Immunotherapy has revolutionized cancer treatment, yielding lasting responses in historically challenging cases. However, the selection of suitable patients poses a persistent challenge and highlights the urgent clinical need for reliable predictive biomarkers. Presently, biomarkers such as programmed death-ligand 1 (PD-L1), assessed through immunohistochemistry, exhibit imperfections. Despite the promise of emerging biomarkers like tumor mutation burden and tumor infiltrating lymphocyte density, their ability to consistently predict treatment response has not seamlessly translated into everyday clinical practice.
Radiopharmaceuticals, notably PET scans utilizing fluorodeoxyglucose (FDG), play a pivotal role in predicting and monitoring treatment responses in patients with early or perioperative non-small cell lung cancer (NSCLC). These imaging tools aid in disease staging, assess treatment efficacy through metabolic response evaluation, and facilitate early detection of recurrence postoperatively. Radiopharmaceuticals inform personalized treatment strategies by gauging the metabolic activity of tumors, acting as prognostic indicators, and guiding decisions on surgery, chemotherapy, and immunotherapy. Additionally, they help assess residual disease after interventions and monitor the response to immunotherapy, which provides valuable insights into the dynamic landscape of NSCLC management and contributes to enhanced patient outcomes.
In the realm of adjuvant immunotherapy for NSCLC, two approved agents, atezolizumab and pembrolizumab, have demonstrated efficacy in recent clinical trials.1,2 Atezolizumab‘s approval stemmed from the IMpower010 study,1 where 1,280 patients with stage IB to IIIA NSCLC were randomized to receive either 1 year of atezolizumab or best supportive care following adjuvant chemotherapy. Notably, patients with PD-L1 expression 1% or more exhibited significantly improved disease-free survival with atezolizumab. The FDA approved adjuvant atezolizumab for stage II to IIIA resected NSCLC after surgical resection and adjuvant chemotherapy, with preliminary data hinting at a small but significant improvement in overall survival, particularly for those with PD-L1 50% or more. Similarly, the PEARLS clinical trial2 evaluated pembrolizumab (a PD-1 targeting agent) in the adjuvant setting, revealing a notable enhancement in disease-free survival compared to best supportive care and securing FDA approval. Both atezolizumab and pembrolizumab are administered for a duration of one year, providing clinicians with two viable options for adjuvant immunotherapy in NSCLC.
During the European Society of Medical Oncology 2023 Annual Meeting, held in Madrid, Spain, from October 20-24, Physician’s Weekly spoke with Gary Cook, MBBS, MSc, MD, FRCR, FRCP, Professor of Molecular Imaging at King’s College London, UK and an Honorary Consultant Medicine Physician at Guy’s and St. Thomas Hospitals, to gain a better understanding of the role of radiopharmaceuticals in predicting response to inhibition of PD-L1.
PW: What is the role of radiopharmaceuticals in predicting response in patients, particularly for patients with early or perioperative NSCLC?
Dr. Cook: Independent of whichever stage the patient presents, FDA-approved companion diagnostics are mainly used on biopsy material of tumors with immunohistochemical analysis of, for example, PD-L1 expression for anti PD-L1 treatment. We know that there is heterogeneity of PD-L1 expression within a single tumor, so the biopsy needle may miss the positive bit, for example, but there is also heterogeneity between tumors in the same patient. Furthermore, PD-L1 expression changes over time. We obviously can’t biopsy every tumor in every patient, every time we see them. Thus, imaging offers a potential answer to be able to look at all the tumors noninvasively, at multiple time points.3
PW: Can you predict which patients will respond?
Dr. Cook: There’s a lot of interest and development of tracers looking at specific targets, particularly in the molecular imaging field to do just that. Ultimately, we would hope that imaging target expression would take over the role of biopsies to some extent. But we are not at the stage of routine clinical application yet, although we are doing a trial on a PD-L1.
Our preliminary data suggests that imaging is better at predicting response than biopsy. However, the data is not yet sufficiently mature or large enough to be able to say this is the way forward. There’s still a lot of work to do, but there is early promise and lots of interest. We would love to see if our data correspond with responders in trials like IMpower010,1 where PD-L1 inhibition with atezolizumab showed a disease-free survival benefit with atezolizumab versus best supportive care after resection of early NSCLC.
PW: Is there a potential role for stratifying treatment?
Dr. Cook: Yes, certainly for the sort of gross stratification determining whether a patient should get a drug or not, then you know with certainty if they’re either positive above a threshold or below. What we do not yet know, however, is what that threshold might be for each individual tracer. We may well be able to, and we’ve shown good correlations with immunohistochemistry when we’ve matched the imaging results with where we know the biopsy was taken.
PW: Can physicians use PD-L1 imaging to detect and monitor immune-related toxicities?
Dr. Cook: Perhaps. We’ve been interested in looking at that with our PD-L1 tracer and with FDG PET as a sort of specific marker of PD-L1 expression.
In addition, there is potential to identify inflammation caused by autoimmune pseudo progression. We know that FDG can predict some of the immune-related adverse events before patients become symptomatic. As part of an FDG PET report, once we finish describing the tumor and the response, we go on to the potential immune related adverse events to alert the clinician what the role of a more targeted approach with say, a PD L1 tracer. However, we don’t know. In our series of patients, none had immune related adverse events.
We didn’t see any change in normal organs with the tracer. If we did a larger study with patients who had had adverse events, we may well see some changes. One might hypothesize that the higher the PD L1 expression the more likely an organ is to get toxicity. Or it may be the other way around. In fact, we’ve published some early on immune related myocarditis that suggests that we can reliably and specifically measure PD-L1 expression.4 Preclinical models have suggested that a high expression may protect the heart from immune related myocarditis, but these are very early days.
