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The messaging in the well-known sayings "Don't count your chickens before they hatch" and "Don't put the cart before the horse" may well apply to the situation of patients with advanced non-small cell lung cancer (NSCLC) harboring actionable oncogenic drivers (AODs) who get treatment before genomic test results come in as they face worse outcomes, according to a real-world analysis.

Jeffrey A. Scott, MD, of Integra Connect, a precision medicine company in West Palm Beach, Florida, and co-authors, analyzed data from 510 patients with stage IV NSCLC diagnosed from 2018 to 2020, who had the usual-suspect mutations including EGFR, ALK, ROS1, BRAF, and MET. The researchers then looked at whether the outcomes of empirically treated patients were worse than that of patients who waited for test results before initiating therapy.

As the team explained in , patients were divided into groups based on when they started therapy -- either chemotherapy, tyrosine kinase inhibitors (TKIs), or both -- and when their AODs were reported.

The researchers found that overall survival (OS) was significantly worse for patients harboring AODs who received "molecularly uninformed initial treatment with non-TKI therapy."

The outcomes imply, Scott and co-authors explained, that even if National Comprehensive Cancer Network (NCCN) guidelines are followed with an initial cycle of chemotherapy while testing is pending, there may still be an inferior outcome.

In an ideal world, "physicians should wait for test results before making treatment decisions to ensure patients receive appropriate therapy as early as possible and to mitigate exposure to ineffective or inappropriate treatments," the investigators wrote. "Although the full impact of briefly delaying treatment remains unclear, waiting may not negatively impact outcomes and our data suggest patients could benefit from it. Patients with AODs do have inferior outcomes with single-agent immunotherapy. It is critical to identify patients who may benefit from targeted treatment to maximize benefit and avoid harm."

Peter Michael Ellis, MBBS, MMed, PhD, and Arani Sathiyapalan, MD, MSc, both of McMaster University in Hamilton, Ontario, Canada, discussed the findings in an . Below are some of their thoughts on the research.

In addition to NCCN, and the recommend broad-based molecular subtyping for patients with nonsquamous NSCLC. So why has testing uptake lagged in the real world?

Ellis and Sathiyapalan: There are different approaches to molecular genomic testing with variable availability, including single-gene testing (i.e., sequential) or multigene testing, such as next-generation sequencing (NGS). Traditionally, tumor tissue samples have been tested. However, advances in technology allow molecular analysis, including NGS, of circulating tumor DNA in blood samples (liquid biopsies).

Turnaround time from the receipt of a biopsy sample to the receipt of results and initiation of targeted therapy can range from 5.1 weeks for NGS and 9.2 weeks for single-gene strategies. These time frames, though, create concerns as delays to treatment in advanced NSCLC are associated with poorer outcomes, with population modeling on the basis of lung cancer kinetics estimating an approximately 4% death rate per week.

How do the results fit in with previous research?

Ellis and Sathiyapalan: While it is possible that the differences in OS observed in this trial may represent real differences in outcomes for patients with molecularly driven NSCLC, it is very likely that the retrospective study design has contributed to a variety of selection biases that magnify any observed differences in outcomes between the groups.

The apparent large improvement in OS is not consistent with data from comparing in NSCLC. This is likely due to the receipt of TKI therapy on progression.

Therefore, it is not clear why this study would observe such large differences in OS. A significant limitation of the current study is that it does not provide information on the treatment received by patients on disease progression. It would be very informative to know what proportion of patients who received empiric therapy went on to receive TKI therapy at the time of progression. It would be important to know in the real world if patients do not go on to receive TKI therapy and have worse OS.

What are some take-home messages from the study?

Ellis and Sathiyapalan: This should be a call to action. The findings challenge us to think about our current approach to patient management and question the diagnostic and testing systems that currently exist. We need to critically examine the overall systems that are in place to improve efficiency in molecular testing.

There are many questions to be asked: Who orders molecular testing? Is molecular testing ordered reflexively at the time of diagnosis? Should liquid biopsy be the preferred initial test?

The findings also question current guideline recommendations that support starting empiric therapy while awaiting the results of molecular testing. There is a sense of urgency to treat, though -- perhaps due to perceived poor outcomes in untreated advanced NSCLC. Perhaps oncologists and patients need to be more patient and await molecular testing results before finalizing treatment decisions.

Correction: The Q&A about the editorial has been updated to correct the spelling of Dr. Sathiyapalan's name.

Read the study here.