Whole body positron emission tomography quantifies expression of PD-1 and PD-L1 in patients with non-small-cell lung cancer

The latest issue of Nature Communications brings the results of a first-in-human biomarker exploratory study showing that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with advanced non-small-cell lung cancer (NSCLC).

Important findings
The importance of these findings mainly lies in the fact that immunohistochemistry (IHC) data on PD-L1 expression is often conflicting with regard to response and (progression-free) survival following treatment with PD-1/L1 monoclonal antibodies (mAb). Even though durable responses are seen in about 20% of treated advanced NSCLC patients, and 3-year survival reported to be 17% in the second-line setting, approximately 10% of patients respond favorably to PD-1/L1 therapy despite negative PD-L1 expression as ascertained by IHC.
These contrasting outcomes may be related to heterogeneity of PD-L1 expression within tumors, with sampling errors limiting the predictive value of PD-L1 expression based on IHC. In other words, the heterogeneity of tumor PD-L1 expression might limit the predictive value of small biopsies.

Whole-body PD-1/L1 PET-CT
Differently, whole-body PD-1/L1 PET-CT is able to show significant heterogeneity in tumor tracer uptake between patients, as well as between different tumor lesions in a single patient. More specifically, preclinical PET studies with 18F-BMS-986192 and 89Zirconium-labeled nivolumab (89Zr-nivolumab) have successfully demonstrated non-invasive tumor imaging of PD-1/L1 expression, allowing the assessment of inter- and intratumoral heterogeneity. Based on this knowledge, the current study aimed to assess whether the expression of PD-1/L1 in tumors may serve as biomarker to guide decisions regarding mAb treatment.
Initially, an 18F-anti-PD-L1 PET-CT scan was performed. 18F-BMS-986192 (synthesized at the Department of Radiology & Nuclear Medicine of the VU University Medical Center, Amsterdam) was injected in all patients, immediately followed by a 60-min dynamic PET-CT scan and a subsequent 30-min static PET-CT scan covering from the brain to the upper legs.

Treatment with nivolumab
On day 2, an 89Zr-Nivolumab PET-CT scan was performed in all patients upon injection of 89Zr-nivolumab (also produced at the VUmc, Amsterdam). Patients received the first cycle of nivolumab treatment on day 12, followed by a second injection of 89Zr-nivolumab within two hours. Static PET-CT scans were obtained at various intervals, encompassing the brain to the mid-femur.
Patients were treated with nivolumab every two weeks until disease progression or discontinuation for safety reasons or withdrawal of consent. Treatment response was classified as partial (PR) or complete (CR) after 12 weeks of nivolumab according to RECIST 1.1 criteria, as measured by a reduction in lesion size of ≥ 30% from the start of treatment. For IHC comparison, tumor biopsies were obtained before the start of the study.

The results showed that tracer uptake was heterogeneous both between patients and between different tumor lesions in a single patient. The uptake of 18F-BMS-986192 in tumor lesions correlated with tumor PD-L1 expression as measured by IHC. Likewise, 89Zr-nivolumab uptake correlated with PD-1 positive tumor-infiltrating immune cells. A correlation between tumor tracer uptake and response to nivolumab treatment could also be demonstrated for both tracers.

PD-1/L1 ready for clinical applications
These findings confirmed the assumption that 18F-BMS-986192 and 89Zr-nivolumab PET-CT may be useful imaging biomarkers to non-invasively evaluate PD-L1 and PD-1 expression. This may facilitate the definition of treatment strategies targeting tumors expressing these cell surface proteins, and identifying patient subgroups that could respond to therapy despite low PD-L1 expression in a small biopsy specimen. Moreover, the correlation between uptake of 18F-BMS-986192 and 89Zr-nivolumab and expression of PD-1/L1 by IHC in tumor tissues indicates that these tracers could potentially be applied for serial and non-invasive quantification of PD-1/L1 expression (dynamics) in clinical studies. A relationship between uptake values (SUVpeak) and response was also found for both tracers, but larger datasets are needed to validate these promising results.

Niemeijer AN, Leung D, Huisman MC, Bahce I, Hoekstra OS, van Dongen GAMS, Boellaard R, Du S, Hayes W, Smith R, Windhorst AD, Hendrikse NH, Poot A, Vugts DJ, Thunnissen E, Morin P, Lipovsek D, Donnelly DJ, Bonacorsi SJ, Velasquez LM, de Gruijl TD, Smit EF, de Langen AJ. Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer. Nat Commun. 2018 Nov 7;9(1):4664. PMID: 30405135.