed a higher frequency of treatment-emergent grade 3
hypertension than patients without a documented history of
hypertension. During selpercatinib treatment, these patients also
were more likely to have had
an
antihypertensive medication added
a
preexisting antihypertensive medication regimen adjusted, and
a
selpercatinib dose modification.5
References
1.
Retsevmo [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
2.
Phase 1/2 study of LOXO-292 in patients with advanced solid tumors,
RET fusion-positive solid tumors, and medullary thyroid cancer
(LIBRETTO-001). ClinicalTrials.gov
identifier: NCT03157128. Updated July 2, 2020. Accessed January 11,
2020. https://www.clinicaltrials.gov/ct2/show/NCT03157128
3.
Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in
RET-altered thyroid cancers. N Engl J Med.
2020;383(9):825-835. https://dx.doi.org/10.1056/NEJMoa2005651
4.
Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in
RET fusion-positive non-small-cell lung cancer. N Engl J
Med. 2020;383(9):813-824.
https://dx.doi.org/10.1056/NEJMoa2005653
5.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
6.
US Department of Health and Human Services; National Institutes of
Health and National Cancer Institute. Common terminology criteria for
adverse events (CTCAE). Version 4.03.
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
Published May 28, 2009. Updated June 14, 2010. Accessed January 30,
2020.
Glossary
AE =
adverse event
CTCAE
= Common Terminology Criteria for Adverse Events
Lilly
= Eli Lilly and Company
MedDRA
= Medical Dictionary for Regulatory Activities
MTC
= medullary thyroid cancer
NCI
= National Cancer Institute
RET
= rearranged during transfection
SAE
= serious adverse event
▼ This
medicinal product is subject to additional monitoring. This will
allow quick identification of new safety information. Healthcare
professionals are asked to report any suspected adverse reactions.