Larotrectinib Exhibits Rapid and Sustained HRQoL Improvement in TRK Fusion Cancers

Shivaani Kummar, MD, FACP

Clinically meaningful improvements in health-related quality of life (HRQoL) were rapid and sustained in the majority of adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion lung cancer who were treated with larotrectinib (Vitrakvi), according to results from an expanded dataset presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

“In this expanded data set, most adults and children with TRK fusion cancers treated with larotrectinib continued to experience rapid, sustained, and clinically meaningful improvements in health-related quality of life. Quality of life scores for most patients two years of age and older were either maintained within or moved into the normal healthy range during larotrectinib treatment,” said Shivaani Kummar, MD, FACP, the DeArmond Endowed Chair of Cancer Research professor & head, of Medicine, Division of Hematology/Medical Oncology, School of Medicine, and co-director, Center for Experimental Therapeutics Knight Cancer Institute at the Ohio State University, during the ASCO presentation.

Neurotrophic tyrosine kinase receptor (NTRK) gene fusions are primary oncogenic drivers in many tumors that affect adults and children. As a first-in-class, highly selective TRK inhibitor, larotrectinib was granted FDA approval to treat TRK fusion cancers. Prior findings from 57 adult and pediatric patients showed that larotrectinib rapidly improved HRQoL.

“Maintaining or improving health-related quality of life is a key treatment goal of anti-cancer therapy so that patients not only live longer but also live better. This analysis supports updated quality of life data with longer follow up,” Kummar, explained.

For the HRQoL analysis, investigators pooled data from the phase 1/2 SCOUT study (NCT02637687) and phase 2 NAVIGATE study (NCT02576431) and focused on patients with non-primary central nervous system TRK fusion cancers. All patients completed the European Organization for the Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ-C30), and the EuroQol Group EQ-5D-5L questionnaire.

With the questionnaires, investigators were able to determine the baseline global health score (GHS), visual analog score, and the pediatric QoL (PedsQL) score ranging from 0 to 100. Higher scores were indicative of better HRQoL, a measurement that was correlated with minimally important difference (MID), defined for adults as ≥ 10 points EORTC QLQ-C30 GHS as well as in EQ-5D-5L. For pediatric patients ages 2 years old and younger, MID was defined as ≥ 4.5 points in PedsQL total score.

The investigators also looked at HRQoL as is related to best response and median response, the proportion of patients normal/above-normal, and below-normal HRQoL scores compared with published literature, time to sustained improvement and deterioration, and objective response rate (ORRs).

At the data cutoff date of July 20, 2021, a total of 198 patients had been treated with larotrectinib and completed a baseline and post-baseline HRQoL questionnaire. Adults made up 113 of the patients, and the remaining 47 patients were children.

Results showed that 96% of adult patients with normal baseline scores or above remained in this category while on larotectinib treatment. Ninety-one percent of adults with baseline scores below normal improved and went into the above-normal category. Children aged 2 years and older who had a normal or above-normal score at baseline remained in this category while on treatment, and 56% who were below normal at baseline moved into the above-normal category.

“For their best change from baseline, 89% or 90% of adults had quality of life improvements depending upon the specific instrument used in the assessment. Of these, 61% of the adults had reported improvements that exceeded the MID. Ninety-six percent of pediatric patients had their best post-baseline score equal to or greater than their baseline measurement. And of these, 72% had improvements exceeding the MID. Not shown, the mean pediatric quality of life score for infants was 80 with their best mean change from baseline being 11.8,” Kummar stated, explaining the results further.

EORTC QLQ-C30 GHS MID improvement was also observed in 10 out 21 patients who achieved a complete response (CR) on larotrectinib, 38 out of 54 patients who achieved a partial response (PR), 16 out of 28 patients who had stable disease (SD), and 3 out 8 patients who had progressive disease (PD).

Among those who completed the EQ-5D-5L VAS MID improvement was observed in 13 out of 21 patients who achieved a CR, 35 out of 54 patients with a PR, 17 out of 27 patients with SD, and 3 out of 9 patients with PD.

For the PedsQL total score, MID improvement was observed in 8 out of 10 pediatric patients who achieved a CR, 18 out of 22 who achieved a PR, 4 out of 8 who had SD, and 1 out 2 who had PD.

Some patients sustained improvements lasting ≥ 2 consecutive cycles of larotrectinib, and this included 50% of those who completed the EORTC QLQ-C30 questionnaire, 51% who completed the EQ-5D-5L questionnaire, and 32% of those who completed the PedsQL questionnaire.

Sustained improvement that lasted until the end of assessment was observed in 26% of those who completed the EORTC QLQ-C30 questionnaire, 24% who completed the EQ-5D-5L questionnaire, and 185 of those who completed the PedsQL questionnaire. In terms of sustained deterioration lasting for ≥ 2 consecutive cycles, this was observed in 21% of patients who completed the EORTC QLQ-C30 questionnaire, 24% of those who did the EQ-5D-5L questionnaire, and 12% of those who completed the PedsQL questionnaire.

The analysis was limited by the lack of a control group. However, the findings still demonstrated the clinically meaningful HRQoL benefit of larotrectinib across a spectrum of TRK fusion tumors, explained Kummar.

“Continued robust quality of life improvement documented here are consistent with the rapid onset of clinical benefit and favorable safety profile of larotrectinib in both adult and pediatric patients,” said Kummar in conclusion.

_REFERENCES:

_{Kummar S, Shen L, van Tilburg C, et al. Updated health-related quality of life of patients with TRK-fusion cancer treated with larotrectinib in clinical trials. J Clin Oncol. 2022; 40 (suppl 16): 6563. doi: 10.1200/JCO.2022.40.16_suppl.6563}