Stefano Indraccolo, Associate Professor, University of Padova & IOVIRCCS discussed some of the translational research taking place at his Institute and the use of liquid biopsy to track therapeutic and adverse effects of immunotherapy in lung cancer patients. The objective of this method is to predict patient responses and identify potential toxic effects early.
Non-small cell lung cancer is a leading cause of death for cancer and approximately 70% of patients are diagnosed at an advanced stage. When it is metastatic the 5-year survival rate is very poor. If the cancer is at stage 4 it is typically treated with a combination of chemotherapy and immunotherapy or just immunotherapy.
However, clinical responses are very heterogeneous and Indraccolo proposed that we need more biomarkers to help predict who will respond better to immunotherapy. Furthermore, some very severe toxic or unexpected effects of immunotherapy appear in patients, and at present, this is difficult to predict. So Indraccolo has used liquid biopsy to try to anticipate these events.
Several years ago, he conducted a translational trial called MAGIC (Monitoring Advanced non-small cell lung cancer through plasma genotyping during immunotherapy). The trial centred on a subset of patients with a known KRAS mutation in their tumour and identified it in the plasma and followed it over time. This trial showed that an increase in the mutated allele fraction of K-Ras in plasma was associated with worse progression-free and overall survival.
Following up on this, Indraccolo carried out the MAGIC 1.5 trial which relied on NGS to capture genetic changes in a broader set of patients and follow them along the same timeline. A nomogram combining cfDNA levels, mutation abundance, PDD-L1 expression, and histology improved the prediction of treatment response.
Within a cohort of over 130 patients, five displayed hyperprogressive disease (HPD), and 12 experienced early death. A critical finding was that a sharp increase in cfDNA concentration between the baseline and the second time point was strongly affiliated with early death. Elevated baseline and rising levels of inflammatory cytokines (IL-6 and IL-8) were also linked to early death which indicates a cytokine storm response.
Indraccolo also introduced a small lung cancer study called the CATS study which was aimed at evaluating whether liquid biopsy tests and molecular biomarkers derived from liquid biopsy could be useful in monitoring the outcome of chemotherapy and immunotherapy in small lung cancer patients. Early results implied that cfDNA and chromosomal instability are potential biomarkers for treatment response.
Ultimately, liquid biopsy is a powerful tool for early prediction of both positive and adverse outcomes in lung cancer immunotherapy. Indraccolo proposed that future work should aim to distinguish chemotherapy vs. immunotherapy responses and explore additional biomarkers like methylation profiles.
