Opinion: Liquid Biopsy and Tissue Testing Yield Comparable Results for ROS1 in NSCLC

Amanda Brink, DNP, APRN, FNP-BC, AOCNP

As an oncology nurse, one of the most frustrating situations I encounter is ordering biomarker testing for a patient, only to discover that the tissue sample is insufficient for analysis. Adding to this frustration is the often-lengthy wait for results from tissue-based testing, which can delay critical treatment decisions. This challenge is particularly concerning for patients with advanced or metastatic non-small cell lung cancer (NSCLC), where comprehensive biomarker testing is essential before initiating first-line treatment. For these patients, precise biomarker identification is crucial, as it guides the selection of targeted therapies for specific mutations, such as EGFR and ALK.

For those with EGFR mutations, targeted therapies like erlotinib (Tarceva)¹ or osimertinib (Tagrisso)² can lead to improved progression-free survival and overall response rates. Similarly, patients with ALK rearrangements can benefit significantly from therapies such as crizotinib (Xalkori)3 or alectinib (Alecensa).⁴ Conversely, patients without these actionable mutations may be considered for immunotherapy.⁵ However, studies indicate that individuals with EGFR or ALK mutations may experience worse outcomes when treated with immunotherapy instead of targeted therapies.⁶

This underscores the critical importance of accurate biomarker testing; suboptimal treatment choices based on inaccurate results can lead to delayed effective therapy, increased toxicity, and poorer survival outcomes. Therefore, ensuring reliable testing methods is essential to maximize the potential benefits of personalized treatment approaches for patients with NSCLC. While I recognize that circulating cell-free DNA—commonly known as liquid biopsy—can help mitigate the limitations of tissue sampling, I often question the accuracy and reliability of the results it provides compared to traditional tissue testing.

The Blood First Assay Screening Trial: ROS1-Positive Cohort

Blood First Assay Screening Trial (BFAST; NCT03178552) is a global, open-label, multicohort clinical trial that assesses the efficacy and safety of targeted therapies or immunotherapy in patients with advanced or metastatic NSCLC who have actionable genetic alterations identified exclusively through genomic testing in liquid biopsies. Recently, the results of the ROS1-positive cohort were published.⁷

ROS1 fusions occur in approximately 1-2% of NSCLC cases. Approximately 40% of patients with ROS1 positivity also have brain metastases, underscoring the necessity for central nervous system (CNS)-penetrating therapies for this population.

Entrectinib (Rozlytrek) is a tyrosine kinase inhibitor (TKI) that targets ROS1, TRK, and ALK and can cross the blood-brain barrier. Results from an integrated analysis of three phase 1/2 studies—ALKA-372-001 (NCT02097810), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267)—showed that entrectinib produces significant and lasting responses in patients with ROS1-positive NSCLC. The overall response rate (ORR) was 67% (95% CI; 59.9%–74.4%), with a median duration of response (DoR) of 20.4 months (95% CI; 14.8–34.8) and a median progression-free survival (PFS) of 16.8 months (95% CI; 12.2–22.4). These trials included patients diagnosed with ROS1-positive NSCLC using standard tissue-based testing methods.

Between January 2018 and December 2020, 5220 patients were screened, with 92 identified as having ROS1-positive advanced or metastatic NSCLC via liquid biopsy, representing a 1.8% prevalence. Out of these, 55 treatment-naive patients were enrolled, with a median age of 56 years, 58% female, and 75% nonsmokers. Most had nonsquamous adenocarcinoma, and a small percentage had CNS metastases at baseline (7.3%). The study had a median follow-up of 18.3 months.

Efficacy results showed a confirmed ORR of 81.5%, with a median DoR of 13.0 months and median PFS of 12.9 months. CNS progression-free rates were high, with a 12-month CNS progression-free rate of 83.5%.

Safety data revealed that most treatment-related adverse events (TRAEs) were non-serious, with no treatment-related deaths. Serious TRAEs occurred in 12.7% of patients. The most common grade 3 to 5 AE was weight gain.

Biomarker analyses confirmed a high concordance between the assays used to identify ROS1 fusions, indicating consistent and reliable detection across different tests. The most common fusion partner was CD74, a gene linked to ROS1 in most cases. Notably, there were no significant differences in treatment response rates based on the specific ROS1 fusion partner, meaning that patients responded similarly regardless of which gene was fused with ROS1. Additionally, TP53 mutations, which are associated with more aggressive cancer behavior, were common and linked to shorter DoR and PFS.

Exploratory analyses showed no significant association between circulating tumor DNA (ctDNA) levels and clinical outcomes, meaning that ctDNA levels did not reliably predict how well patients would respond to the treatment. However, molecular analysis at treatment discontinuation identified emerging resistance mutations, including the ROS1 G2032R mutation, which is known to cause resistance to ROS1 inhibitors like entrectinib. This indicates that while ctDNA levels alone may not be predictive, new mutations that develop during treatment can lead to drug resistance, causing the treatment to eventually fail.

Nursing Considerations

The BFAST trial, which evaluated entrectinib in treatment-naive patients with ROS1-positive, advanced or metastatic NSCLC identified solely by liquid biopsies, demonstrated clinical outcomes consistent with those observed in patients identified using tissue-based testing. The ORRs and PFS were comparable between the 2 methods, suggesting that liquid biopsy is a viable alternative to tissue biopsy for identifying patients who may benefit from ROS1-targeted therapies like entrectinib. Therefore, oncology nurses can have increased confidence in recommending liquid biopsy to detect mutations such as ROS1, knowing it leads to similar clinical outcomes as traditional tissue-based methods.

Oncology nurses also play a key role in educating patients about the possible need for repeat liquid biopsies when there is evidence of disease progression, as liquid biopsies can identify specific mutations that may have emerged during treatment, including resistance mutations. This education helps patients understand the rationale behind this important monitoring tool and its implications for their treatment.

References

1. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. doi:10.1016/S1470-2045(11)70184-X
2. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
3. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer [published correction appears in N Engl J Med. 2015 Oct 15;373(16):1582. doi: 10.1056/NEJMx150036]. N Engl J Med. 2013;368(25):2385-2394. doi:10.1056/NEJMoa1214886
4. Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024;390(14):1265-1276. doi:10.1056/NEJMoa2310532
5. Roque K, Ruiz R, Mas L, et al. Update in Immunotherapy for Advanced Non-Small Cell Lung Cancer: Optimizing Treatment Sequencing and Identifying the Best Choices. Cancers (Basel). 2023;15(18):4547. Published 2023 Sep 13. doi:10.3390/cancers15184547
6. Calles A, Riess JW, Brahmer JR. Checkpoint Blockade in Lung Cancer With Driver Mutation: Choose the Road Wisely. Am Soc Clin Oncol Educ Book. 2020;40:372-384. doi:10.1200/EDBK_280795
7. Peters S, Gadgeel SM, Mok T, et al. Entrectinib in ROS1-positive advanced non-small cell lung cancer: the phase 2/3 BFAST trial. Nat Med. 2024;30(7):1923-1932. doi:10.1038/s41591-024-03008-4