Blood-based tests may offer noninvasive way to determine immunotherapy candidates

Blood-based tests that identify cancer markers may offer a noninvasive way to determine if a patient is a candidate for immunotherapy, according to a Frederick National Laboratory for Cancer Research study to be presented at the 2023 Annual Meeting of the American Society for Clinical Oncology, June 2-6 in Chicago. 

Chris Karlovich, Ph.D. of the Frederick National Laboratory Molecular Characterization Laboratory will present the poster, “Blood-based assessment of patients with mismatch repair-deficient tumors enrolled in NCI-MATCH Arm Z1D (nivolumab)” at section 402 in Hall A at 8 a.m. CDT on Saturday, June 3. 

When a cancer patient’s disease becomes resistant to a particular treatment, determining next steps involves evaluating the evolving molecular makeup of the tumor to determine if there are available treatments to target its acquired mutations.  

But obtaining repeated biopsies of the patient’s tumor is not always clinically feasible, as it involves invasive procedures, among other factors. Technology has progressed to the point that some markers detected in the blood can complement tumor-based assessments of the status of a patient’s cancer. 

The FNL study showed analysis of circulating tumor DNA (ctDNA) taken from the plasma can identify microsatellite instability (MSI), tumor mutational burden (TMB) and other complex biomarkers. 

Many mutations found in tumors also found in blood 

Karlovich and colleagues analyzed the tumor biopsies and blood samples of patients in the Z1D arm of the NCI-MATCH study of the drug nivolumab whose tumor cells were mismatch repair-deficient (MMRd), which indicates many DNA mutations. Patients known to be MMRd have been shown to respond particularly well to immunotherapy treatments like nivolumab, so it is important to have an assay that can identify them. 

NCI-MATCH was the largest precision medicine clinical trial conducted to date and sought to learn if treating cancer based on specific genetic changes in a person’s tumor is effective, regardless of the cancer type. FNL’s Molecular Characterization Laboratory developed the assay used to identify mutations in patients’ cancers, led a large laboratory network that looked for those mutations, and created a software platform that analyzed the mutation data and assigned patients to a suitable precision medicine. 

Of 136 mutations identified in the Arm Z1D participants’ tumor biopsies, 107 (78.6%) were also detected in the blood. The most frequently mutated genes in plasma were TP53, RNF43, PIK3CA, and MHL1. MSH2 mutations were also identified.  

Among the 39 patients whose plasma showed a complete or partial response to the treatment, 34 (87%) were classified as microsatellite unstable by ctDNA at baseline.  Since microsatellite instability is a surrogate for MMRd, these data demonstrate that blood testing could have identified almost 90% of patients that tissue testing identified for treatment with nivolumab and thus potentially spared these patients a tumor biopsy. 

“Blood-based testing can complement biopsy testing to identify patients who might be candidates for immunotherapy,” Karlovich said. “In our study, we determined that we could effectively measure the key tumor biomarkers MSI and TMB in the blood, which may greatly benefit patients who cannot be biopsied.” 

For this test to be approved by the Food and Drug Administration and be available to patients, a clinical trial would need to use the test to identify patients with microsatellite instability and then show that those patients benefited from treatment with nivolumab, Karlovich said. 

Some blood-based tests have been approved by the FDA but only for use when a tissue biopsy is not available, he said. An example is the FoundationOne Liquid CDx.  

Additional posters 

The Molecular Characterization Laboratory team collaborated with colleagues from Illumina and Massachusetts General Hospital on two additional NCI-MATCH-related posters which will also be presented on June 3 at 8 a.m. CDT. 

• Poster 245: Molecular profiling of ctDNA from NCI-MATCH patients enrolled for treatment with mTOR1/2 inhibitor sapanisertib (Arm M) and the Hedgehog pathway inhibitor vismodegib (Arm T) 
• Poster 310: Discovery of gene fusions in driver-negative NCI-MATCH screening samples