Advanced non-small cell lung cancer: Is treatment before genetic testing harmful to patients?

As the saying goes, “the chicken has not yet hatched” and “putting the cart before the horse”, it is likely to apply to the situation of patients with advanced non-small cell lung cancer (NSCLC). received treatment before genomic test results came back because they faced worse outcomes.

Jeffrey A. Scott, MD, of Integra Connect, a precision medicine company in West Palm Beach, Florida, and co-authors analyzed data from 510 stage IV NSCLC patients diagnosed between 2018 and 2020 who had common suspect mutations, including epidermal growth factor receptor, ALK, Reactive oxygen species 1, Bluffand Met. The researchers then looked at whether patients who were treated empirically had worse outcomes than those who waited for test results before starting treatment.

As the team explains in JCO Oncology Practicepatients were divided into groups based on when they started treatment (chemotherapy, tyrosine kinase inhibitors (TKIs), or both) and when AOD was reported.

Researchers found that patients with AOD who received “initial treatment with non-TKIs with unknown molecular information” had significantly worse overall survival (OS).

Scott and co-authors explained that these results mean that even if one follows National Comprehensive Cancer Network (NCCN) guidelines for an initial chemotherapy cycle while waiting for testing, outcomes may still be poor.

In an ideal world, “physicians should wait for test results before making treatment decisions to ensure patients receive appropriate treatment early and reduce the chance of receiving ineffective or inappropriate treatment,” the researchers wrote. “While treatment is delayed for the time being, The full impact is unknown, but waiting may not have a negative impact on outcomes, and our data suggest that patients with AOD who receive single-agent immunotherapy do have worse outcomes. It is critical to identify patients who may benefit. Targeted treatment to maximize benefits and avoid harm.

Peter Michael Ellis, MBBS, MBBS, PhD, and Arani Sathiyapala, MD, MSc, of McMaster University in Hamilton, Ontario, Canada, discuss these findings in an accompanying editorial. Here are some of their thoughts on the research.

In addition to NCCN, ASCO and the European Society of Medical Oncology also recommend broad molecular subtyping for patients with nonsquamous NSCLC. So why do real-world testing applications lag?

Ellis and Satyapala: There are different approaches to molecular genomic testing that vary in availability, including single-gene testing (i.e., sequential) or multi-gene testing such as next-generation sequencing (NGS). Traditionally, samples of tumor tissue have been tested. However, technological advances allow molecular analysis of circulating tumor DNA in blood samples (liquid biopsy), including NGS.

The turnaround time from receipt of biopsy sample to receipt of results and initiation of targeted therapy was 5.1 weeks for NGS and 9.2 weeks for single-gene strategies. However, these time frames raise concerns because treatment delays in advanced NSCLC are associated with poorer prognosis, with population models based on lung cancer dynamics estimating a weekly mortality rate of approximately 4%.

How do the results fit with previous research?

Ellis and Satyapala: Although the differences in OS observed in this trial may represent true differences in outcomes for patients with molecularly driven NSCLC, the retrospective study design likely resulted in various selection biases that amplified any observed differences in outcomes between groups.

The apparent large improvement in OS is inconsistent with data from randomized trials comparing molecularly targeted therapies with chemotherapy in non-small cell lung cancer. This may be due to receipt of TKI treatment during disease progression.

Therefore, it is unclear why this study observed such a large difference in OS. A significant limitation of the current study is that it did not provide information on disease progression as a result of the treatments patients received. It would be useful to know the proportion of patients who receive empiric therapy who continue to receive TKIs as their disease progresses. It will be important to understand if patients do not continue TKI therapy and have worse OS in the real world.

What are the take-home messages from this study?

Ellis and Satyapala: This should be a call to action. These findings prompt us to think about current approaches to patient management and question existing diagnostic and testing systems. We need to critically examine the overall system in place to improve the efficiency of molecular testing.

There are many questions to ask: Who ordered the molecular testing? Is molecular testing instinctively performed at the time of diagnosis? Should liquid biopsy be the initial test of choice?

The findings also question current guideline recommendations that support initiating empiric treatment while awaiting molecular test results. However, the urgency for treatment may be due to the perceived poor prognosis of untreated advanced NSCLC. Perhaps oncologists and patients need to be more patient and wait for molecular test results before final treatment decisions can be made.

Read the study here.