Measuring Pre-Treatment ctDNA May Predict Long-Term Lung Cancer Survival

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Medical Lab technician hold sample blood for testing
[Source: Douglas Sacha/Getty Images]

Pre-treatment circulating tumor (ct)DNA levels may more accurately predict long-term survival than classical survival surrogates and might be useful for the design of new clinical trials, according to research presented on the Neo-Adjuvant Immunotherapy Study (NADIM) at the recent IASLC 2021 World Conference on Lung Cancer.

There are currently no predictive biomarkers for long-term survival after neoadjuvant immunotherapy (IO) for lung cancer. However, identifying patients with non-small lung cancer (NSCLC) who obtain long-term benefit from IO is essential to optimize treatment, said Atocha Romero, who led the study, and is from the Hospital Universitario Puerta de Hierro, Majadahonda, Spain.

NSCLC is the most prevalent type of lung cancer, accounting for 84% of all diagnoses of this disease.

Using samples from the NADIM clinical trial, in which patients with resectable stage IIIA NSCLC were treated with neoadjuvant nivolumab, Romero and her colleagues evaluated ctDNA levels before treatment initiation to see if they could predict overall survival and progression-free survival. The researchers compared this measure’s predictive value with classical survival surrogates — the pathologic response and clinical response assessed according to RECIST criteria v.1.1.

Romera’s team say this is the first multicentric study to test CT- IO in the neoadjuvant setting in stage IIIA lung cancer.

Neoadjuvant CT-IO with nivolumab in resectable IIIA NSCLC yielded a complete pathologic response rate higher than ever seen previously, together with a promising progression free survival, which may translate into increased overall survival.

The ctDNA was analyzed by next-generation sequencing, using the Oncomine Pan-Cancer Cell-Free Assay. For each positive plasma sample, the sum of the mutant allele frequency (MAF) for all detected mutations was calculated.

According to Romero, MAF, VAF (variant allele fraction) or AF (allele frequency or allele fraction), can be defined as the number of times a mutated base is read, divided by the total number of times any base is observed at a given position in the genome.  There is no standard procedure to calculate how much ctDNA a person has in their blood, she said.

In this study, neither pathologic response nor clinical responses based on RECIST criteria were predictive for overall survival or progression-free survival. However, when excluding patients who died from COVID-19 (N = 2), pathologic complete response (but not major pathologic response) identified patients with improved PFS and overall survival.

RECIST (Response Evaluation Criteria in Solid Tumors) provides a simple and pragmatic methodology to evaluate the activity and efficacy of new cancer therapeutics in solid tumors, using validated and consistent criteria to assess changes in tumor burden.

“On the contrary, in the multivariate analysis, patients with low ctDNA levels (< 1% MAF), in the baseline sample, had significantly improved progression-free survival and overall survival than patients in whom the opposite situation occurred,” she said. (Adjusted HR: 0.22; 95%CI: 0.06-0.75; P = 0.016 and adjusted HR: 0.04; 95%CI: 0.00-0.45; P = 0.008 for PFS and OS, respectively).

“Pre-treatment ctDNA levels more accurately predicted long-term survival than radiologic assessments in NADIM study and might be useful for the design of new clinical trials,” Romero said.

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