In the Journals

Liquid biopsies predict response to immunotherapy

Razelle Kurzrock
Yulian Khagi

Patients with a higher number of DNA alterations detected by a liquid biopsy appeared more likely to respond to immune checkpoint inhibitors, according to retrospective study results published in Clinical Cancer Research.

“Immune checkpoint inhibitors, a class of immunotherapy, are transforming cancer treatment; however, overall only about 20% of patients respond to these drugs, and the drugs sometimes have significant side effects,” Razelle Kurzrock, MD, director of the Center for Personalized Cancer Therapy at University of California San Diego Moores Cancer Center, said in an American Association for Cancer Research-issued press release. “Therefore, it is important to have biomarkers that can help predict response to these relatively new drugs.”

Tumor mutational burden detected by next-generation sequencing is associated with response to checkpoint inhibitors. However, tissue biopsy is a costly and invasive procedure.

“Biopsies can be painful, expensive, risky and not always representative of the tumor characteristics overall,” Yulian Khagi, MD, a hematology/oncology fellow at University of California San Diego Moores Cancer Center, said in the AACR press release. “We wanted to identify an easily obtainable and easily interpretable biomarker that can predict response to checkpoint inhibitor therapy utilizing genomic sequencing of DNA that is shed from cancer cells into the bloodstream.”

The analysis included 69 patients who received checkpoint inhibitor-based immunotherapy for a variety of malignancies, the most common of which included non-small cell lung cancer (27.7%), skin cancer (21.7%), melanoma (14.5%), and head and neck cancer (13%).

Researchers collected blood samples from the patients and evaluated variants of unknown significance in their circulating tumor DNA using the Guardant360 assay (Guardant Health). The goals of the study included to compare the burden of variants of unknown significance with stable disease for at least 6 months, partial and complete response, PFS and OS.

Twenty-nine percent of patients harbored more than three variants of unknown significance — considered a high alteration number — whereas 71% had three or fewer.

A greater proportion of patients with a high alteration number achieved stable disease for at least 6 months, a partial response or a complete response than patients with a low alteration number (45% vs. 15%; P = .014). This association persisted when researchers increased the cutoff to more than six variants of unknown significance (40.9% vs. 15.9%: P = .025).

Median PFS for all patients was 2.3 months (95% CI, 0.7-5) and median OS was 15.3 months (95% CI, 10.6-23.9). Patients with a high alteration number demonstrated significantly longer median PFS (3.84 months vs. 2.07 months; HR = 0.52; 95% CI, 0.31-0.87) and OS (not reached vs. 10.72 months; HR = 0.39; 95% CI, 0.18-0.83).

A landmark analysis among those with high alteration number showed significantly longer median PFS among responders compared with nonresponders (23.2 months vs. 2.3 months; HR = 0.15; 95% CI, 0.03-0.61).

“Tumors that have the most mutations, and used to be considered the worst tumors, are now considered the best cancers in that they are the most amenable to treatment with immunotherapy,” Kurzrock said in a press release from UC San Diego. “We can take a simple blood sample, which is less painful, less expensive and can be repeated, to determine who is at an increased chance of response to immunotherapy. This technology opens up a whole new approach to immunotherapy.” – by Alexandra Todak

Disclosures: Kurzrock reports employment and ownership interests with CureMatch, Inc.; consultant/advisory roles with Actuate Therapeutics and Xbiotech; and research grants from Foundation Medicine, Genentech, Guardant, Merck Serono, Pfizer and Sequenom. Khagi reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.

Razelle Kurzrock
Yulian Khagi

Patients with a higher number of DNA alterations detected by a liquid biopsy appeared more likely to respond to immune checkpoint inhibitors, according to retrospective study results published in Clinical Cancer Research.

“Immune checkpoint inhibitors, a class of immunotherapy, are transforming cancer treatment; however, overall only about 20% of patients respond to these drugs, and the drugs sometimes have significant side effects,” Razelle Kurzrock, MD, director of the Center for Personalized Cancer Therapy at University of California San Diego Moores Cancer Center, said in an American Association for Cancer Research-issued press release. “Therefore, it is important to have biomarkers that can help predict response to these relatively new drugs.”

Tumor mutational burden detected by next-generation sequencing is associated with response to checkpoint inhibitors. However, tissue biopsy is a costly and invasive procedure.

“Biopsies can be painful, expensive, risky and not always representative of the tumor characteristics overall,” Yulian Khagi, MD, a hematology/oncology fellow at University of California San Diego Moores Cancer Center, said in the AACR press release. “We wanted to identify an easily obtainable and easily interpretable biomarker that can predict response to checkpoint inhibitor therapy utilizing genomic sequencing of DNA that is shed from cancer cells into the bloodstream.”

The analysis included 69 patients who received checkpoint inhibitor-based immunotherapy for a variety of malignancies, the most common of which included non-small cell lung cancer (27.7%), skin cancer (21.7%), melanoma (14.5%), and head and neck cancer (13%).

Researchers collected blood samples from the patients and evaluated variants of unknown significance in their circulating tumor DNA using the Guardant360 assay (Guardant Health). The goals of the study included to compare the burden of variants of unknown significance with stable disease for at least 6 months, partial and complete response, PFS and OS.

Twenty-nine percent of patients harbored more than three variants of unknown significance — considered a high alteration number — whereas 71% had three or fewer.

A greater proportion of patients with a high alteration number achieved stable disease for at least 6 months, a partial response or a complete response than patients with a low alteration number (45% vs. 15%; P = .014). This association persisted when researchers increased the cutoff to more than six variants of unknown significance (40.9% vs. 15.9%: P = .025).

Median PFS for all patients was 2.3 months (95% CI, 0.7-5) and median OS was 15.3 months (95% CI, 10.6-23.9). Patients with a high alteration number demonstrated significantly longer median PFS (3.84 months vs. 2.07 months; HR = 0.52; 95% CI, 0.31-0.87) and OS (not reached vs. 10.72 months; HR = 0.39; 95% CI, 0.18-0.83).

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A landmark analysis among those with high alteration number showed significantly longer median PFS among responders compared with nonresponders (23.2 months vs. 2.3 months; HR = 0.15; 95% CI, 0.03-0.61).

“Tumors that have the most mutations, and used to be considered the worst tumors, are now considered the best cancers in that they are the most amenable to treatment with immunotherapy,” Kurzrock said in a press release from UC San Diego. “We can take a simple blood sample, which is less painful, less expensive and can be repeated, to determine who is at an increased chance of response to immunotherapy. This technology opens up a whole new approach to immunotherapy.” – by Alexandra Todak

Disclosures: Kurzrock reports employment and ownership interests with CureMatch, Inc.; consultant/advisory roles with Actuate Therapeutics and Xbiotech; and research grants from Foundation Medicine, Genentech, Guardant, Merck Serono, Pfizer and Sequenom. Khagi reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.

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