Administering an HIV drug concurrently with chemoradiotherapy resulted in promising local control and overall survival in patients with unresectable, locally advanced non–small cell lung cancer, researchers reported.
There was no overt exacerbation of the toxic effects of chemoradiotherapy with the addition of nelfinavir, a protease inhibitor, in the prospective, open-label, phase 1/2 study, the researchers wrote.
Nelfinavir plus chemoradiotherapy yielded a median progression-free survival of 11.7 months and median survival of 41.1 months, while the cumulative local failure incidence was 39% according to their report.
Those outcomes compare favorably with historical data, the investigators wrote in JAMA Oncology.
In benchmark results of the RTOG 0617 study of chemoradiotherapy in locally advanced non–small cell lung cancer, median overall survival was 28.7 months receiving radiotherapy at a standard dose of 60 Gy, and 20.3 months for those receiving high-dose (74 Gy) radiotherapy.
However, a randomized, phase 3 trial is needed to confirm these latest results with a protease inhibitor added to chemotherapy, according to Ramesh Rengan, MD, PhD, of the University of Washington, Seattle, and coinvestigators.
“As nelfinavir is a U.S. Food and Drug Administration–approved oral drug, this treatment approach is feasible and is potentially a readily exportable platform for daily clinical use,” Dr. Rengan and coauthors wrote.
In vitro and in vivo studies have shown that nelfinavir inhibited PI3K and Akt signaling, sensitized tumor cells to ionizing radiation, and improved tumor perfusion in animal models. “We hypothesize that it is these properties that drive the clinical results observed in this study,” Dr. Rengan and coauthors wrote.
They reported on a total of 35 patients with stage IIIA/IIIB non–small cell lung cancer who received nelfinavir at either 625 mg or 1,250 mg twice daily, starting 7-14 days before starting radiotherapy to 66.6 Gy at 1.8 Gy per fraction, and throughout the full course of radiotherapy.
There were no dose-limiting toxic effects observed in the study, and toxic effects were “acceptable,” with no grade 4 nonhematologic toxic effects seen, according to investigators. Leukopenia was the primary grade 3-4 hematologic toxic effect, observed in 2 of 5 patients receiving the lower nelfinavir dose and 18 of 30 at the higher dose.
Beyond non–small cell lung cancer, the efficacy and safety nelfinavir given concurrently with radiotherapy has been looked at in other disease settings. Data from those trials suggest that this protease inhibitor could “augment tumor response” not only in non–small cell lung cancer, but in locally advanced pancreatic cancer and glioblastoma, all of which are relatively radioresistant, according to Dr. Rengan and colleagues.
Study support came from grants from the National Institutes of Health and Abramson Cancer Center, and an American Society for Radiation Oncology training award to Dr. Rengan. Study authors reported disclosures related to Pfizer, 511 Pharma, Progenics Pharmaceuticals, Siemens, Actinium, AstraZeneca, Merck, Bristol-Myers Squibb, and others.
SOURCE: Rengan R et al. JAMA Oncol. 2019 Aug 22. doi: 10.1001/jamaoncol.2019.2095.