Leoni, Mollie

Ziftomenib - a potent, selective, oral menin inhibitor - is approved as monotherapy for adults with relapsed/refractory (R/R) NPM1-mutated acute myeloid leukemia (NPM1-m AML). The KOMET-007 phase 1 trial investigated clinical activity and tolerability of ziftomenib in combination with standard therapies for R/R and newly diagnosed AML. Here, we report outcomes of adults with R/R NPM1-m AML treated with ziftomenib plus venetoclax/azacitidine. In phase 1a, patients received ziftomenib 200, 400, or 600 mg once daily with standard doses of venetoclax/azacitidine. In phase 1b, ziftomenib 600 mg was selected for expansion. Sixty-seven patients were treated (27 phase 1a; 40 phase 1b). Median age was 66 years, and 55% were men. Median number of prior therapies was 1 (range 1-8); 55% received prior venetoclax and 22% had prior transplantation. Most common (≥20%) grade ≥3 treatment-emergent adverse events were leukopenia (34%), thrombocytopenia (28%), febrile neutropenia and neutropenia (25% each). Six patients developed QTc prolongation (1 ziftomenib-related; grade 1), and 2 experienced differentiation syndrome (grade 3); all events were successfully managed. In patients receiving ziftomenib 600 mg, composite complete remission (CRc) rate was 46% (22/48), with 67% (12/18) achieving central measurable residual disease (MRD) negativity (<0.01% threshold). In venetoclax-naïve and -exposed patients, CRc rates were 70% (16/23) and 24% (6/25), with MRD-negativity rates of 75% (9/12) and 50% (3/6), respectively. Median duration of response was 8.6 months, and median overall survival was not reached. The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.

Abstract Introduction: Leukemogenesis is driven by nucleophosmin 1 mutations(NPM1-m) or lysine methyltransferase 2A rearrangements(KMT2A-r) in ~35–40% of acute myeloid leukemia (AML) cases. Nearly half of AML patients will develop relapsed/refractory (R/R) disease within a year, with <20% expected response rate following venetoclax/azacitidine (Ven/Aza) and progressively poorer outcomes with each subsequent line of therapy. Ziftomenib–a potent, highly selective, oral, investigational menin inhibitor–has demonstrated clinical activity as both monotherapy and in combination for adults with R/R NPM1-m or KMT2A-r AML. KOMET-007 (NCT05735184) is an ongoing, open-label, ph1a/b study of ziftomenib in combination with standard chemotherapies in adults with newly diagnosed and R/R NPM1-m or KMT2A-r AML. Here we present updated safety and clinical activity in patients with R/R AML treated with the recommended ph2 dose (RP2D) of ziftomenib 600 mg in combination with Ven/Aza across ph1a/b. Methods: Adults (≥18y) with R/R NPM1-m or KMT2A-r AML enrolled independently into separate arms; patients in dose escalation (ph1a) and expansion (ph1b) were treated with oral ziftomenib 600 mg once daily (QD; continuously from C1D8 onward) plus standard doses of Ven/Aza. Primary endpoints: AEs, complete remission (CR; ELN 2022), dose limiting toxicities (DLT; ph1a only). Key secondary endpoints: composite CR (CRc; CR with full, partial or incomplete hematologic recovery), overall response, duration of response. Results: As of June 25, 2025, 80 patients (51 NPM1-m, 29 KMT2A-r) with R/R AML were enrolled (20 ph1a; 60 ph1b) and treated with ziftomenib 600 mg QD + Ven/Aza. Median age was 63y (range 19–85), 50% were female, 74% had ECOG PS 0–1; 22 (28%) had FLT3 co-mutations and 7 (9%) had IDH co-mutations. Median number of prior therapies was 1 (range 1–6); 18% (14/80) had prior stem cell transplant; 25 (49%) NPM1-m and 19 (66%) KMT2A-r patients had prior Ven exposure. 71 patients (89%) had Gr ≥3 treatment-emergent AEs, most commonly (≥20% of patients) febrile neutropenia (31%), decreased platelet count (28%), decreased white blood cell count (26%) and decreased neutrophil count (23%). Gr ≥3 ziftomenib-related AEs occurred in 30 patients (38%), most commonly febrile neutropenia (9%) and anemia (8%). 6% of patients discontinued ziftomenib treatment due to AEs. Differentiation syndrome (DS) occurred in 1 (1%) NPM1-m patient (Gr 3), which lasted 1d and successfully resolved with protocol-specified DS mitigation. No ziftomenib-related QTc prolongation was reported with the combination, and no DLTs were observed in ph1a. 70 patients (43 NPM1-m; 27 KMT2A-r) were response-evaluable (≥1 response assessment or death). Median follow-up was 18.0 wks for NPM1-m and 16.4 wks for KMT2A-r. Overall response rates (ORRs) were 65% (28/43) for NPM1-m and 33% (9/27) for KMT2A-r. CRc rates were 49% (21/43) for NPM1-m and 22% (6/27) for KMT2A-r after median time to first CRc of 4.9 wks (range 2.7–15.6) and 5.5 wks (range 2.6–18.9), respectively; measurable residual disease (MRD)-negativity rates (local) among tested CRc responders were 50% (9/18) for NPM1-m and 60% (3/5) for KMT2A-r after median time to first MRD-negativity of 5.9 wks (range 2.9–15.6) and 8.1 wks (range 7.7–18.9), respectively. During continuous ziftomenib administration in patients who achieved CRc, median time to neutrophil recovery (≥1×109/L) was 43d overall (43d for NPM1-m; 71d for KMT2A-r), and median time to platelet recovery (≥100×109/L) was 27d overall (27d for NPM1-m; 23d for KMT2A-r). As of the data cutoff, overall median duration of CRc was not estimable; median overall survival was not estimable for NPM1-m and 21.1 wks for KMT2A-r. In Ven-naive patients, CRc rates were 71% (15/21) for NPM1-m and 33% (3/9) for KMT2A-r; CR rates were 48% (10/21) and 11% (1/9); and ORRs were 81% (17/21) and 56% (5/9), respectively. The study is ongoing with 44% (19/43) of NPM1-m and 11% (3/27) of KMT2A-r patients still on treatment, with responses continuing to evolve.Updated data to be presented.Conclusions: In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg QD + Ven/Aza was well tolerated with robust clinical activity in patients with R/R NPM1-mor KMT2A-rAML. No ziftomenib-related QTc prolongation was reported. One case of DS (NPM1-m, Gr 3) successfully resolved with protocol-specified mitigation. These data support further investigation of ziftomenib-based combinations in R/R NPM1-mand KMT2A-rAML.

Abstract Introduction: Nucleophosmin 1 mutations (NPM1-m) drive leukemogenesis in approximately 30% of acute myeloid leukemia (AML) cases. Ziftomenib is a potent, highly selective, oral, investigational menin inhibitor that has demonstrated clinical activity as both monotherapy and in combination for adults with NPM1-m or lysine methyltransferase 2A-rearranged (KMT2A-r) AML. KOMET-007 (NCT05735184) is an ongoing, open-label, dose-escalation (phase 1a) and expansion (phase 1b) study of ziftomenib in combination with standard chemotherapies in NPM1-m or KMT2A-r AML. Here we present phase 1b safety and clinical activity in patients with newly diagnosed NPM1-m AML who received the recommended phase 2 dose (RP2D) of ziftomenib 600 mg in combination with venetoclax and azacitidine (Ven/Aza). Methods: Adults (≥18 years) with newly diagnosed NPM1-m AML who were not eligible for intensive chemotherapy were enrolled in phase 1b and received ziftomenib 600 mg once daily plus standard doses of Ven/Aza. Ziftomenib was orally administered once daily continuously from Cycle 1 Day 8 onward. Phase 1b primary endpoints were adverse events (AEs) and complete remission (CR) per ELN 2022. Secondary endpoints included composite CR (CRc; defined as CR with full, partial, or incomplete hematologic recovery), overall response, and duration of response. Local measurable residual disease (MRD) was assessed by next-generation sequencing, RT-qPCR, and multiparameter flow cytometry. Results: As of June 25, 2025, 39 patients with newly diagnosed NPM1-m AML were enrolled and treated with ziftomenib 600 mg once daily plus Ven/Aza in phase 1b. Median age was 75 years (range 53–93), 54% were female, 46% had ECOG PS 0–1; 12 (31%) had FLT3 co-mutations and 9 (23%) had IDH co-mutations. Median duration of follow-up was 16.3 weeks (range 1.6–41.1). Twenty-nine patients (74%) had grade ≥3 treatment-emergent AEs, most commonly (≥20% of patients) decreased neutrophil count (31%) and decreased platelet count (23%). Grade ≥3 ziftomenib-related AEs occurred in 14 patients (36%), most commonly decreased neutrophil count (15%) and decreased platelet count (13%). No ziftomenib treatment discontinuations occurred due to AEs. Differentiation syndrome occurred in 1 (3%) patient (grade 2), which successfully resolved with protocol-specified mitigation. One patient (3%) had investigator-assessed ziftomenib-associated QTc prolongation (grade 3); however, there were concomitant significant electrolyte abnormalities and event resolved with electrolyte repletion. At time of data cutoff, 31 NPM1-m patients were response-evaluable (≥1 response assessment or death). CRc rate was 84% (26/31) after a median time to first CRc of 3.5 weeks (range 2.4–9.4), with local MRD-negativity rates among tested CRc responders of 54% (13/24) after a median time to first MRD-negativity of 8.4 weeks (range 2.9–17.4). CR rate was 58% (18/31) and overall response rate was 94% (29/31), with responses and MRD-negativity rates continuing to evolve. During continuous ziftomenib administration in patients who achieved CRc, median time to neutrophil recovery (≥1×109/L) was 36 days, and median time to platelet recovery (≥100×109/L) was 28 days. The median duration of response and median overall survival were not reached as of the data cutoff, at a median follow-up of 16.3 weeks. The study is ongoing, with 81% (25/31) of NPM1-m patients still on-study and 77% (24/31) still on ziftomenib treatment. Updated safety and clinical activity results will be presented.Conclusions: In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg once daily combined with Ven/Aza was well tolerated and demonstrated robust clinical activity in patients with newly diagnosed NPM1-m AML, including 84% CRc after a median of 3.5 weeks and 54% CRc MRD-negativity after a median of 8.4 weeks. Low rates of ziftomenib-related cytopenia and no additional myelosuppression were observed with this combination. One case each of differentiation syndrome (grade 2) and investigator-assessed QTc (grade 3) were successfully resolved. Taken together, these data support the RP2D determination and advancement of this ziftomenib-based combination in the KOMET-017 (NCT07007312) randomized phase 3 study in patients with newly diagnosed NPM1-m AML.

PURPOSE Ziftomenib—a potent, highly selective, oral menin inhibitor—was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1 -mutated ( NPM1 -m) and KMT2A -rearranged AML in the KOMET-001 phase I trial. METHODS In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1 -m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh). RESULTS From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events. CONCLUSION Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1 -m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.

6506 Background: NPM1 -m drives leukemogenesis in ~30% of AML. Despite current risk stratification, nearly half will have R/R disease within a year, after which outcomes are poor with <10% complete response following chemotherapy. Ziftomenib – a potent, highly selective, oral, investigational menin inhibitor – has shown clinical activity as monotherapy and in combination for adults with R/R NPM1 -m and KMT2A -r AML, with 600 mg once-daily (QD) as the recommended phase 2 monotherapy dose for NPM1 -m. Here we present the primary analysis for NPM1 -m patients (pts) treated with ziftomenib 600 mg QD in the pivotal KOMET-001 study. Methods: KOMET-001 (NCT04067336) is a multicenter, open-label phase 1/2 study of ziftomenib in adults with R/R AML. In phase 2, pts with NPM1 -m R/R AML received ziftomenib 600 mg QD. Phase 2 primary endpoint: complete remission with full/partial hematologic recovery (CR/CRh); key secondary endpoints: composite complete remission (CRc), durations of CR/CRh and CRc, and safety. The analyses below include NPM1 -m pts pooled from phase 1b/2. Results: The phase 2 primary endpoint was met ( p =0.0058). As of 20 Dec 2024, 112 pts were enrolled (51% US/Canada, 49% Europe/UK) in phase 1b/2 and treated with ziftomenib 600 mg QD, with a median follow-up of 4.2 months. Median age was 69 yrs (range 22–86), 56% female, 83% ECOG PS 0–1, median of 2 prior therapies (range 1–7), including 60% prior venetoclax (VEN) and 23% prior transplant. CR/CRh rate in all phase 1b/2 pts was 25% (28/112; 95% CI 17–34) and overall response rate was 35% (39/112; 95% CI 26–44). In phase 2 pts, 23% (21/92; 95% CI 15–33) achieved CR/CRh (Table), with 67% (10/15) MRD negativity among CR/CRh responders tested (local). Comparable CR/CRh rates were observed in both VEN-naïve and exposed pts (21% vs. 24%). Ziftomenib was well tolerated with 3% (3/112) discontinuing due to treatment-related adverse events (TRAEs). 40% (45/112) of pts had Grade (Gr) ≥3 TRAEs, including 13% differentiation syndrome (all Gr3), ≤5% each anemia, febrile neutropenia and thrombocytopenia, and 2% QTc prolongation (Gr3). Updated clinical activity and safety data will be presented. Conclusions: In the pivotal KOMET-001, the phase 2 primary endpoint was met: Ziftomenib achieved deep and durable responses in R/R NPM1 -m AML, regardless of prior VEN. Ziftomenib was well tolerated with limited myelosuppression and only 3% ziftomenib-related discontinuations. Taken together, these data support the potential use of ziftomenib monotherapy as a new treatment option for R/R NPM1 -m AML. Clinical trial information: NCT04067336 . Response, n (%) Phase 2600 mg QDN=92 Phase 1b/2600 mg QDN=112 CR 13 (14) 20 (18) CR/CRh 21 (23) 28 (25) CRc 24 (26) 32 (29) Median duration, months (95% CI) CR/CRh 3.7 (1.9–NE) 3.7 (1.9–7.7) CRc 4.6 (2.8–11.4) 5.1 (2.8–8.1) Restricted mean duration, months (95% CI) CR/CRh 4.3 (3.1–5.6) 5.2 (3.6–6.7) CRc 5.9 (4.0–7.7) 6.4 (4.6–8.1)

Abstract A phase 2, international, open-label, nonrandomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary end point was objective response rate (ORR); secondary end points included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n = 38 angioimmunoblastic T-cell lymphoma (AITL), n = 25 PTCL not otherwise specified, and n = 2 other T-cell lymphomas. The ORR was 39.7% (95% confidence interval [CI], 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in patients with AITL (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the nonresponder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pretreated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. This trial was registered at www.ClinicalTrials.gov as #NCT02464228.

Abstract The T-cell non-Hodgkin lymphomas continue to be an area of unmet need for new therapies that offer novel mechanisms of action. Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). Tipifarnib inhibits farnesylation of key regulatory proteins involved in CXCL12 production (Gualberto et al, EHA 2019). CXCL12 is a chemokine that is essential for T-cell homing to lymphoid organs and bone marrow, and for the maintenance of immune cell progenitors via its receptor CXCR4 (Susek et al, Front Immunology, 2018). Angioimmunoblastic T-cell lymphoma (AITL) is associated with high levels of CXCL12 expression, which is also a negative prognostic factor (Witzig et al, Blood, 2019). Additionally, Peripheral T-Cell lymphoma Not Otherwise Specified (PTCL-NOS) patients with the CXCL12 rs2839695 A/A wildtype genotype (PTCL-CXCL12+) have also been found to have elevated levels of CXCL12. Therefore, there is strong rationale for targeting these subsets of PTCL with tipifarnib. This Phase 2 study (NCT02464228) was a multi-institutional, single-arm, open-label trial determining the efficacy, safety, and potential predictive biomarkers for tipifarnib in adult patients with relapsed or refractory (R/R) PTCL. Patients received tipifarnib 300 mg orally twice daily on Days 1-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. The primary objective of the study was to determine the antitumor activity by overall response rate (ORR) per Lugano Classification. Secondary objectives included safety, duration of response (DoR) and progression-free survival (PFS), and exploratory analyses included overall survival (OS) and identification of potential biomarkers associated with tipifarnib activity. Sixty-five R/R PTCL patients (38 AITL, 14 PTCL-NOS, 11 PTCL-CXCL12+, 2 other (1 ALCL-ALK negative, 1 PTCL-subtype not specified) were treated with tipifarnib. The population was heavily pretreated with a median of 3 prior regimens (range 1-8). All patients had at least one treatment-emergent adverse event (TEAE); most patients (87.7%) had at least one treatment-related TEAE, and 18 (27.7%) patients had at least one treatment-related serious TEAE. The most frequently observed (≥20%) treatment-related TEAEs (all grades) were hematological (neutropenia, thrombocytopenia, anemia,) and gastrointestinal (nausea, diarrhea), as well as fatigue, which is consistent with the known safety profile of tipifarnib. Fifty-eight patients were efficacy evaluable and had an associated ORR of 39.7% (23/58) with most responses observed in the AITL and PTCL-CXCL12+ cohorts. In the 32 patients with AITL, the ORR was 56.3% (18/32), including 9 complete responses (CR) and 9 partial responses (PR). In the 10 patients with PTCL-CXCL12+, the ORR was 40.0% (4/10), including 1 CR and 3 PR. The median OS for patients with AITL was 32.8 months, and the median OS had not been reached for patients with PTCL-CXCL12+. Previously, a strong association between KIR3DL2 C336R/Q386E mutation and the activity of tipifarnib was observed and reported in AITL patients (Witzig et al, EHA 2020). Extensive gene expression and gene variant analyses of samples from the study population is currently ongoing to evaluate this correlation and explore other potential predictors of response. Final data will be presented at the time of the conference. Overall, the results from this Phase 2 study with tipifarnib demonstrated very encouraging efficacy in patients with CXCL12-expressing subtypes of PTCL (AITL and PTCL-CXCL12+) and showed a tolerable safety profile. Disclosures Witzig: Karyopharm Therapeutics, Abbvie/Genentech, Seattle Genetics, Celgene/BMS, Incyte, Epizyme, Cellectar, Tessa Therapeutics, Portola Pharmaceuticals, MorphoSys, ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Kim: IGM Biosciences: Research Funding; Kyowa Kirin: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Celltrion: Research Funding; Dong-A Pharmaceutical: Research Funding; Johnson & Johnson: Research Funding; Eisai: Research Funding. de la Cruz Vicente: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Marin Niebla: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kiowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau. Terol: BMS: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hospital Clinico Valencia: Current Employment; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Eva: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bendris: Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Ahsan: Gilead: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Leoni: Kura Oncology: Current Employment. Foss: Daiichi Sankyo: Honoraria; Mallinckrodt: Honoraria; Acrotech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Kyowa: Honoraria; Kura: Honoraria.

PURPOSEMutations in the HRAS (m HRAS) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function. We evaluated the efficacy of tipifarnib in patients with R/M m HRAS HNSCC.METHODSWe enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m HRAS malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with m HRAS variant allele frequency (VAF) data, enrollment was limited to those with a m HRAS VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles.RESULTSOf the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%).CONCLUSIONTipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with HRAS mutations for whom limited therapeutic options exist ( NCT02383927 ).