Local Ablative Therapy of Oligoprogressive Disease Prolongs Disease Control by Tyrosine Kinase Inhibitors in Oncogene-Addicted Non–Small-Cell Lung Cancer

Abstract

Introduction Many patients with oncogene driven non-small cell lung cancer treated with TKIs experience limited sites of disease progression. This study investigated retrospectively the benefits of local ablative therapy (LAT) to CNS and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively. Materials and Methods Patients with metastatic ALK+ NSCLC treated with crizotinib (n=38) and EGFR-MT NSCLC treated with erlotinib (n=27) were identified at a single institution. Initial response to the respective kinase inhibitors, median progression free survival (PFS1) and site of first progression were recorded. A subset of patients with either non-leptomeningeal CNS and/or ≤4 sites of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same TKI. The subsequent median progression free survival from the time of first progression (PFS2) and pattern of progression were recorded. Results PFS1 in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. 25 of 51 (49%) patients who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, 1 with surgery, and continuation of the same targeted therapy. Post LAT, 19/25 patients progressed again, with median PFS2 of 6.2 months Discussion Oncogene addicted NSCLC with CNS and/or limited systemic disease progression (oligoprogressive disease) on relevant targeted therapies is often suitable for LAT and continuation of the targeted agent, and is associated with >6 months of additional disease control.

Successful treatment of hepatic oligometastases with stereotactic ablative radiotherapy and radiofrequency ablation in an anaplastic lymphoma kinase fusion‐positive lung cancer patient

“…However, most patients will eventually progress within 8–11 months, either in the brain and/or extra‐cranial sites, as was the case with our patient 4, 5. There is evidence suggesting that NSCLC patients with actionable mutations in the ALK or EGFR genes may have a longer progression‐free survival if they are kept on targeted therapy while efforts to control oligometastases by other means are taken 6. In theory, resistant clones could be eradicated with local therapies, thus allowing for continued effectiveness of targeted therapy.…”

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

“…63 For example, one study showed that for 46% of patients on crizotinib, the CNS represents the site of first progression, and that the CNS was the sole site of progression in 85% of these patients. 69 It was also shown, at least in one case report, that less than 0.3% of the plasma concentration of crizotinib enters the cerebrospinal fluid, indicating that crizotinib may not present at therapeutic concentrations in the brain. 70 The activity of a drug in the brain, especially in diseases with a high rate of brain metastases, such as NSCLC, may be better addressed in future trials through defining separate cohorts of patients with specific oncogenic driver and CNS disease, and adding those cohorts to the earliest phase I studies of the relevant molecularly targeted therapies.…”

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

“…It is thought that radiation can increase the permeability of the blood–brain barrier, thereby rendering TKI more effective. One retrospective study showed that patients with only intracranial progression had a continued mPFS of 7.1 months when resumed on crizotinib post-radiation [65]. While it is generally recommended to continue the same TKI post-radiation, the benefit of switching TKI at that time has not been specifically addressed.…”