OPTIC primary analysis: A dose-optimization study of 3 starting doses of ponatinib (PON).

Abstract

7000 Background: PON, a third-generation tyrosine kinase inhibitor (TKI), demonstrated deep and long-lasting responses and survival in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) resistant/intolerant to second-generation TKI therapy (PACE; NCT01207440); post hoc analysis suggested a relationship between dose and both adverse events and response. Here we present the primary analysis of OPTIC (NCT02467270), an ongoing, randomized, phase 2 trial with a novel response-based dosing regimen of PON in pts with resistant/intolerant CP-CML. Methods: Pts with CP-CML resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to PON starting doses of 45 mg (cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg →15 mg), and 15 mg (C) once daily. Doses were reduced to 15 mg with achievement of ≤1% BCR-ABL1IS in cohorts A and B. The primary endpoint is ≤1% BCR-ABL1IS at 12 mo; secondary endpoints include cytogenetic and molecular responses and safety outcomes. AOEs were adjudicated prospectively by an independent review committee. Results: 283 pts were randomized (A/B/C: n=94/95/94) and had the following baseline characteristics: median age 48 y (18‒81 y); 98% received ≥2 (55% ≥3) TKIs; 99% had resistant disease; 40% had ≥1 baseline mutations (23% T315I). At the primary analysis with 32 mo median follow-up, 134 pts (47%; n=50/41/43) remained on treatment and 204 pts (72%) had PON exposure ≥12 mo. At 12 mo, 44% (41/93) in A, 29% (27/93) in B, and 23% (21/91) in C achieved ≤1% BCR-ABL1IS (Table); primary endpoint was met by cohort A. Dose reductions to 15 mg after achieving response (A/B) were 48/29%. Most common grades ≥3 TEAEs were thrombocytopenia, 27%; neutropenia, 17%; and anemia, 7%. AOEs/serious AOEs were reported in cohorts A (10%/4%), B (5%/4%), and C (3%/3%). Dose reductions or discontinuations for TEAEs (A/B/C) were 46/35/32% and 19/16/14%, respectively. Conclusions: The OPTIC primary analysis demonstrates the optimal benefit:risk profile for PON was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤ 1% BCR-ABL1IS; 30 mg→15 mg and 15 mg cohorts may provide benefit, especially in pts without T315I mutation (Table). The observed ≤1% BCR-ABL1IS responses are supported by robust survival outcomes in pts with CP-CML resistant to second-generation BCR-ABL1 TKI therapy, both with and without BCR-ABL1 mutations. Clinical trial information: NCT02467270. [Table: see text]

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia

“… 50 Furthermore, primary analysis results from the Optimizing Ponatinib Treatment in Chronic Phase CML (OPTIC) trial in patients with chronic myeloid leukemia reported incidence of treatment-emergent arterial occlusive events of 3.2% to 9.6% depending on the starting dose (15, 30, or 45 mg once daily). 51 In our study, risk factors that include older age and age-related comorbidities, such as hypertension and dyslipidemia, may have played a role in the development of cardiovascular and other toxicities. Therefore, accurate cardiac screening is recommended before patients start ponatinib treatment.…”

“… 52 A similar response-based strategy was also shown to be effective in the ponatinib dose-optimization study in patients with chronic myeloid leukemia. 51 As such, it is possible that either a reduced starting dose of ponatinib or a dose-reduction strategy based on response may have an improved benefit–risk profile compared with continuous 45-mg daily dosing in older or unfit patients with Ph + ALL.…”

Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results

“…Discontinuation due to PD (6.1%) and AEs (11.3%) occurred infrequently; 2 patients died on treatment, unrelated to asciminib. In studies of other TKIs (including nilotinib, dasatinib, bosutinib, and ponatinib) in heavily pretreated patients, 24%-62% remained on treatment [9,10,17,19,21,22,24,[34][35][36][37], including 24% to ≈56% in bosutinib studies [9,24] and 33%-53% in ponatinib studies [10,37].…”

Eine klinische Perspektive auf die Behandlung von chronischer myeloischer Leukämie in der chronischen Phase

“…Nilotinib könnte jedoch aufgrund der niedrigen Ödemraten, die zu diesem Mittel berichtet wurden, in Betracht gezogen werden [18]. Obwohl Ponatinib bei Patienten mit CML, die gegenüber 2G-TKIs resistent/intolerant sind, und bei Patienten mit T3151-Mutation Wirksamkeit gezeigt hat [58, 59], wird es allgemein für die Behandlung von CML bei diesen Patienten empfohlen [11, 13]. Da die Patientin in dieser Fallstudie keine T315I-Mutation trägt, empfehlen wir Ponatinib in diesem Falle nicht.…”