Monitoring circulating tumor DNA (ctDNA) levels with liquid biopsies could help physicians accurately assess treatment responses and predict future prognoses in patients with operable esophageal or gastroesophageal junction cancer receiving an immunotherapy doublet, according to a recent study published by Kelly et al in Nature Medicine.
Background
Following standard treatment with chemoradiotherapy and subsequent surgery, many patients with gastroesophageal cancer may see their cancer recur. Therefore, researchers are currently exploring new immunotherapy approaches as well as more accurate methods to assess the tumors’ response to treatment.
Nivolumab and relatlimab are both immune checkpoint inhibitors designed to prevent cancer cells from reducing the body’s anticancer immune response. Liquid biopsies are capable of detecting ctDNA and tracking patients’ minimal residual disease.
“Immunotherapy has not yet been broadly effective for patients with gastroesophageal cancer,” explained co–senior study author Vincent Lam, MD, Assistant Professor of Oncology and Director of the Esophageal Cancer Research Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. “By testing new treatments in patients prior to surgery, we can make these powerful observations linking treatment-induced molecular changes with survival outcomes, thus accelerating the development of different immunotherapy approaches for our patients,” he suggested.
Study Methods and Results
In the recent phase IIb trial, researchers used liquid biopsies to examine the ctDNA of 32 patients with operable esophageal or gastroesophageal junction cancer who received treatment with either nivolumab plus relatlimab or nivolumab alone prior to and during their standard therapy with chemotherapy and radiation—with the goal of determining whether the new strategy may provide insights into treatment outcomes over time. The liquid biopsies were employed at different timepoints during treatment. They further measured levels of tumor-recognizing T cells and other components of tumor-specific immune responses. The absence of ctDNA was observed occurring together with specific activation of T cells.
The researchers discovered that about 21.4% of the patients in the combination therapy group vs 40% of the patients in the nivolumab alone group achieved a pathologic complete response. Over 50% of the patients in both groups experienced a major pathologic response.
“Historically, about two-thirds of patients treated with standard chemoradiation prior to surgery are alive after 2 years,” Dr. Lam noted. “In our study, some 72.5% of participants had no signs of cancer and 82.6% were still living after 2 years. Notably, patients with undetectable ctDNA at different time points following immunotherapy had significantly longer cancer-free survival,” he highlighted.
Conclusions
“[The recent findings] open the door for more personalized treatment. We can either de-escalate or intensify the treatment for patients who have gone through the standard protocol. If we see ctDNA is still there, and they don’t have robust T-cell response, these are the patients who may benefit most from additional treatment,” underscored lead study author Ronan Kelly, MD, MBA, Chief of Oncology at Baylor Scott & White Health–North Texas.
The research adds to a growing collection of evidence demonstrating the potential value of molecular readouts like ctDNA to assess response to therapy and guide future treatment plans. For instance, a separate study showed that ctDNA clearance can predict the success of immunotherapy in patients with advanced lung cancer.
“We found that the elimination of ctDNA was a good indicator of patients’ cancer-free survival. We were gratified to see tumor shrinkage at a molecular level together with the immune system flaring up and clearing the tumor,” emphasized co–senior study author Valsamo “Elsa” Anagnostou, MD, PhD, Associate Professor of Oncology, Leader of Precision Oncology Analytics, Co-Leader of the Molecular Tumor Board, Director of the Thoracic Oncology Biorepository, and Co-Director of the Lung Cancer Precision Medicine Center of Excellence at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. “You can imagine that liquid biopsies may be used to capture and monitor cancer spread in the body and determine tumor regression across all types of cancers and therapies. There’s ever-growing evidence to support the use of ctDNA in the full range of the cancer care continuum. We think it’s the future,” she concluded.
Disclosure: The research in this study was supported by Bristol Myers Squibb and in part by the National Institutes of Health, the Cancer Research Institute, the Torrey Coast Foundation GEMINI CLIP Award, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center grant, the Mark Foundation for Cancer Research, and the Conquer Cancer Foundation of ASCO Career Development Award. For full disclosures of the study authors, visit nature.com.
