Background Resistance to immune checkpoint inhibitors (ICIs) is a persistent challenge in treating advanced malignancies. Our preclinical data showed that nelfinavir (NFV), an HIV protease and Ras-PI3K-Akt pathway inhibitor, augments tumor response to ICIs. We hypothesized that NFV will synergize with concurrent hypofractionated radiotherapy (HRT) and ICIs.
Methods We conducted a phase II trial of concurrent NFV (1250mg PO BID), HRT (8Gy x3) and nivolumab in ICI-naïve (ICI-N) or ICI-refractory (ICI-R) patients with melanoma (MEL), renal cell carcinoma (RCC) or non-small cell lung cancer (NSCLC) (6 cohorts total). The primary endpoint was investigator-assessed objective response rate (ORR), per RECIST 1.1, in unirradiated lesions. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity. Patients receiving ≥1 dose of NFV, ICI and RT were eligible for efficacy analyses. Patients receiving NFV or ICI were assessed for toxicity.
Results Twenty patients (8-MEL, 11-RCC, 1-NSCLC; 15/20 (75%) ICI-R), 30% female with median age 59.4 years (range: 30.5 – 73.8), enrolled before the trial was suspended due to toxicity. Irradiated lesions included lung, liver, bone, soft tissue, nodal and other visceral metastases. Out of 17 evaluable patients, 2 (11.8%) patients had an objective response, 1 partial response (MEL ICI-R) and 1 complete response (MEL ICI-N). Six-month PFS rates were 25% (2/8) for ICI-R RCC and 40% (2/5) for ICI-R melanoma, with 3 ICI-R patients having prolonged disease control lasting 10.4, 15.5 and 15.7 months, respectively.
Most common clinical AEs were grade 1–2 diarrhea (70%), fatigue (40%) or nausea (30%). Three clinical grade 3 AEs were observed (2 arthralgia, 1 hyperglycemia). Eight patients (40%) had grade 2–4 immune-mediated AST/ALT elevation requiring steroids.
Conclusions PI3K/Akt-pathway inhibition with NFV, HRT & ICI resulted in higher-than-anticipated hepatotoxicity. Immune-correlate studies will investigate if toxicity is related to immune activation. Formal evaluation of clinical efficacy was compromised by toxicity-related treatment discontinuation.
Trial Registration ClinicalTrials.gov ID: NCT03050060
Ethics Approval This study was approved by the Fred Hutchinson Cancer Center’s IRB (9712).
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.