Supplementary Figure S1 shows mean (+SD) plasma concentrations of nemtabrutinib vs time following single (C1D1) oral doses of MK-1026 (linear and semi-log plots) nM

Abstract Nemtabrutinib is an orally bioavailable, reversible inhibitor of Bruton tyrosine kinase (BTK) and C481S mutant BTK. We evaluated the safety, pharmacology, and antitumor activity of nemtabrutinib in relapsed/refractory hematologic malignancies. Forty-eight patients with chronic lymphocytic leukemia (CLL), B-cell non–Hodgkin lymphoma (NHL), or Waldenström macroglobulinemia (WM), relapsed/refractory after ≥2 prior therapies were enrolled in the open-label, single-arm, phase I MK-1026-001 study (NCT03162536) to receive nemtabrutinib 5 to 75 mg once daily in 28-day cycles. Dose finding progressed using a 3 + 3 dose escalation design. Primary endpoints were safety and the recommended phase II dose (RP2D). Among 47 treated patients, 29 had CLL, 17 had NHL, and 1 had WM. Grade ≥3 treatment-emergent adverse events occurred in 37 (89%), most commonly neutropenia (11; 23.4%), febrile neutropenia (7; 14.9%), and pneumonia (7; 14.9%). The RP2D was 65 mg daily. An overall response rate of 75% was observed in patients with CLL at 65 mg daily. Significance: This first-in-human phase I study demonstrates the safety and preliminary efficacy of nemtabrutinib in patients with relapsed/refractory B-cell malignancies. These data support further exploration of nemtabrutinib in larger clinical studies. This article is featured in Selected Articles from This Issue, p. 5

Background:The BTK inhibitor ibrutinib has been approved for multiple indications based on marked treatment benefit in B cell lymphoma/leukemia. Although ibrutinib provides durable, disease control, resistance is emerging as an area of unmet medical need. ARQ 531 is a reversible ATP competitive inhibitor of BTK that inhibits both wild type and ibrutinib‐resistant BTK‐C481S mutant CLL cells and has demonstrated antitumor activity in CLL, Richter's transformation, and DLBCL mouse models.Aims:The primary objectives of the clinical study are to assess the safety and tolerability of ARQ 531, and to determine the recommended Phase 2 dose and schedule. The secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of anti‐tumor activity.Methods:This is a first in human, Phase 1 dose escalation study in patients with relapsed/refractory CLL/SLL, B‐cell NHL or Waldenstrom's macroglobulinemia who received at least 2 prior lines of systemic therapy. Prior therapy must have included a BTK inhibitor. Dose escalation was performed according to a 3+3 study design. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v.4.03. Tumor responses were evaluated per disease specific guidelines.Results:As of February 15, 2019, a total of 26 patients have been treated: CLL/SLL (n = 19), DLBCL (n = 2), FL (n = 4), MCL (n = 1). Baseline demographics were: median age 65 (48–82) years, male/female 24/2 and median number of prior lines of therapy 5 (range 2–12). Enrolled patients received ARQ 531 orally once daily in 28‐day cycles at doses of 5, 10, 15, 20, 30, 45 and 65 mg QD.Drug related TEAEs that occurred in ≥2 subjects were nausea (15.4%), neutrophil count decreased (11.5%), constipation, diarrhea, vomiting, fatigue, decreased appetite, arthralgia, dizziness, dysgeusia and headache (7.7% each). The majority of the TEAEs were grade 1 or 2. Drug related grade 3 or worse TEAEs included neutrophil count decreased (11.5%), platelet count decreased (3.8%), lipase increased (3.8%), and rash (3.8%). The only grade 3 TEAE of rash occurred in one subject treated with 65 mg QD and was a SAE and assessed as a dose limiting toxicity (DLT). The 65 mg QD cohort was expanded to enroll more subjects. The maximum tolerated dose (MTD) has not been reached.Preliminary PK data show that cohorts receiving ≥ 45 mg QD of ARQ 531 exhibited steady‐state trough concentrations (Cmin) of above 1 micromolar; the estimated plasma half‐life generally ranged from 20–30 hours and was associated with complete pBTK inhibition and CCL3 suppression. Furthermore, increasing tumor suppression seen at higher dose levels was also correlated with higher Cmin concentrations.Among the 14 subjects who have received doses ≥ 45 mg QD, either as starting dose or dose escalated, 9 were evaluable for response (on study treatment for at least one cycle and had at least one post‐treatment tumor measurement). Among them, 2 patients had partial responses (1 CLL with BTK C481S mutation who had received 3 prior lines of therapy including acalabrutinib, 1 FL who had received 3 prior lines of therapy and is on study for >83 weeks) and 5 achieved stable disease with tumor reduction between 30% to 49% with median lines of prior therapy of 9.Summary/Conclusion:Based on the emerging data, ARQ 531 has a manageable safety profile and shows preliminary anti‐tumor activity as a single agent in heavily treated B‐cell NHL and BTK inhibitor resistant CLL patients. Dose escalation continues, updated safety, PK, biomarker and anti‐tumor activity data will be presented at the meeting.

Introduction: Resistance to covalent BTK inhibitors such as ibrutinib and acalabrutinib is a common mechanism of resistance that portends a poor long-term clinical outcome. ARQ 531 is a potent, reversible inhibitor of both wild type and ibrutinib-resistant C481S-mutant BTK. ARQ 531 suppresses oncogenic BCR signaling in CLL cells resistant to ibrutinib and has demonstrated antitumor activity superior to ibrutinib in CLL, Richter's transformation, and DLBCL mouse models. Methods: The primary objectives of the clinical study were to assess the safety and tolerability of ARQ 531, and to determine the recommended Phase 2 dose (RP2D) and schedule. The secondary objectives were to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of anti-tumor activity. Eligible patients had relapsed/refractory CLL/SLL, B-cell NHL or Waldenstrom's macroglobulinemia, had received at least 2 prior lines of systemic therapy and had good organ function including creatinine clearance ≥ 60 mL/min as estimated by the Cockcroft-Gault equation or by 24-hour urine collection, absolute neutrophil count ≥ 1000/µL, platelet count ≥ 50,000/µL and hemoglobin ≥ 8.0 g/dL. Prior therapy for CLL must have included an irreversible BTK inhibitor. Dose escalation was performed according to a 3+3 study design. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v.4.03. Tumor responses were evaluated per disease specific guidelines. Results: As of July 19, 2019, a total of 40 patients have been treated: CLL/SLL (n=26), Richter's transformation (n=6), DLBCL (n=3), FL (n=4), MCL (n=1). Baseline demographics were: median age 65.5 (range 47-82) years, male/female 36/4 and median number of prior lines of therapy 4 (range 2-12). BTK-C481S mutation was documented in 22/26 (85%) CLL patients. Enrolled patients received ARQ 531 orally once daily, continuously, in 28- day cycles at doses of 5, 10, 15, 20, 30, 45, 65 and 75 mg QD. The most common drug-related TEAEs that occurred in > 2 patients were nausea (n=4), diarrhea (n=4), fatigue (n=3), neutrophil count decreased (n=3), dysgeusia (n=3) and rash (n=3). The majority of the drug-related TEAEs were grade 1 or 2. Drug-related grade 3 or 4 TEAEs included neutrophil count decreased (n=3), as well as febrile neutropenia, cellulitis, platelet count decreased, lipase increased, and rash (one each). One subject treated at 65 mg experienced a DLT of grade 3 rash. The 65 mg cohort was expanded to a total of 10 patients, and no other DLTs were observed. At the 75 mg QD dose level (n =4), drug-related grade 2 adverse events were reported which led to dose reduction to 65 mg QD (n=3) or treatment discontinuation (n=1). Preliminary PK data show that patients receiving ARQ 531 at 65 mg QD exhibit steady-state trough concentrations (Cmin) above 1 µM; the estimated plasma half-life generally ranged from 20-30 hours and was associated with complete pBTK inhibition. Clinical responses to ARQ 531 were observed in multiple patients with B-cell malignancies. Ten partial responses (PRs) were achieved mainly in the higher dose cohorts, and included patients with CLL (n=7), Richter's transformation (n=1), DLBCL (n=1) and follicular lymphoma (n=1). Of the 7 CLL patients who attained PRs, 5 were initiated at 65 mg, 1 was initiated at 45 mg and was dose escalated to 65 mg and 1 was initiated at 75 mg and dose reduced to 65 mg. Together, the safety, PK/PD and clinical activity results suggest that ARQ 531 at 65 mg QD is safe, well tolerated and has clear signs of anti-tumor efficacy. Thus, 65 mg QD dose has been selected as the RP2D in patients with B-cell malignancies. Conclusion: ARQ 531 has a manageable safety profile and shows anti-tumor activity as single agent therapy in heavily pre-treated patients with B-cell NHL and in patients with CLL resistant to covalent BTK inhibitor. The Phase 1 dose escalation portion of this study is complete. Enrollment of patients with multiple B-cell malignancies is ongoing at 65 mg QD in the phase 1b expansion portion of the study. Updated safety, PK, biomarker and anti-tumor activity data will be presented. Disclosures Woyach: Morphosys: Research Funding; Verastem: Research Funding; Loxo: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Flinn:F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding. Bhat:Pharmacyclics: Consultancy; Janssen: Consultancy. Savage:ArQule, Inc.: Employment. Chai:ArQule, Inc.: Employment. Eathiraj:ArQule, Inc.: Employment. Granlund:ArQule, Inc.: Employment. Schwartz:ArQule, Inc.: Employment. Byrd:Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding.

BACKGROUND:KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC).MATERIALS AND METHODS:Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted.RESULTS:Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm.CONCLUSION:In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.

Abstract Background: Dysregulation of the PI3K-AKT signaling pathway is associated with a number of cancers. and plays a critical role in cancer initiation and progression. AKT can be activated through activated receptor tyrosine kinases, gain-of-function mutations of PIK3CA, PTEN deficiency, and AKT amplification or activating mutations such as AKT1E17K. As the second generation of allosteric AKT inhibitor, ARQ 751 potently inhibits AKT1, 2 and 3 with biochemical IC50 values of 0.55 nM, 0.81 nM and 1.31 nM receptively. In addition, ARQ 751 is very selective; it does not inhibit any other kinase (out of the 245 tested) by greater than 50% at 5 µM. The objective of this study is to determine maximum tolerated dose in patients with advanced solid tumors. Material and Methods: This is Phase 1 Dose Escalation Study to assess the safety and tolerability of ARQ 751 in subjects with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations, PTEN-null, or other known actionable PTEN mutations. Treatment emerging adverse events (TEAE) were assessed per NCI CTCAE v. 4.03. Tumor response were evaluated per RECIST 1.1. Blood samples were collected for PK. Results: A total of 15 pts have been enrolled [73% female; median age 61 years; 5 Breast (5), endometrial (2), and others (9); activating PI3K mutation (9), PTEN null/other known actionable PTEN mutations (5), AKT 1 mutation (1)] and treated at dose levels of 5 mg QD, 10 mg QD, 20 mg QD, 25 mg QOD and 25 mg QD. There have been no DLTs reported so far. ARQ 751 related TEAEs included nausea (27%), stomatitis, vomiting, fatigue, mucosal inflammation, white blood cell count decreased, hyperkalaemia, cough, oropharyngeal pain, sinus congestion, pain of skin, puritus and hot flushes (7% each). All these TEAEs were grade 1 or 2. There was no ≥ Grade 3 drug related TEAEs or any grade drug-related SAEs. Four pts achieved a best response of stable disease (SD) including 1 with breast cancer treated at 25 mg QOD for 42+ weeks, 1 with head and neck cancer treated at 20 mg QD for 16 weeks, 1 with breast cancer treated at 25 mg QD for 12+, and 1 with endometrial cancer treated at 25 mg QD for 10+ weeks. 3 of 4 SD pts are currently on therapy. Conclusions: ARQ 751 demonstrated a manageable safety profile at Dose level up to 25 mg QD. The dose escalation is ongoing. PK and updated safety, efficacy data will be presented. Citation Format: Shubham Pant, Vivek Subbiah, Jordi Rodon, Filip Janku, David Hong, Daniel Karp, Sarina Piha-Paul, Apostolia M. Tsimberidou, Aung Naing, Siqing Fu, Ron E. Savage, Feng Chai, Yi Yu, Brian Schwartz, Funda Meric-Bernstam, Tim Yap. Results of a phase I dose escalation study of ARQ 751 in adult subjects with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations, PTEN-null, or other known actionable PTEN mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT024.

Abstract Background: Activating PI3K pathway mutations are common in endometrial and a subset of non-serous ovarian cancers and are frequently found in tumors that co-express the estrogen receptor (ER). We evaluated the safety and preliminary efficacy of miransertib, a potent pan-AKT inhibitor, in combination with the aromatase inhibitor (AI) anastrozole in pts with PIK3CA and AKT1-mutant ER+ endometrial and ovarian cancer. Methods: Eligible patients included endometrial and ovarian cancer patients (pts) with ER+ by immunohistochemistry and a PIK3CA or AKT1 mutation documented by local sequencing assays. There was no limit to prior lines of therapy including prior AIs. Miransertib dose was escalated according to a 3+3 design. TEAEs were assessed per CTCAE v. 4.03. Tumor responses were evaluated per RECIST 1.1. Results: A total of 11 pts (8 endometrial, 3 ovarian) were enrolled (median age 60 years). Pts were treated at one of 2 miransertib doses: 200 mg QD, 5 days on/9 days off (n=6) or 150 mg QD, 5 days on/9 days off (n=5). All pts received anastrozole 1 mg QD administered continuously. 2 DLTs observed (both at the miransertib 200mg): grade 3 ALT increase and grade 3 rash. Across all cycles, a total of 4 pts experienced a Grade 3 miransertib-related AE including rash (n=2), ALT increase (n=1), and hyperglycemia (n=1). There were no grade 4/5 miransertib-related AEs. Miransertib 150mg was selected as the recommended dose. 4 pts achieved a response (1 confirmed CR, 3 unconfirmed PRs - 1 pending confirmation, see Table). All responses (confirmed and unconfirmed) were in endometrial cancer (4/8 pts). In responding pts, mutations involved PIK3CA (n=3) and AKT1 (n=1). 50% (2/4) responding pts had received ≥1 prior line of endocrine therapy. Responses were ongoing in 2 of 4 patients, with the longest continuing at 60 weeks. Conclusions: The combination of miransertib and anastrozole demonstrated a manageable safety profile and preliminary efficacy. Responses were observed in endometrial pts with PIK3CA or AKT1 mutation and those who had received prior endocrine therapy. Enrollment at the recommended combination dose is ongoing and updated response data will be presented. *pt had PD at 24 weeks but continues for ongoing benefit at 56 weeks.Pt IDPrimary SiteHistologyGradeMutationLines of prior therapyBest RECIST response (confirmed)Duration on treatment (weeks)1EndometrialMixed endometriod/serous1PIK3CA H1047R3CR60+2EndometrialEndometriod2PIK3CA H1047R4uPR24*3EndometrialEndometriod1PIK3CA H1047R4SD124EndometrialSerous3PIK3CA R115L1PD85EndometrialEndometriod1PIK3CA E545K and H1047L2NE46OvarySerous3PIK3CA H1047R5PD77OvaryEndometriod1PIK3CA T1025S2PD88EndometrialSerous3PIK3CA N345K2uPR169OvarySerous3PIK3CA E542K5PD510EndometrialSerous3AKT1 E17K1uPR**12+11EndometrialSerous3PIK3CA C901F3PD9*pt had PD at 24 weeks but continues for ongoing benefit at 56 weeks**pending confirmation Citation Format: David Hyman, Michael Bonafede, Roisin O'Cearbhaill, Rachel Grisham, Dmitriy Zamarin, William Tew, Carol Aghajanian, Karen Cadoo, Claire Friedman, Ron E. Savage, Feng Chai, Brian Schwartz, Vicky Makker. A phase Ib study of miransertib (ARQ 092) in combination with anastrozole in patients with PIK3CA or AKT1-mutant ER+ endometrial or ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT035.

2524 Background: ARQ 092 is an oral, potent AKT inhibitor with single agent antitumor activity. P or P+C is the standard therapy or the therapy of choice for pts with various solid tumors. ARQ 092 potentiated antitumor activity of P in in vivo xenograft models, providing the rationale for this study. Methods: This is an open-label, phase Ib study of ARQ 092+C+P (CP Arm) or ARQ 092+P (P Arm) in pts with advanced solid tumors to determine safety and tolerability of these 2 combinations. Blood samples are collected for PK. Results: Enrollment into CP Arm has been completed with 13 pts (15% male; median age 62 years, 4 ovarian, 9 others) being treated in 2 dose cohorts (see table and results below). Enrollment into P Arm is ongoing. Data from P Arm (80 mg/m2 weekly) will be presented during the meeting. In CP Arm, 3 DLTs were observed in 2 pts (both received ARQ 092 at 200 mg BID, 1 day/week) including grade (G) 4 neutrophil count decreased, G 4 thrombocytopenia and G 3 diarrhea. ARQ 092-related adverse events (AEs) in ≥10% pts included diarrhea 69%, fatigue 54%, hyperglycemia 31%, maculopapular rash 31%, nausea 23%, mucosal inflammation 23%, anemia 15%, platelet count decreased 15% and hypokalemia 15%. Paclitaxel- and/or carboplatin-related AEs in ≥10% pts included fatigue 77%, alopecia 62%, thrombocytopenia 39%, platelet count decreased 39%, nausea 31%, lymphocyte count decreased 31%, neutrophil count decreased 31%, white blood cell count decreased 31%, anemia 23%, mucosal inflammation 23%, hypomagnesaemia 23%, peripheral sensory neuropathy 23%, neutropenia 15%, vomiting 15% and hypokalemia 15%. Two ovarian pts previously treated with CP achieved complete response (mutant AKT) and partial response (AKT mutation unknown) respectively and 3 pts (Gastroesophageal, pancreatic, ovarian mixed mullerian) experienced stable diseases for >12 weeks. PK data will be presented during the meeting. Conclusions: Encouraging anticancer activity was demonstrated in heavily pretreated ovarian cancer pts, but full dose CP was not tolerated by most patients. Clinical trial information: NCT02476955. [Table: see text]

SummaryPurpose This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors. Materials and Methods A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed. Results Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD ≥8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients. Conclusions The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors.

Abstract Background: The AKT pathway is critical in cancer initiation and progression, it can be constitutively activated by mutations in AKT (8% breast, 6% colorectal, 6.8% meningioma) and PIK3CA (27% breast, 28% endometrial, 13% colorectal)12. ARQ 092 is a potent and selective AKT inhibitor in phase 1 clinical development. Also, ARQ 092 has been shown to have anti-growth activity in cells from patients with Proteus syndrome, a non-cancer disease solely driven by AKT1E17K3. Methods: Biochemical IC50 for AKT 1/2/3 and the selectivity profile of ARQ 092 or ARQ 751 (more potent next generation AKT inhibitor) against over 300 kinases were determined. The binding of both inhibitors to wild-type AKT1 and AKT1E17K was assessed using intrinsic tryptophan fluorescence quench. Inhibitory effect on AKT1E17K was determined in transient transfection cell system. AKT1 membrane translocation was performed in cells transiently transfected with GFP-fused AKT1 or AKT1E17K. AKT pathway in select cell lines was assessed using Western blot analysis. Anti-proliferative effects were tested in a panel of 18 breast cancer cell lines, 4 with H1047R. In vivo efficacy was tested in 2 mouse xenografts and 2 patient-derived tumors with endometrial and breast cancer cells bearing AKT1E17K or PIK3CAH1047R mutations. In a phase 1 clinical trial, patients have been enrolled to receive oral ARQ 092 at multiple doses and schedules4. Results: ARQ 092 inhibited AKT1, 2, and 3 activity with IC50 values of 5.0, 4.5, and 16 nM, respectively whereas ARQ 751 had IC50 values of 0.54, 0.79, and 1.3 nM, respectively; MK-2206 exerted less potency (40.5, 29.5 and 36.4 nM) and GDC-0068 showed potency of 2.0, 27.0, and 6.3 nM. For the AKT1E17K mutant, Kd values were 42 and 8.6 nM for ARQ 092 and ARQ 751 respectively, accompanied with inhibition of its phosphorylation; whereas over 1 μM for MK-2206. ARQ 092 and ARQ 751 but not MK-2206 at 1 μM blocked AKT1E17K membrane translocation. ARQ 092 and ARQ 751 were efficacious on all 4 PIK3CAH1047R cells with GI50 of less than 1 μM. In an endometrial PDX model bearing AKT1E17K, ARQ 092 at 100 mg/kg and ARQ 751 at 75 mg/kg obtained respectively 78% and 98% tumor growth inhibition. In vivo models with PIK3CAH1047R treated with ARQ 092 at 100-120 mg/Kg exhibited tumor growth inhibition between 32% and 84%. In the ongoing clinical trial, in 7 patients with AKT1E17K enrolled at doses close to MTD for each schedule, 2 RECIST partial responses (breast cancer and follicular lymphoma), 2 minor responses (parotid cancer, 19.3% tumor reduction; endometrial cancer, 17.5% reduction), 3 stable diseases (ovarian, neuroendocrine, meningioma, 120-277 days on therapy) were observed. One patient with PIK3CAH1047R mutant endometrial carcinoma was treated and obtained a partial response. Conclusions: ARQ 092, and the next generation ARQ 751, are potent, selective allosteric AKT inhibitors. They both bind tightly to and inhibit membrane translocation and activation of AKT1E17K and of PI3K-stimulated AKT. Preclinical and clinical findings from oncology and non-oncology studies show that AKT1 E17K and PIK3CAH1047R mutations may be used for patient selection. 1Kim MS, Br J Cancer 2008. 2Yuan TL, Oncogene 2008. 3Biesecker L, ASHG 2014 4Tolcher A, ESMO 2015. Citation Format: Giovanni Abbadessa, Yi Yu, Sudharshan Eathiraj, Justin Meade, Michael J. Wick, Anthony Tolcher, Kyri Papadopoulos, Mansoor Saleh, Jasgit Sachdev, Feng Chai, Brian Schwartz. Association of AKT1E17K and PIK3CAH1047R mutations with efficacy of ARQ 092 in vitro, in vivo and in patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B181.

Background: ARQ 092 is an oral allosteric, potent and selective AKT inhibitor with in vitro and in vivo activity in solid and hematological tumors. ARQ 092-101, the first clinical trial of ARQ 092, has enrolled more than 100 subjects with advanced solid tumors or recurrent malignant lymphoma. As reported previously, the dose escalation portion of the study has been completed and two dosing schedules (intermittent and weekly), are recommended for phase 2 studies. The recommended phase 2 dose (RP2D) for the intermittent dosing schedule is 200 mg once daily (QD) (one week on, one week off) and for the weekly dosing schedule is 300 mg twice daily (BID) (one day on, six days off). [1, 2] Enrollment in an expansion cohort at RP2Ds is ongoing. Here we report the results from 11 subjects with lymphoma/CLL.

Abstract Background: In endometrial cancer more frequently than in other tumors, abnormal activation of the AKT pathway drives tumorigenesis and can be induced by both PI3K and AKT alterations, being associated with aggressive disease and poor prognosis. ARQ 092 is a highly selective, allosteric, potent AKT inhibitor currently under clinical investigation, and ARQ 751 is the next generation AKT inhibitor, with different physical-chemical properties. Methods: ARQ 092 and ARQ 751 were profiled using a Cell-TiterGlo® viability assay and the inhibition of AKT and downstream targets were measured by Western and immunohistochemistry analyses in an AN3CA endometrial cell line with activated PI3K (via PIK3R1 mutation). The efficacy and pharmacodynamics effect of ARQ 092 and ARQ 751 on phospho-AKT and phospho-pRAS40 were determined in AN3CA xenografts after repeated daily oral dosing. ARQ 092 was also tested against 23 endometrial patient-derived tumor models (PDX). Lastly, endometrial cancer patients are being enrolled in the expanded cohort of ARQ 092-101, a phase 1 study, at 2 schedules: intermittent (200mg once a day, 1 week on, 1 week off) or weekly (300mg twice daily, 1 day on, 6 days off). Results: In AN3CA cell lines, ARQ 092, and more potently ARQ 751, inhibited AKT signaling including inhibition of phosphorylation of downstream targets in a dose dependent manner. Both inhibitors exhibited strong anti-proliferative activity. However, while ARQ 092 inhibited 6 out of 9 cell lines with GI50 below 1 μM, ARQ 751 inhibited all 5 cell lines with GI50 below the 150 nM range. Of the 22 tested PDX models, 12 responded (>50% tumor control compared to placebo). Both ARQ 092 and ARQ 751 exhibited over 90% AKT inhibition after 6 hrs exposure to a 40 mg/kg dose in an AN3CA mouse xenograft. In this model, at the maximum tolerated dose of 120mg/Kg, ARQ 092 and ARQ 751 resulted in 79% and 92% tumor growth reduction, respectively. Additionally, for ARQ 092, plasma Cmax in mouse models at the 100 mg/kg dose was compared to the Phase I human results. Plasma Cmax in mice was 2.1 μM whereas in patients enrolled at the intermittent and weekly schedules Cmax were 1.3 and 1.5 μM, respectively. Of the 19 enrolled patients with endometrial cancer, only one was treated at full dose, had a PIK3CA mutation (H1047R), and obtained a durable partial response after 2 months on therapy. Conclusions: Both ARQ 092 and ARQ 751 demonstrated potent inhibition of p-AKT and downstream pathway signaling. In addition, both compounds exhibited potent antitumor activity in human endometrial cancer cells in vitro and in vivo. Such preclinical observations were recapitulated in the clinic by the rapid objective response observed in the first endometrial patient with PIK3CA mutation enrolled at full dose in the expanded cohort of the ongoing ARQ 092-101 Phase I clinical trial. Overall, these data provide a strong mechanistic rationale for further evaluation of ARQ 092, and possibly ARQ 751, in patients with PI3K-driven endometrial malignancies. Citation Format: Sudharshan Eathiraj, Brian Schwartz, Yi Yu, Michael J. Wick, Terence Hall, Feng Chai, Jasgit Sachdev, Giovanni Abbadessa. Targeting PI3K pathway dependent endometrial tumors with allosteric AKT inhibitors, ARQ 092 and ARQ 751. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B183.

In NSCLC, KRAS mutations are associated with poor prognosis and resistance to therapy. MET may be implicated in malignant progression of KRAS-mutant tumors. In a prespecified subset analysis of KRAS mutant cancers in a randomized, placebo-controlled, phase 2 study of erlotinib + the oral MET inhibitor tivantinib (ET) vs erlotinib+placebo, ET was associated with substantial clinical benefit (PFS HR 0.18; 95% CI, 0.1-0.7; P=.01). This study was conducted to evaluate further ET combination therapy in this population. Ninety-six pts with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily with food) + erlotinib (150 mg daily without food) or single-agent chemotherapy (investigator's choice: pemetrexed, docetaxel, or gemcitabine) at standard approved doses and schedules. Eligible pts had ECOG PS ≤2, adequate organ function, and received ≥ 1 prior chemotherapy regimen but no prior EGFR or MET inhibitor. Treatment continued until disease progression or intolerable toxicity. At progression, pts assigned to single-agent chemotherapy were eligible to cross over to ET. The primary endpoint of PFS was measured by central review. Secondary endpoints included overall survival, objective response rate, and safety. Fifty-one pts were randomized to ET and 45 to the chemotherapy (C) arm. After progression, 20 pts in the C arm crossed over to ET. Mean age was 63.8 yrs, 66% were female, and 56% received ≥2 prior lines of therapy. PFS and overall survival (OS) were not statistically different. Median PFS was 1.7 months (mos) for ET and 4.3 mos for C with (HR 1.19; 95% CI, 0.71-1.97; P=.50). Median OS was 6.9 mos for ET and 8.5 mos for C (HR 1.07; 95% CI, 0.66-1.74; P=.79). There were 4 partial responses in the C arm, and none in the ET arm. Adverse events rates (both related and ≥3 grade) were generally higher in the C arm, with more cytopenia, nausea, fatigue, and alopecia observed, while there was more rash and dermatitis observed with ET arm. Rates of treatment-related SAEs were 5% in ET arm and 11% in C arm. Seven fatal SAEs were reported: 2 in ET arm and 5 in C arm; none were related to ET and 1 was related to gemcitabine. The combination of tivantinib and erlotinib in advanced KRAS mutant NSCLC does not appear to be superior to conventional chemotherapy. The safety profile favored ET and in general was consistent with the known tivantinib profile.

4545 Background: Inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptor are standard therapy for RCC, and the MET signaling pathway is implicated in tumor angiogenesis. Tivantinib is an oral, selective MET inhibitor. In several tumor models, tivantinib plus sorafenib exhibited synergistic antitumor activity vs single-agent activity. This phase I dose-escalation study assessed the safety of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Previously, dose escalation established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with RCC or other tumors. Patients were treated until disease progression or unacceptable toxicity. Results: 20 pts (mean age, 60 yr) including 16 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts received treatment at the RP2D (n = 19) or tivantinib 360 mg BID plus sorafenib 200 mg BID (n = 1). 4 pts are still on study. 16 pts (13 with clear cell RCC) received ≥ 1 previous systemic therapy (median, 2; range, 0-4) including VEGF (14 pts) and/or mTOR (5 pts) inhibitors. The most common (≥ 25%) adverse events were rash (65%), diarrhea (45%), alopecia (40%), hypophosphatemia (35%), and fatigue, stomatitis, palmar-plantar erythrodysesthesia syndrome, and pruritus (25% each). Best response was partial response (PR) in 3 pts (all clear cell RCC pts) and stable disease (SD) in 15 pts (11 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts). 7 pts with SD had ≥ 10% tumor size reduction. The overall response rate (ORR) and disease control rate (DCR; PR + SD) were 15% and 90%, respectively. Median progression-free survival (mPFS) was 12.7 mo (95% CI, 7.1-14.5 mo). In 14 pts previously treated with a VEGF inhibitor, best response was 2 PR and 10 SD, the ORR and DCR were 14% and 86%, respectively, and mPFS was 12.7 mo (95% CI, 5.3-NR mo). Conclusions: Oral combination therapy with tivantinib plus sorafenib was well tolerated and exhibited preliminary anticancer activity in pts with RCC, including pts pretreated with VEGF inhibitors.

BACKGROUND:Amplification of the mesenchymal-epithelial transition factor (MET) gene can promote tumor resistance to epidermal growth factor receptor (EGFR) inhibition. Dual EGFR-MET inhibition may overcome this resistance. Tivantinib (ARQ 197) is a selective, oral, non-ATP-competitive, small-molecule inhibitor of the MET receptor tyrosine kinase. This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of tivantinib combined with the EGFR inhibitor erlotinib. METHODS:Patients with advanced solid malignancies were administered oral tivantinib at escalating doses of 120, 240, 360, and 480 mg twice daily (BID) plus 150 mg erlotinib once daily (QD). Single or multiple intrapatient dose escalation was planned in the absence of dose-limiting toxicity in the first cycle of therapy (21 days). RESULTS:Thirty-two patients received combination treatment. Tivantinib serum concentrations were not dose-proportional. The most common (≥ 20%) adverse events (AEs) regardless of causality included rash (n = 17), fatigue (n = 12), nausea (n = 10), abdominal pain (n = 10), diarrhea (n = 9), bradycardia (n = 9), and anemia (n = 7). AEs considered related to study treatment occurred in 28 patients (87.5%), and 5 patients (15.6%) had treatment-related serious AEs, including neutropenia, leukopenia, syncope, sinus bradycardia, and sick sinus syndrome. Fifteen of 32 patients (46.8%) had a partial response (n = 1) or stable disease (n = 14) as assessed by Response Evaluation Criteria in Solid Tumors. Six of 8 patients with nonsmall cell lung cancer achieved stable disease. The recommended phase 2 dose is tivantinib 360 mg BID plus erlotinib 150 mg QD. CONCLUSIONS:Tivantinib plus erlotinib was well tolerated with encouraging clinical activity, especially in patients with nonsmall cell lung cancer.