Blood test identifies those with lung cancer who may benefit from further immunotherapy
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Circulating tumor DNA analyses can be used as an early marker of immunotherapy response, according to data published in Nature Medicine.
Researchers at Johns Hopkins Kimmel Cancer Center and its Bloomberg-Kimmel Institute for Cancer Immunotherapy, BC Cancer and Canadian Cancer Trials Group recently conducted a clinical trial designed to establish the role of circulating tumor DNA as a potential early measurement of immunotherapy response in patients with advanced non-small cell lung cancer.
The first stage of the BR.36 trial found that serial testing of circulating tumor DNA via next-generation sequencing detected immunotherapy responses within an average of 8 weeks after the start of treatment — earlier than typically anticipated — according to Valsamo ‘Elsa’ Anagnostou, MD, PhD, director of the thoracic oncology biorepository at Johns Hopkins.
“We didn’t know prior to BR.36 how exactly to use circulating tumor DNA to inform therapeutic decision-making,” Anagnostou told Healio. “We know that reduction of levels at some point was predictive of outcomes, but we didn’t know the specifics.”
Anagnostou spoke with Healio about the usefulness of the BR.36 trial in identifying potential patients for advanced immunotherapy through liquid biopsies, while also pondering the future role of such testing.
Healio: What motivated you to conduct this study?
Anagnostou: Liquid biopsy is a very exciting and emerging approach to track initial tumor burden and potentially monitor therapeutic response. Despite the hype, there are technology-based limitations that need to be resolved before implementing liquid biopsies as part of cancer early detection or in detection of minimal residual disease. An area that is likely ready to integrate liquid biopsies into decision-making is therapeutic response monitoring.
We’ve been working on therapeutic response monitoring in the context of immunotherapy for several years and, as a field, we know if one looks at circulating cell-free tumor DNA in the circulation of patients with cancer who receive immunotherapy, there are different patterns that reflect clinical outcomes. These studies are proof-of-concept or pilot studies .... so what prompted us is that despite ever-growing evidence that circulating tumor DNA dynamic can be an early endpoint of response to immunotherapy, all such studies have been retrospective.
Healio: Can you briefly describe the results?
Anagnostou: Three main unanswered questions served as our primary endpoints — what is circulating tumor DNA response, when does it happen and how tightly is it correlated with imaging, which is the gold standard. There’s been multiple studies with that proof of concept, but no definitive answers.
We started with 50 patients; five were excluded based on lack of blood samples and then 10 more had undetectable circulating tumor DNA. This is important to note because, even in the context of metastatic disease, current technology doesn’t allow us to detect circulating tumor DNA for all patients.
We found that circulating tumor DNA clearance or drop to undetectable 6 weeks on cycle 3 of pembrolizumab (Keytruda, Merck) was predictive of a therapeutic response. Therefore, we defined the pattern — that it happens immediately prior to the third cycle of pembrolizumab for patients with metastatic non-small cell lung cancer.
Concordance between circulating tumor DNA and radiographic imaging was 82% in terms of sensitivity and 75% for specificity, thus meeting the study’s primary endpoint, which gave a signal for the second stage of the trial.
Healio: What is the most important take-home message from these results?
Anagnostou: We didn’t know prior to the BR.36 study exactly how to use circulating tumor DNA to inform therapeutic decision-making; we knew that reduction of levels at some point was predictive of outcomes, but we didn’t know the specifics. The take-home message here is that we defined what circulating tumor DNA response is and when it happens, which is very important to determine before designing a clinical trial to assess circulating tumor DNA response in a randomized fashion.
Healio: What are the next steps in this research and key questions that still need to be answered?
Anagnostou: The first question is, now that we have established an approach molecular response, when it occurs, and its concordance with imaging, how will we change clinical practice based on these findings? The other is whether circulating tumor DNA response changes outcomes. That’s exactly what we did here from the onset — stage 1 of this study was planned with stage 2 in mind, which is fully designed and soon to be activated.
Practically, what we’re going to be asking with stage 2 is which patients with metastatic non-small cell lung cancer whose tumors express PD-L1 can be treated with pembrolizumab alone compared with a step-up approach where chemotherapy is added.
Healio: Is there anything additional you would like to mention?
Anagnostou: I want to highlight two things: one is the potential additional utility of liquid biopsies for patients with stable disease. This is, in my opinion, a very heterogeneous group of patients in terms of outcomes, yet we tend to classify them in the same kind of stable disease bucket, so you can imagine that these patients could be the focus of another clinical trial.
The other point is that liquid biopsy therapeutic response monitoring approaches could be helpful for determining the early efficacy of an investigational therapy. These results may never become public, but they can be used as a ‘go/no-go’ decision maker in drug development.
For more information:
Valsamo ‘Elsa’ Anagnostou, MD, PhD, can be reached at vanagno1@jhmi.edu.
Reference:
Anagnostou A, et al. Nat Med. 2023;doi:10.1038/s41591-023-02598-9.
Perspective
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Michael E. Menefee, MD
Immunotherapy has revolutionized the treatment of lung cancer. Identifying patients who have the greatest potential to derive therapeutic benefit from these agents is essential. Equally important is determining who has lower potential for benefit, so that a regimen either may be intensified — if appropriate — or discarded to pursue alternative therapeutic strategies. Although there is still much work to do, the findings reported by Anagnostou and colleagues provide a glimpse into what the future management of patients receiving immunotherapy for advanced NSCLC could look like.Currently, we rely on anatomical imaging to assess response and make management decisions. Circulating tumor DNA has demonstrated promise for determining response to an ongoing therapy for patients with advanced disease. Although the results of this small investigation are intriguing, the critical issue is whether earlier changes in therapeutic management, driven by the absence of a circulating tumor DNA molecular response, ultimately will improve PFS and OS.
The investigators are poised to answer this question with stage 2 of their study. However, questions will remain regarding the implementation of such an approach in community practice. In this well-designed study, it takes 6 to 8 days to receive the circulating tumor DNA results that will inform management decisions; this will invariably take longer with commercial assays in the real world, which may reduce the impact of an earlier intensification of therapy. PET imaging is another strategy that has been explored to identify the presence or absence of benefit early in treatment, and it has the advantage of producing results immediately.
Another area of interest is how this approach may inform the management of patients who experience pseudoprogression. Perhaps the circulating tumor DNA molecular response data could help delineate who is truly progressing and needs modification and who should continue on therapy.
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