Journal of Oncology Pharmacy Practice - January 2022 - 176

176
Journal of Oncology Pharmacy Practice 28(1)
MTC. Three hundred and thirty patients were randomized
to receive cabozantinib 140 mg or placebo. The estimated
median progression-free survival (PFS) was 11.2 months
for patients in the cabozantinib arm compared to 4.0
months for patients in the placebo arm (HR=0.28; 95%
CI, 0.19-0.40; P< 0.001).12 The median PFS for patients
in the RET mutation positive subgroup was 13.9 months
for patients in the cabozantinib arm compared to 4.0 in
the placebo arm (HR= 0.15; 95% CI, 0.08-0.28; P<
0.0001). The median overall survival (OS) for patients in
the RET-mutation positive subgroup and placebo was
44.3 and 18.9 months, respectively (HR= 0.60; 95% CI,
0.38-0.94; P= 0.03).13 The efficacy of vandetanib was
assessed in a randomized, double-blind, multicenter phase
III trial where 331 patients with locally advanced or metastatic
MTC were randomized to receive either vandetanib
300 mg or placebo. Although the median PFS was not
reached for the patients in the vandetanib group, the predicted
median PFS was 30.5 months compared to 19.3
months for the placebo group.14 Cabozantinib and vandetanib
both proved to be efficacious compared to placebo.
However, due to the various off-target kinases of these
agents, significant adverse effects such as diarrhea and
hypertension, often occur and lead to discontinuation or
dosage adjustment.12,14,15 This treatment approach is not
ideal and led to the development of RET-specific agents.
There are currently two FDA-approved RET inhibitors,
selpercatinib which was approved in May 2020, and praseltinib
which was approved in September 2020.16-19 The goal
of these selective inhibitors is to achieve efficacy in those
with RET mutation tumors while minimizing toxicity.
The LIBRETTO-001 trial and the ARROW trial were conducted
to assess the safety and efficacy of selpercatinib and
praseltinib, respectively.20-23
Based on the preliminary data from these trials and FDA
approval, selpercatinib and pralsetinib are now recommended
as a first-line or subsequent therapy option for
patients with RET rearranged metastatic NSCLC. For
patients with RET-fusion positive thyroid tumors who are
not amenable to radioactive iodine (RAI) therapy, selpercatinib
or pralsetinib can be considered as well.
The objective of this article was to review the current
RET inhibitors for the use in patients with RET-mutated
cancers and their future directions. Table 1 outlines
dosing and drug interactions of each agent.
Selpercatinib
Efficacy
In May 2020, selpercatinib, the first RET-selective inhibitor,
was granted accelerated approval by the FDA for
advanced or metastatic RET fusion-positive NSCLC,
RET-mutant MTC, and RET fusion-positive thyroid
cancer.18
Table 1. Summary of RET inhibitors and multikinase inhibitors
that target RET.10,11,16,17
Acid suppressive
therapy
Agent
Dosing
Selpercatinib < 50 kg: 120
mg orally
twice daily
< 50 kg:
160 mg
orally
twice daily
Pralsetinib 400 mg orally
once daily
on empty
stomach
Cabozantinib 140 mg orally
once daily
on empty
stomach
Vandetanib 300 mg orally
once daily
interaction
PPI: take with
food H2RA:
take 2 h
before or 10 h
after Antacid:
take 2 h
before or after
N/A
Selected
metabolism/
transport effects
Substrate of
CYP3A4
(major)
Inhibitor of
CYP2C8
(moderate),
CYP3A4
(weak)
Substrate of
CYP3A4
(major), P-gp
N/A
Substrate of
CYP3A4
(major),
CYP2C9
N/A
Substrate of
CYP3A4
(major)
Inhibitor of
OCT2
H2RA: H2 receptor antagonist; PPI: proton pump inhibitor.
LIBRETTO-001 was an open-label, phase 1-2 trial that
included patients with any RET-altered solid tumor. All
patients received selpercatinib at doses ranging from 20
mg once daily to 240 mg twice daily during phase 1 and
160 mg twice daily during phase 2.20,21 There were 105
patients included in the NSCLC cohort with a median age
of 61 years (range, 23-81) who all had previously received
platinum-based chemotherapy. These patients were heavily
pretreated, having received a median of three previous systemic
therapy regimens (range, 1-15). The most common
fusion gene was KIF5B-RET (56%) followed by
CCDC6-RET (23%). In addition to platinum-based chemotherapy,
55% had received anti-programmed cell death
protein 1 (PD-1) or anti-programmed cell death ligand 1
(PD-L1) therapy and 48% had received at least one multitargeted
kinase inhibitor. Majority of patients in this
cohort had adenocarcinoma (86%) subtype and never
smoked (71%). About one-third of patients had brain
metastases. The overall response rate (ORR) was 64%
(95% CI, 54-73), with two complete responders and the
median PFS was 16.5 months (95% CI 13.7-not be estimated
(NE)) at a median follow-up of 13.9 months
(Table 2). Among 38 patients with brain metastases, 11
were deemed to have measurable lesions and 91% (10/11)
demonstrated an objective intracranial response to selpercatinib.
The study also evaluated 39 previously untreated
patients with advanced RET fusion-positive NSCLC.
Journal of Oncology Pharmacy Practice - January 2022

Table of Contents for the Digital Edition of Journal of Oncology Pharmacy Practice - January 2022
