LIBRETTO-431: A Multicenter, Randomized, Open-label, Phase 3 Trial Comparing Selpercatinib to Platinum-Pemetrexed Chemotherapy Plus Investigator*s Choice of Pembrolizumab in Patients with Advanced, Treatment-Naïve RET Fusion-Positive Non-Small Cell Lung Cancer

Rationale:

Patients with RET fusion-positive non-small cell lung cancer (NSCLC) represent
a population with high unmet need. Combination chemotherapy has short-term
palliative potential in advanced NSCLC. While anti-programmed cell death
protein 1 (anti-PD-1) monoclonal antibodies (e.g., nivolumab and pembrolizumab)
have extended progression-free survival (PFS) and recently been approved for
patients with NSCLC in some geographies, they may be less effective as
monotherapy in tumors marked by single-gene driver oncogenic kinase alterations
(including kinase fusions) with otherwise low mutation burdens and low
neo-antigen production.

The identification of activating genetic alterations in specific tyrosine
kinases has led to a new classification of NSCLC based on molecular genotype
rather than histology. Agents targeting specific alterations such as EGFR and
BRAF activating mutations and ALK and ROS1 gene fusions have demonstrated
compelling efficacy in patients with cancers that harbor the respective
activating genetic alteration. Selpercatinib, a selective RET tyrosine kinase
inhibitor, has demonstrated a favorable safety profile and evidence of durable
antitumor activity in patients with advanced RET fusion-positive patients with
NSCLC (both treatment naïve and those previously treated with approved
first-line chemotherapy with or without immunotherapy). As a result,
selpercatinib may be of benefit as an initial treatment for advanced or
metastatic RET fusion-positive NSCLC.

This study has been transitioned to CTIS with ID 2023-506783-14-00 check the CTIS register for the current data.

The proposed Study J2G-MC-JZJC (hereafter referred to as JZJC) will evaluate
selpercatinib in comparison to platinum-based (carboplatin or cisplatin) and
pemetrexed therapy with or without pembrolizumab in patients with locally
advanced or metastatic RET fusion-positive NSCLC.

Overall Design:

Study JZJC is a global, multicenter, randomized, open-label, controlled Phase 3
study of selpercatinib (Arm A) compared to platinum-based and pemetrexed
therapy with or without pembrolizumab (Arm B) in patients with locally advanced
or metastatic, RET fusion-positive non-squamous NSCLC. Enrolled patients will
be stratified based on geography (East Asian vs. non-East Asian), brain
metastases per investigator assessment (presence vs. absence), and
investigator*s choice of treatment if randomized to Arm B (with or without
pembrolizumab and cisplatin vs. carboplatin - choice/intent of treatment
regimen must be declared prior to randomization). Patients will be allowed
cross over from the comparator Arm B to Arm A upon confirmation of disease
progression by a blinded independent central review if they meet the
eligibility criteria for crossover. The primary endpoint being evaluated is
PFS per RECIST 1.1 by BICR

Disclosure Statement: This is a randomized, active treatment study with 2 arms
where the participant and investigator will not be blinded, but the aggregate
data in the clinical research database will be blinded to sponsor personnel.

You will get selpercatinib or one of the medication combinations listed below.
You will know which medicine you are taking. Whether you receive selpercatinib
or the medications listed below will be decided by chance. The chance that you
will receive selpercatinib is 2 in 3.

If you are not assigned to selpercatinib, your doctor will decide which of the
following combinations you will get:
• Cisplatin plus pemetrexed with pembrolizumab
• Cisplatin plus pemetrexed without pembrolizumab
• Carboplatin plus pemetrexed with pembrolizumab
• Carboplatin plus pemetrexed without pembrolizumab


Selpercatinib- Arm A- Tablets only

Comparator- Arm B- IV injection.

During the study, you will visit the hospital approximately 3 times a month,
the frequency of study visits may be higher than visits required as routine
practice by your doctor for looking after your illness, but these are required
for study participation. A visit will take approximately 2-4 hours during the
treatment period. The follow-up visits will take 1-2 hours.

Venapunction : Yes

Biopsy: Possible

Intra-venous injection: Possible if on Arm B

Refer to section E6 and J.