Early promise for HIV drug–CRT combination in locally advanced NSCLC
medwireNews: The HIV protease inhibitor nelfinavir plus concurrent chemoradiotherapy (CRT) has shown acceptable toxicity and promising efficacy in unresectable, stage IIIA/B non-small-cell lung cancer (NSCLC) in a phase I/II trial.
The study authors explain that local tumor control can be poor with definitive CRT in this patient population, and concomitant treatment with a radiosensitizing agent has been proposed as a potential solution.
They add that nelfinavir is one such drug, as preclinical studies have shown that it “inhibits PI-3 kinase and Akt signaling and sensitizes tumor cells to killing by ionizing radiation in vitro and in vivo.”
A total of 35 patients were treated with oral nelfinavir mesylate at a dose of 625 or 1250 mg twice daily, starting 7–14 days before the start of CRT and continuing for the complete course, which comprised chemotherapy with cisplatin and etoposide and 66.6 Gy of radiation, administered in 37 fractions.
Overall, 94% of 33 patients with evaluable posttreatment computed tomography scans showed a partial response and the remaining two patients had stable disease, results that Ramesh Rengan (University of Washington School of Medicine, Seattle, USA) and co-researchers describe as “very promising.”
The study, published in JAMA Oncology, reports a local failure rate of 26% at 2 years and 34% at 4 years, with corresponding distant failure rates of 46% and 54%. The median time to local failure was not reached, while that to distant failure was 15.8 months.
Median progression-free survival was 11.7 months and median overall survival (OS) was 41.1 months. Mean OS rates were 57.1% at 2 years, 51.4% at 3 years, and 37.1% at 5 years.
By comparison, the benchmark RTOG 0617 study reported a median OS of 28.7 months and a 2-year local failure rate of 30.4% for patients receiving standard-dose CRT. The researchers therefore say that the current study’s results “compare favorably” with these historical findings.
There were no dose-limiting toxicities at either nelfinavir dose, and no grade 4 or worse nonhematologic adverse events, with the exception of one case of grade 4 dizziness. The main nonhematologic grade 3 event was esophagitis, which was seen in 20% of five patients treated at 625 mg and 10% of 30 patients treated with nelfinavir 1250 mg. And 7% patients given the 1250 mg dose experienced grade 3 or worse pneumonitis. All other toxicities were grades 1 or 2, report Rengan and colleagues.
The most common grade 3 or 4 hematologic toxicity was leukopenia, which was experienced by 40% of patients taking the 625 mg dose and 60% taking the 1250 mg dose. However, no patients required reductions in their dose of either chemotherapy or nelfinavir.
“As nelfinavir is a US Food and Drug Administration-approved oral drug, this treatment approach is feasible and is potentially a readily exportable platform for daily clinical use,” says the team. “Additional testing in the randomized phase 3 setting should be conducted before this approach can be adopted more broadly for this study population.”
By Catherine Booth
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