Janes, Matthew R.

Abstract Background: CXCL12 is a negative prognostic factor for head & neck (HNSCC) and pancreatic (PDCA) cancers, among others. Its receptor, CXCR4, is a negative prognostic factor in lymphoma/leukemia. CXCR4 signals in part through RAS species, and the expression of CXCL12 and CXCR4 appears to be itself regulated by farnesylated proteins. We provide evidence that targeting the CXCL12/CXCR4 pathway with the farnesyltransferase inhibitor tipifarnib translates to long term clinical benefit. Methods: Next generation sequencing and analyses of gene expression were conducted in tumor samples from squamous cell carcinoma, lymphoma, and acute myeloid leukemia (AML) patients treated in tipifarnib trials (studies KO-TIP-001, KO-TIP-002, CTEP20), and complemented with analyses of related tumor gene expression databases in TCGA and GEO. Results: Activating HRAS mutations in HNSCC and KRAS mutations in PDCA were mutually exclusive with CXCL12 expression, consistent with a role for RAS downstream from CXCR4. Contrary to KRAS and NRAS, HRAS is exclusively farnesylated, and treatment with tipifarnib in patients (pts) with advanced HNSCC tumors with a HRAS mutation variant allele frequency (VAF) >20% resulted in 8 partial responses (PR) in 14 pts. Two complete responses (CR), 3 PRs and 4 disease stabilizations (90% clinical benefit) were observed in 10 pts with relapsed/refractory peripheral T cell lymphoma overexpressing CXCL12. Decreases in plasma CXCL12 levels during treatment were observed. Seven CRs were observed in 11 elderly/unfit AML pts overexpressing CXCL12 in bone marrow (NRAS wt or unknown). Ex vivo treatment of bone marrow stromal cell cultures with tipifarnib decreased secretion of CXCL12. Finally, based on the reported relationship between CXCL12 expression and the suppression of pain in PDCA, we conducted a retrospective analysis of a phase 3 study of gemcitabine plus tipifarnib (GT) in advanced PDCA. Notably, absence of abdominal pain at study entry was associated with higher median survival in the GT arm (no pain, pain): 10.2 vs 5.9 months, HR=0.52, p<0.0001, whereas no significant effect was observed in the control arm: 6.1 vs 6.1 months. PDCA with <7% VAF of KRAS mutation (~30% PDCA pts) overexpressed CXCL12. Conclusions: The mechanism of action of tipifarnib appears to involve targeting the CXCL12/CXCR4 pathway and demonstrates a crucial association with the tumor microenvironment and objective clinical responses. Citation Format: Antonio Gualberto, Catherine Scholz, Vishnu Mishra, Matthew R. Janes, Linda Kessler, Eric Van Cutsem, Alan L. Ho, Thomas Witzig. Mechanism of action of the farnesyltransferase inhibitor, tipifarnib, and its clinical applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT191.

Background:Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post‐translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors.Aims:Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T‐cell lymphoma (AITL) and CXCL12+ peripheral T‐cell lymphoma (PTCL) patients (pts).Methods:This Phase 2 study (NCT02464228) is a multi‐institutional, single‐arm, open‐label trial initially designed as a two‐stage (11+7 pts) design to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL age >/ = 18 years and a performance status of 0–2. Based on initial findings, the study was amended to include a cohort of AITL (n = 12) and PTCL (n = 12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1–21 of 28‐day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in pts who received tipifarnib and standard of care treatment.Results:As of 20 February 2019, 43 PTCL pts (20 AITL, 21 PTCL‐NOS, 1 ALK‐ ALCL, 1 gamma‐delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 24 pts in the ongoing AITL histology and CXCL12 cohort. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts had at least one treatment‐emergent adverse event (TEAE); 39 (90%) had at least 1 study drug‐related TEAE and 12 (28%) at least 1 drug related SAE. The most frequently observed drug‐related TEAEs of Grade ≥3 occurring in 10% or more of pts were blood and lymphatic system disorders, including neutropenia (44%), thrombocytopenia (37%), leukopenia (28%), anemia (21%) and febrile neutropenia (21%). There have been 14 deaths on study; none were related to study drug. Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable pts), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the CXCL12+ cohort (n = 3 evaluable pts), 1 PR and 2 SD have been observed, with 4 pts pending cycle 2 response evaluation. CXCL12 expression correlated with favorable outcome to tipifarnib treatment. Pre‐treatment high CXCL12 expression had 90% sensitivity and 93% specificity to identify pts who experienced CR/PR/SD on study in a preliminary analysis of 24 pts. The prognosis of CXCL12 was also retrospectively investigated in 73 pts who received standard of care therapy (AITL N = 50, PTCL NOS = 23). A trend for poor prognosis (22 vs 40 months median OS from diagnosis, HR = 1.8, p = 0.09) was observed using the high CXCL12 subset using the cut‐off point that predicted clinical benefit under tipifarnib therapy. Fifty percent of AITL and 35% of non‐AITL samples overexpressed CXCL12.Summary/Conclusion:Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment in the CXCL12+ cohort continues.