Ho, Alan L.

The NCCN Guidelines for Squamous Cell Skin Cancer provide recommendations for diagnostic workup, clinical stage, and treatment options for patients with cutaneous squamous cell carcinoma. The NCCN panel meets annually to discuss updates to the guidelines based on comments from panel members and the Institutional Review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new surgical recommendation terminology (peripheral and deep en face margin assessment), as well as recent updates on topical prophylaxis, immunotherapy for regional and metastatic disease, and radiation therapy.

6076 Background: HCC is a rare subtype of follicular cell thyroid cancer that has been poorly studied in the past. Recent genomic studies have shown the PI3K/Akt/mTOR pathway is frequently altered in HCC. In addition, a phase II study of sorafenib (S) and everolimus (E) showed promising data in HCC. A study to evaluate this was initiated through Alliance and the International Thyroid Oncology Group. Methods: Patients (pts) were randomized to either sorafenib and everolimus (SE) vs. sorafenib alone (S). Inclusion criteria included; (1) diagnosis of HCC (confirmed through central review), no prior S or E, refractory to radioactive iodine, progressive disease by RECIST over prior 14 months. Primary endpoint was a comparison of progression-free survival (PFS) between SE and S using a stratified 1-sided log-rank test with 0.20 significance level and a power of 80%. 28 events were needed at final analysis. Secondary endpoints consisted of overall survival (OS), confirmed response rate (RR), and adverse events. Results: 35 pts were randomized from 10/2014 to 9/2019, 34 of which were evaluable for analysis (17-SE; 17-S) because 1 patient cancelled prior to receiving treatment. Median age was 66.5 years and 74% were male. ECOG performance status (PS) was 0 (47%) and PS 1 (53%). 41% had prior systemic treatment for HCC. No significant differences in baseline characteristics were observed between treatment arms. Median follow-up in 22 alive patients was 39.2 months (range: 15.1-64.9). Seven (21%) patients remain on treatment. PFS was significantly improved in the SE arm as compared to the S arm (HR=0.65 (95% CI: 0.26, 1.57); median PFS: SE=24.7 months (95% CI: 6.1-no upper), S=10.9 months (95% CI: 5.5-no upper); stratified 1-sided p=0.1662). OS was similar between the arms (2-sided p=0.4138). Confirmed response rate was similar between arms as well (SE: 18% (3 partial response (PR) vs. S: 24% (3 PR, 1 complete response)); Fisher’s exact p=1.00). Grade 3 adverse event (AE) rates (regardless of attribution) were similar between arms (SE: 77% vs. S: 77%; p=1.00). Each arm had 1 patient with at least one grade 4 AE (SE patient: cardiac arrest, tracheal obstruction, encephalopathy; S patient: mucositis oral) and no grade 5 AEs. Conclusions: PFS was improved with the addition of E to S in this small randomized multi-institutional phase II study done. Accrual was difficult, but these promising results suggest that this combination should be further studied. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Novartis/GSK; ClinicalTrials.gov Identifier: NCT02143726. Clinical trial information: NCT02143726.

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 ).

Abstract Background Patients with human papillomavirus–related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy. Methods In 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided. Results Fifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation–related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03). Conclusions Deescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy.

Abstract Background: This Phase 2 study (NCT02383927) is a multi-institutional, open-label trial to determine the efficacy and safety of tipifarnib in patients (pts) with locally advanced/unresectable and/or metastatic solid tumors that carry HRAS missense mutations. HRAS is a proto-oncogene that is overexpressed and mutated in head and neck squamous cell carcinomas (HNSCC) and other SCCs. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity. Methods: Pts received tipifarnib at a starting dose of 600 – 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. Disease assessments were conducted according to RECIST v1.1 criteria. Null hypothesis and objective response of interest were respectively 10% and 30%. Prior to its completion, this study met its primary objective and, based on preliminary efficacy results (Ho, et. al, ESMO 2018), was amended to continue enrolling only pts with HNSCC (Cohort 2) and other SCC tumors (Cohort 3) carrying HRAS missense mutations at a high variant allele frequency (VAF >35% or ≥20% if baseline serum albumin is >3.5 g/dL). Results: As of May 1, 2019, 23 pts with HNSCC and 10 pts with tumors with other SCC histologies have been treated with tipifarnib. Pts had relapsed/refractory disease with a median of 2 prior regimens. Of note, no objective partial responses were observed on their last therapy prior to study entry, including platinum, immunotherapy and cetuximab +/- chemotherapy. In 15 HNSCC pts meeting the HRAS mutation high VAF inclusion criteria, a 53% overall response rate (ORR) was observed, with 8 confirmed partial responses (PR) and 5 disease stabilizations (SD). Two pts await first on-study tumor response assessment. Overall median progression free survival (PFS) was 5.4 mos (95% CI 4.5 to 19.5 mos, N=15); 19 mos (95% CI 5.3 to 19.5 mos) for pts experiencing a PR and 4.5 mos (95% CI 1.6 to 5.4 mos) for those experiencing SD. Median PFS on last prior therapy was 3.2 mos. All pts had at least 1 treatment-emergent adverse event (TEAE). The most frequently observed drug-related Grade >3 TEAEs occurring in ≥10% pts were blood and lymphatic system disorders, gastrointestinal disorders and renal disorders. Conclusions: Encouraging activity of tipifarnib was observed in HRAS mutant HNSCC. Based on these data, a pivotal study (AIM-HN and SEQ-HN Study, NCT03719690) evaluating the efficacy of this agent in HRAS mutant HNSCC (AIM-HN) and the impact of HRAS mutations on first line therapy of HNSCC (SEQ-HN) has been initiated. Citation Format: Alan Ho, Irene Brana, Robert Haddad, Jessica Bauman, Keith Bible, Laurence Faugeras, Sjoukje Oosting, Deborah J Wong, Myung-Ju Ahn, Valentina Boni, Caroline Even, Jerome Fayette, Maria Jose Flor, Kevin Harrington, Sung-Bae Kim, Lisa Licitra, Ioanna Nixon, Nabil F Saba, Cyrus Sayehli, Pol Specenier, Francis Worden, Binaifer Balsara, Jeanne Britt, Vishnu Mishra, Catherine Scholz, Antonio Gualberto. Preliminary results from a phase 2 trial of tipifarnib in squamous cell carcinomas (SCCs) with HRAS mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR08. doi:10.1158/1535-7163.TARG-19-PR08

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.

6020 Background: A subset of salivary gland cancer (SGCs) express the androgen receptor (AR). This phase II trial evaluated the anti-androgen enzalumatide (Astellas) for patients with AR+ SGCs. Methods: Locally advanced/unresectable or metastatic AR+ SGCs were enrolled (AR status was centrally confirmed). Prior therapy with AR-targeted drugs was allowed. Enzalutamide 160 mg orally once daily was given (1 cycle= 28 days). The primary endpoint was confirmed response (RR) according to RECIST v1.1 within the first 8 cycles. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. A Simon-Optimal two-stage design was used to detect a 20% RR (vs. 5%) (alpha = 5%; beta = 90%). > 1 response(s) in the first 21 would trigger accrual to 41; > 4 responses would be considered promising. Results: 46 eligible patients (pts) were enrolled (40 M, 6 F; median age 65) in 22 months. In the first 21 pts, we initially had 2 confirmed PRs allowing for full study accrual, though one was later changed to stable disease. Among the 46 pts, 7 had PR as best response, though only 2 were confirmed within the first 8 cycles (4% (95% CI: 0.5-15%). Two other PRs did not count towards the primary endpoint due to 1) development beyond 8 cycles (cycles 12-18) and 2) a confirmatory scan completed <4 weeks apart. The other 3 pts with unconfirmed PR developed progression of disease (PD) after the first PR scan. 24 pts had stable disease; 15 pts PD as best response. Among 11 pts previously treated with AR-targeted therapy, best responses were 1 confirmed PR, 7 SD, 3 PD. With a median follow-up of 11.7 months (mo), OS at 12 mo was 66% (95% CI: 52-83%), PFS at 12 mo was 24% (95% CI: 14-42%), and median PFS was 5.5 mo (95% CI: 3.7-7.3). Conclusions: This is the first prospective trial evaluating an antiandrogen alone for AR+ SGCs. The failure to meet the protocol-defined measure of success was due in part to the lack of durability of initial responses. The clinical activity observed suggests the AR-dependence of AR+ SGCs, even among those previously treated with other hormonal therapies. Support: U10CA180821, U10CA180882; Astellas; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02749903.

TPS2618 Background: Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). FT catalyzes the post-translational attachment of farnesyl groups to signaling proteins that are requisite for localization to the inner cell membrane. While all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, only HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation, making HRAS mutant tumors uniquely susceptible to tipifarnib mediated inhibition of FT. Tipifarnib has demonstrated robust activity in HRAS mutant head and neck squamous cell carcinoma (HNSCC) and HRAS mutant squamous non-small cell lung cancer (NSCLC) patient derived xenograft (PDX) models resistant to standard therapies. Methods: This is a multi-institutional, open-label Phase II trial evaluating the efficacy and safety of tipifarnib for pts with HRAS mutant solid tumors. Pts must have either unresectable, locally advanced or metastatic non-hematological malignancies that harbor a missense HRAS mutation. The primary endpoint of the study is overall response rate. Secondary endpoints include safety and tolerability, PFS, duration of response. Two cohorts (N = 18 each) are enrolling, each being evaluated with a Simon two-stage design. Cohort 1 is for patients with malignant thyroid tumors of any histology. Cohort 2 was originally designated for pts with any other solid tumor. The prespecified activity goal for the first stage of accrual in Cohort 2 was met. Based on data observed in the first stage of this group, enrollment to the second stage of Cohort 2 has been limited to HRAS mutant HNSCC since August 2016. Enrolled patients are treated with tipifarnib 900 mg administered orally twice daily on days 1-7 and 15-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. Clinical trial information: NCT02383927.

Abstract Background: HRAS is a proto-oncogene that is mutated in head and neck, bladder, thyroid, and salivary gland tumors, among others. While discovered over 40 years ago, no specific therapies have yet been developed targeting mutant HRAS. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme requisite for HRAS activation. Over 5,000 patients (pts) have been treated with tipifarnib; although responses have been documented in several tumor indications, the mechanisms of response are still poorly understood. Tipifarnib has demonstrated robust activity in HRAS mutant patient derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC) and squamous non-small cell lung cancer that are resistant to standard therapies. This Phase 2 study (NCT02383927) was conducted to test the hypothesis that inhibition of mutant HRAS oncogenic activity with tipifarnib could translate to objective responses in HNSCC pts driven by the HRAS oncogene. Methods: The study was originally designed to enroll pts into 2 single-arm study cohorts: Cohort 1 (thyroid cancer) and Cohort 2 (other solid tumors), each one with a 2-stage design (11+7 evaluable pts) to determine overall response rate (ORR) as the primary objective. This design has 80% power to detect a difference between 10% and 30% ORR at one-sided significance level of 0.087. Two objective responses were needed to be observed in the first stage for each cohort to proceed to stage 2. The study is considered positive if at least 4 responses are observed in one of the 2 cohorts (N=18 each, stages 1 and 2 combined). The prespecified activity goal for the first stage of accrual in Cohort 2 was met and based on data observed in the first stage of this Cohort, ongoing enrollment to the second stage of Cohort 2 was limited to HRAS mutant HNSCC. For enrollment, pts must have an HRAS mutant, locally advanced/unresectable and/or metastatic solid tumor malignancy and RECIST v1.1 measurable disease. Tipifarnib is given at 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. Response assessments are conducted every 8 weeks. Results: As of August 30, 2017, 28 pts have been enrolled. Tipifarnib was generally well tolerated with myelosuppression, gastrointestinal disturbances (nausea, vomiting and diarrhea) and fatigue constituting the most common adverse events (≥30% of pts, all grades). Twenty four pts are currently evaluable for efficacy: 10 in Cohort 1 and 14 in Cohort 2. Stage 1 enrollment continues in Cohort 1. The primary objective was met for Cohort 2 prior to completing full enrollment, with 4 confirmed responses observed out of 14 evaluable pts. Notably, of the 6 pts in Cohort 2 with HNSCC currently evaluable for efficacy, 4 (67%) achieved a confirmed partial response. Three of these pts remain on treatment in cycles 3, 5, and 19, and one subject discontinued at Cycle 21. Two (33%) pts had disease stabilization as best response (4 cycles, ongoing and 7 cycles). Importantly, 4 of these pts were refractory to prior therapies, including regimens containing immunotherapy (pembrolizumab, nivolumab) or cetuximab +/- chemotherapy. None of the 6 HNSCC patients experienced an objective partial response on their last prior therapy. Conclusions: These data suggest that HRAS mutant HNSCC pts may be refractory to standard therapies but can derive prolonged clinical benefit from tipifarnib treatment. Based on the encouraging activity of tipifarnib in pts with HNSCC with HRAS mutations, enrollment continues in this cohort. Citation Format: Alan Ho, Nicole Chau, Deborah J. Wong, Maria E. Cabanillas, Jessica Bauman, Marcia S. Brose, Keith Bible, Valentina Boni, Irene Brana, Charles Ferte, Caroline Even, Francis Burrows, Linda Kessler, Vishnu Mishra, Kelly Magnuson, Catherine Scholz, Antonio Gualberto. Preliminary results from a phase 2 proof of concept trial of tipifarnib in tumors with HRAS mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A10.