Can radiotracers predict response to PD-L1 inhibitors in early NSCLC?

Immunotherapy has revolutionised cancer treatment, yielding lasting responses in historically challenging cases. However, the selection of suitable patients poses a persistent challenge, highlighting 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 tumour mutation burden (TMB) and tumour-infiltrating lymphocyte (TIL) density, their ability to consistently predict treatment response has not seamlessly translated into everyday clinical practice.

Radiopharmaceuticals, notably PET scans utilising fluorodeoxyglucose (¹⁸F-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 personalised treatment strategies by gauging the metabolic activity of tumours, acting as prognostic indicators and guiding decisions on surgery, chemotherapy, and immunotherapy. Additionally, they help to assess residual disease after interventions and monitor the response to immunotherapy, offering valuable insights into the dynamic landscape of NSCLC management and contributing to enhanced patient outcomes.

In the realm of adjuvant immunotherapy for NSCLC, 2 approved agents, atezolizumab and pembrolizumab, have demonstrated efficacy in recent clinical trials [1,2]. Atezolizumab's approval stemmed from the IMpower010 study (NCT02486718), where 1,280 patients with stage IB–IIIA NSCLC were randomised to receive either 1 year of atezolizumab or best supportive care following adjuvant chemotherapy [1]. Notably, patients with PD-L1 expression ≥1% exhibited significantly improved disease-free survival with atezolizumab. The FDA approved adjuvant atezolizumab for stage II–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%. Similarly, the PEARLS clinical trial (NCT02504372) evaluated pembrolizumab (a PD-1-targeting agent) in the adjuvant setting, revealing a notable enhancement in disease-free survival compared with best supportive care and securing FDA approval [2]. Both atezolizumab and pembrolizumab were administered for a duration of 1 year, providing clinicians with 2 viable options for adjuvant immunotherapy in NSCLC.

During the ESMO 2023 Annual Meeting, held in Madrid, Spain, from 20–24 October, Medicom Medical Publishers spoke with Prof. Gary Cook (King's College London and Guy's and St Thomas Hospitals, UK) to gain a better understanding of the role of radiopharmaceuticals in predicting response to inhibition of PD-L1.

What is the role of radiopharmaceuticals in predicting response in patients, in particular for patients with early or perioperative NSCLC?

“Independent of the stage the patient is at the moment, FDA-approved companion diagnostics are mainly used on biopsy material of tumours, with immunohistochemical analysis of, for example, PD-L1 expression for anti PD-L1 treatment. However, we know that there is not only heterogeneity of PD-L1 expression within a single tumour, so the biopsy needle may ‘miss’ the positive bit, but there is also heterogeneity between tumours in the same patient. Furthermore, PD-L1 expression changes over time. We obviously can't biopsy every tumour in every patient, every time we see them. Thus, imaging offers a potential answer to be able to look at all the tumours non-invasively, at multiple timepoints [3].”

Can you actually predict which patients will respond?

“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 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 tracer at the moment.

Our preliminary data suggests that imaging is better at predicting response than a biopsy. However, the data is not yet sufficiently mature or in large enough numbers to be able to say this is definitely the way forward. There's still a lot of work to do, but there’s certainly early promise and lots of interest. We would love to see if our data corresponds with responders in trials like IMpower010, where PD-L1 inhibition with atezolizumab showed a disease-free survival benefit versus best supportive care after resection of early NSCLC [1].”

Is there any role potentially for stratifying treatment?

“Yes, certainly for gross stratification, determining whether a patient should get a drug or not, then you know if they're either above a threshold or below. What we do not yet know, however, is what that threshold might be for each particular tracer, for example. At the moment, we've shown good correlations with immunohistochemistry when we've matched the imaging results with the location from where the biopsy was taken.”

Can you use PD-L1 imaging to detect and monitor immune-related toxicity?

“Yes, perhaps. We've been trying to look at that with our PD-L1 tracer as a specific marker of PD-L1 expression, in combination with ¹⁸F-FDG PET which has the potential to identify inflammation caused by the autoimmune local response, the so-called ‘pseudo’ progression. We know that ¹⁸F-FDG PET can predict some of the immune-related adverse events, even before the patients become symptomatic. It is fairly standard now that as part of an ¹⁸F-FDG PET report, once we finish describing the tumour and the response, we then go on to the potential immune-related adverse events to alert the clinician. We don’t know yet what the role of a more targeted approach with a PD-L1 tracer might be. None of the patients in our current study had any immune-related adverse events, so we never saw any change in normal organs with the tracer.

If we do a larger study with patients who have adverse events, we may well see some changes; that is yet to be determined. One might hypothesise that the higher the PD-L1 expression, the more likely an organ is to get toxicity, but it may as well be the other way around. In fact, preclinical models have suggested that a high PD-L1 expression protects the heart from immune-related myocarditis, and we've got some early data that we've published on immune-related myocarditis that we can look at [4]. At the very least, this study confirmed that we can reliably and specifically measure PD-L1 expression, but of course we need further validation; these are very early days.”

1. Felip E, et al. Lancet. 2021 Oct 9;398(10308):1344-1357.
2. O'Brien M, et al. Lancet Oncol. 2022 Oct;23(10):1274-1286.
3. Hughes DJ, et al. Radiology. 2022 Aug;304(2):246-264.
4. Nazir MS, et al. EJNMMI Res. 2023 May 17;13(1):44.

 

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Posted on 20 November 202327 November 2023