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Expert Critique

FROM THE ASCO Reading Room

Amit Reddy, MBBS Postdoctoral Fellow Mitchell Cancer Institute, University of South Alabama

Checkpoint inhibitor therapeutic regimens have transformed the treatment of many malignant neoplasms. Still, only about 20% of patients respond to checkpoint inhibitors. Recently, there have been studies involving predictive biomarkers for checkpoint immunotherapy such as detection of circulating tumor DNA alternations that could be consistent, reproducible, and simply available. Thus, patients with circulating tumor DNA who had more mutations had a better response to immunotherapy compared with patients whose tumors had less mutations. This article describes a new study that uses a simple blood test for a predictive biomarker for response to checkpoint inhibitors. The cohort consisted of 69 patients with various neoplasms who received checkpoint inhibitor immunotherapy and blood-derived circulating tumor DNA next-generation sequencing. About 29% of the patients had more than three variants of unknown significance (VUS) alterations and 71% had three or fewer VUS in each of their circulating tumor DNA. The patients with more than three VUS had increased response rates to immunotherapy -- 45%, compared with 15% for patients with less than three VUS. In addition, patients with a higher VUS alteration status had significant increased overall survival rates. Thus the patients with neoplasms of more alterations advanced slower, lived longer, and had a healthier response to checkpoint inhibitor immunotherapy.

Even though this was a small cohort study, the results were quite unexpected, showing the high response rate of 45% in the group with high alterations; if a study was done with a larger group, of course, the significance would be greater. With the results of the association of checkpoint immunotherapy and alterations, further research investigations are needed to warrant use of hypermutated DNA as a predictive biomarker.

Full Critique

Detection of circulating tumor DNA alterations may be a reliable, reproducible, and easily obtainable predictive biomarker for checkpoint inhibitor immunotherapy. Patients with tumors harboring more mutations as detected by circulating tumor DNA were found to have a better response as compared with patients whose tumors harbored fewer mutations. Additionally, there was a difference in progression-free survival (PFS) and overall survival.

Although immune checkpoint inhibitors are transforming cancer treatment, overall only about 20% of patients respond, and the drugs sometimes have significant side effects. Biomarkers could help predict response to these relatively new drugs.

Unlike traditional predictive biomarkers for use of checkpoint inhibitors, which require invasive and often costly tissue biopsy, a new . "To our knowledge, this is the first study demonstrating that high circulating tumor DNA alteration number can correlate with response to checkpoint inhibitor therapy," Yulian Khagi, MD, of the University of California, San Diego School of Medicine, told 名媛直播. "This potentially makes available these effective new drugs to a broader population of patients with a variety of cancers."

He and his colleagues assessed 69 patients with diverse malignancies who received checkpoint inhibitor-based immunotherapy and blood-derived circulating tumor DNA next-generation sequencing. Of the 69 patients, 29% had more than three variants of unknown significance (VUS) alterations and 71% had three or fewer VUS in their circulating tumor DNA.

After treatment with an immune checkpoint inhibitor, patients with more than three VUS in their circulating tumor DNA had significantly higher response rates (45%) compared with those who had three or fewer VUS (15%). A 2-month landmark analysis showed that responders with more than three VUS had a significantly higher median PFS (23 months) versus non-responders (2.3 months). Similar results were seen with high versus low total alteration number.

A statistically significant overall survival improvement was also associated with high VUS alteration status. Among patients who had higher numbers of alterations of the VUS type, median survival was not reached, while those who had lower numbers of alterations of the VUS type had a median survival of only about 11 months.

"Patients whose tumors harbored more alterations progressed slower, lived longer, and responded more favorably to checkpoint inhibitor-based immune therapy," Khagi said. "The alteration number that predicted response in our study was not arbitrary, but defined as six or more total circulating tumor DNA alterations or more than three VUS alterations. These bright-line cutoffs might allow clinicians to use the objective results of this simple blood test to make determinations about whether to use checkpoint inhibitor-based immune therapy in a variety of tumor types.

'Results Surprising'

"The results were surprising, mainly due to the significant difference in response rate of 45% versus 15% in the high versus low alteration groups," Khagi continued. "Although the study was small, a statistically significant difference could be identified for a longer survival without progression and even a longer overall survival in the high versus low VUS alteration group. It is likely that with larger studies, this difference will become more significant."

Currently, the most widely used predictive biomarkers for checkpoint inhibitor immunotherapy come from , he noted. The amount of programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) protein expressed has been shown to correlate with a better response to checkpoint inhibitor therapy.

"In fact, the majority of studies retrospectively analyze the PD1/PD-L1 expression of the tumor. Some patients -- up to 17% in studies who do not meet the criteria for a 'positive' result -- will still respond to therapy. Conversely, a significant portion of patients who do have a 'positive' result will not respond to therapy. This means additional markers are needed."

An additional test that can predict response to checkpoint inhibitor therapy includes detecting changes at the DNA level, Khagi explained. In many cancers, the DNA of the tumor is not able to repair itself appropriately when injured. This is the result of a . "We can detect this by evaluating the proteins involved in mismatch repair and also by detecting broken pieces of DNA. It has been shown that tumors, regardless of their origin, with mismatch-repair deficiency and microsatellite instability respond better to checkpoint inhibitor therapy."

In fact, this led to the first non-tumor specific FDA approval of the checkpoint inhibitor pembrolizumab for tumors with these characteristics, he noted. "Although it is important to identify, only about 1% to 5% of patients will have these characteristics -- therefore, additional biomarkers are still needed."

Blood-derived circulating tumor DNA alterations could be exploited clinically, Khagi observed. "The purpose of our study was to find a predictive biomarker for checkpoint inhibitor response utilizing non-invasive next-generation sequencing of circulating tumor DNA. We believe this can give us a representation of the tumor's mutational burden and thus predict response to novel immunotherapy. We believe this assay can be added to the armamentarium of predictive biomarkers available for checkpoint inhibitor therapy."

Khagi said the cutoff points might be different as these blood tests evolve to detect more mutations in more genes, adding, though, that larger prospective studies must be done to corroborate the findings. "It would be important to evaluate if these blood-derived tests have prognostic use. In other words, one might evaluate whether the alteration number in and of itself can predict how well a patient does with or without checkpoint inhibitor immune therapy. We are actively investigating these topics."