Could hemorrhagic events occur with Retsevmo® ▼ (selpercatinib)?

Warnings and Precautions

Serious including fatal hemorrhagic events can occur with selpercatinib. Permanently discontinue selpercatinib in patients with severe or life-threatening hemorrhage.¹

Dosing Modifications for Hemorrhagic Events

Modification guidelines for hemorrhagic events are provided in Table 1.¹

Table 1. Dose Management for Hemorrhagic Events¹

Grade	Dose Modification
Grade 1 or 2	No dose modification is required.
Grade 3 or 4	Hold dose until toxicity resolves . Discontinue selpercatinib for severe or life-threatening hemorrhagic events.

Selpercatinib and Hemorrhagic Events

Clinical Trial Experience

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

Serious including fatal hemorrhagic events can occur with selpercatinib. Grade ≥3 hemorrhagic events occurred in 2% of patients treated with selpercatinib including 3 (0.4%) patients with fatal hemorrhagic events of

• cerebral hemorrhage (1)

• tracheostomy site hemorrhage (1), and

• hemoptysis (1).¹

Overall, 17% of the LIBRETTO-001 population experienced a grade ≤4 hemorrhagic event with 2% of the events being grades 3/4. Of the grades 3/4 events, there was one grade 4 event of hematemesis.^1,5

Forty-one preferred terms were included in the hemorrhage analysis. The grade 1/2 events (%) that occurred in ≥1% of the population were  

• epistaxis (5)

• hematuria (3)

• contusion (2)

• hemoptysis (2)

• rectal hemorrhage (1), and

• vaginal hemorrhage (1).⁵

Of the grade 1/2 events (%) that occurred in ≥1% of the population, those considered related to selpercatinib were

• epistaxis (8)

• contusion (2)

• hematuria (3), and

• vaginal hemorrhage.⁵

Grade ≥3 hemorrhagic events occurred in 2% of patients treated with selpercatinib including 3 (0.4%) patients with fatal hemorrhagic events, as seen in Table 2.^1,5

Table 2. Grade ≥3 Hemorrhagic Events in the LIBRETTO-001 (N=746)⁵

	Severity by Gradea
Event, n (%)b	Grade 3	Grade 4	Grade 5
Gastric hemorrhage	1 (0.1)	NA	NA
Abdominal wall hemorrhage	1 (0.1)	NA	NA
Anal hemorrhage	1 (0.1)	NA	NA
Contusion	1 (0.1)	NA	NA
Cerebral hemorrhage	1 (0.1)	NA	1 (0.1)
Diverticulum intestinal hemorrhagic	1 (0.1)	NA	NA
GI hemorrhage	1 (0.1)	NA	NA
Hematemesis	N/A	1 (0.1)	NA
Hemorrhage intracranial	1 (0.1)	NA	NA
Hemoptysis	1 (0.1)	NA	1 (0.1)
Intra-abdominal hemorrhage	1 (0.1)	NA	NA
Pelvic hematoma	1 (0.1)	NA	NA
Postprocedural hemorrhage	N/A	NA	1 (0.1)
Retroperitoneal hematoma	1 (0.1)	NA	NA
Subdural hemorrhage	1 (0.1)	NA	NA
Traumatic hematoma	1 (0.1)	NA	NA
Upper GI hemorrhage	1 (0.1)	NA	NA

Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; GI = gastrointestinal; NA = not applicable.

^a Severity grade assignment based on CTCAE (v4.03): grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening/debilitating), and grade 5 (fatal).

^b Data cut-off March 2020.

Of the grade 3/4 TEAEs that occurred in LIBRETTO-001, hemorrhage intracranial (1 patient) and retroperitoneal hematoma (1 patient) were considered related to selpercatinib.⁵

Serious Adverse Events

Of the reported hemorrhagic TEAEs, those considered serious and related were hemorrhage intracranial (2 patients) and retroperitoneal hematoma (1 patient).⁵

Fatal Hemorrhagic Events

The fatal hemorrhagic events reported in LIBRETTO-001 were 

• cerebral hemorrhage

• hemoptysis, and

• postprocedure hemorrhage.¹

None of the fatal events were considered to be related to selpercatinib.⁵

Dosing Modification

Selpercatinib-related dose reductions occurred due to eye hemorrhage (1 patient) and hemorrhage intracranial (1 patient). One patient discontinued selpercatinib due to retroperitoneal hematoma considered related to study drug.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 25, 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.

Glossary

MTC = medullary thyroid cancer

RET = rearranged during transfection

TEAE = treatment-emergent 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.