High-Resolution Analysis of the Relationship Between Dose and Molecular Response in CP-CML Patients Treated with Ponatinib or Imatinib
Authors: Pritchard Justin R. , Lustgarten Stephanie , Hodgson Graeme , Baccarani Michele , Cortes Jorge E. , Deininger Michael W. , Guilhot Francois , Hochhaus Andreas , Hughes Timothy P. , Shah Neil P. , Talpaz Moshe , Clackson Tim , Haluska Frank G. , Knickerbocker Ronald , Rivera Victor M. 
Published: November 2019

Abstract
Background:
Ponatinib is a potent pan-BCR-ABL tyrosine kinase inhibitor (TKI). The phase 2 PACE study demonstrated that ponatinib is highly active in heavily pretreated CP-CML patients, 58% of whom received ≥3 prior TKIs. The phase 3 EPIC study, in which ponatinib was compared with imatinib, was terminated early due to concerns about arterial thrombotic events observed in the ponatinib development program, though analysis of existing data suggests that ponatinib has improved efficacy over imatinib in newly diagnosed CP-CML patients. Fixed starting doses of ponatinib and imatinib were used in these studies (45 mg and 400 mg once daily, respectively), but the allowance for treatment interruptions and dose reductions, coupled with multiple assessments of molecular response per patient, enables exploration of dose-response relationships. Here we describe a novel approach called BARD (BCR-ABL Response-Dose association) that allows associations between dose, based on patient daily dosing records, and efficacy, based on frequent measurement of BCR-ABL transcript levels, to be examined with high resolution.
Methods:
BCR-ABL levels were measured every 1-3 months in peripheral blood samples from CP-CML patients in the PACE (N=267) and EPIC studies (N=154 [ponatinib] and 152 [imatinib]), which had median follow-ups of 27.9 and 5.1 months, respectively. The change in BCR-ABL levels (expressed as 1/doubling time [1/DT]) and average daily dose were calculated for every measurement interval (window). Local regression was utilized to smooth scatter plots of 1/DT values across all patients versus dose. Smoothing-adjusted 1/DT values were replotted relative to the average daily dose for each window. Scatter plots of 1/DT values for ranges of dose levels were analyzed for differences by t-test. Average 1/DT values were transformed using an exponential growth/decay model to estimate the number of days required to achieve a 10-fold decrease in BCR-ABL levels.
Results:
In newly diagnosed patients (EPIC), across all dose levels, BARD analysis showed that the average number of days required to decrease BCR-ABL levels 10-fold was 47.5 (± 3.2) for ponatinib and 89.9 (± 4.6) for imatinib, consistent with the more rapid molecular responses observed in the ponatinib arm. Though increased doses of both ponatinib and imatinib were associated with trends towards more rapid decreases in BCR-ABL levels, the rate of decrease induced by ponatinib was greater overall (Table). Within windows that included only continuous dosing at starting dose levels, 10-fold decreases in BCR-ABL levels were achieved significantly more rapidly (p<0.0001) with 45 mg ponatinib than 400 mg imatinib. Moreover, compared with 400 mg imatinib, 10-fold decreases in BCR-ABL levels were also achieved more rapidly with average ponatinib dose levels <15 mg (p>0.05), 15 to <30 mg (p<0.02) and 30 to <45 mg (p<0.0001).
In heavily pretreated patients (PACE), increased doses of ponatinib were also associated with a trend towards more rapid decreases in BCR-ABL levels, although the rate of decrease induced by 45 mg ponatinib (129.9 [± 18.5] days to reduce BCR-ABL levels 10-fold in the first 6 months) was reduced compared with that observed in newly diagnosed patients. Importantly, across the entire PACE study, average daily doses of ponatinib as low as 10 mg were associated with net decreases in BCR-ABL levels.
Conclusions:
BARD enables a detailed exploration of dose-response relationships in CP-CML. In newly diagnosed patients, ponatinib doses as low as 15 mg induced more rapid decreases in BCR-ABL levels than 400 mg imatinib. Consistent with the possibility that sequential treatment with TKIs increases the degree of BCR-ABL independence, the magnitude of BCR-ABL decreases induced by ponatinib in heavily pretreated patients was reduced compared with newly diagnosed patients. Nonetheless, ponatinib doses as low as 10 mg were still associated with disease control overall. These analyses will help inform the design of future studies aimed at optimizing the benefit/risk of ponatinib treatment for patients with CML.
Table. BCR-ABL Response Dose Association (BARD) from EPIC Drug Dose range (mg) Time to 10-fold BCR-ABL decrease (Days) Windows* (N) Ponatinib <15 66.4 ± 23.2 40 15 to <30 55.2 ± 8.2 60 30 to <45 48.1 ± 8.6 136 45 41.5 ± 2.8 184 Imatinib 400 82.8 ± 4.3 374
*Number of BCR-ABL measurement intervals when average dose was within the indicated range

Disclosures
Pritchard: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Hodgson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, BMS, Novartis, Pfizer, Teva: Honoraria, Speakers Bureau. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Hughes:Novartis, BMS, ARIAD Pharmaceuticals, Inc.: Honoraria, Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Knickerbocker:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership.