Entrectinib Improves Patient-Reported Outcomes in ROS-1- and TRK Fusion-Positive NSCLC

Anthony P. Conley, MD

Entrectinib (Rozlytrek) entered the lung cancer space when it received approval from the FDA for the treatment of patients with ROS1-positive metastatic non–small cell lung cancer (NSCLC) in 2019, as well as for the treatment of patients with solid tumors harboring an NTRK gene fusion and who have no alternative effective treatment options. The availability of this targeted therapy, however, underscores the importance of identifying TRK fusions in patients with lung cancer.

TRK fusions tend to only occur in about 0.3% of solid tumors, which makes it a very rare event in patients with cancer. Nonetheless, the prognosis of these patients can be dismal depending on the type of disease, stage of disease, and other potential factors. Data from the phase 2 STARTRK-2, phase 1 STARTRK-1, and the phase 1 ALKA-372-001 studies supported the approval of entrectinib for this patient population after demonstrating promising activity among patients with solid tumors harboring NTRK gene fusions.

During the 2020 European Society of Medical Oncology (ESMO) Annual Congress, findings from an analysis of the patient-reported outcomes (PROs) data in the STARTRK-2 study demonstrated that entrectinib appeared to improve several parameters in regard to patient outcomes, as well as symptoms. The agent overall appeared well-tolerated, similar to what was noted in findings that supported the FDA’s approval of this treatment.

In an interview with Targeted Oncology, Anthony P. Conley, MD, associate professor, Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed findings from an analysis of the efficacy and safety of entrectinib in patients with NSCLC harboring a ROS1 or TRK fusion.

TARGETED ONCOLOGY: Could you discuss the prevalence of TRK fusions and what the prognosis is like for these patients?

Conley: TRK-associated fusions are found in approximately 0.3% of all tumors, so it's a very rare event, but it's a highly significant event when it's discovered. The prognosis may vary depending on the type of disease. As a sarcoma specialist, we generally see that patients with advanced metastatic disease have overall survivals of about 24 months. Obviously, patients that are dealing with advanced NSCLC may have outcomes that vary depending on the molecular type of the disease, but in general, outcomes can be as poor as being less than 18 months, and in some cases even worse than that, depending on the subtype and lack of molecular operations.

TARGETED ONCOLOGY: What efficacy and safety were observed with entrectinib prior to your patient-reported outcomes analysis?

Conley: The efficacy and safety analysis is largely been based on STARTRK-2 for this particular project, although there's a pooled analysis of 2 phase 1 trials that were presented and published within the last few years. Essentially, what led to the FDA approval of entrectinib in the United States for NTRK fusion-positive patients and ROS1 NSCLC is 54 patients with the NTRK fusion were found at a response rate of 57% while approximately 51 patients with ROS1 fusion-related lung cancers had a response rate of 78%.

TARGETED ONCOLOGY: What was the goal of your analysis?

Conley: The goal of the research that was presented at ESMO was to understand the PROs that were associated with the STARTRK-2 clinical trial involving the use of entrectinib for patients that had fusions involving NTRK1/2/3, ROS1, or ALK fusions. Essentially, what we did was we looked at several PRO measures, in particular, the EORTC, QLQC30, and then for patients with lung cancer or colorectal cancer, there were more specialized modules that they had to complete in addition. The goal was to understand what effect entrectinib has on a patient's quality of life over time.

TARGETED ONCOLOGY: What were the findings from this analysis?

Conley: What we did was we looked at 3 quality of life measures, and essentially, patients were asked to fill out a questionnaire on day 1 of cycle 1, and they were tracked monthly on the first day of each cycle, up to maximum of cycle 13. What we did then was we applied several statistical analyses to look at the differences within each of these questionnaires to see if there were any relevant changes. We considered a clinically relevant change to be 1 where the baseline change was approximately 10 or more points.

The PROs data suggests that while most patients may have a high functioning status at baseline, there does seem to be an incremental improvement in certain parameters such as role functioning, meaning one's ability to carry out daily activities. We also found that there were certain patients that developed improvement in symptoms such as cough or fatigue. Overall, in the patients that were included in this particular analysis with NTRK-related fusions, patients appear to have improved PROs noted between baseline and 13 cycles later.

TARGETED ONCOLOGY: What is next for entrectinib?

Conley: Now that we have these PROs data, I think that this will help clinicians to understand how this particular medicine may impact the quality of care provided to the patient when they use entrectinib. In terms of the future of entrectinib, I think that that largely depends on a clinician's ability to molecularly profile their cancer patients when necessary and to use this particular drug. I think in the future, things to be thinking about are whether there will be a role for combination therapy or looking at possible factors that impart resistance or intolerability. However, overall, as I mentioned before, this is a well-tolerated drug that appears to be associated with improvement in several parameters reported by patients.