Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-Mutated, Non-Small Cell Lung Cancer After Treatment With Osimertinib

Lung Neoplasms Clinical Trial

Official title: A Pilot Study of Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-mutated, Non-Small Cell Lung Cancer (NSCLC) After Treatment With Osimertinib (AZD9291, Tagrisso)

Status Completed

Clinical Trial Summary

Background:

Some non-small-cell lung cancers (NSCLC) have a mutation in a gene that makes a protein called EGFR. This particular cancer can be treated with certain drugs such as erlotinib (Tarceva), gefitinib (Iressa) and osimertinib (Tagrisso). But many tumors become resistant to these drugs because of a second mutation. Researchers want to test if adding local ablative therapy (LAT) extends the benefits of the drug, osimertinib. LAT can include techniques such as surgery, radiofrequency ablation, cryotherapy or radiation therapy.

Objective:

To test if re-taking osimertinib after LAT is safe, tolerable, and effective for people whose NSCLC has progressed after initial treatment with osimertinib.

Eligibility:

Adults ages 18 and older with certain types of NSCLC. Participants will be divided into various groups as described below.

Design:

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

Tumor scans

Eye exam

Review of tumor sample.

Participants will take the study drug by mouth once a day. They will continue until they can no longer tolerate it or their disease worsens. They will keep a dosage diary.

All participants will start each 21-day course with physical exam; blood, urine, and saliva tests; and electrocardiogram. They will have scans every 6 weeks and echocardiogram every 3 months.

Groups 1 and 2 will:

Start osimertinib right away.

Have LAT if their disease progresses and is suitable for LAT. If LAT cannot be performed or LAT consists of a procedure other than surgery, a tumor biopsy will be performed.

Re-start osimertinib after LAT, or other treatments if not suitable for LAT.

Group 3 will:

Have LAT.

If LAT consists of a procedure other than surgery, a tumor biopsy will be performed.

Start osimertinib after LAT.

After participants stop taking the drugs, they will have a final visit. This will include:

Medical history

Physical exam

Blood tests

Participants will be called every year for follow-up.

Clinical Trial Description

Background:

• Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have significantly improved the response rate (RR) and survival in patients with tumors harboring EGFR-sensitizing mutations.

• An invariable consequence of treatment with EGFR-TKIs is the development of acquired resistance. The most common mechanism of resistance observed in approximately 50% of all cases in patients treated with 1st and 2nd generation EGFR-TKIs is the emergence of a secondary mutation (T790M) in exon 20.

• Osimertinib is a 3rd-generation EGFR-TKI designed to target the T790M mutation, which has shown impressive responses in both first- and second-line settings.

• Despite these developments, it is almost certain that selection pressure will lead to the emergence of newer clones that are resistant to treatment with osimertinib. One common mechanism of acquired resistance to osimertinib is the generation of EGFR C797S mutation.

• The use of local ablative therapies for patients who develop limited metastatic disease or oligoprogressive disease on EGFR-TKI therapy is promising.

• We hypothesize that following local ablative therapy to treat oligoprogressive disease after emergence of resistance, osimertinib can be resumed safely and re-initiation of osimertinib results in additional progression-free survival benefits.

Objectives:

• Determine the safety, tolerability, and efficacy (as assessed by progression free survival (PFS) upon re-initiation of osimertinib following local ablative therapy (LAT) for patients with oligoprogressive disease after treatment with osimertinib

• Assess mechanisms of acquired resistance to osimertinib

Eligibility:

• Histologically confirmed advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation and no prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1); OR progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (Cohort 2); or patients with progressive disease after treatment with osimertinib who are eligible for local ablative therapy (Cohort 3). If biopsy for EGFR mutation status confirmation is not clinically feasible, EGFR mutations may be confirmed by circulating tumor deoxyribonucleic acid (ctDNA) analysis using a Clinical Laboratory Improvement Amendments of 1988 (CLIA) certified assay.

• Presence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Adequate end organ function

• If patients are not eligible for LAT, they will be referred for standard of care chemotherapy as per treating physician's discretion. These patients may also be considered for other clinical trials.

Design:

• This is a single-institution, open-label phase II trial of osimertinib treatment in EGFR mutant lung cancer.

• Eligible patients not previously treated with osimertinib will be treated with osimertinib daily until disease progression. At the time of progression, patients with oligoprogressive disease (no more than 5 sites of progressive disease) will be assessed for LAT.

• If patients are eligible for LAT, osimertinib will be resumed after LAT and they will be followed for second progression on osimertinib (PFS2).

• If patients progress at the same site where LAT has been performed before, the progression will be considered to be a result of inadequate ablation and they will be considered for repeat LAT and again re-challenged with osimertinib if clinically feasible.

• Tumor samples will be obtained at baseline by a mandatory biopsy. At the time of first progression on osimertinib if a patient is eligible for surgery as a form of LAT, then a tissue sample will be obtained for genomic and proteomic studies to identify mechanisms of acquired resistance. For patients who are not eligible for LAT or a form of LAT that is not surgery (radiation, radiofrequency ablation, cryoablation), then a mandatory biopsy will be performed, if clinically safe, to obtain tissue for above studies.

• Re-treatment will be allowed for a small number of subjects. ;

Related Conditions & MeSH terms

• Adenocarcinoma of Lung
• Lung Adenocarcinoma
• Lung Neoplasms

• NCT number: NCT02759835
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 2
• Start date: April 13, 2016
• Completion date: September 20, 2022