Braña, Irene

4079 Background: HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs) and are associated with poor overall survival (OS) in patients with metastatic disease. HER2 overexpression is associated with an increased risk of disease recurrence in patients with resected BTC. There is limited data on targeting HER2 in BTC harboring activating somatic HER2 mutations. Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has demonstrated activity in several HER2-mutant solid tumors. Methods: SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumors harboring oncogenic HER2 somatic mutations. The primary objective of the BTC cohort was to estimate objective response rate (ORR). Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), OS, response duration, safety, and tolerability. Retrospective central confirmation of locally reported HER2 mutation (next-generation sequencing on archival or fresh tumor tissue using MSK-IMPACT or in cfDNA extracted from plasma by MSK-ACCESS) and association with outcome was an exploratory endpoint. This trial is registered with ClinicalTrials.gov (NCT01953926). Results: 25 treatment-refractory patients with metastatic BTC were enrolled (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers). ORR was 16% (95% CI 4.5–36.1%) and CBR was 28% (95% CI 12.1–49.4%). Median PFS and OS were 2.8 (95% CI 1.1–3.7) and 5.4 (95% CI 3.7–11.7) months, respectively. Median PFS for the gallbladder, cholangiocarcinoma and ampulla cohorts was 3.7 (95% CI 0.8–6.4), 1.4 (95% CI 0.5–9.1), and 1.1 (95% CI 1.1–3.8) months, respectively. Corresponding median OS values in these cohorts were 9.8 (95% CI 2.4–NE), 5.4 (95% CI 0.8–16.2), and 5.0 (95% CI 3.7–10.2) months, respectively. Central mutation confirmation was feasible for 23 of 25 patients; 22 were concordant with enrolment assays. The most common HER2 mutations were S310F (n = 11; 48%) and V777L (n = 4; 17%). Exploratory analyses suggested worse outcomes for HER2-mutant tumors with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations were identified at progression in one of four responders. Diarrhea (56% any grade) was the most common toxicity. Conclusions: Neratinib is tolerable with modest antitumor activity in patients with BTC harboring HER2 mutations. Although the primary endpoint was met, future studies should evaluate rational combinations to augment and/or prolong responses. Clinical trial information: NCT01953926.

Abstract HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2-mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (NCT01953926). The primary objective of the BTC cohort was objective response rate (ORR). Among 25 treatment-refractory patients (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers), the ORR was 16%. The most common HER2 mutations were S310F (n = 11; 48%) and V777L (n = 4; 17%). Outcomes appeared worse for ampullary tumours or those with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations were identified at progression in one responder. Neratinib demonstrated anti-tumour activity in patients with refractory BTC harbouring HER2 mutations. Future studies of rational combinations are warranted.

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 ).

320 Background: Genomic profiling studies have reported somatic HER2 mutations in ~2–5% of biliary tract cancers (BTC). Clinical data from the SUMMIT study demonstrate that neratinib, a pan-HER irreversible tyrosine kinase inhibitor, has encouraging clinical activity in multiple types of HER2-mutant solid tumor malignancies. Methods: SUMMIT is a multi-histology, open-label, phase II ‘basket’ study of neratinib in patients with somatic HER2 mutations (ClinicalTrials.gov NCT01953926). Patients with activating somatic HER2 mutations with different histologies, including BTC, received neratinib monotherapy (240 mg oral daily). Loperamide prophylaxis was mandatory during cycle 1. Efficacy endpoints: objective response rate (ORR, RECIST v1.1); clinical benefit rate (CBR); duration of response; progression-free survival (PFS). Adverse events (AEs) were assessed by CTCAE v4.0. Genomic profiling from fresh/archival tumor tissues and/or plasma cfDNA was performed retrospectively by next-generation sequencing (MSK-IMPACT). Results: As of 3-Sep-2020, 25 patients with HER2-mutant BTC were enrolled: gallbladder (40%); intrahepatic (24%); extrahepatic (20%); ampulla of Vater (16%). 68% of patients received ≥2 systemic regimens (96% received prior gemcitabine-based regimens). The S310F/Y variant accounted for nearly half of HER2 mutations (n=11). Other HER2 mutations: V777L (n=5); L755S (n=2); V842I (n=2); R678Q (n=2). Confirmed ORR in 25 evaluable patients was 12% (95% CI 3–31%) and CBR was 20% (95% CI 7–41%), including 3 confirmed PRs and 2 patients with SD for ≥16 weeks. Tumor shrinkage was observed in multiple HER2-activating mutations and enriched in gallbladder and extrahepatic subtypes of BTC. Median PFS was 2.8 (95% CI 1.1–3.7) months; median overall survival (OS) was 5.4 (95% CI 3.7–11.7) months. Nine (36%) patients (3 of whom with ECOG PS 2) came off study within 28 (range 6–47) days of treatment due to clinical deterioration (unrelated to study drug) followed by death. The most common treatment-related AEs (any grade) were diarrhea (56%) and vomiting (48%). Diarrhea was the most common Grade 3 event (24%); 4 patients (16%) required a neratinib dose reduction; no patients discontinued treatment due to diarrhea. Conclusions: Neratinib is safe and tolerable in patients with advanced BTC patients and somatic HER2 mutations. The antitumor activity of neratinib appears comparable to current standards of care, with similar PFS and OS in heavily pretreated patients. Analysis of co-occurring oncogenic mutations and response is ongoing, and consideration is being given to neratinib-based combination regimens to further improve outcomes in this setting. Clinical trial information: NCT01953926.

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

3027 Background: Two rational strategies to interrogate the IGF-1R pathway were investigated in this parallel-arm phase I trial: 1) vertical inhibition with D and MK-2206 to potentiate PI3K pathway targeting, 2) horizontal crosstalk inhibition with D and MK-0752 to exert effects against cellular proliferation, angiogenesis and stem cell propagation. Methods: Patients (pts) with advanced solid tumors and no prior exposure to agents of the same targets were eligible. Dose escalation was based on a modified toxicity probability interval method (Ji et al, 2010). Arm A is comprised of fixed D dose of 10 mg/m2 IV weekly plus MK-2206 at escalating doses of 90-200 mg PO weekly. Arm B is comprised of fixed MK-0752 dose of 1800 mg PO weekly plus D at escalating doses of 7.5-10 mg/m2 IV weekly. Each cycle = 4 weeks in both arms. Primary objectives were to determine DLT and RP2D of these combinations. Results: 30 patients were enrolled in the dose escalation phase (18 in Arm A and 12 in Arm B) with: median age = 56 (range 36-74); M:F = 13:17; ECOG 0:1 = 12:18; primary diagnosis = colorectal (CRC) (9), NSCLC (3), others (17); prior metastatic regimens = 3 (range 1-4). In Arm A, 1/6 DLT was observed with MK-2206 at 135 mg (G3 serum sickness-like reaction); 2/3 DLTs with MK-2206 at 200 mg (G4 leukopenia/neutropenia; G3 rash). No other G4 or worse adverse events (AEs) were observed. RP2D of Arm A = D 10mg/m2 IV weekly and MK-2206 150 mg PO weekly. Other common AEs in Arm A included: fatigue, rash and nausea. In Arm B, 2/6 DLTs were observed with D at 10 mg/m2 (G3 rash; G3 nausea/vomiting). RP2D of Arm B = D 10mg/m2 IV weekly and MK-0752 at 1800 mg PO weekly based on Ji et al. Other common AEs in Arm B included: anorexia, nausea and fatigue. No PR was observed and SD > 4 months occurred in 4 pts (all in Arm A). PK analyses are ongoing. Conclusions: Targeted combinations of D with MK-2206 or with MK-0752 were both tolerable. Expansion cohorts based on biomarker selection are underway, specifically ovarian cancer with high IGF1 expression/low RAS score for Arm A; and KRAS wild-type CRC with high IGF1/low IGF2 expression for Arm B.

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.

Abstract Purpose: To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. Experimental Design: Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation. Results: Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4–5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration–time profile for PF-05212384 (half-life, 30–37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. Conclusions: These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies. Clin Cancer Res; 21(8); 1888–95. ©2015 AACR.