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Circulating Tumor Cells Could Be Key to Noninvasive PD-L1 Tracking in Small Cell Lung Cancer

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NEW YORK – Biomarker analysis of circulating tumor cells (CTCs) may present an alternative to tissue biopsy for identifying immunotherapy benefit among small cell lung cancer patients, a group that hasn't benefited from precision medicine advances in the same way as those with non-small cell lung cancer.

The US Food and Drug Administration approved Roche's Tecentriq (atezolizumab) combined with chemotherapy for first-line treatment of extensive-stage SCLC in 2019, and AstraZeneca's Imfinzi (durvalumab) with chemotherapy in 2020. However, only a subset of SCLC patients benefits from those treatments.

Prior to that, the FDA granted accelerated approval to Merck's Keytruda (pembrolizumab) and Bristol Myers Squibb's Opdivo (nivolumab) as third-line treatments for SCLC patients who had progressed on other therapies. However, in Phase III randomized controlled trials, these drugs failed to improve overall survival.

Given the mixed evidence on immune checkpoint inhibitors in SCLC, assessment of biomarkers, for example, PD-L1 expression, could be useful in identifying patients most likely to benefit from these treatments. But surgery and biopsy are not part of the standard treatment in metastatic SCLC, and, hence, obtaining sufficient tissue for analysis is not straightforward.

Evaluation of PD-L1 expression in CTCs, therefore, presents a less invasive alternative for biomarker analysis. After seeing the potential of CTC-based PD-L1 expression as a prognostic biomarker in melanoma and NSCLC patients treated with ICIs, a group of Australian researchers embarked on a pilot study to test the approach in SCLC.

The study, led by Elin Gray, associate professor of cancer research at Edith Cowan University, and published earlier this year in Translational Lung Cancer Research, offers some support for using PD-L1 expression in CTCs to predict which SCLC patients will respond to ICIs, although further research is needed to validate the findings.

Conventional collection of CTCs is based on selection of cells expressing epithelial cellular adhesion molecule (EpCAM). However, because cancer cells often go through an epithelial-to-mesenchymal transition during dissemination into the bloodstream, Gray and colleagues used Angle's Parsortix system, in addition to an EpCAM-based system similar to Menarini's CTC platform CellSearch, to isolate CTCs from blood.

The Parsortix system separates cells based on size and deformability. The FDA cleared Angle's test in May for harvesting metastatic breast cancer CTCs from blood for analysis. Their study was published in March.

In the pilot study, Gray's group analyzed samples from 21 SCLC patients, most of whom had extensive disease. They found CTCs in approximately 50 percent of the samples collected with the Parsortix and EpCAM-based system, and PD-L1 was detectable in 7.3 percent of the CTCs collected by EpCAM-coated beads and 8.3 percent of the cells collected by Parsortix. Because of the small number of patients, an analysis of the predictive value of PD-L1 for response was not possible.

"We did find that we can clearly see the PD-L1 on the circulating tumor cell," said Gray. "That warrants a larger study to evaluate whether this really has a prognostic significance."

There is reason to be optimistic that further studies may demonstrate prognostic significance in SCLC patients. In similar work published in The Oncologist in 2020, for example, Gray and her colleagues found that PD-L1 expression in CTCs collected by multiparametric flow cytometry was an independent predictor of response and prolonged progression-free survival in patients with melanoma treated with Keytruda.

Arutha Kulasinghe, a research fellow at the University of Queensland Diamantina Institute, reflected that the SCLC pilot study adds to the field's knowledge of alternative sources of potential immunotherapeutic biomarkers in SCLC. He suggested that in follow-up case studies, researchers should compare tumor microenvironment PD-L1/PD-1 characteristics, tissue-based tumor mutational burden, and blood-based biomarkers like CTCs, ctDNA, and blood TMB.

"Ultimately, the field requires an assay that will predict response to immunotherapy," said Kulasinghe, who was not involved in the pilot study by Gray's group. "Blood represents a noninvasive means by which to determine this over the course of therapy, whereas a tumor sample is static and single time-point, which often doesn't reflect the tumor dynamics under the stressors of therapy."

Nicola Normanno, director of the cell biology and biotherapy unit at INT-Fondazione Pascale in Naples, Italy, noted as a point of interest that in the pilot study the EpCAM-negative CTCs did not express vimentin, which suggests that other mechanisms might be involved in the metastatic potential of SCLC CTCs. "It has been previously hypothesized that EpCAM-based methods might not be able to detect cells in epithelial-to-mesenchymal transitions that are supposed to express vimentin," noted Normanno, who also wasn't involved in the work by Gray and colleagues.

The research, although preliminary, is of interest because in the US, lung cancer is the number one cause of cancer-related deaths. NSCLC makes up about 85 percent of all lung cancer cases, and has been the main beneficiary of precision oncology advances.

"Small cell lung cancer is still 15 percent of a very large group of patients diagnosed each year," said Francesca Edwards, Angle's manager of business intelligence. She pointed out that more than two dozen targeted therapeutics are FDA-approved for treatment of NSCLC, but for SCLC, the treatment, prognosis, and outlook haven't significantly changed.

Edwards said it's notable that the Parsortix device was used to capture PD-L1 expressed on CTCs, since in small cell lung cancer, CTCs tend to be smaller. The Parsortix system aims to address the challenge of CTC size variability by providing a range of cassette sizes.

While CellSearch is the first FDA-approved CTC sorting system, its commercial use is currently limited to isolating epithelial CTCs expressing EpCAM. However, as CTCs go through the epithelial-to-mesenchymal transition when traveling through the blood stream, they often lose their EpCAM marker, and can then reverse this process once established at a new metastatic site. Parsortix does not rely on EpCAM and can capture a broad range of CTCs, according to Edwards.

"Increasingly we're seeing the importance of a biomarker-independent approach to capture the complete cohort of CTCs," she said. "Cancer cells are less compressible than the usual blood cells, so using the Parsortix cassette, we're able to capture a broad range of CTCs." 

The cells can also be harvested more readily from the system, because they are not bound to a membrane or by antibodies. "With Parsortix, you can flush the cassette in reverse, and you're able to harvest the CTCs, which is great for researchers, and also in the long term for clinical use, because it enables you to do any downstream molecular analysis techniques that you want to do," said Edwards. 

Edwards said UK-based Angle is pursuing two routes to market for Parsortix, a clinical lab model and a pharmaceutical services model. The firm also operates two laboratories, one in the US and one in the UK, and is in the process of getting these facilities up to regulatory standards and offer Parsortix as a laboratory-developed test to physicians.

"We've got several pharma services contracts and we're working with multiple pharmaceutical companies to provide support and solutions to their clinical trial needs," said Edwards. The second prong of Angle's commercialization plan is selling the device and the cassette to laboratories so they can develop their own LDTs. 

Edwards added Angle is prioritizing introducing the Parsortix system for prostate, breast, and ovarian cancer indications. Lung cancer is "not one of research streams at the moment, but could be one for future development given the unmet clinical need."