Larotrectinib Continues to Exhibit Excessive DCR, Elicit Sturdy Responses in TRK Fusion+ CNS Tumors

Larotrectinib continued to supply speedy and sturdy responses, with a excessive illness management fee and an appropriate toxicity profile in sufferers with TRK fusion–optimistic, major central nervous system tumors.

Larotrectinib (Vitrakvi) continued to supply speedy and sturdy responses, with a excessive illness management fee (DCR) and an appropriate toxicity profile in sufferers with TRK fusion–optimistic, major central nervous system (CNS) tumors, in keeping with long-term information from 2 scientific trials offered in the course of the 2022 ASCO Annual Assembly.1

Knowledge from the long-term evaluation of these handled on the part 1/2 SCOUT research (NCT02637687) and the part 2 NAVIGATE research (NCT02576431) confirmed that larotrectinib elicited an goal response fee (ORR) of 30% (95% CI, 16%-47%). In 28 pediatric sufferers, the ORR was 39% (95% CI, 22%-59%). The very best responses included full response (CR) in 8% of sufferers, partial response (PR) in 22%, steady illness (SD) for twenty-four weeks or extra in 43%, SD for lower than 24 weeks in 14%, and progressive illness (PD) in 14%.

A DCR for twenty-four weeks or extra was noticed in 73% of sufferers (95% CI, 56%-86%); in grownup sufferers, this fee was 24% (95% CI, 14%-79%) and in pediatric sufferers, it was 82% (95% CI, 63%-94%). At a median follow-up of 25.6 months, the median DOR was not reached (95% CI, 4.9-not evaluable [NE]). The 24-month DOR was 53% (95% CI, 23%-83%).

Knowledge from SCOUT and NAVIGATE served as partial foundation for an accelerated FDA approval granted in 2018 for larotrectinib as remedy of grownup and pediatric sufferers with stable tumors which have a NTRK gene fusion with out a identified acquired resistance mutation. Larotrectinib can be utilized in these whose illness is both metastatic or the place surgical resection is prone to lead to extreme morbidity, and who haven’t any passable different remedy choices or whose most cancers has progressed following remedy.

A previous report from these trials confirmed that larotrectinib achieved an ORR of 30% (95% CI, 16%-49%) and a 24-week DCR of 73% (95% CI, 54%-87%) in 33 evaluable grownup and pediatric sufferers with TRK fusion major CNS tumors. As well as, remedy with larotrectinib resulted in tumor shrinkage in 82% of sufferers who had measurable illness.2

The dataset for the long-term evaluation included 26 pediatric sufferers from SCOUT who have been beneath 21 yr of age with domestically superior metastatic stable tumors or CNS tumors and 12 grownup and adolescent sufferers from NAVIGATE who have been 12 years of age or older with superior stable tumors and TRK fusion most cancers. Collectively, the 38 sufferers have been evaluated for the first finish level of investigator-assessed ORR per RECIST v1.1 standards. The secondary finish factors assessed for the long-term evaluation included length of response (DOR), progression-free survival (PFS), total survival (OS), and security.

Grownup sufferers have been administered oral larotrectinib at 100 mg twice day by day, and pediatric sufferers acquired 100 mg/m2 twice day by day.

Sufferers enrolled had a median age of 10.8 years (vary, 1.3-79.0) and 50% have been feminine. The commonest sort of NTRK gene fusion recognized in sufferers at baseline was NTRK2 in 74%, adopted by NTRK1 in 16%, and NTRK3 in 11%. ECOG efficiency rating ranged from 0 to 2; most sufferers (53%) had a rating of 0, 34% had a rating of 1, and 11% had a rating of two.

Nearly all of sufferers assessed had high-grade glioma (61%) and low-grade glioma (24%). Sixteen p.c of sufferers had different histologies.

By way of prior therapies, 71% of sufferers had undergone surgical procedure, 58% acquired radiotherapy, and 87% had systemic remedy, and the median variety of prior systemic therapies was 1 (vary, 0-8). In reality, the vast majority of affected person assessed had a median of 1 prior remedy (42%), whereas 21% had 2, one other 21% had 3 or extra, and 16% had 0.

On prior remedy, 6% of affected person achieved a CR and three% achieved a PR. The commonest response to prior remedy was SD in 36%. Furthermore, 30% of sufferers had PD throughout prior remedy, and 24% had different responses.

Knowledge from SCOUT and NAVIGATE confirmed that remedy with larotrectinib lasted for 0.1 months to 38.7 months. The median time to response was 1.9 months (vary, 1.0-3.8). Fifty-eight p.c of sufferers progressed on larotrectinib and 4 continued the remedy post-progression for 4 weeks or extra.

The median follow-up for PFS evaluation was 27.4 months, and larotrectinib achieved a median PFS of 16.5 months (95% CI, 6.7-NE). At 24 months, the PFS fee noticed with larotrectinib was 40% (95% CI, 24%-57%). At a median follow-up of 26.7 months, the median OS was not reached (95% CI, 22.6-NE). The 24-months OS fee among the many sufferers evaluated was 65% (95% CI, 47%-83%).

Fifty-five p.c of sufferers within the dataset skilled treatment-related hostile results (TRAEs), however 86% of them have been grade 1 or 2. Eight p.c of sufferers expertise grade 3 and 4 TRAEs, which included gamma-glutamytransferase improve, hyperglycemia, hypernatremia, hyponatremia, and neutrophil depend lower. The commonest TRAEs of any grade included higher respiratory tract an infection, vomiting, diarrhea, alanine aminotransferase improve, headache, anemia, and aspartate aminotransferase improve.

Remedy-related neurologic AEs have been additionally noticed within the cohort. Notably, the vast majority of occasions have been grades 1 and a couple of and occurred in the identical sufferers. Nevertheless, reminiscence impairment was noticed in 2 sufferers, 1 of whom was an grownup and different a pediatric affected person.

No sufferers within the research discontinued remedy because of a TRAE.

Primarily based on the collective findings, investigators consider that you will need to check for NTRK gene fusions in grownup and pediatric sufferers with major CNS tumors.

References

  1. Perreault S, Drilon AE, Lassen LN, et al. Lengthy-term management and security of larotrectinib in a cohort of grownup and pediatric sufferers with tropomyosin receptor kinase (TRK) fusion major central nervous system (CNS) tumors. J Clin Oncol. 2022; 40 (suppl 16):2010. doi:10.1200/JCO.2022.40.16_suppl.2010
  2. Doz F, van Tilburg, Geoerger B, et al. Efficacy and security of larotrectinib in TRK fusion-positive major central nervous system tumors. Neuro Oncol. 2022;24(6):997-1007. doi:10.1093/neuonc/noab274

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