A Study of Amivantamab (JNJ-61186372) Among Participants With Advanced NSCLC Harboring ALK, ROS1, and RET Gene Fusions in Combination With Tyrosine Kinase Inhibitors (TKIs)

Inclusion criteria: Participant has locally advanced (unresectable) or metastatic NSCLC with a known RET fusion. Participants must have clinical progression on at least one prior RET therapy. They must be on a RET inhibitor at the same dose for at least 3 months prior to enrolling on this study. RET inhibitors that will be considered include but not limited to selpercatinib and pralsetinib. The patient cannot have received an EGFR TKI (e.g. osimertinib, afatinib), EGFR-directed monoclonal antibody (e.g. cetuximab), MET-inhibitor (e.g., tepotinib, capmatinib, telisotuzumab vedotin, etc.) at any point prior to study entry.

Sponsor/Collaborator: University of Colorado, Denver and Janssen Research & Development, LLC

Contact and Locations:
Study contact: Principal Investigator: Tejas Patil Febin Elias
Phone: 303-724-9459
Email: febin.elias@cuanschutz.edu
Locations: Colorado Research Center, Colorado Outpatient CTRC, UCHealth Metro Denver, University of Michigan Rogel Cancer Center

Mechanism of action: In many of these cases, increased activation of the (epidermal growth factor receptor (ERBB) or mesenchymal-epithelial transition (cMet) pathways appears to be a bypass signaling mechanism that allows cancer cells to circumvent the selective pressure from RET TKIs. Amivantamab is a bispecific antibody that binds to the extracellular domains of EGFR and MET.

Phases: Phase 1, Phase 2

NCT Number: NCT05845671

URL: https://classic.clinicaltrials.gov/ct2/show/NCT05845671

Status: Recruiting

This first-in-human (FIH) study for BNT116 aims to establish the safety profile and a safe dose for BNT116 monotherapy as well as for BNT116 in combination with approved medicinal products and/or in combination with investigational medicinal products (IMPs) including, but not limited to, cemiplimab, docetaxel, carboplatin, paclitaxel, osimertinib, anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), rearranged during transfection (RET) TKIs, BNT316 (an anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] antibody), an anti-B7-H3 antibody conjugated to a topoisomerase I inhibitor, an anti-human epidermal growth factor receptor 3 (HER3) antibody conjugated to a topoisomerase I inhibitor or a bispecific antibody for programmed death ligand 1 (PD-L1) and vascular endothelial growth factor A (VEGF-A) in participants with non-small cell lung cancer (NSCLC). The study will comprise several cohorts for dose confirmation in monotherapy as well as in combinations of BNT116 as mentioned above. The study will enroll participants with NSCLC in advanced or metastatic stage in Cohorts 1 to 4 and Cohorts 7 to 10, unresectable NSCLC Stage III in Cohorts 5 and 11, resectable NSCLC of Stage II and III in Cohort 6, advanced/metastatic epidermal growth factor receptor (EGFR)-mutant NSCLC in Cohort EGFR, and advanced/metastatic ALK rearranged or RET rearranged NSCLC in Cohort ALK/RET. Cohort EGFR and Cohort ALK/RET will enroll only at selected sites in the US.

Inclusion Criteria

• Participants must have histologically confirmed NSCLC and measurable disease by RECIST v1.1. Note: Participants in Cohorts 1, 5 and 11 do not have to present with measurable disease.
• Participants must present with unresectable Stage III or metastatic Stage IV NSCLC by American Joint Commission on Cancer (AJCC) Cancer Staging Manual, Eighth Edition. EXCEPT
• Participants in Cohorts 5 and 11 must present with unresectable Stage III NSCLC by AJCC Cancer Staging Manual, Eighth Edition before receiving pre-study chemoradiotherapy.
• Participants in Cohort 6 with the initial diagnosis of resectable Stage II and Stage III NSCLC by AJCC Cancer Staging Manual, Eighth Edition.
• Participants in Cohorts 2, 4, 5, 6, 10 and 11 must be able to tolerate (additional) anti-PD-1 therapy (i.e., did not permanently discontinue anti-programmed death protein 1 [PD-1] / programmed death ligand 1 [PD-L1] therapy due to toxicity).
• Participants must have an Eastern Cooperative Oncology Group performance status (ECOG-PS) less than or equal to (<=) 1, except for participants in Cohorts 1, 4, 5, 10 and 11 who are eligible with an ECOG-PS of 0-2. Cohort-specific inclusion criteria: Cohort 1:
• Participants' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen as well as one other line of systemic therapy (except if a participant is not candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor and/or another line of systemic therapy). Note: Participants newly enrolled in Cohort 1B under protocol v 5.0 and subsequent versions of the protocol must consent to mandatory blood sampling for peripheral blood mononuclear cells (PBMCs).
• Participants who are to start cemiplimab at Cycle 3 must present with PD-L1 expression of tumor proportion score (TPS) greater than or equal to (>=) 1% in tumor cells (as determined locally). Cohort 2:
• Participants must present with PD-L1 expression of tumor proportion score (TPS) >= 50% in tumor cells (as determined locally prior to inclusion in this study).
• Participants must present with progressive disease either
• in the advanced or metastasized stage of NSCLC: while on a PD-1/PD-L1 inhibitor therapy or within 6 months of termination of this treatment as first-line treatment. Or
• be refractory to ongoing adjuvant therapy/maintenance treatment after CRT with a PD-1/PD-L1 inhibitor that has been given for at least 3 months in monotherapy (i.e., after an initial combination therapy) before being enrolled into this study. Cohort 3:
• Participants' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a participant is not candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor).
• Participants must present with progressive disease. Cohort 4:
• Participants who are not candidates for chemotherapy as first-line treatment for the advanced or metastasized stage of NSCLC may be enrolled if presenting with PD-L1 expression: TPS >= 1% in tumor cells (as determined locally). Cohort 5:
• Participants' NSCLC must have been considered unresectable due to participant's condition and/or tumor-related factors and the participants must have undergone chemoradiotherapy before entering the study. Cohort 6:
• Participants' NSCLC must be considered technically and medically resectable.
• Participants must be considered eligible for neo-adjuvant treatment. Cohort 7:
• Participants' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a participant is not a candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor). Note 1: Participants may have received prior therapy targeting CTLA-4, lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain (TIGIT), VEGF or VEGF receptor (VEGFR) inhibitor as monotherapy or part of a combination therapy. Note 2: If the participants' prior therapies included a CTLA-4 inhibitor, the participant must be able to tolerate (additional) treatment with the CTLA-4 inhibitor.
• Participants must present with progressive disease at study enrollment.
• Participants must consent to mandatory blood sampling for PBMCs. Cohorts 8 & 9:
• Participants' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a participant is not a candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor).
• Participants must present with progressive disease at study enrollment. Cohort 10:
• Participants who are not candidates for chemotherapy as first-line treatment for the advanced or metastasized stage of NSCLC may be enrolled. Cohort 11:
• Participants' NSCLC must have been considered unresectable due to participants condition and/or tumor related factors and the participants must have undergone chemoradiotherapy before entering the study. Cohort EGFR (will enroll only at selected sites in the US):
• Participants' NSCLC must have classical EGFR mutations, i.e., ex19Del or L858R.
• Participants must have ongoing treatment with osimertinib. Cohort ALK/RET (will enroll only at selected sites in the US):
• Participants' NSCLC must have ALK rearrangement or RET rearrangement.
• Participants must have ongoing treatment with a standard of care ALK TKI or RET TKI. 

Exclusion Criteria:

• Ongoing active systemic treatment against NSCLC.
• Presence of a driver mutation for which approved target therapies are available except if the participant is not a candidate for the respective targeted therapy. EXCEPT participants in Cohort EGFR and Cohort ALK/RET.
• Ongoing or recent evidence (within the last 5 years) of significant autoimmune disease that required treatment with systemic immunosuppressive treatments which may suggest risk for immune-related adverse events. Note: Participants with autoimmune-related hyperthyroidism, autoimmune-related hypothyroidism who are in remission, or on a stable dose of thyroid-replacement hormone, vitiligo, or psoriasis may be included.
• Current evidence of new or growing brain or spinal metastases during screening. Participants with leptomeningeal disease are excluded. Participants with known brain or spinal metastases may be eligible for all Cohorts, except for Cohorts 5, 6 and 11, if they:

- had radiotherapy or another appropriate therapy for the brain or spinal metastases, AND
- have no neurological symptoms that can be attributed to the current brain lesions, AND
- have stable brain or spinal disease on the computed tomography (CT) or magnetic resonance imaging (MRI) scan within 4 weeks before signing the informed consent (confirmed by stable lesions on two scans at least 4 weeks apart), AND
- do not require steroid therapy for the treatment of brain or spinal metastases within 14 days before the first dose of study treatment. Note: Spinal bone metastases (that is, of the vertebrae) are allowed, unless imminent fracture or cord compression is anticipated.

Systemic immune suppression:

• Current use of chronic systemic steroid medication (<= 5 mg/day prednisolone equivalent is allowed); participants using physiological replacement doses of prednisone for adrenal or pituitary insufficiency are eligible. Note: Steroid medication given for supportive or prophylactic reasons during CRT for participants in Cohorts 5 and 11 needs to be tapered to <= 5 mg/day prednisolone equivalent at latest on the day before the study treatment starts.
• Other clinically relevant systemic immune suppression within the last 3 months before study enrollment.
• Known history of seropositivity for human immunodeficiency virus (HIV) with cluster of differentiation 4 (CD4)+ T-cell (CD4+) counts less than (<) 350 cells/microlitre (mcL) and with a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections.
• Prior splenectomy.
• History/risk of interstitial lung disease or low baseline lung function (baseline pulse oximetry of less than 92% oxygen saturation [SpO2] without additional oxygen). NOTE: Other protocol defined Inclusion/Exclusion criteria apply to all or some participants depending on the cohort.

Sponsor/Collaborator: Pfizer-BioNTech

Locations:
United States:

Kentucky
Lexington
University of Kentucky/Markey Cancer Center
Status:Temporarily closed to accrual

Maryland
Baltimore
Johns Hopkins University/Sidney Kimmel Cancer Center
Status:Approved

Ohio
Columbus
Ohio State University Comprehensive Cancer Center
Status:Approved

Texas
Houston
M D Anderson Cancer Center: Status:Active

NCT Number: NCT05142189

URL:
https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-10531

A study testing a the anti-TROP2 antibody-drug conjugate sacituzumab tirumotecan (MK-2870) versus chemotherapy in previously treated non-small cell lung cancer (NSCLC) with genomic alterations including RET

Inclusion criteria: Metastatic non-squamous NSCLC with RET alterations. Documentation of locally assessed radiological disease progression while on or after last treatment.

Sponsor/Collaborator: Merck Sharp & Dohme LLC

Contact and Locations:
Study email: Trialsites@msd.com
Phone Number: 1-888-577-8839
Locations (U.S. and outside the U.S.): https://clinicaltrials.gov/study/NCT06074588#study-overview

Mechanism of action: Sacituzumab tirumotecan is an investigational trophoblast cell-surface antigen 2 (TROP2)-directed antibody drug conjugate (ADC).

Phases: Phase 3

NCT Number: NCT06074588

URL: https://clinicaltrials.gov/study/NCT06074588#study-overview

Status: Recruiting

A Study of EP0031-101 in Patients With Advanced RET-altered Malignancies

Inclusion criteria: Advanced Solid Tumor. Patients with RET-altered tumors who have progressed following first-generation selective RET inhibitor (SRI) therapy and patients with RET-altered tumors with no prior SRI therapy.

Sponsor/Collaborator: Ellipses Pharma

Contact and Locations:
Study Contact: Sonia Serrano
Phone Number: +44 (0)20 3743 0992
Email: sonia@ellipses.life
Locations: https://clinicaltrials.gov/study/NCT05443126#contacts-and-locations

Mechanism of action: EP0031 selectively binds to various RET fusions and mutations, including solvent front resistance mutations.

Phases: Phase 1, Phase 2

NCT Number: NCT05443126

URL: https://clinicaltrials.gov/study/NCT05443126

Status: Recruiting

A Study of Selpercatinib After Surgery or Radiation in Participants With Non-Small Cell Lung Cancer (NSCLC)

Inclusion criteria: The reason for this study is to see if the study drug, selpercatinib, compared to placebo is effective and safe in delaying cancer return in participants with early-stage non-small cell lung cancer (NSCLC), who have already had surgery or radiation.

Sponsor/Collaborator: Loxo Oncology, Inc.|Eli Lilly and Company

Contact and Locations:
There may be multiple sites in this clinical trial
Email: ClinicalTrials.gov@lilly.com
Phone Number: 1-877-CTLILLY (1-877-285-4559)
Locations: https://clinicaltrials.gov/study/NCT04819100#contacts-and-locations

Mechanism of action: Selpercatinib, also known as LOXO-292, is a highly selective and potent, oral inhibitor for the treatment of patients with cancers that harbor abnormalities in the RET kinase

Phases: Phase 3

NCT Number: NCT04819100

URL: https://clinicaltrials.gov/study/NCT04819100

Status: Recruiting

 A Study of Multiple Therapies in Biomarker-Selected Patients With Resectable Stages IB-III Non-Small Cell Lung Cancer

Inclusion criteria: This trial will evaluate the efficacy and safety of various therapies in patients with Stage IB, IIA, IIB, IIIA, or selected IIIB resectable and untreated RET positive non-small cell lung cancer (NSCLC).

Sponsor/Collaborator: Genentech, Inc.|Blueprint Medicines Corporation|Chugai Pharmaceutical Co.|Hoffmann-La Roche

Contact and Locations:
Reference Study ID Number: ML41591
Email: global-roche-genentech-trials@gene.com
Phone Number: 888-662-6728
Locations: https://clinicaltrials.gov/study/NCT04302025#contacts-and-locations

Mechanism of action: Pralsetinib is a highly potent, selective RET inhibitor for the treatment of patients with cancers that harbor abnormalities in the RET kinase.

Phases: Phase 2

NCT Number: NCT04302025

URL: https://clinicaltrials.gov/study/NCT04302025

Status: Recruiting

Cabozantinib in Patients With RET Fusion-Positive Advanced Non-Small Cell Lung Cancer or Increased MET or AXL Activity

Inclusion criteria: The purpose of this phase II study is to find out what effects cabozantinib (XL184) has, good and/or bad, in patients whose tumors one of the following gene changes RET, ROS1, or NTRK fusion, or increased MET or AXL activity.

Sponsor/Collaborator: Memorial Sloan Kettering Cancer Center|Exelixis

Contact and Locations:
Study contact: Alexander Drilon, MD
Phone Number: 646-888-4206
Locations: https://clinicaltrials.gov/study/NCT01639508#contacts-and-locations

Mechanism of action: Cabozantinib is an oral medicine that inhibits of RET, ROS1, NTRK, MET, and AXL. In many of these cases, increased activation of the mesenchymal-epithelial transition (cMet) pathway appears to be a bypass signaling mechanism that allows cancer cells to circumvent the selective pressure from RET inhibitors.

Phases: Phase 2

NCT Number: NCT01639508

URL: https://clinicaltrials.gov/study/NCT01639508

Status: Recruiting

Real Word European Registry of NTRK Fusions and Other Rare Actionable Fusions (TRacKING)

Inclusion criteria: This registry will make it possible to describe real life management of patients with rare actionable fusions (including RET) and to better understand these cancers. In addition of clinical data from the medical files, a quality of life questionnaire (QLQ-C30) will be complete at inclusion, at each new treatment and then every 6 months. The patients will be followed for a period of at least 2 years after the inclusion.

Sponsor/Collaborator: Centre Leon Berard

Contact and Locations: 
Name: Julien Bollard
Phone Number: 04 78 78 28 28
Email: julien.bollard@lyon.unicancer.fr

Phases: Observational

NCT Number: NCT04921553

URL: https://classic.clinicaltrials.gov/ct2/show/NCT05653869

Status: Recruiting

Epidemiology of Young Lung Cancer Study (Participants needed)

Inclusion criteria: This study is open to adults who were diagnosed with lung cancer before age 50 and have completed comprehensive biomarker testing. Only individuals who live in the United States are eligible.

Sponsor/Collaborator: Dr. Jorge J. Nieva, ALCMI, GO2

Contact and Locations: 
Dr. Jorge J. Nieva, associate professor of clinical medicine at the University of Southern California’s Keck School of Medicine in Los Angeles.
ALCMI and GO
Phone: 888-44-EOYLC (888-443-6952)
https://happylungsproject.org/study-epidemiology-of-young-lung-cancer-study/

URL: https://alcmi.org/research/eoylc/

A Study of LP-300 With Carboplatin and Pemetrexed in Never Smokers With Advanced Lung Adenocarcinoma (HARMONIC)

Inclusion criteria: The goal of this clinical trial is to determine clinical advantages for LP-300 in combination with carboplatin and pemetrexed in the never smoker patient population Patients who are never smokers with lung adenocarcinoma and have relapsed after treatment with tyrosine kinase inhibitors (TKIs) will be eligible for enrollment.

Sponsor/Collaborator: Lantern Pharma Inc

Contact and Locations: 
https://www.harmonictrial.com/
Name: Ernest Kitt
Phone Number: 972-277-1136
Email: ekitt@lanternpharma.com

Mechanism of action: LP-300, works together with chemotherapy by interacting in the TK gene pathways, interrupting their activity to slow or prevent tumor growth and spread.

Phases: Phase 2

NCT Number: NCT05456256

URL: https://clinicaltrials.gov/study/NCT05456256

Status: Recruiting