Selpercatinib for Advanced Non-Small Cell Lung Cancer

(LIBRETTO-431 Trial)

Recruiting at 348 trial locations

Overseen By There will be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Eli Lilly and Company

Must not be taking: Steroids

Disqualifiers: Cardiovascular disease, CNS metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 31 months

261 Participants Needed

Trial Summary

What is the purpose of this trial?

The reason for this study is to see if the study drug selpercatinib compared to a standard treatment is effective and safe in participants with rearranged during transfection (RET) fusion-positive non-squamous non-small cell lung cancer (NSCLC) that has spread to other parts of the body. Participants who are assigned to the standard treatment and discontinue due to progressive disease have the option to potentially crossover to selpercatinib.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on chronic steroid treatment, you may not be eligible to participate.

What data supports the effectiveness of the drug Selpercatinib for advanced non-small cell lung cancer?

Research shows that Selpercatinib is effective in treating advanced non-small cell lung cancer with RET fusion, leading to strong and lasting responses, even in patients with brain metastases. It has been approved by the FDA for this use based on positive results from clinical trials, demonstrating its promise as a new treatment option. ^{1 2 3 4 5}

Is selpercatinib safe for humans?

Selpercatinib, also known as RETEVMO, has been shown to have an acceptable safety profile in clinical trials for advanced non-small cell lung cancer. Most side effects were manageable with dose adjustments, and only a few patients stopped treatment due to side effects. Common serious side effects included high blood pressure and elevated liver enzymes. ^{1 2 3 4 6}

How is the drug Selpercatinib unique for treating advanced non-small cell lung cancer?

Selpercatinib is unique because it is an oral medication specifically designed to target and inhibit the RET kinase, which is involved in certain genetic alterations in non-small cell lung cancer. It has shown strong and lasting responses, even in patients who have already undergone other treatments, and is effective in treating cancer that has spread to the brain. ^{1 2 3 7 8}

Research Team

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Eligibility Criteria

This trial is for adults with advanced non-squamous NSCLC that has spread and have a RET gene fusion. They must be in fairly good health, able to take pills, and not had certain treatments for metastatic disease. Women can't be pregnant or breastfeeding, and participants need effective birth control.

Inclusion Criteria

My cancer has a RET gene mutation.

I can take care of myself and am up and about more than half of my waking hours.

My blood, liver, and kidney functions are all within normal ranges.

Exclusion Criteria

I have no active cancer except for certain skin cancers, cervical pre-cancers, or any cancer that was treated over 2 years ago and is not currently active.

I haven't had radiotherapy for symptom relief within a week or high-dose lung radiotherapy in the last 6 months.

I need to take steroids regularly for my condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Selpercatinib or a combination of Pemetrexed and Platinum with or without Pembrolizumab

Up to 31 months

Crossover

Participants on standard treatment may crossover to Selpercatinib upon disease progression

Variable

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 38 months

Treatment Details

Interventions

• Selpercatinib

Trial Overview The study tests Selpercatinib against standard treatments (Pemetrexed, Pembrolizumab, Carboplatin, Cisplatin) for NSCLC with RET fusion. If standard treatment fails, patients may switch to Selpercatinib. The goal is to compare effectiveness and safety.

Participant Groups

Group I: Selpercatinib - Treatment A (TRT A) Experimental Treatment 1 Intervention

160 milligram (mg) Selpercatinib administered orally twice daily (BID) continuously in 21-day cycles.

Group II: Pemetrexed and Platinum with or without Pembrolizumab - (TRT B) Active Control 4 Interventions

Pemetrexed 500 milligrams per meter squared (mg/m2) administered intravenously (IV) on Day 1, every 3 weeks (Q3W), plus investigator's choice of carboplatin area under the concentration versus time curve 5 (AUC 5 \[maximum dose of 750 mg\] IV), or cisplatin (75 mg/m2 cisplatin IV) on Day 1 Q3W for 4 cycles, plus investigator's choice with or without 200 mg pembrolizumab IV on Day 1 Q3W up to 35 cycles.

Selpercatinib is already approved in United States, European Union for the following indications:

Approved in United States as RETEVMO for:

• RET fusion-positive or RET mutant thyroid cancers
• non-small cell lung cancer
• advanced or metastatic medullary thyroid cancer
• advanced or metastatic thyroid cancer with RET gene fusion
• locally advanced or metastatic solid tumors with RET gene fusion

Approved in European Union as RETEVMO for:

• RET-driven non-small cell lung cancer
• medullary thyroid cancer
• thyroid cancer

Who Is Running the Clinical Trial?

Eli Lilly and Company

Lead Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Loxo Oncology, Inc.

Industry Sponsor

Trials

72

Recruited

11,600+

Jacob Van Naarden

Loxo Oncology, Inc.

Chief Executive Officer since 2019

A.B. in Molecular Biology from Princeton University

Dr. Jennifer Low

Loxo Oncology, Inc.

Chief Medical Officer since 2014

MD and PhD from Georgetown University; Undergraduate degree from California Institute of Technology

Findings from Research

Selpercatinib (RETEVMO™) is a targeted therapy that inhibits the RET receptor tyrosine kinase, specifically designed for cancers with RET alterations.

It received FDA approval based on the promising results from the phase I/II LIBRETTO-001 trial for treating RET fusion-positive non-small-cell lung cancer, RET fusion-positive thyroid cancer, and RET-mutant medullary thyroid cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selpercatinib: First Approval. Markham, A.[2021]

Selpercatinib is an effective oral treatment for advanced RET fusion-positive non-small cell lung cancer (NSCLC), showing strong and lasting responses in both previously treated and treatment-naïve patients during a pivotal phase 1/2 clinical trial.

The drug has a manageable safety profile, with most adverse events being manageable through dose adjustments, and only a small number of patients discontinuing treatment due to side effects, which primarily included hypertension and elevated liver enzymes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selpercatinib: A Review in Advanced RET Fusion-Positive NSCLC. Nie, T., Syed, YY.[2023]

Selpercatinib showed a high objective response rate (ORR) of 84% in treatment-naive patients and 61% in those previously treated with platinum-based chemotherapy, indicating its efficacy in RET fusion-positive non-small-cell lung cancer (NSCLC).

The treatment demonstrated durable responses, with a median duration of response (DoR) of 20.2 months for treatment-naive patients and 28.6 months for those pretreated, along with a significant intracranial ORR of 85% in patients with CNS metastasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial. Drilon, A., Subbiah, V., Gautschi, O., et al.[2023]

In a case series of 8 patients with RET-altered advanced non-small-cell lung cancer (NSCLC) and brain metastases, selpercatinib showed a high overall systemic response rate of 75%, with significant intracranial activity where 80% of patients with measurable CNS lesions achieved a confirmed response.

Despite 63% of patients experiencing grade ≥3 treatment-related adverse events, there were no treatment discontinuations due to these adverse effects, indicating that selpercatinib can be administered safely while providing meaningful clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial Activity of Selpercatinib in Chinese Patients With Advanced RET Fusion-Positive Non-Small-Cell Lung Cancer in the Phase II LIBRETTO-321 Trial. Cheng, Y., Huang, D., Zhou, J., et al.[2023]

Selpercatinib, a selective RET inhibitor, demonstrated a high objective response rate (ORR) of 87.2% in patients with RET-fusion-positive advanced non-small-cell lung cancer (NSCLC) compared to 66.7% in a real-world control group, indicating its efficacy as a treatment option.

After adjusting for patient characteristics, selpercatinib showed significantly better outcomes in terms of progression-free survival and overall survival compared to both real-world and clinical trial control cohorts, although the findings should be interpreted cautiously due to limitations in data and assumptions made.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

External control cohorts for the single-arm LIBRETTO-001 trial of selpercatinib in RET+ non-small-cell lung cancer. Rolfo, C., Hess, LM., Jen, MH., et al.[2022]

In a study of 329 patients with RET fusion-positive NSCLC, 7% experienced hypersensitivity reactions to selpercatinib, with a higher incidence in patients previously treated with immune checkpoint inhibitors (ICIs) (77% of cases).

Hypersensitivity reactions to selpercatinib were manageable with supportive care, and many patients were able to continue treatment after dose modifications, indicating that while there is a risk, it is generally low and reversible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypersensitivity Reactions to Selpercatinib Treatment With or Without Prior Immune Checkpoint Inhibitor Therapy in Patients With NSCLC in LIBRETTO-001. McCoach, CE., Rolfo, C., Drilon, A., et al.[2022]

Selpercatinib is a highly effective RET-selective tyrosine kinase inhibitor, showing strong efficacy and safety in treating advanced non-small-cell lung cancer (NSCLC) with RET fusions, which are common genetic alterations in this cancer type.

The drug is currently approved for adult patients with metastatic RET fusion-positive NSCLC, and it demonstrates both systemic and intracranial efficacy, making it a promising treatment option in the evolving landscape of targeted cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selpercatinib in RET-fusion positive metastatic non-small cell lung cancer: achievements and gray areas. Belluomini, L., Avancini, A., Pasqualin, L., et al.[2022]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Selpercatinib: First Approval. [2021]

2. France pubmed.ncbi.nlm.nih.gov

Selpercatinib: A Review in Advanced RET Fusion-Positive NSCLC. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Intracranial Activity of Selpercatinib in Chinese Patients With Advanced RET Fusion-Positive Non-Small-Cell Lung Cancer in the Phase II LIBRETTO-321 Trial. [2023]

5. England pubmed.ncbi.nlm.nih.gov

External control cohorts for the single-arm LIBRETTO-001 trial of selpercatinib in RET+ non-small-cell lung cancer. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Hypersensitivity Reactions to Selpercatinib Treatment With or Without Prior Immune Checkpoint Inhibitor Therapy in Patients With NSCLC in LIBRETTO-001. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Selpercatinib in RET-fusion positive metastatic non-small cell lung cancer: achievements and gray areas. [2022]

8. Japan pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety Analysis of Selpercatinib in Patients with RET Fusion-Positive Non-Small Cell Lung Cancer-Results from the Japanese Subset of a Global Phase 1/2 Study]. [2022]