BACKGROUND:Patients with recurrent head and neck cancer (HNC) often present with severe, persistent dysphagia and xerostomia following prior chemoradiation. Although swallowing impairments and salivary dysfunction have been reported in this population, prior longitudinal studies have not examined changes in salivary composition or how these changes relate to swallowing physiology. PURPOSE:This study characterized longitudinal changes in swallowing and salivary function-including composition-following treatment with CLR 131, a novel tumor-selective radiotherapeutic, combined with external beam radiation therapy (EBRT). METHODS:Twelve patients with locoregionally recurrent HNC demonstrating CLR 131 uptake on SPECT/CT imaging were enrolled. Videofluoroscopic swallowing (VFS) studies and stimulated saliva collections were performed at baseline, 3, 6, and 12 months posttreatment. Outcomes included Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scores, swallowing temporal measures, patient-reported dysphagia using Eating Assessment Tool (EAT-10), and salivary flow rate, pH, and extensional viscosity. RESULTS:At baseline, participants demonstrated significantly worse swallowing and salivary function than published normative data (p < 0.001). Most swallowing measures remained stable following treatment; however, time to laryngeal vestibule closure with 5 mL pudding was prolonged at 3 months (p < 0.02). Stimulated salivary flow rate declined significantly at 12 months (p < 0.001), while pH decreased at 3 months (p < 0.05) and extensional viscosity increased at 6 months (p < 0.02). From baseline to 3 months, EAT-10 scores were strongly associated with salivary pH and viscosity changes (r = 0.84 and -0.99, respectively). No swallowing timing measures predicted DIGEST safety or efficiency grades. CONCLUSIONS:These findings suggest that CLR 131 + EBRT did not exacerbate objective swallowing impairment in the early post-treatment period, but patient-reported dysphagia was sensitive to post-treatment salivary alterations. Integrating salivary assessments with instrumental and patient-reported outcomes may enhance detection of functional toxicity and guide targeted dysphagia management in recurrent HNC.

Purpose/Objective(s) Cetuximab (CTX) is an approved anti-EGFR monoclonal antibody for the treatment of metastatic head and neck squamous cell carcinoma (HNSCC) and as a radiosensitizer during radiation therapy (RT) for locally advanced cases. However, resistance to CTX, either intrinsic or acquired, remains a major clinical challenge. Preclinical studies identified phosphorylation of tyrosine 821 (Y821) on AXL as a mediator of resistance to CTX and RT through activation of the tyrosine kinase c-Abl. Blocking of c-Abl with the tyrosine kinase inhibitor imatinib (IMT) restored sensitivity to CTX and RT, ultimately resulting in complete tumor regression without recurrence in models of head and neck cancer (HNC). This window-of-opportunity trial evaluated the biological effects of combining CTX with IMT in HNSCC patients. Materials/Methods Eligible patients (pts) with HNSCC scheduled for definitive surgery, radiation, or chemoradiation underwent baseline research biopsy prior to treatment. Pts received CTX (400 mg/m2 loading dose on Day 1; 250 mg/m2 on Day 8) plus IMT (400 mg orally daily for 8-14 days). The primary endpoint was the change in Ki67 expression between pre- and post-treatment biopsies/surgical specimens. Results Nineteen pts consented to enroll; 15 were eligible and treated (2 recurrent, 13 newly diagnosed). All pts completed CTX; 13 had complete IMT dosing. All underwent definitive surgical resection. One grade ³ 4 AE (tumor hemorrhage) occurred related to disease. Common treatment-related AEs included fatigue (27%), acneiform rash (47%), nausea (20%), headache (20%) and lymphopenia (13%). Ki67 decreased in 7 pts (median: -13%; range -32 to +7), increased in 1 pt, and 1 pt did not have sufficient carcinoma at the time of surgical resection. Ki67 results remain pending for 6 pts. Reduction in primary tumor size was observed in 6 pts by physical examination (median -0.4 cm; range -8 to -0.2 cm). Conclusion This window trial demonstrated that IMT plus CTX produced consistent decrease in Ki67 with preliminary evidence of tumor shrinkage. Physical measurements were limited by tumor location. A future trial is planned to incorporate cross-sectional imaging and targeted biopsies to better assess pathologic response. These findings support further investigation of IMT plus CTX in HNSCC.

Background: Head and neck cancer (HNC) evades immune responses by manipulating the tumor immune microenvironment (TIME). Tumor-bound Axl has been implicated in promoting an immunosuppressive TIME in HNC, though its precise role remains unclear. Understanding Axl’s contribution to immune evasion in HNC could lead to the identification of new therapeutic targets; therapies directed at these targets could be combined with and thereby enhance immunotherapies. Results: Using Axl knockout (Axl KO) cell lines derived from the immunologically “cold” MOC2 mouse model, we found that Axl loss delayed tumor growth in immunocompetent mice. This was accompanied by reduced immunosuppressive cells, including MDSCs, Tregs, B cells, and neutrophils, and increased infiltration of cytotoxic CD8 T cells and NK cells. To identify the immune population(s) responsible for these changes, Axl KO tumors were implanted in immune-deficient mice. Axl KO tumor growth in athymic nude mice (which lack T cells) was unchanged, whereas tumor growth in NCG mice (which lack NK cells) was rescued, suggesting that NK cells mediate the Axl KO tumor growth delay. Further, Axl loss enhanced NK cell cytotoxicity in vitro and in vivo, and NK cell depletion reversed delayed Axl KO tumor growth. Mechanistically, Axl KO tumors showed decreased expression of CD73 and CCL2, which inhibit NK cells, and increased expression of CCL5 and CXCL10, which promote NK cell recruitment and activation. Conclusions: These novel findings suggest that tumor-bound Axl fosters an immunosuppressive TIME by inhibiting NK cell recruitment and function, thereby promoting tumor growth. Targeting Axl may enhance NK cell-mediated tumor killing and improve immunotherapy efficacy in HNC.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain provide recommendations for the comprehensive management of pain in patients with cancer. This article will focus on methods for screening for pain, safe and appropriate prescription of opioid and miscellaneous analgesics, and the optimization of nonpharmacologic interventions including integrative and interventional strategies for treatment of cancer-related pain. Additionally, the NCCN Guidelines discuss methods for the safe reduction of opioids when appropriate, as well as techniques for encouraging the judicious use of opioids. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional issues that are not covered here, including management of pain during a pain crisis, management of procedure-related pain and anxiety, pain management for cancer survivors, and the use of nonopioid and adjuvant analgesics for cancer-related pain.

Background Re-irradiation of recurrent head and neck cancer (HNC) is often limited by tumour adherence to critical structures and/or radiation tolerance of critical normal tissues. Iopofosine I 131 (CLR 131) is a targeted small molecular phospholipid ether (PLE) drug conjugate that delivers iodine-131 selectively to tumour cells. We conducted a phase 1, single-centre, open-label study to determine whether CLR 131 given with reduced dose of external beam radiation therapy (EBRT) would be tolerable and feasible. Methods All participants received previous curative intent treatment with radiotherapy as primary or adjuvant treatment. Eligible participants demonstrated uptake of CLR 131 as indicated via single photon emission CT/CT (SPECT/CT) imaging following CLR 131 test dose. Participants received two therapeutic doses of CLR 131 (days 1 and 8) with SPECT/CT imaging performed to quantitate the biodistribution of CLR 131. Participants subsequently received EBRT to achieve the designated radiation dose (60-70 Gy). The primary endpoint was safety. This trial was registered with ClinicalTrials.gov, NCT04105543, and enrolment and follow-up are complete. Findings Twelve participants completed treatment with CLR 131 and EBRT. Eight participants experienced grade 4 non-DLT haematologic toxicities (2 anaemia, 8 leukopenia, 5 thrombocytopenia) at least probably attributed to CLR 131, consistent with the expected toxicity profile. Haematologic toxicities occurred during weeks 6-8 from the fi rst dose of CLR 131 and resolved within three weeks without sequelae. There were no treatment-related grade 3-4 non-haematologic toxicities. Interpretation CLR 131 in combination with EBRT did not confer any safety concerns, and was tolerable in participants with recurrent/metastatic HNC. Myelosuppression was consistent with the known toxicity profile of CLR 131. Copyright Published by Elsevier B.V.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of nasopharynx cancer and ongoing research in this area.

1005 Background: EV, a Nectin-4–directed antibody–drug conjugate, is approved for use in urothelial cancer. Nectin-4 is expressed in several solid tumors, including BC. EV monotherapy was evaluated in TNBC and HR+/HER2- BC in EV-202 (NCT04225117). Methods: In this open-label, multicohort, phase 2 trial, eligible adults had locally advanced or metastatic (la/m) solid tumors, measurable disease, and ECOG PS 0–1. In BC cohorts, patients (pts) had prior taxanes or anthracyclines, ≥1 standard-of-care cytotoxic regimen and ≤2 lines (L) of cytotoxic therapy for la/mBC, and prior PD-1/L1 inhibitor (TNBC) or endocrine treatment (tx) with a CDK4/6 inhibitor (HR+/HER2- BC). Nectin-4 expression was not required but was assessed retrospectively. Pts received EV 1.25 mg/kg intravenously days 1, 8, and 15 of each 28-d cycle until discontinuation criteria (eg, disease progression, unacceptable toxicity) were met. Primary endpoint was confirmed objective response rate (ORR); ≥10 (TNBC) or ≥12 (HR+/HER2- BC) responders out of 40 evaluable pts were needed to claim promising antitumor activity. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Antitumor activity was investigator-assessed per RECIST v1.1. Results: In the TNBC cohort, 42 female pts received EV as of Mar 3, 2023 (median follow-up, 11.8 mo). Median age was 53 y, 64% had ≥2L systemic tx for metastatic BC, and 33% had prior sacituzumab govitecan. ORR was 19.0%. Grade ≥3 tx-related adverse events (TRAEs) in >1 pt were decreased neutrophil count (n=3, 7%), decreased white blood cell count (n=2, 5%), and increased aspartate aminotransferase (n=2, 5%). Selected TRAEs of special interest were skin reactions (n=25, 60%), peripheral neuropathy (n=11, 26%), and hyperglycemia (n=2, 5%). In the HR+/HER2- BC cohort (median age, 57.0 y), 45 female pts received EV as of Dec 3, 2022 (median follow-up, 11.2 mo). Most (73%) had ≥3L systemic tx for metastatic BC. ORR was 15.6%. Grade ≥3 TRAEs in >1 pt were maculopapular rash (n=7, 16%), pruritus and increased aspartate aminotransferase (both n=3, 7%), and abdominal pain and erythema (both n=2, 4%). Selected TRAEs of special interest were skin reactions (n=28, 62%), peripheral neuropathy (n=12, 27%), and hyperglycemia (n=5, 11%). Additional efficacy data for both cohorts are in the table. Conclusions: EV showed antitumor activity in heavily pretreated TNBC. Safety in both cohorts was manageable and consistent with previous reports. Clinical trial information: NCT04225117 . [Table: see text]

TPS6117 Background: Single agent pembrolizumab in relapsed / metastatic head and neck squamous cell carcinoma (R/M HNSCC) has an estimated ORR of 19% and median OS of 13.6 months. There are several factors which may influence which patients respond to antibodies targeting the PD-1 axis. Regulatory T cells (Tregs) play a significant role in an immunosuppressive tumor microenvironment. Anti-PD-1 antibodies induce Treg activation in part through AKT pathway activation, which may contribute to low response rates to checkpoint inhibitor therapy. AKT blockade selectively inhibits the proliferation of human Tregs. Additionally, inhibition of the PI3K-AKT-mTOR pathway limits myeloid-derived suppressor cells (MDSC) infiltration and differentiation, and boosts CD8+ T cell memory and effector function. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. This phase 2 trial is designed to compare progression-free survival (PFS) in first line R/M, HNSCC patients treated with the combination ipatasertib and pembrolizumab versus pembrolizumab monotherapy treatment. Methods: In this open-label randomized phase 2 multicenter trial, patients with R/M HNSCC are treated with pembrolizumab 200mg on day 1 +/- ipatasertib 400mg QD days 1-14 of 21-day cycles. Patients must have PD-L1 CPS score ³ 1, have measurable disease per RECIST 1.1, and consent to on-treatment biopsy. Patients will be excluded if they have received prior systemic therapy for R/M HNSCC, cannot swallow a pill, or require insulin for diabetes. The primary objective is to compare the PFS between the two arms. We will estimate the relative hazard ratio associated with ipatasertib plus pembrolizumab compared to pembrolizumab alone using the Cox Model where randomized treatment assignment is the only variable in the model. Secondary objectives include ORR, safety and tolerability of the combination, and changes in tumor immune cell infiltration, AKT signaling, and changes in peripheral blood immune cells. Ultimately, a total of 48 patients will be enrolled, with 24 patients in each cohort. To date, a total of 22 patients have been enrolled from 15 sites. Accrual is ongoing (NCT05172258). Clinical trial information: NCT05172258 .

Head and neck cancers (HNCs) arise from the mucosal lining of the aerodigestive tract and are often associated with alcohol use, tobacco use, and/or human papillomavirus (HPV) infection. Over 600,000 new cases of HNC are diagnosed each year, making it the sixth most common cancer worldwide. Historically, treatments have included surgery, radiation, and chemotherapy, and while these treatments are still the backbone of current therapy, several immunotherapies have recently been approved by the Food and Drug Administration (FDA) for use in HNC. The role of the immune system in tumorigenesis and cancer progression has been explored since the early 20th century, eventually coalescing into the current three-phase model of cancer immunoediting. During each of the three phases-elimination, equilibrium, and escape-cancer cells develop and utilize multiple strategies to either reach or remain in the final phase, escape, at which point the tumor is able to grow and metastasize with little to no detrimental interference from the immune system. In this review, we summarize the many strategies used by HNC to escape the immune system, which include ways to evade immune detection, resist immune cell attacks, inhibit immune cell functions, and recruit pro-tumor immune cells.

PurposeTargeted radiopharmaceutical therapy (RPT) in combination with external beam radiotherapy (EBRT) shows promise as a method to increase tumor control and mitigate potential high-grade toxicities associated with re-treatment for patients with recurrent head and neck cancer. This work establishes a patient-specific dosimetry framework that combines Monte Carlo based dosimetry from the two radiation modalities at the voxel level using deformable image registration (DIR) and radiobiological constructs for patients enrolled in a phase I clinical trial combining EBRT and RPT.MethodsSerial SPECT/CT patient scans performed at approximately 24, 48, 72, and 168 hours post-injection of 577.2 MBq/m2 (15.6 mCi/m2) iodine-131 containing RPT agent called XXX 131. Clinical EBRT treatment plans were created on a treatment planning CT (TPCT) using RayStation; SPECT/CT images were deformably registered to the TPCT using the Elastix DIR module in 3D Slicer and assessed by measuring mean activity concentrations and absorbed doses. Monte Carlo EBRT dosimetry was computed using EGSnrc. RPT dosimetry was conducted using a GEANT4 based RPT dosimetry platform named XXX. Radiobiological metrics (BED, EQD2) were utilized to combine the two radiation modalities.ResultsThe DIR method provided good agreement for the activity concentrations and calculated absorbed dose in the tumor volumes for the SPECT/CT and TPCT; the maximum mean absorbed dose difference was -11.2%. Based on the RPT absorbed dose calculations, two to four EBRT fractions were removed from patients’ EBRT treatments. From the combined treatment, the absorbed dose to target volumes ranged from 57.14 – 75.02 Gy. When including partial volume corrections (PVC), the mean EQD2 to the PTV from EBRT+RPT was -3.11% to 1.40% different compared to EBRT alone.ConclusionThis work demonstrated the clinical feasibility of performing combined EBRT+RPT dosimetry on TPCTs. Dosimetry guides treatment decisions for EBRT and this work provides a bridge for the same paradigm to be implemented within the rapidly emerging clinical RPT space.

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in more than 71,000 patients each year in the United States, with nearly 16,000 associated deaths. One significant hurdle in the treatment of HNSCC is acquired and intrinsic resistance to existing therapeutic agents. Over the past several decades, the University of Wisconsin has formed a multidisciplinary team to move basic scientific discovery along the translational spectrum to impact the lives of HNSCC patients. In this review, we outline key discoveries made throughout the years at the University of Wisconsin to deepen our understanding of therapeutic resistance in HNSCC and how a strong, interdisciplinary team can make significant advances toward improving the lives of these patients by combatting resistance to established therapeutic modalities. We are profoundly grateful to the many scientific teams worldwide whose groundbreaking discoveries, alongside evolving clinical paradigms in head and neck oncology, have been instrumental in making our work possible.

PURPOSE:Despite advances in immunotherapy, unresectable recurrent/metastatic head and neck cancer (HNC) carries a poor prognosis, and effective treatments are needed. As nectin-4 is widely expressed in HNC, enfortumab vedotin (EV), a nectin-4-directed antibody-drug conjugate, was explored in HNC in EV-202 (ClinicalTrials.gov identifier: NCT04225117). METHODS:This open-label, multicohort, phase II study evaluated intravenous EV 1.25 mg/kg on days 1, 8, and 15 of each 28-day cycle. In the HNC cohort, eligible patients had recurrent/metastatic HNC and had received platinum-based therapy for locally advanced/metastatic disease and a PD-1/PD-L1 inhibitor. The primary end point was investigator-assessed confirmed objective response rate (ORR) per RECIST version 1.1. Secondary end points were investigator-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); overall survival (OS); and safety. RESULTS:The primary analysis included 46 patients; all received EV (median follow-up, 9.3 months). Most patients (52.2%) had ≥3 previous lines of systemic therapy in the metastatic setting. Confirmed ORR was 23.9%, DCR was 56.5%, and median DOR was not reached (median DOR was 9.4 months at a later data cutoff [median follow-up, 11.3 months]). Median PFS and OS were 3.9 and 6.0 months, respectively. Treatment-related adverse events (TRAEs) occurring in >20% of patients were alopecia (28.3%), fatigue (26.1%), and peripheral sensory neuropathy (23.9%). Sixteen patients (34.8%) experienced grade ≥3 TRAEs; anemia and decreased neutrophil count occurred in ≥1 patient (both n = 2; 4.3%). CONCLUSION:EV demonstrated antitumor activity in heavily pretreated HNC. Safety was consistent with the known safety profile of EV; no new safety signals were identified. These data support further evaluation of EV for advanced HNC not amenable to definitive local therapy.

TPS4607 Background: Farnesyl transferase inhibitors (FTIs) block post-translational modification of RAS and other farnesylated proteins. HRAS-driven tumors are highly sensitive to FTI treatment. Recent clinical trials (NCT03719690, NCT02383927) of the FTI, tipifarnib, in patients with HRAS-mutant ( HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%), showed objective response rates of up to 50% and favorable long-term outcomes. KO-2806 is a next-generation FTI that has increased potency and improved pharmacokinetic properties. In preclinical studies, KO-2806 has been shown to: (1) enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell renal cell carcinoma (ccRCC) cell line- and patient-derived xenograft models; and (2) enhance activity of KRAS inhibitors, including adagrasib, in KRAS mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC) mouse models. These preclinical data support clinical investigation of KO-2806 alone and in combination therapy. Methods: FIT-001 is a first-in-human, multicenter, open-label clinical trial that will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics (Pd), and preliminary antitumor activity of KO-2806 as monotherapy or in combination therapy in advanced solid tumors (KO-2806-001; NCT06026410). Up to 270 patients will be enrolled in phase 1a and phase 1b combined across 50 sites. Phase 1a will have separate monotherapy and combination dose-escalation arms. As monotherapy, the study will enroll patients with N/K/HRAS alterations in specific solid tumor types, such as NSCLC, CRC, and PDAC, who are refractory to standard-of-care therapies. KO-2806 and cabozantinib will be combined in patients with advanced or metastatic ccRCC who progressed on ≥1 prior line of immunotherapy-based systemic therapy; KO-2806 and adagrasib will be combined in patients with KRAS-G12C mutant locally advanced or metastatic NSCLC who received ≥1 prior systemic therapy. On the basis of emerging data from phase 1a, two Pd cohorts (n≤12) with mandatory pre- and on-treatment tumor biopsies may be enrolled. In each Phase 1b dose expansion, patients will receive the recommended phase 2 dose [RP2D] of KO-2806 with cabozantinib (in ccRCC) or adagrasib (in NSCLC), or will be randomized by dose if 2 potential KO-2806 RP2Ds are identified for a combination. Other combination arms may also be considered. The study began accrual in October 2023. Clinical trial information: NCT06026410 .

Bruce, Glazer, and Kimple discuss advances in the management of advanced thyroid carcinoma and the role of surgery and radiation to provide context to the review by Yun and Cohen focused on systemic therapy.

Purpose/Objective(s)Retreatment of recurrent HNC is often limited by tumor adherence to critical structures or normal tissue tolerance to radiation therapy. Iopofosine I-131 (CLR 131) is a novel targeted small molecular phospholipid ether (PLE) drug conjugate that delivers iodine-131 selectively to malignant tumor cells optimized through specialized regions called lipid rafts. Radiation exposure is selective to cancer cells due to the interaction of the PLE with the highly enriched lipid rafts of the plasma membrane, which are non-reliant on cell surface markers. In this trial, CLR 131 given with a reduced dose of EBRT will be safe and produce favorable tumor response rates.Materials/MethodsAll patients (pts) must have previously received treatment with curative intent radiotherapy to the HN region. Pts may have metastatic disease, as long as the site of recurrence is eligible for radiotherapy and takes precedence over systemic treatment. Eligible pts must demonstrate uptake of CLR 131 as indicated via SPECT/CT imaging after administration of a CLR 131 test dose. Pts received 2 doses of CLR 131 (days 1 and 8) with SPECT/CT imaging performed to quantitate the biodistribution of CLR 131. The Monte Carlo method was utilized to calculate the absorbed dose of CLR 131 by the targeted tumor. Pts subsequently received EBRT to complete the designated radiation dose outlined in the standard of care reirradiation plan (60-70 Gy).ResultsSixteen pts were consented, and 12 were treated on study. Four pts were ineligible (2 had insufficient CLR 131 uptake, 2 had rapidly progressive disease). Six pts were treated at first recurrence, 6 pts had multiply recurrent disease, and 2 pts had metastatic disease. All pts completed treatment with CLR 131 and EBRT. One pt died from aspiration pneumonia unrelated to CLR 131 but possibly related to EBRT. The median total absorbed tumor dose of CLR 131 was 6.23 Gy [range 2.65 - 8.69 Gy]. Eight pts experienced gr 4 non-DLT hematologic toxicities (2 anemia, 8 leukopenia, 5 thrombocytopenia) at least probably attributed to CLR 131, which was consistent with the expected toxicity profile. The hematologic toxicities occurred during weeks 6-8 from the first dose of CLR 131, and resolved within 3 weeks without sequelae. There were no treatment related gr 3-4 non-hematologic toxicities.ConclusionCLR 131 at a fractionated dose of 15.6 mCi/m2 in combination with EBRT was safe and tolerable in pts with recurrent/metastatic HNC. Observed myelosuppression was consistent with the known toxicity profile of CLR 131. The Monte Carlo method provides a novel approach for calculating the tumor-absorbed dose of radionuclide agents, allowing for accurate tumor targeting and personalized dosing strategies in future combination therapy studies, which may improve efficacy and reduce toxicity.

Abstract Background: Farnesyl transferase inhibitors (FTIs) block post-translational modification of RAS and other farnesylated proteins. HRAS-driven tumors are highly sensitive to FTI treatment. Recent clinical trials (NCT03719690, NCT02383927) of the FTI, tipifarnib, in patients with HRAS-mutant (HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%), showed objective response rates of up to 50% and favorable long-term outcomes. KO-2806 is a next-generation FTI that has increased potency and improved pharmacokinetic properties. In preclinical studies, KO-2806 has been shown to: (1) enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell renal cell carcinoma (ccRCC) cell line- and patient-derived xenograft models; and (2) enhance activity of KRAS inhibitors, including adagrasib, in KRAS mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC) mouse models. These preclinical data support clinical investigation of KO-2806 alone and in combination therapy. Study Design: FIT-001 is a first-in-human, multicenter, open-label clinical trial that will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics (Pd), and preliminary antitumor activity of KO-2806 as monotherapy or in combination therapy in advanced solid tumors (KO-2806-001; NCT06026410). Up to 270 patients will be enrolled in phase 1a and phase 1b combined across 50 sites. Phase 1a will have separate monotherapy and combination dose-escalation arms. As monotherapy, the study will enroll patients with N/K/HRAS alterations in specific solid tumor types, such as NSCLC, CRC, and PDAC, who are refractory to standard-of-care therapies. KO-2806 and cabozantinib will be combined in patients with advanced or metastatic ccRCC who progressed on ≥1 prior line of immunotherapy-based systemic therapy; KO-2806 and adagrasib will be combined in patients with KRAS-G12C mutant locally advanced or metastatic NSCLC who received ≥1 prior systemic therapy. On the basis of emerging data from phase 1a, two Pd cohorts (n≤12) with mandatory pre- and on-treatment tumor biopsies may be enrolled. In each Phase 1b dose expansion, patients will receive the recommended phase 2 dose [RP2D] of KO-2806 with cabozantinib (in ccRCC) or adagrasib (in NSCLC), or will be randomized by dose if 2 potential KO-2806 RP2Ds are identified for a combination. Other combination arms may also be considered. The study began accrual in October 2023. Citation Format: Glenn J. Hanna, Douglas R. Adkins, Jacob S. Thomas, Justine Y. Bruce, Manish R. Patel, Guru Sonpavde, Jason Henry, Nawal Bendris, Zijing Zhang, Amitava Mitra, Amaya Gascó, Andrew Saunders, Stephen Dale. FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT163.

TPS6116 Background: Novel treatment strategies are needed to treat recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) given the poor durability of response and prognosis with standard therapy. In KEYNOTE-048, among patients with R/M HNSCC and PD-L1 combined positive score (CPS) ≥1, first-line (1L) treatment with pembrolizumab demonstrated a median overall survival (OS) of 12.3 months. Nectin-4 is widely expressed in a variety of solid tumors, including bladder cancers and HNSCC. Enfortumab vedotin (EV) is a Nectin-4–directed antibody–drug conjugate approved for use in previously treated (EV monotherapy) or 1L (EV + pembrolizumab) locally advanced or metastatic urothelial carcinoma (la/mUC). EV + pembrolizumab showed superior OS and progression-free survival (PFS) vs chemotherapy in 1L la/mUC. EV-202 is a multicenter, open-label, phase 2 study (NCT04225117) evaluating the efficacy and safety of EV in multiple tumor-specific cohorts. In the previously treated R/M head and neck cancer cohort, 11 of 46 patients (23.9%) had a confirmed objective response with EV monotherapy; median PFS was 3.9 months (Swiecicki P, et al. ASCO 2023. Poster #6017). We hypothesize that EV + pembrolizumab may demonstrate benefit as a 1L therapy in patients with R/M HNSCC and CPS ≥1. Methods: Patients in the R/M HNSCC cohort of EV-202 have histologically or cytologically confirmed HNSCC, an ECOG performance status 0 or 1, no prior systemic therapy administered in the R/M setting (with the exception of systemic therapy completed >6 months prior if given as part of treatment for locally advanced disease), and CPS ≥1. A total of 40 patients are expected to be enrolled. An interim analysis will be conducted when 20 patients are evaluable for tumor response; 5 responders will be needed to proceed. Of 40 total patients, 14 must demonstrate response to claim promising antitumor activity. Patients will receive EV 1.25 mg/kg intravenously on days 1 and 8 and 200 mg of pembrolizumab intravenously on day 1 of each 21-day cycle until discontinuation, for reasons including disease progression or toxicity. Disease assessments will be performed 9 weeks from the first dose and every 6 weeks thereafter until disease progression, start of subsequent anticancer therapy, death, consent withdrawal, loss to follow-up, or study end, whichever occurs first. The primary endpoint is investigator-assessed, confirmed ORR per RECIST v1.1. Secondary endpoints include investigator-assessed duration of response, disease control rate, PFS, OS, and safety/tolerability. Analyses will also be evaluated per iRECIST. Exploratory analyses will include pharmacokinetics, immunogenicity, quality of life, and assessment of biomarkers that may correlate with treatment outcome, including Nectin-4 expression. Recruitment for this cohort began in November 2023 and is ongoing. Clinical trial information: NCT04225117 .

Background: Farnesyl transferase inhibitors (FTIs) block post-translational modification of RAS and other farnesylated proteins. HRAS-driven tumors are highly sensitive to FTI treatment. Recent clinical trials (NCT03719690, NCT02383927) of the FTI, tipifarnib, in patients with HRAS-mutant (HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%), showed objective response rates of up to 50% and favorable long-term outcomes. KO-2806 is a next-generation FTI that has increased potency and improved pharmacokinetic properties. In preclinical studies, KO-2806 has been shown to: (1) enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell renal cell carcinoma (ccRCC) cell line- and patient-derived xenograft models; and (2) enhance activity of KRAS inhibitors, including adagrasib, in KRAS mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC) mouse models. These preclinical data support clinical investigation of KO-2806 alone and in combination therapy. Study Design: FIT-001 is a first-in-human, multicenter, open-label clinical trial that will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics (Pd), and preliminary antitumor activity of KO-2806 as monotherapy or in combination therapy in advanced solid tumors (KO-2806-001; NCT06026410). Up to 270 patients will be enrolled in phase 1a and phase 1b combined across 50 sites. Phase 1a will have separate monotherapy and combination dose-escalation arms. As monotherapy, the study will enroll patients with N/K/HRAS alterations in specific solid tumor types, such as NSCLC, CRC, and PDAC, who are refractory to standard-of-care therapies. KO-2806 and cabozantinib will be combined in patients with advanced or metastatic ccRCC who progressed on ≥1 prior line of immunotherapy-based systemic therapy; KO-2806 and adagrasib will be combined in patients with KRAS-G12C mutant locally advanced or metastatic NSCLC who received ≥1 prior systemic therapy. On the basis of emerging data from phase 1a, two Pd cohorts (n≤12) with mandatory pre- and on-treatment tumor biopsies may be enrolled. In each Phase 1b dose expansion, patients will receive the recommended phase 2 dose [RP2D] of KO-2806 with cabozantinib (in ccRCC) or adagrasib (in NSCLC), or will be randomized by dose if 2 potential KO-2806 RP2Ds are identified for a combination. Other combination arms may also be considered. The study began accrual in October 2023. Citation Format: Glenn J. Hanna, Douglas R. Adkins, Jacob S. Thomas, Justine Y. Bruce, Manish R. Patel, Guru Sonpavde, Jason Henry, Nawal Bendris, Zijing Zhang, Amitava Mitra, Amaya Gascó, Andrew Saunders, Stephen Dale. FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT163.