Intensified Analysis of CGP Results Likely Necessary Among Some Patients With NSCLC

Comprehensive genomic profiling (CGP) was found to be clinically useful in assisting in treatment selection, facilitating clinical trial enrollment, and improving patient outcomes in patients with advanced non–small cell lung cancer (NSCLC); however, some patients’ results may require more rigorous analysis prior to administering therapy, according to a new study.

The study, published in BMC Medicine, found that careful interpretation of CGP results is warranted among patients with potentially actionable alternations that do not have targeted drugs available, due to the use of off-label or investigational therapies among these patients for which the likelihood of benefit may be low.

Genetic testing for actionable mutations is a standard-of-care practice for patients with advanced NSCLC and broadly applying CGP in clinical care in lieu of routine testing for classic drivers is recommended in light of new targetable drivers and the emergence of effective targeted therapies.

However, the key assumption justifying CGP testing has not been proven. Past research on this concept primarily occurred prior to the development of targeted therapies against RET, BRAF, V600E, and MET exon 14 alterations, suggesting that a reevaluation on the clinical implications of CGP in the current treatment landscape of advanced NSCLC is needed.

The investigators enrolled 1564 Chinese patients (2094 samples) who had an Eastern Cooperative Oncology Group performance status between 0 and 2 and adequate tumor tissue for genomic sequencing. From October 2016 to October 2019, the patients were considered to have either completed genomic profiling (n = 1166) or potentially actionable alterations (n = 781). The mean age of the patients with completed CGP was 59 years, and 60% were men. The mean age of those with potentially actionable alterations was 57 years, and 54% were men.

EGFR alterations were the most common alterations reported in patients (84.9%), followed by TP53 (69.7%), KRAS (15.1%), ALK (14.3%), PIK3CA (8.7%), and ERBB2 (6.4%).

Level 1 alterations were defined as those that had targeted therapies approved in China. A level 2 label was applied to alterations of genes that had targeted therapies approved by the FDA but not yet by the National Medical Products Administration in China. Alterations ranked at level 3 or 4 were considered to be potentially actionable targets that do not have available targeted therapies.

Level 1 alterations were detected in 480 (41.2%) patients, level 2 alterations in 110 (9.4%) patients, level 3 alterations in 72 (6.2%) patients, and level 4 alterations in 151 (13.0%) patients. A directed targeted therapy was offered to 70.8% of patients with level 1 mutations and 21.2% of patients with level 2-4 mutations.

Additionally, 40.7% of patients with level 1 alterations and 8.0% of patients with level 2-4 alterations were matched with a clinical trial testing a novel targeted agent or new combination therapy.

At the time of data cutoff (December 31, 2020), patients with potentially actionable mutations and a matched targeted therapy had a median progression-free survival (PFS) of 9.0 months and a median overall survival (OS) of 3.9 years. Patients with potentially actionable alterations who were not matched with a therapy had a median PFS of 4.9 months and a median OS of 2.9 years.

During the multivariate analysis, the main independent factors that correlated with a better PFS were fewer lines of prior treatments (HR, 0.37; 95% CI, 0.30-0.44; P < .001) and a matched targeted therapy (HR, 0.45; 95% CI, 0.38-0.53; P < .001). The factors that independently correlated with a better OS included better performance status (HR, 0.84; 95% CI, 0.70-0.99; P = .048) and a genotype-matched targeted therapy (HR, 0.23; 95% CI, 0.19-0.28; P < .001).

The nonrandomized nature of the study, the limited drug approval status and innovative drug availability in China, and the various sizes of next-generation sequencing panels that were used were listed at study limitations.

“Increased availability of novel targeted drugs may further expand the utility of comprehensive tumor profiling in clinical care,” the investigators noted.

Reference

Zhao S, Zhang Z, Zhan J, et al. Utility of comprehensive genomic profiling in directing treatment and improving patient outcomes in advanced non-small cell lung cancer. BMC Med. Published online October 1, 2021. doi:10.1186/s12916-021-02089-z