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A host of professional organizations, including ASCO, call for PD-1/PD-L1 blockade, with or without CTLA-4 inhibition, along with platinum-doublet chemotherapy as first-line treatment for metastatic non-small cell lung cancer (mNSCLC) without driver mutations. But what happens when a patient still has disease progression despite this multicomponent treatment course? What options are available?

Not many, according to Stephen V. Liu, MD, of Georgetown University in Washington, D.C., and colleagues, who assessed treatment patterns and real-world clinical outcomes in a global set of patients. The researchers pooled data from patients in the U.S., Europe, and Japan for a "retrospective, physician panel-based medical chart review," with 160 physicians providing de-identified data from 487 patient charts. Most of the patients had nonsquamous disease.

As the team reported in , the most common treatment regimens upon progression after anti–PD-(L)1/platinum-doublet chemotherapy were non-platinum chemotherapy (50.5%), nonplatinum chemotherapy plus vascular endothelial growth factor receptor inhibitor (12.9%), and platinum-doublet chemotherapy (6.6%).

In addition, median overall survival was 8.8 months, while median time to treatment discontinuation was 4.3 months and median real-world progression-free survival (PFS) was 5.1 months.

Liu and colleagues called these results "suboptimal" -- possibly because the "physicians tried regimens with no proven efficacy or guideline recommendation in the [second-line] setting because of the limited treatment options available."

The findings emphasize the "large unmet need for additional treatment options that may improve survival in later lines of therapy," the researchers wrote. "Therefore, clinical trials of novel agents that may offer benefit in this patient population are needed."

In a bit of good news, the authors found that 99.5% of the physicians reported biomarker testing -- next-generation sequencing (NGS), hotspot, or single gene -- at initial mNSCLC diagnosis; physicians performed NGS testing for a mean of 85.2% of their patients."

That data, however, doesn't quite line up with showing that only about 7% of 1.3 million people with cancer in the U.S. received genetic testing, while a 2022 study found that Black patients with mNSCLC were less likely to undergo NGS testing post-diagnosis than their white counterparts.

So do other countries do better at utilizing NGS? Several groups of researchers shared their experiences:

How have you made the most of NGS in mNSCLC?

Daniel Shao Weng Tan, MD, PhD, of National Cancer Centre Singapore, and colleagues (): The Asia-Pacific Oncology Drug Development Consortium recommends NGS testing in mNSCLC. High-throughput NGS]testing facilitates rapid and reliable identification of the most common and defined genetic aberrations in cancer patients beyond specific hotspot mutation loci.

Lately, NGS-based diagnostics that profile somatic mutations in tumors have demonstrated clinical utility in the identification of single-nucleotide mutations, insertions, deletions, and large genomic rearrangements. Multigene NGS testing can provide a molecular portrait to the oncologist, which can offer additional insights into determining the response to targeted drug therapies.

There is a clear epidemiological difference in the subtypes of NSCLC found in East Asia. The study reported the prevalence of EGFR-mutant lung cancer in 7 countries in Asia, including Thailand, China, Hong Kong, Taiwan, Vietnam, Philippines, and India, at a prevalence of 47-64%.

India, however, had a lower prevalence than the rest of the countries (22%). In the de novo disease setting, an exclusionary workflow approach of only carrying out NGS testing in samples from patients who have tested negative for EGFR has been proposed and modeled and was found to be cost- and time-saving for the overall population in Hong Kong.

In Singapore, however, a similar study indicated that upfront NGS in all patients may still be cost-effective, despite a high prevalence of EGFR-mutant lung cancer. This may be due to the relatively lower costs of NGS testing using an in-house, small-panel, multiplex-gene NGS assay.

Udit Nindra, MD, of Liverpool Hospital Sydney, in New South Wales, Australia, and colleagues (): Stratification of NGS mutation tiers is currently based on the European Society for Medical Oncology Scale of Clinical Actionability of Molecular Targets () Tiers I-V and X. Our aim was to analyze NSCLC tumor samples for the prevalence of Tiers I-V mutations to establish guidance for current and novel treatments in patients with metastatic disease.

In our cohort, 161 of 210 samples (77%) had at least one gene mutation identified, with 41 of 210 (20%) having two or more concurrent mutations. Tier I mutations included 42 of 210 (20%) EGFR mutations and 5 of 210 (3%) MET exon 14 skipping mutations. Non-Tier I variants included 22 of 210 (11%) KRAS G12C hotspot mutations, with a further 47 of 210 (22%) having non-G12C KRAS mutations.

NGS testing revealed an additional 15% of cases with Tier II ESCAT mutations in NSCLC. The 45-gene NGS panel has significant potential in identifying potentially actionable non-Tier 1 mutations that may become future standard clinical practice in NSCLC.

Sarai Palanca, PhD, of the Hospital Universitario y Politécnico La Fe in Valencia, Spain, and colleagues (): The accreditation of NGS testing with UNE-EN ISO [Asociación Española de Normalización-International Organization for Standardization] standards requires an exhaustive validation of the technique, ensuring the traceability of samples and reagents and performing internal and external quality controls. We report the integration of NGS studies into a reference public healthcare hospital under the UNE-EN ISO 15189:2022 quality standard.

The clinical-pathological characteristics of the recruited patients show that our work is representative of the clinical reality of NSCLC in our community setting. The frequency of molecular alterations in our cohort is concordant with that in previously published studies. We also found significant differences in the molecular profile according to sex and smoking status. The application of NGS to the diagnostics routine provided an overview of tumor heterogeneity, revealing co-occurring and mutual exclusion relationships among molecular alterations.

The implementation of NGS has been a milestone for biomarker-selected treatments in our institution, since 36.4% of patients who started a first-line treatment have received targeted therapies based on the provided NGS results; targeted therapies were associated with better outcomes in our patients.

Jin-Yuan Shih, MD, PhD, of National Taiwan University Hospital in Taipei, and colleagues (): Guardant360 is a commercially available, FDA-approved liquid biopsy test that uses hybrid-capture technology to isolate cell-free DNA fragments that include portions of relevant genes and then analyzes such fragments for the presence of genetic alterations. Due to the characteristics of short turnaround time and high concordance with tissue testing, we conducted a prospective randomized trial to assess the performance of Guardant360 on patients with suspected advanced NSCLC.

The addition of liquid NGS identified over 40% more patients whose tumors harbored driver mutations, including actionable genomic alterations. This can facilitate more patients benefiting from targeted therapies. The median time from informed consent to test results was faster with liquid NGS (11 days) than with standard tissue testing (14 days), and the results were highly concordant for the four genes assessed by standard tissue testing methods (EGFR, ALK, ROS1, and BRAF).

Regarding clinical outcomes, we found there was no difference in PFS of tyrosine kinase inhibitor-treated patients among the two groups (NGS results after tissue genotyping or as soon as possible after histological diagnosis of advanced NSCLC).

Though a longer PFS of patients treated with immune checkpoint inhibitors with or without chemotherapy was observed in the immediately reported patients, the limited sample size and potential imbalances in patient demographics and PD-L1 expression prevented us from reaching a clinically meaningful conclusion.

Read the study by Liu and co-authors here.