What is the incidence of hypertension using Retsevmo® ▼ (selpercatinib)?

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.