End-of-study results from the ICON3 pines trial, a phase 3, randomized trial of eltrombopag vs. standard first-line treatment for newly diagnosed immune thrombocytopenia in children

Abstract Background: The Pediatric ITP Newly diagnosed patients Eltrombopag vs Standard therapy (PINES) trial, NCT03939637, was an investigator-initiated, prospective, open label, randomized, multi-center trial sponsored by the ITP Consortium of North America (ICON) and funded by Novartis. Patients (pts) ages 1-<18 with primary ITP, ≤3 months from diagnosis, with platelet count <30 x109/L who required pharmacologic treatment per the treating clinician were randomized 2:1 to receive the experimental treatment, eltrombopag (epag), or investigator's choice of one of 3 standard first-line therapies (SOC): prednisone, IVIg, or anti-D globulin at specified doses. The primary platelet response endpoint within 12 weeks was achieved by 67% pts in the epag arm, compared with 35% pts in the SOC arm; the trial closed early for efficacy per DSMB recommendation (Shimano et al, ASH 2024). We now report secondary objectives from study completion. Methods: Pts were followed on study for 1 year. From weeks 13-52, pts randomized to epag could continue the study drug, with dosage weans per protocol. Pts in the SOC arm who had persistent ITP and those in the epag arm who had not responded could receive second-line therapies after week 12. Platelet counts were measured at 6 months and 1 year, as well as at monthly intervals for those remaining on epag. Complete response (CR) at 1 year was defined as platelet count ≥150 x109/L. Disease resolution at 1 year was defined as CR ≥3 months after discontinuing most recent platelet active medication, without having received rituximab or splenectomy. Pts were evaluable for secondary objectives if they received at least one dose of protocol therapy. Analyses were performed a) within the subgroup with known data at 1 year, and b) with last-observation-carried-forward (LOCF) to address missing data. Results: 78 pts were randomized to epag and 40 to SOC therapy. 12 pts came off study early due to withdrawal of consent (4), lost to follow-up (6), or other (2). Median duration of therapy in the epag arm was 111 days (range 7-390). 27 (35%) pts in the epag arm vs 22 (56%) in the SOC arm did not require any treatment after week 12, p=0.02, and 43 (55%) vs 25 (64%) did not require any treatment after 6 months, p=0.35. The most commonly used subsequent agents were romiplostim, rituximab, and mycophenolate mofetil in pts randomized to epag, and epag and romiplostim for pts randomized to SOC. 106 pts completed the full 1-year study (73 [94%] for epag; 33 [83%] for SOC).18 pts (25%) in the epag arm remained on study drug at 1 year. 24/73 (33%) pts in the epag arm vs 11/33 (33%) pts in the SOC arm remained on platelet active medication at 1 year. Disease resolution by 1 year occurred in 50 (47%) pts overall, and in 33 (45%) epag pts vs 17 (52%) SOC pts, p=0.55, with similar results for CR and for LOCF analyses. Disease resolution at 1 year was no different among age groups [15/28 (54%) epag arm vs 7/11 (64%) SOC ages 1-<6; 11/26 (42%) vs 5/12 (42%) ages 6-<12; and 7/19 (37%) vs 5/10 (50%) ages 12-<18]. Disease resolution at 1 year occurred in 16/26 (62%) epag vs 10/13 (77%) SOC treatment-naïve pts who enrolled on the trial as upfront therapy. 33 (45%) pts in epag arm vs 15 (45%) in SOC arm had “primary remission,” defined as CR at 1 year with no second-line agents and ≥3 months after discontinuing most recent platelet active medication. 8 (11%) in epag arm vs 3 (9%) in SOC arm had “disease stability,” defined as platelets between 50-150 x109/L and were ≥3 months after discontinuing most recent platelet active medication. Sustained response off treatment (SROT, inclusive of those with disease resolution or disease stability) occurred in 41 (56%) in epag arm vs 20 (61%) in SOC. There were 14 adverse events (AEs) (including 4 serious AEs) during weeks 13-52 in 9 pts (6 epag, 3 SOC). Conclusions: In this population of pediatric pts with newly diagnosed ITP, 47% overall had disease resolution by 1 year, with no difference between treatment arms in 1-year response rates. SROT at 12 months was 56% in epag and 61% in SOC. Many pts on the epag arm were able to discontinue medication quickly, within a median of 4 months. Given these findings and the improved sustained platelet response to epag compared to SOC during weeks 6-12, epag should be considered for upfront and early use in pediatric pts with newly diagnosed ITP who require pharmacologic treatment in order to obtain a more stable platelet count.