Tipifarnib May Be Effective and Safe in Select Patients with CMML, MDS, or MPNs

A phase 2 study suggests that tipifarnib may be more beneficial for patients with CMML, MDS, or MPNs and RAS pathway mutations than the general population of patients with these disease.

Tipifarnib (Zarnestra) demonstrated modest efficacy benefit in patients with chronic myelomonocytic leukemia (CMML) and other myelodysplastic (MDS)/myeloproliferative neoplasms (MPNs) and was reasonably well-tolerated, according to results from a phase 2 study (NCT02807272).

As a potent and highly selective farnesyl transferase inhibitor, tipifarnib therapy can be administered to work against the RAS pathway mutation that occurs in about 30% of patients with CMML and other MDS and MPNs. These mutations include NRASKRASCBL, and PTPN11. Earlier results of tipifarnib treatment showed that the agent is especially efficacious in patients with RAS wild-type CMML and in the MDS/MPN population, having high CXCR4/CXCR2 may be predictive of tipifarnib’s activity.

A total of 44 patients were included in the study and treated with tipifarnib 400 mg orally twice daily on days 1–21 of 28-day cycles. The primary end point was objective response rate (ORR) assessed per the MDS/MPN International Working Group (IWG) criteria in CMML patients with KRAS-positive or NRAS wild-type disease, and in the MDS/MPN population with high and low CXCR4/CXCR2. Secondary end points explored in the study include the adverse event profile of tipifarnib, progression-free survival (PFS) at 1 year, overall survival (OS) at 1 year, and duration of response (DOR).

According to patient demographics, of the 37 patients in the CMML cohort, 70.3% of the patients were CMML-1 and 29.7% were CMML-2. The CMML population had a median age of 71 years (range, 57-80), were largely male (59%), and White (84%). Sixty-two percent of patients in the CMML cohort received prior anticancer therapy, and baseline ECOG status was 1 for 78% of the patients. Of the prior anticancer therapies received by patients with CMML, the most common were azacytidine (22%), hydrea (11%), and hydroxyurea (11%).

In MDS/MPN cohort, the median age was 69 years (range, 64-76). Unlike the CMML group, patients with MDS or a MPN were mostly female (57%), and all of the patients identified as White. Prior anti-cancer therapy was received by 57% of the MDS/MPN cohort, of which the most common therapies received were decitabine (29%) and hydroxyurea (29%). Finally, most patients in the MDS/MPN cohort (71%) had an ECOG performance status of 1 at baseline.

The ORR observed in the overall CMML group was 21.9%. In patients with CMML and KRAS/NRAS wild-type, the ORR was 14.3%, and in the subgroup with KRAS or NRAS mutations, the ORR was 33.5%. The DOR in the CMML cohort was 14.6 months in the wild-type subgroup but not reached in the group of patients with KRAS or NRAS mutation-positive CMML.

In all patients with CMML who were assessed for response (n = 32), the best response was. Complete cytogenetic remission was overserved in 1 patient. Marrow responses occurred in 9.4% of patients and clinical benefit was observed 9.4%. Stable disease (SD) was achieved in 65.6% of patients, and progressive disease (PD) was observed in 12.5%.

The ORR in patients with MDS or an MPN was 25.0%, which included patients with either high or low CXCR4/CXCR2.

The best response observed in the MDS/MPN cohort was a partial remission in 1 patient. Fifty percent of the cohort had SD while 25% had PD.

In terms of survival, the OS among patients with KRAS or NRAS wild-type CMML was 14.4 months versus not reached in those with KRAS or NRAS mutations (HR, 1.345; 95% CI, 0.396-4.575; log-rank =.6335). The PFS was 9.2 months in those with KRAS or NRAS wild-type CMML compared with 4.1 months in those with KRAS or NRAS mutation-positive CMML (HR, 1.060; 95% CI, 0.357-3.149; log-rank P =.9169). The number of patients in the MDS/MPN cohort was too small for a survival analysis.

All patients in the study were evaluable for safety, and the analysis showed that all patients experienced at least 1 treatment-related AE. Serious treatment-related AEs were observed in 34% of patients. In the overall study population, the most common treatment-related AEs were platelet count decreased (55%), anemia (52%), nausea (50%), and diarrhea (41%). There were no treatment-related deaths observed in the study, but 16% of patients discontinued tipifarnib due to a treatment-related AE.

CMML and MDS/MPNs are difficult-to-treat malignancies for which there are limited therapeutic options. Based on these phase 2 data, tipifarnib may be beneficial to patients with RAS pathways mutations.


Patnaik MM, Sekeres MA, DeZern A, et al. Final results of a phase II study of tipifarnib in chronic myelomonocytic leukemia (CMML) and other myelodysplastic/myeloproliferative neoplasms (MDS/MPN). Ann Oncol. 2021; 32 (suppl_5): S773-S785. doi: 10.1016/annonc/annonc676