Background

The optimal first-line approach to treating non–small cell lung cancer (NSCLC) varies in accordance with a patient’s biomarkers. Comprehensive genomic profiling (CGP) tests can be used to determine the course of first-line treatment best attuned to a patient’s biomarkers, because they concurrently detect single-nucleotide variants, genetic insertions, genetic deletions, copy number amplifications, and fusions. Immune checkpoint inhibitor (ICI) immunotherapies for the treatment of NSCLC require patients to have a specific biomarker profile detectable via CGP—negativity for ALK rearrangement (fusions) and EGFR mutations (alterations L858R/EXON19 deletions)—or to have had prior toxicity or progression on oral therapies targeting mutations in these genes.¹ Although CGP results can guide care for multiple types of cancer, empirical data suggest that CGP has the greatest impact on the course of treatment for patients with NSCLC.²

ASCO and NCCN have recommended that biomarker testing for ALK and EGFR at the time of diagnosis of advanced NSCLC, and before the administration of ICIs, be considered the standard of care.^3,4 Nonetheless, testing continues to be underutilized, underdiagnosis occurs, and evidence shows that patients receiving contraindicated therapy may experience hyperprogression.^5,6 One study found that 64.4% of potentially eligible patients with advanced NSCLC were not benefiting from precision oncology care appropriate for their disease.⁷ A study examining a population of patients with NSCLC who tested positive for EGFR mutation found that 16.0% initiated treatment before EGFR testing results were available.⁸ Although the evidence supporting the use of genomically targeted treatments is substantial, the real-world evidence is generally sparse on how using CGP in guiding treatment impacts outcomes and utilization.⁹

CGP enables physicians to rapidly obtain a comprehensive view of a patient’s biomarkers. In contrast, sequential testing introduces delays into the care process, because the results of initial tests are used to make subsequent testing decisions. A model of genomic testing for patients with metastatic NSCLC found that panel and next-generation sequencing approaches to testing yielded results nearly 3 weeks faster than exclusionary and sequential testing.¹⁰

Previous researchers have characterized first-line treatment patterns found in the SEER database pertaining to patients with traditional Medicare health plans, aged ≥65 years, with advanced NSCLC, initially diagnosed between 2007 and 2011.¹¹ Since then, numerous new ICIs have been brought to market, including pembrolizumab (in 2014), nivolumab (in 2014), and durvalumab (in 2017), which are not suitable first-line treatments for patients with ALK rearrangement and EGFR mutation.¹² As a consequence, research is needed to explore treatment patterns in an environment in which more options are available.

Previous research has shown that receipt of genomic testing and targeted therapy is associated with significantly longer progression-free survival in a matched cohort of patients with metastatic cancer.⁵ When EGFR testing for patients with nonsquamous metastatic NSCLC was introduced in Alberta, Canada, there was a significant improvement in overall survival.¹³ Likewise, a study of patients with diverse refractory cancers who underwent CGP and then were treated in a manner that was either matched or unmatched to their genomic profile concluded that patients receiving matched therapy had longer time-to-treatment failure and observed overall survival.¹⁴

The purpose of this study was to assess the consequences of receipt of suboptimal first-line treatment in a population of patients who were determined at some point during their treatment to have ALK rearrangement or EGFR mutation. Although all patients included in the study ultimately received CGP, had they all received it more promptly or the results been uniformly heeded, it is possible that the patients would have experienced better outcomes. To highlight the consequences of optimal versus suboptimal first-line treatment, this study examines the association between the first-line treatment selected and downstream clinical outcomes, utilization, and adverse events.

Discussion

This study found that patients who received suboptimal first-line treatment had significantly worse rwTTNT and rwTTD regardless of whether adjustments were made for potential confounders. Furthermore, patients receiving optimal first-line treatment had significantly lower ED and outpatient utilization at 3, 6, and 12 months and fewer adverse events. Collectively, these findings suggest that ensuring that patients are optimally treated leads to improved clinical outcomes and reduced utilization. In doing so, these findings build upon the literature suggesting that patients should receive CGP before initiating first-line treatment.^3,24

Prior analysis has suggested that the use of CGP to guide the treatment of NSCLC is associated with both better patient outcomes and a modest financial impact driven by increased survival.^{10–12,25–27} Furthermore, patients with EGFR mutations have been shown to have significantly longer time to next treatment or death if they receive an EGFR tyrosine kinase inhibitor as first-line treatment, rather than immunotherapy or chemotherapy.⁸ The findings of this study build upon the literature by highlighting the inferior outcomes that patients may have if they receive suboptimal first-line treatment. Despite the evidence supporting CGP, patients struggle to access it, particularly in developing countries.²⁷

Patients from states with higher percentages of households living in rural areas were found to have had significantly shorter rwTTNT and rwTTD. Although the urbanicity of the patients in this study is not known, patients from states with proportionally larger rural populations are more likely to come from rural backgrounds themselves. Prior research has found that rural patients have worse access to oncologists and inferior cancer outcomes compared with urban patients.^28,29

A few limitations must be considered when interpreting the findings of this study. Patient medical records were not available, and patients were not categorized by stage or subtype of lung cancer in the analysis. Although diagnosis codes listed on claims were used to identify patients with advanced or metastatic lung cancer, it is possible that some patients had claims that were inappropriately coded. Because clinical data were not available, it is unknown why some patients were given suboptimal first-line treatments. It is possible that the patients initiated them while awaiting findings from CGP and then pursued optimal therapy after a washout period. Patients receiving optimal treatment had a significantly lower average Elixhauser comorbidity index (4.55 vs 5.65; P=.001), suggesting that this population was in somewhat better health than the population receiving suboptimal treatment (Table 1). There was likewise a higher proportion of female patients in the optimal group (66.07% vs 54.43%; P=.052), although the difference was not statistically significant using P=.05 as a cutoff. Although the reasons that patients received suboptimal first-line treatment after CGP testing are not documented in the data, a prior study with a similar observation suggested that this may have been due to discrepancies in notifying physicians about test results.⁸

It is also unclear why no significant differences in inpatient care utilization were observed between the optimal and suboptimal groups. Only procedure codes associated with inpatient care were available, not the diagnosis-related groups into which they are customarily aggregated for billing purposes.³⁰ This omission may have reduced the fidelity of the inpatient care utilization data.

Finally, although the study considered a national sample, the patients were not distributed uniformly across the country. The patients who were included in this study may not have been perfectly representative of American patients with NSCLC, because all included patients had access to CGP and received it. Likewise, all the patients included received a specific CGP test; a different CGP test may have yielded different findings.

Conclusions

In the population examined, when patients with ALK rearrangement or EGFR mutation were provided with optimal NSCLC treatment, they had significantly longer rwTTNT and rwTTD, lower ED and outpatient utilization in the first 12 months, and fewer adverse events. These findings suggest that treatment concordant with CGP findings is associated with better health outcomes. These findings provide further support for the ASCO and NCCN recommendations that treatment of NSCLC be tailored to a patient’s biomarkers as ascertained through CGP