Pembrolizumab After Completion of Locally Ablative Therapy for Oligometastatic Non–Small Cell Lung Cancer

Abstract

IMPORTANCE Patients with oligometastatic non-small cell lung cancer (NSCLC) may benefit from locally ablative therapy (LAT) such as surgery or stereotactic radiotherapy. Prior studies were conducted before the advent of immunotherapy, and a strong biological rationale for the use of immunotherapy exists in a minimal residual disease state.OBJECTIVE To evaluate whether the addition of pembrolizumab after LAT improves outcomes for patients with oligometastatic NSCLC. DESIGN, SETTING, AND PARTICIPANTSThis single-arm phase 2 trial of pembrolizumab therapy was performed from February 1, 2015, through September 30, 2017, at an academic referral cancer center. The 51 eligible patients enrolled had oligometastatic NSCLC (Յ4 metastatic sites) and had completed LAT to all known sites of disease. Data were analyzed from February 1, 2015, to August 23, 2018.INTERVENTIONS Within 4 to 12 weeks of completing LAT, patients began intravenous pembrolizumab therapy, 200 mg every 21 days, for 8 cycles, with provision to continue to 16 cycles in the absence of progressive disease or untoward toxic effects. MAIN OUTCOMES AND MEASURESThe 2 primary efficacy end points were progression-free survival (PFS) from the start of LAT (PFS-L), which preceded enrollment in the trial, and PFS from the start of pembrolizumab therapy (PFS-P). The study was powered for comparison with historical data on the first efficacy end point. Secondary outcomes included overall survival, safety, and quality of life as measured by the Functional Assessment of Cancer Therapy-Lung instrument.RESULTS Of 51 patients enrolled, 45 (24 men [53%]; median age, 64 years [range, 46-82 years]) received pembrolizumab. At the time of analysis, 24 patients had progressive disease or had died. Median PFS-L was 19.1 months (95% CI, 9.4-28.7 months), significantly greater than the historical median of 6.6 months (P = .005). Median PFS-P was 18.7 months (95% CI, 10.1-27.1 months). Eleven patients died. Overall mean (SE) survival rate at 12 months was 90.9% (4.3%); at 24 months, 77.5% (6.7%). Neither programmed death ligand 1 expression nor CD8 T-cell tumor infiltration was associated with PFS-L. Pembrolizumab after LAT yielded no new safety signals and no reduction in quality of life.

Local ablative radiotherapy for oligometastatic non-small cell lung cancer

“…With the development of novel biomarkers, targeted therapies, and immuno-oncologic agents, LAT, including SABR and ablative hypofractionated radiotherapy, will be an attractive new treatment strategy for oligometastatic NSCLC in the near future. Bauml et al [55] ≤4 N/A LAT for all known disease sites followed by pembrolizumab treatment for 6 or 12 months 1-year PFS rate post-LAT, 64%; 1-year OS rate post-LAT, 90.9% PEMBRO-RT [56] N/A N/A SABR to single tumor site followed by pembrolizumab versus pembrolizumab alone…”

“…A recent single-arm phase II study evaluated LAT combined with pembrolizumab treatment targeting PD-1 in patients with NSCLC with ≤4 metastatic lesions [55]. After performing LAT to all known sites of disease, pembrolizumab was administered for 6 months and continued to 12 months in the absence of disease progression or untoward toxic effects.…”

Oligometastatic non-small cell lung cancer (NSCLC): Does number of metastasis matter?

“…The maximum number of metastases ranged from 1 to 8 in 21 selected articles [2]. Additionally, the definition of sOM-NSCLC in prospective clinical trials is also heterogeneous and vary between 1 and 6 [2][3][4][5]. Further, 74-100% of 1211 included in the systematic review patients had ≤2 metastatic sites.…”

“…Therefore, as described in EORTC articles [2,5], 18 FDG-PET-CT, brain MRI-scan and a possible pathological proof of a metastasis are necessary. The promising data about immunotherapy and radiation combination are inspiring new sOM-NSCLC trials, investigating the association of these treatments [3]. Hence, a single definition and recommended staging work-up are crucial.…”

A phase 2 study of combined chemo-immunotherapy with cisplatin-pembrolizumab and radiation for unresectable vulvar squamous cell carcinoma

“…Lastly, immunotherapy maintenance after immunogenic interventions such as local ablative therapy or radiation therapy has been shown to be bene cial. For instance, patients with non-small cell lung (NSCLC) cancer treated with maintenance pembrolizumab after ablative therapy on a phase 2 study demonstrated statistically signi cant improvement in progression free survival (PFS) compared to historic controls 25 . In another report by Bersanelli et al 26 , patients who revived concurrent immunotherapy with radiotherapy had a longer PFS compared to patients who received radiation alone.…”