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Table 3 Summary of future treatment landscape

From: A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase

Key trial information

Key efficacy

Key safety

2G TKIs

  

Radotinib: 2G TKI with activity against native and kinase-domain mutant BCR::ABL, currently undergoing testing to assess efficacy in CML-CP with failure or intolerance to prior TKI therapy [106]

RERISE (NCT01511289) [107]: phase 3 trial comparing radotinib with imatinib in patients with ND CML-CP in the Republic of Korea, Indonesia, the Philippines, and Thailand

MMR at 12 months (primary endpoint):

 Radotinib 300 mg BID 52% (P = 0.0044 vs. imatinib)

 Radotinib 400 mg BID 46% (P = 0.0342 vs. imatinib)

 Imatinib 30%

CCyR at 12 months (secondary endpoint):

 Radotinib 300 mg BID 91% (P = 0.0120 vs. imatinib)

 Radotinib 400 mg BID 82% (not significant vs. imatinib)

 Imatinib 77%

Grade 3–4 neutropenia was the most frequently reported hematologic AE:

 Radotinib 300 mg 19%

 Radotinib 400 mg 23%

 Imatinib 32%

Phase 3 multinational (Republic of Korea, Turkey, Russian Federation, and Ukraine) trial to assess efficacy in CML-CP with failure or intolerance to prior TKI therapy (NCT03459534; currently recruiting)

Data not yet available.

Data not yet available.

Flumatinib: imatinib derivative that displays increased efficacy over imatinib in Chinese patients with ND CML-CP with a similar safety profile [96]

FESTnd (NCT02204644) [96]: phase 3 trial: flumatinib vs. imatinib in ND CML-CP

MMR at 6 months (primary endpoint):

 Flumatinib 34%, imatinib 18% (P = 0.0006)

EMR at 3 months (secondary endpoint):

 Flumatinib 82%, imatinib 53% (P < 0.0001)

All-grade AEs more frequent in flumatinib arm:

 Diarrhea (n = 79/196, 40%)

 Alanine transaminase elevation (n = 51/196, 26%)

All-grade AEs more frequent in imatinib arm:

 Edema (n = 70/198, 35%)

 Pain in extremities (n = 49/198, 25%)

 Rash (n = 28/198, 14%)

 Neutropenia

 Thrombocytopenia

 Anemia

 Hypophosphatemia

NCT04677439: currently recruiting patients to a phase 4 trial in China: efficacy and safety of flumatinib in patients with Ph + CML-CP post-imatinib failure

Data not yet available.

Data not yet available.

3G TKIs

  

Vodobatinib: novel 3G TKI with limited off-target activity effective against native and mutated BCR::ABL [108]

NCT02629692: multinational phase 1/2 trial in ponatinib-treated and naive patients with CML-CP who failed ≥ 3 TKIs (or fewer, if not eligible for other approved 3G TKIs) to determine MTD and RP2D [97]

MTD (primary endpoint): 204 mg

Efficacy (secondary endpoint):

 MMR: 3/16 in ponatinib-treated and 4/15 in ponatinib-naive patients

 MCyR: 5/16 in ponatinib-treated patients

 CCyR: 3/15 in ponatinib-naive patients

 Disease progression: 2/16 in ponatinib-treated and 4/15 in ponatinib-naive patients

TEAEs grade ≥ 3 reported in > 1 ponatinib-treated patient:

 2 (13%) each of neutropenia, amylase increase, and thrombocytopenia

TEAEs grade ≥ 3 reported in 7 (47%) ponatinib-naive patients:

 1 of each: anemia, pneumonia, neutropenia, gout, hypokalemia and thrombocytopenia, dementia, amnesia, and increased liver and pancreatic enzymes

Olverembatinib: a novel, broad-spectrum BCR::ABL1 TKI active against T315I mutations [98]

Phase 1 dose escalation/expansion trial assessing safety, preliminary efficacy, and pharmacokinetic and dynamic properties in Chinese patients with TKI-resistant CML-CP/AP [99]

CHR within 3 cycles (primary endpoint):

 CML-AP: 58% (n = 7/58)

MCyR ≥ 3 cycles (primary endpoint):

 CML-CP: 54% (n = 21/58)

≥ 1 grade 3–4 TRAE:

 44 (63%) of all patients

Dose-limiting toxicities:

 2/3 patients in 60 mg cohort

Phase 1 dose escalation/expansion trial to determine maximum tolerated dose and dose-limiting toxicity in Chinese patients with TKI-resistant CML-CP/AP [98]

CHR:

 CML-CP: 95% (n = 52/55)

 CML-AP: 85% (n = 11/13)

CCyR:

 CML-CP: 61% (n = 49/81)

 CML-AP: 36% (n = 5/14)

Most common grade ≥ 3 AEs in > 10% patients:

 Thrombocytopenia (n = 50/101, 50%)

 Leukopenia (n = 20/101, 20%)

 Anemia (n = 12/101, 12%)

4G TKI

  

PF-114: potent 4G TKI selective against native BCR::ABL and BCR::ABL harboring the T315I mutation [109]

NCT02885766: phase 1 trial in patients with CML-CP/AP failing ≥ 2 TKIs or with BCR::ABL1 T315I with ≥ 6 months’ therapy to determine MTD and dose-limiting toxicity. Interim analysis at ≥ 6 months [101]

MTD (primary endpoint):

 600 mg

Dose-limiting toxicity (primary endpoint):

 600 mg manifesting as grade 3 psoriasis-like skin lesions

MCyR:

 6/11 patients receiving 300 mg dose

 4/12 patients with the BCR::ABL1 T315I mutation

Discontinuations due to progression:

 n = 18/51 (35%)

Discontinuations due to AEs:

 n = 6/51 (12%)

Reversible grade 3 skin toxicity (psoriasis-like skin lesions):

 11 patients ≥ 400 mg dose

STAMP inhibitor

  

Asciminib: novel, first-in-class STAMP inhibitor that binds to the myristoyl pocket of BCR::ABL [91]

NCT03106779: multicenter phase 3 trial comparing asciminib and bosutinib in patients with CML-CP previously treated with ≥ 2 TKIs [110]

MMR at 24 weeks (primary endpoint)

 Asciminib 26%; bosutinib 13% (P = 0.029)

Grade ≥ 3 TRAEs reported in 51% asciminib- and 61% bosutinib-treated patients

1 patient died due to treatment-related serious AE in the bosutinib arm

  1. 1G first-generation; 2G second-generation; 3G third-generation; 4G, fourth-generation; AE adverse event; AP accelerated phase; BID twice daily; CCyR complete cytogenetic response; CHR complete hematologic response; CML-AP chronic myeloid leukemia in acute phase; CML-CP chronic myeloid leukemia in chronic phase; EMR early molecular response; MCyR major cytogenetic response; MMR major molecular response; MTD maximum tolerated dose; ND newly diagnosed; Ph +  Philadelphia positive; STAMP specifically targeting the ABL myristoyl pocket; TEAE treatment-emergent adverse event; TKI tyrosine kinase inhibitor; and TRAE treatment-related adverse event