AUTHORS
Anna Turkina, MD, Olga Vinogradova, MD, PhD2, Nuriya Kalimulina, MD3, Tatyana Shelekhova, MD, PhD, DrSci4, Igor Davydkin, MD, PhD, DrSci5, Bulat Bakirov, MD, PhD6, Tatiana Pospelova, MD, PhD, DrSci7, Elza Lomaia, MD, PhD, DrSci8, Ekaterina Chelysheva, MD, PhD9, Jitendra Pehalajani, MD10, Vishvdeep Khushoo, MD11, Shashikant Sagar Apte, MD (Medicine), FRCPA12, Ranjit Sahoo, MD13, Shailesh Lavana, MD14, Sergey Kulikov15
AFFILIATIONS
1 National Medical Research Center, Moscow, Russian Federation
2 Botkin Hospital, Moscow, Russian Federation
3 UZI Clinic 4D, Pyatigorsk, Russian Federation
4 Saratov State Medical Center, Saratov, Russian Federation
5 Samara State Medical University, Samara, Russian Federation
6 Bashkir State Medical University, Ufa, Russian Federation
7 Novosibirsk State Medical University, Novosibirsk, Russian Federation
8 Federal Almazov North-West Medical Research Centre, Saint Petersburg, Russian Federation
9 National Medical Research Center, Moscow, Russian Federation
10 Marudhar Hospital Jaipur, Jaipur, India
11 All India Institute of Medical Sciences, Nagpur, India
12 Institute of Haematology & Transfusion Medicine, Kolkata, India
13 All India Institute of Medical Sciences, New Delhi, India
14 Kailash Cancer Hospital & Research Centre, Goraj, India
15 National Medical Research Center for Hematology, Moscow, Russian Federation
ABSTRACT
Background. Vamotinib is a third-generation, ATP-competitive oral tyrosine kinase inhibitor (TKI) structurally analogous to ponatinib but rationally designed to minimize off-target kinase inhibition and associated life-threatening toxicity. This study compared the efficacy and safety of vamotinib with those of high-dose imatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to conventional-dose imatinib.
Materials and methods. A total of 180 patients with Ph+, BCR::ABL1p210+ CP-CML, were included in the multicenter, open-label, randomized phase III study from 33 centers of Russia and India. Patients were resistant to imatinib 400–600 mg in 1st line and were randomized to vamotinib 300 mg (n=89) or imatinib 600–800 mg (n=91). Cumulative incidences of molecular response (MR2), major molecular response (MMR), and deep molecular response (MR4) and the safety data were evaluated; the planned treatment duration in a study was 24 months.
Results. At 24 months, cumulative incidences of MR2 and MMR were significantly higher with vamotinib than imatinib: MR2 62% vs 37% (p=0.0007) and MMR 56% vs 22% (p<0.0001). MR4 was achieved in 45% vs 14% (Hazard ratio 3.84; 95% CI 2.01–7.35; p<0.0001). Baseline BCR::ABL1 mutations (n=30) did not compromise MMR probability. Progression free survival (PFS) favored vamotinib (1 event vs 6 events; p=0.05). Therapy was completed per protocol by 57.3% vs 16.5% of patients; discontinuation due to resistance/progression occurred in 14.6% vs 47.3%. In 45 patients switched from imatinib to vamotinib (18 toxicity, 27 resistance), MR2 and MMR were reached in 68% and 55%. Vamotinib was well tolerated; skin toxicity was the most common adverse events (AE) – 45 patients (50,6%), grade 3–4 in 4 patients (4,5%), with a safety profile generally comparable to imatinib. Only 14 AEs were classified as serious (7 AEs after administration of vamotinib, 6 AEs after administration of imatinib, and 1 AE after switching from imatinib to vamotinib).
Conclusions. At 24 months, vamotinib 300 mg demonstrated significantly higher efficacy than high-dose imatinib in CP-CML, with substantially deeper molecular responses, favorable PFS, and good tolerability. The drug is promising and has already approved for use in clinical practice in CML patients.
DISCLOSURES
Anna Turkina, MD: Novartis - Honoraria; R-Pharm - Honoraria