Novartis' Tasigna Phase 2 Trial Shows 42.6% of Patients Achieving 5-Year Treatment-Free Remission After Discontinuation
Clinical Design and Discontinuation Criteria
The ENESTfreedom trial, sponsored by Novartis AG (NVS), was a global, single-arm, multi-center Phase 2 clinical trial evaluating the discontinuation of Tasigna (nilotinib) in patients with chronic-phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML-CP). Tasigna is a second-generation tyrosine kinase inhibitor (TKI) that inhibits the ATP-binding site of the BCR::ABL1 tyrosine kinase, which drives the proliferation of cancer cells. The trial was designed to control the risk of relapse by enrolling patients who had received nilotinib as first-line therapy for at least two years and achieved MR4.5, followed by one year of consolidation therapy, and only attempted treatment-free remission (TFR) in those who maintained stable deep molecular response (DMR).
Clinical Results and Patient Benefit
Of the 215 enrolled patients, 190 discontinued nilotinib, and at the 48-week time point, 51.6% maintained major molecular response (MMR) without restarting treatment, meeting the primary endpoint. At 5 years of follow-up, 81 patients, or 42.6%, maintained TFR, and 79 patients, or 41.6%, continued to have MMR or better without medication. The Kaplan-Meier estimated 5-year treatment-free survival was 48.2%. Of the 91 patients who restarted treatment after loss of MMR, 90 (98.9%) regained MMR, and 84 (92.3%) regained MR4.5. No accelerated-phase or blast-phase progression or CML-related deaths occurred, demonstrating the reversibility of the discontinuation strategy with careful molecular monitoring.
Competitive Landscape and Regulatory Changes
In the first-line treatment of CML, Gleevec (imatinib), Sprycel (dasatinib), Bosulif (bosutinib), Tasigna, and Scemblix (asciminib) compete. Iclusig (ponatinib) is primarily used in patients with resistance or the T315I mutation. The FDA approved Tasigna on October 29, 2007, and on December 22, 2017, incorporated information on treatment discontinuation in patients with sustained MR4.5 into the label, based on the ENESTfreedom and ENESTop trials, and granted priority review without a separate advisory committee (AdComm) vote. In Europe, it was approved on November 19, 2007, and TFR data were added to the product information on June 6, 2017. In Japan, PMDA approved it on January 21, 2009, as a treatment for CML resistant or intolerant to imatinib.
Market and Investment Implications
Novartis' global sales of Tasigna in 2024 were USD 1.671 billion, a 10% decrease from the previous year, which the company attributed to declining demand and increased competition. TFR represents a clinical advance that reduces the long-term drug costs and cardiovascular/metabolic toxicity burden in eligible patients, but as more patients successfully discontinue treatment, the duration of treatment with existing TKIs and the lifetime revenue per patient will decrease. However, as the value of drugs that achieve deep molecular response more quickly increases, nilotinib must differentiate itself in terms of TFR rate and safety while competing with the cost advantage of generic imatinib and the efficacy/tolerability of asciminib, which has expanded into first-line treatment.
From an investor's perspective, ENESTfreedom provides long-term evidence that 42.6% of 190 patients in the Phase 2 trial maintained 5-year TFR and 98.9% of retreated patients regained MMR, but the expansion of treatment discontinuation creates structural pressure to shorten the duration of Tasigna treatment, which generated USD 1.671 billion in sales in 2024. For researchers, it establishes data confirming that MR4.5 and frequent BCR::ABL1 testing are key biomarkers for selecting safe candidates for discontinuation. For the industry, it demonstrates that clinical competitive criteria have shifted from simple response rates to the speed of achieving deep molecular response, TFR durability, and cardiovascular safety. In the short term, generic imatinib and dasatinib will put pressure on prices, and in the medium to long term, asciminib, which has entered first-line treatment, will be a competitive variable that reshapes sales within the same company, Novartis.
Source: ClinicalTrials.gov (api_ct)