FDA Alert| Selpercatinib accelerates approval for RET gene fusion-positive locally advanced or metastatic solid tumors

On September 21, 2022, the U.
S.
Food and Drug Administration (FDA) accelerated approval of the Selpercatinib extended indication for the treatment of patients
with locally advanced or metastatic solid tumors who carry positive RET gene fusions.
These patients have progressed during or after prior systemic therapy, or there are no other satisfactory alternative treatment options ^[1].

The approval was based on data from the Phase 1/2 LIBRETTO-001 trial (NCT03157128), a multicenter, open-label, multi-cohort trial that enrolled 41 patients with RET fusion-positive solid tumors (except non-small cell lung cancer and thyroid cancer).

RET fusion was detected by next-generation sequencing (NGS) in 97.
6% of patients and by FISH in 2.
4% of patients
.
Most patients (95%) have metastatic disease
.
90% of patients had received prior systemic therapy, with a median line of 2 (range, 0-9), and 32% had received ≥ 3 regimens
.

Results showed that the overall response rate (ORR) of selpercatinib in all populations was 44% (95% CI, 28%-60%), with 4.
9% achieving a complete response (CR) and 39% achieving a partial response (PR).

The median duration of response (DOR) for Selpercatinib was 24.
5 months (95% CI, 9.
2-NE), with remission lasting at least 6 months
in 67% of patients.

Types of tumors that achieve remission include pancreatic, colorectal, salivary gland cancer, unknown primary cancer, breast cancer, soft tissue sarcoma, bronchial carcinoid, ovarian, small bowel, and cholangiocarcinoma
.

➤ In 11 patients with pancreatic cancer, the ORR of selpercatinib was 55% (95% CI, 23%-83%), and the DOR ranged from 2.
5 months to more than
38.
3 months.

➤ Among 10 colorectal cancer patients, selpercatinib had an ORR of 20% (95% CI, 2.
5%-56%) and a DOR ranging from 5.
6 months to 13.
3 months
.

➤ In 4 patients with salivary cancer, selpercatinib had an ORR of 50% (95% CI, 7%-93%) and a DOR ranging from 5.
7 months to 28.
8+ months
.

➤ In 3 patients with cancer of unknown primary, selpercatinib had an ORR of 33% (95% CI, 0.
8%-91%) and a DOR of 9.
2 months
.

Regarding safety, the most common adverse reactions (≥25%) in patients included edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache
.

The LIBRETTTO trial, the largest RED inhibitor study to date, based on data from the non-small cell lung cancer (NSCLC) cohort and thyroid cancer cohort in the LIBRETTO-001 study, the FDA accelerated approval of selpercatinib in May 2020 for the treatment of patients with RET-positive NSCLC, medullary thyroid cancer, and other types of thyroid cancer, and the approval was converted from accelerated to traditional approval on September 21
。

Analytical data from the LIBRETTO-001 trial, updated at the 2022 European Conference on Lung Cancer (ELCC) ^[2], showed that among 247 patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy, the selpercatinib confirmed ORR was 61.
1% (95% CI, 54.
7%-67.
2%), with a CR rate of 7.
3%, a PR rate of 54%, and a median DOR of 28.
6 months (95% CI, 20-NE), 63% of patients achieved remission
lasting 12 months or more.

The confirmed ORR achieved with selpercatinib in 69 patients with treatment-naïve RET fusion-positive NSCLC was 84.
1% (95% CI, 73.
3%-91.
8%), with a CR rate of 5.
8% and a PR rate of 78%.

The median DOR was 20.
2 months (95% CI, 13-NE), and remission lasted at least 12 months
in half of patients.
In addition, in 26 patients with measurable central nervous system (CNS) metastases at baseline, selpercatinib produced a CNS-ORR of 84.
6%.

Of note, 22 of the 26 patients were confirmed to have the best response as complete or partial response
.

References:

FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors.
News release.
FDA.
September 21, 2022.
Accessed September 21, 2022.
 https://bit.
ly/3f8Wzr7

2.
Drilon A et al.
, Durability of efficacy and safety with selpercatinib in patients with RET fusion+ non-small-cell lung cancer: LIBRETTO-001.
ELCC 2022, abstract 27P.