FDA Grants Fast Track Designation to Tipifarnib for T-Cell Lymphomas

The FDA has granted a Fast Track Designation to tipifarnib for the treatment of adult patients with relapsed/refractory angioimmunoblastic T-cell lymphoma (AITL), follicular T-cell lymphoma (FTCL), and nodal peripheral T-cell lymphoma with T follicular help (TFH) phenotype.¹

“This important designation from the FDA comes just 2 months after tipifarnib was awarded Fast Track for the treatment of patients with HRAS-mutant head and neck squamous cell carcinomas,” Bridget Martell, MA, MD, acting chief medical officer of Kura Oncology, the developer of tipifarnib, stated in a press release. “We believe that this designation reflects tipifarnib’s significant potential in these devastating disease settings, and we are now actively preparing to initiate a second registration-directed trial of tipifarnib in advanced nodal lymphomas of TFH phenotype, including AITL.”

Peripheral T-cell lymphomas comprise ≤20% of all aggressive non-Hodgkin lymphomas and consist of many different subtypes of fast-growing lymphomas, and represent approximately 20,000 incident cases annually worldwide. The 5-year overall survival (OS) rates are approximately 30%, and although there are FDA-approved agents, none have led to improvements in survival, according to Kura Oncology.

Tipifarnib is a potent, selective farnesyl transferase inhibitor that has demonstrated anticancer activity in select patient subtypes.

Updated findings of promising clinical findings with single-agent tipifarnib in patients with relapsed/refractory AITL were presented at the 2019 ASH Annual Meeting. Results showed that the objective response rate (ORR) was approximately 50% in a heavily pretreated patient population who had received a median of 3 prior regimens.² The data also showed that there was enhanced antitumor activity in patients who carried mutations in the killer-cell immunoglobulin—like receptor, which is a CXCL pathway-associated biomarker. In this subgroup, the ORR was 70% and the complete response (CR) rate was 40%.

In the multi-institutional, single-arm, open-label, phase II study (NCT02464228), investigators evaluated the efficacy, safety, and biomarkers of tipifarnib in patients with relapsed/refractory AITL in a 2-stage design. Oral tipifarnib was administered orally twice daily on days 1 to 21 of 28-day treatment cycles until disease progression or unacceptable toxicity. The primary endpoint is rate ORR.

Patients were ≥18 years old and had an ECOG performance status of 0 to 2. The median number of prior therapies was 3, and 19 patients had undergone prior stem cell transplant.

As of May 24, 2019, there were 50 patients who were treated with PTCL, which comprised of AITL (n = 23), PTCL-NOS (n = 25), ALK-positive anaplastic large cell lymphoma (n = 1), and gamma-delta T-cell lymphoma (n = 1). Nineteen patients were in stages 1 and 2, and 31 patients were in ongoing cohorts of AITL histology and CDXL12 3’UTR wild-type that were later added to the study design.

Moreover, whole-exon sequencing (WES) was generated by next-generation sequencing and gene expression data generated by RNA Sequencing Ancillary studies was also evaluated to determine the prognostic value of CXCL12 expression in those who received standard therapy.

Of 18 evaluable patients who were enrolled on the 2 stages, there were 3 partial responses (PRs), 2 of which occurred in patients with AITL histology, and 5 patients had stable disease (SD).

In the AITL cohort, in which 11 of 16 patients were evaluable, the ORR was 45% and the clinical benefit rate (CBR) was 73%, which included 3 CRs, 2 PRs and 3 patients with SD.

In the CXCL12 3'UTR wild-type cohort of 12 evaluable patients, the ORR was 42% and included 3 CRs and 2 PRs; 2 of the 3 CRs were reported in patients of AITL histology (n = 4).

Moreover, 16 of the 23 patients with AITL had WES results. In patients with the KIR3DL2 gene variants C336R/Q386E, tipifarnib led to a 100% CBR, which included a 75% ORR and a 50% CR rate.

Secondly, high allele frequency of KIR3DL2 variants predicted CR to tipifarnib treatment (receiving operating characteristic area under the curve, 0.94; P <.0001) and patients with AITL who harbored KIR3DL2 gene variants experienced a better outcome with tipifarnib compared with prior standard therapy.

AITL tumors expressed high levels of CXCL12 and response to tipifarnib; however, there was a trend toward poor prognosis. The median OS from diagnosis was 22 versus 40 months (HR, 1.8; P = .09) in a series of 50 patients with PTCL who were treated with standard treatment. Fifty percent of AITL and 35% of non-AITL samples overexpressed CXCL12.

Forty-eight patients had available safety data, all of whom had ≥1 treatment-emergent adverse event (TEAE). Eighty percent of patients experienced ≥1 TEAE that was treatment related, and ≥1 serious treatment-related adverse event.

The most common grade ≥3 TEAEs (≥10%) were blood and lymphatic system disorders, which included neutropenia (40%), thrombocytopenia (33%), leukopenia (25%), anemia (19%), and febrile neutropenia (19%). Fourteen deaths occurred on study; 1 was related to treatment and was due to lung infection.

References

1. Kura Oncology Receives Fast Track Designation for Tipifarnib in T-Cell Lymphomas [news release]: San Diego, CA. Kura Oncology. Published March 3, 2020. https://bit.ly/39mxSzB. Accessed March 3, 2020.
2. Witzig TE, Sokol L, Foss FM, et al. Proof of concept for tipifarnib in relapsed or refractory angioimmunoblastic t-cell lymphoma (AITL) and CXCL12+ peripheral t-cell lymphoma (PTCL): preliminary results from an open-label, phase 2 study. Blood. 2019;134(suppl_1):468. doi: 10.1182/blood-2019-128513