FDA Updates Nilotinib CML Label With Discontinuation Provision

Richard Pazdur, MD

The FDA has updated the label for nilotinib (Tasigna) with a provision stipulating that patients with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (Ph+ CML-CP) who have received the BCR-ABL tyrosine kinase inhibitor for at least 3 years and have achieved specific predetermined criteria may be eligible to stop treatment.

Specifically, the label states that to discontinue treatment, patients must achieve a sustained deep molecular response of MR4.5 (BCR-ABL1 International Scale ≤ 0.0032%).

“Patients diagnosed with CML generally face a lifetime of treatment to keep their leukemia from growing or recurring,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“Today’s approval shows that some patients may be able to stop treatment with Tasigna altogether if they are showing a strong response to therapy. While we welcome this progress in patient care, it’s important to note that any discontinuation of treatment still means patients must be regularly monitored for disease recurrence.”

Nilotinib is approved for the treatment of patients with chronic phase and accelerated phase Ph+ CML who are resistant/intolerant to prior therapy that included imatinib (Gleevec).The drug also has an approved indication for patients with newly diagnosed Ph+ CML-CP.

The label update is based on 2 single-arm trials of patients with Ph+ CML-CP that assessed the length of time patients could cease nilotinib therapy and remain in remission (treatment-free remission [TFR]). The TFR data in the trials involved the use of the FDA-authorized companion diagnostic MolecularMD MRDxTM BCR-ABL, which measures BCR-ABL transcript levels down to MR4.5.

The first trial, the phase II ENESTop study, included 163 Ph+ CML-CP patients and was conducted at 63 sites across 18 countries. The discontinuation assessment involved 126 patients who received imatinib, switched to nilotinib, and then had a sustained molecular response for 1-year before stopping treatment.

Over half (53.2%) of patients remained in TFR at 96 weeks (95% CI, 44.1%-62.1%). Fifty-six patients with confirmed loss of MR4.0 or loss of MMR restarted nilotinib by the cutoff date. Fifty-two (92.9%) of these patients regained both MR4.0 and MR4.5.

The investigators continually monitored patients for potential loss of molecular response after treatment discontinuation. BCR-ABL transcript levels and complete blood count with differential were assessed monthly in the first year of discontinuation, every 6 weeks for the second year, and then every 12 weeks.

There were no new safety signals compared with previously reported nilotinib data. There was a decrease from 47.9% to 15.1% in the rate of musculoskeletal pain-related AEs (all grades) during the first and second 48 weeks of the TFR phase. This compared with 13.7% during the treatment consolidation phase.

The second trial, the open-label phase II ENESTfreedom study, was conducted at 132 locations across 19 countries. In this study, 190 patients with Ph+ CML-CP had received frontline Tasigna, achieved a response of MR4.5, and had a deep molecular response for 1 year prior to discontinuation.

Overall 48.9% of the patients (95% CI, 41.6%-56.3%) who discontinued therapy remained in MMR at 96 weeks. Eighty-eight patients restarted nilotinib due to loss of MMR by the cut-off date, 87 of whom were able to regain MMR. The one remaining patient discontinued at 7.1 weeks after failing to regain MMR after nilotinib reinitiation. Patients who discontinued therapy were monitored with the same approach as the ENESTop trial.

As with the ENESTop study, there were no new safety signals. There was a decrease from 34.0% to 9.0% in musculoskeletal pain-related AEs (all grades) during the first and second 48 weeks of the TFR phase, respectively. This compared with 17.0% during the treatment consolidation phase.

"It has long been our ambition at Novartis to make it possible for some people with CML to discontinue therapy," Bruno Strigini, CEO, Novartis Oncology, said in a press release. "We are proud that Tasigna is now the first and only TKI with TFR data in its labeling in the United States and several countries around the globe. This achievement would not have been possible without the partnership of patients around the world who participated in our groundbreaking TFR trials, helping Novartis to once again reimagine what is possible for people living with CML."

Novartis drug Tasigna is approved by FDA as first and only CML therapy with Treatment-free Remission data in its label. Novartis. Available at: https://www.novartis.com/news/media-releases/novartis-drug-tasignar-approved-fda-first-and-only-cml-therapy-treatment-free-remission-data-its-label. Accessed December 22, 2017.