Ponatinib Monotherapy after Combination with Chemotherapy in Patients with Newly Diagnosed Ph Plus ALL: Post Hoc Subgroup Analysis of the Phase 3 Phallcon Study

Introduction: BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy and/or steroids are standard of care for newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a potent third-generation BCR::ABL1 TKI. The phase 3 PhALLCON study (NCT03589326) is comparing frontline TKIs + chemotherapy in Ph+ ALL. After minimum follow-up of 3 months (mos) for all patients (pts), PhALLCON met its primary endpoint, showing a significantly higher rate of minimal residual disease (MRD)-negative (BCR::ABL1IS ≤0.01%; MR4) complete remission (CR) at end of induction (EOI) with ponatinib vs imatinib (34.4% vs 16.7%; P=0.002) and a safety profile comparable to imatinib. Per study protocol, pts who did not proceed to stem cell transplant or other alternative therapy could receive monotherapy with ponatinib or imatinib after 20 cycles of the chemotherapy combination. We report post hoc analyses of the subset of pts who received maintenance monotherapy post Cycle 20. Methods: Adults with newly diagnosed Ph+ ALL were randomized 2:1 to ponatinib (30 mg once daily [QD] reduced to 15 mg upon achievement of MRD-neg CR at EOI) or imatinib 600 mg QD plus 20 cycles of reduced-intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; maintenance combination: 11 cycles), followed by maintenance monotherapy with ponatinib or imatinib starting on Day 1, Cycle 21 until disease progression or unacceptable toxicity. The decision to proceed to monotherapy was solely per investigator's discretion. This post hoc analysis evaluated baseline characteristics, cumulative molecular response rates (MR4: BCR::ABL1IS ≤0.01%; MR4.5: BCR::ABL1IS ≤0.0032%), and safety in pts who received TKI monotherapy post Cycle 20. Data cutoff: Aug 12, 2022. Results: Among 41 pts who initiated TKI monotherapy in Cycle 21, the proportion proceeding to monotherapy was higher with ponatinib (21%; 34/163) vs imatinib (9%; 7/81). Pts who received monotherapy appeared to be older (≥60 y: 56%), and a higher proportion had ECOG score 1 at baseline (68%) compared with the overall population (n=245; ≥60 y: 37%; ECOG 1: 52%); other pt characteristics (female: 63%; region: Europe: 37%, North America: 34%; BCR::ABL1 p190/p210: 71%/20%) were comparable to the overall population (female: 54%; Europe: 42%, North America: 31%; p190/p210: 68%/27%). Among pts who initiated TKI monotherapy at Cycle 21 and had p190/p210 confirmed by central laboratory at baseline, the MRD-negativity (MR4) rate was 53% (16/30) with ponatinib vs 29% (2/7) with imatinib by EOI (Cycle 3) and 97% (29/30) vs 71% (5/7) by end of Cycle 20; the rate of deeper molecular response (MR4.5) was 37% (11/30) vs 29% (2/7) by EOI and 93% (28/30) vs 43% (3/7) by end of Cycle 20. For pts with MR4 at start of Cycle 21 (ponatinib n=26; imatinib n=3), 1 pt (4%) in the ponatinib arm and 1 (33%) in the imatinib arm lost MR4 response after starting monotherapy; by Kaplan-Meier estimates, MR4 was maintained at 12 mos post Cycle 20 in 95% of pts with ponatinib monotherapy vs 67% with imatinib. Median duration of MR4 post Cycle 20 was not reached (NR) in either arm (median follow-up: ponatinib [n=26], 6.1 mos [95% CI: 3.0-11.6]; imatinib [n=3], 18.4 mos [95% CI: 15.7-NR]). Treatment-emergent adverse event (TEAE) rates post Cycle 20 were similar with ponatinib (59%; 20/34) and imatinib (57%; 4/7), as were grade ≥3 TEAE rates (ponatinib: 12% [4/34; hypertension, peripheral arterial occlusive disease, recurrent leukemia, neutropenia, n=1 each]; imatinib: 14% [1/7; depression]). Vascular occlusive events (peripheral arterial occlusive disease and venous thrombosis; both grade 2) occurred in 2/34 pts receiving ponatinib monotherapy; both events resolved following dose reduction or interruption. TEAEs led to few dose modifications post Cycle 20 (ponatinib/imatinib: discontinuation, 1/1; reduction, 1/0; interruption, 3/0). Conclusion: More pts initiated monotherapy maintenance with ponatinib than imatinib. Single-agent ponatinib maintained durable MRD negativity post Cycle 20. Although these post hoc analyses should be interpreted with caution due to the small number of pts entering the maintenance phase, especially in the imatinib arm, and potential selection bias, these data appear to support the continuous clinical benefit and tolerability of ponatinib monotherapy after combination with chemotherapy in pts with newly diagnosed Ph+ ALL.