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In recently performed phase I/II clinical studies, we have demonstrated successful delivery of vectorized transgene-encoding mRNA payloads to solids tumors with substantial clinical benefit. In patients, persistent and prolonged transgene expression correlated with positive clinical outcome, and thus temporal expansion of the transgene expression profile is expected to improve the therapeutic benefit even further. Recently, circular RNA (circRNA) has been discovered as a novel class of endogenously expressed RNA. CircRNAs, in contrast to mRNAs, are resistant to exo-nucleolytic decay which results in high intra-cellular stability and persistent expression within cells. Therefore, circRNA-based systems serve as an interesting new technology towards prolonged effects of treatment. Here, we show that our proprietary vector system, circAde, allows high expression of circRNAs through spliceosome-dependent biogenesis. By comparing the protein output from circAde and mRNA-based vectors, we show that the circAde-system out-performs conventional mRNA-based design, both in terms of transgene yield and temporal sustainability of expression. Moreover, using a panel of proof-of-concept-reporters, we show that certain design-features greatly influence the circRNA production and subsequent protein expression from the vector. Without the 5’cap, circRNAs are dependent on IRESs (internal ribosome entry sequences) for effective translation. By conducting two orthogonal IRES screens on 1000+ putative IRES elements, we have identified the most effective IRES sequence in melanoma and lung-cancer cells supporting effective circRNA production and high-yield protein expression, thereby improving our circAde vector system even further. Our results open a new platform towards development of novel, more effective strategies for the treatment of cancer and other settings in which durable transgene expression is desirable. Citation Format: Eoghan T. O'leary, Sara Vikberg, Emilie Foord, Erik D. Wiklund, Lone Ottesen, Victor Levitsky, Thomas B. Hansen. circAde: a circRNA-based system for prolonged and more effective treatment of cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5335.

Purpose To support future dosing recommendations, the effect of food on the pharmacokinetics of adavosertib, a first-in-class, small-molecule reversible inhibitor of WEE1 kinase, was assessed in patients with advanced solid tumors. Methods In this Phase I, open-label, randomized, two-period, two-sequence crossover study, the pharmacokinetics of a single 300 mg adavosertib dose were investigated in fed versus fasted states. Results Compared with the fasted state, a high-fat, high-calorie meal (fed state) decreased adavosertib maximum plasma concentration (Cmax) by 16% and systemic exposure (area under the plasma concentration–time curve [AUC]) by 6%; AUC0–t decreased by 7% and time to maximum plasma concentration was delayed by 1.97 h (P = 0.0009). The 90% confidence interval of the geometric least-squares mean treatment ratio for AUC and AUC0–t was contained within the no-effect limits (0.8–1.25), while that of Cmax crossed the lower bound of the no-effect limits. Adverse events (AEs) related to adavosertib treatment were reported by 20 (64.5%) of the 31 patients treated in this study. Grade ≥ 3 AEs were reported by four (12.9%) patients (one in the fed state, three in the fasted state); two of these AEs were considered treatment-related by the investigator. Three serious AEs were reported in three (9.7%) patients; these were not considered treatment-related. No patients discontinued because of treatment-related AEs, and no new safety signals were reported. Conclusion A high-fat meal did not have a clinically relevant effect on the systemic exposure of adavosertib, suggesting that adavosertib can be administered without regard to meals.

The incidence of drug hypersensitivity or anaphylactic reactions in clinical trial databases is thought to be underestimated due to variable clinical presentations and lack of clear definitions. Our objective was to develop a more comprehensive, systematic methodology for retrospectively identifying potential hypersensitivity or anaphylactic reactions reported in patients treated with investigational drugs in clinical trials and to accurately assess and characterise the risk. A three-step approach was developed to identify hypersensitivity or anaphylactic reactions: clinical trial database search, medical review, and adjudication to confirm or rule out cases. The database search strategy consisted of the narrow search for Standardized MedDRA Query (SMQ) Hypersensitivity, a modified MedDRA query based on SMQ Anaphylactic reaction, and pyrexia-related MedDRA Preferred Terms. The cases identified from the search were further medically reviewed taking into consideration the temporal relationship, seriousness, severity, course, and management of the events, action taken, and outcomes of adverse events. Those cases deemed to have potentially drug-related hypersensitivity were then adjudicated to be confirmed or ruled out. The method was applied to a clinical trial database containing safety data for 421 patients treated with an investigational drug. Application of the methodology led to 19 hypersensitivity cases being identified. Of these, 12 were classified as immediate reactions and 7 as non-immediate reactions. This three-step method provided a thorough and robust way to identify hypersensitivity reactions, including anaphylaxis, in a clinical trial database. This method could be applied to investigational drugs to improve early detection and monitoring of potential safety concerns, subsequent patient safety management strategies, and potentially programme-wide drug development decisions. Algorithmic tools and narrow and/or broad SMQs should be considered when evaluating safety concerns. The authors also recommend a revision of the MedDRA SMQ of Anaphylactic reaction.

Importance Papillary renal cell carcinoma (PRCC) is the most common type of non-clear cell RCC. Because some cases of PRCC are MET-driven, MET inhibition could be a targeted treatment approach. In previous studies, savolitinib (AZD6094, HMPL-504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in this patient group. Objective To determine whether savolitinib is a better treatment option for this patient population, vs standard of care, sunitinib. Design, setting, and participants The SAVOIR phase 3, open-label, randomized clinical trial was a multicenter study carried out in 32 centers in 7 countries between July 2017 and the data cutoff in August 2019. Overall, 360 to 450 patients were to be screened to randomize approximately 180 patients. Patients were adults with MET-driven (centrally confirmed), metastatic PRCC, with 1 or more measurable lesions. Exclusion criteria included prior receipt of sunitinib or MET inhibitor treatment. Overall, 254 patients were screened. Interventions Patients received 600 mg of savolitinib orally once daily (qd), or 50 mg of sunitinib orally qd for 4 weeks, followed by 2 weeks without treatment. Main outcomes and measures The primary end point was progression-free survival (PFS, assessed by investigator and confirmed by blinded independent central review). Secondary end points included overall survival (OS), objective response rate (ORR), duration of response, and safety/tolerability. Results At data cutoff, 60 patients were randomized (savolitinib n = 33; sunitinib n = 27); most patients had chromosome 7 gain (savolitinib, 30 [91%]; sunitinib, 26 [96%]) and no prior therapy (savolitinib, 28 [85%]; sunitinib, 25 [93%]). For savolitinib and sunitinib, 4 (12%) and 10 (37%) patients were women, and the median (range) age was 60 (23-78) and 65 (31-77) years, respectively. Following availability of external data on PFS with sunitinib in patients with MET-driven disease, study enrollment was closed. Progression-free survival, OS, and ORR were numerically greater with savolitinib vs sunitinib. Median PFS was not statistically different between the 2 groups: 7.0 months (95% CI, 2.8-not calculated) for savolitinib and 5.6 months (95% CI, 4.1-6.9) for sunitinib (hazard ratio [HR], 0.71; 95% CI, 0.37-1.36; P = .31). For savolitinib and sunitinib respectively, grade 3 or higher adverse events (AEs) were reported in 14 (42%) and 22 (81%) of patients and AE-related dose modifications in 10 (30%) and 20 (74%). After discontinuation, 12 (36%) and 5 (19%) of patients on savolitinib and sunitinib respectively, received subsequent anticancer therapy. Conclusions and relevance Although patient numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy vs sunitinib, with fewer grade 3 or higher AEs and dose modifications. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted. Trial registration ClinicalTrials.gov Identifier: NCT03091192.

Summary Background Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study. Methods In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov , NCT02143466 . Findings Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39–56) patients in part B and 23 (64%; 46–79) in part D. Interpretation The combination of osimertinib and savolitinib has acceptable risk–benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs. Funding AstraZeneca.

5505 Background: Wee1 phosphorylates and inhibits cyclin-dependent kinases 1 and 2 and is involved in regulation of the intra-S and G2/M cell cycle checkpoint arrest for premitotic DNA repair. The Wee1 inhibitor, adavosertib, has demonstrated activity alone and in combination with olaparib in PARP inhibitor (PARPi)-resistant preclinical models. We sought to evaluate efficacy of adavosertib (A) with or without olaparib (O) in a phase II noncomparative study of recurrent PARPi-resistant ovarian cancer. Methods: Women with recurrent ovarian, fallopian tube or primary peritoneal cancer with documented progressive disease on a PARPi were eligible. All patients (pts) had measurable disease and adequate end organ function. On the A arm, pts received A 300mg PO daily on days 1-5 and 8-12 of a 21-day cycle. On the A/O arm, pts received A 150mg PO BID on days 1-3 and 8-10 and O 200mg PO BID on days 1-21 of a 21-day cycle. Primary endpoint was objective response per RECIST 1.1 and was assessed every 2 cycles. Clinical benefit rate (CBR) was defined as proportion of pts with objective response or stable disease > 16 weeks. Progression free survival (PFS) was assessed using the Kaplan Meier method and calculated from date of treatment initiation to earliest date of progression, death, or last visit. Results: 116 pts were screened with 80 pts enrolled and randomized (A: n=39, A/O: n=41). Median age was 60 years (range 36-76) and the majority of pts had platinum resistant disease (64%) and high grade serous histology (98%). Pts received a median of 4 prior therapies (range 1-11) and 48% had germline or somatic BRCA mutations. There were 35 pts evaluable for response in each arm. Table demonstrates efficacy data. On the A arm, Grade 3/4 toxicities occurred in 51% of pts, most commonly neutropenia (13%), thrombocytopenia (10%), and diarrhea (8%). 28 (72%) pts required at least one dose interruption and 20 (51%) required dose reduction. On the A/O arm, Grade 3/4 toxicities occurred in 76% of pts, most commonly thrombocytopenia (20%), neutropenia (15%), diarrhea (12%), fatigue (12%), and anemia (10%). 36 (88%) of pts required at least one dose interruption, 29 (71%) required dose reduction, and 4 (10%) did not restart due to toxicity. Conclusions: A given alone and in combination with O demonstrated efficacy in pts with PARPi-resistant ovarian cancer. Although grade 3 and 4 toxicities were observed on both arms, these were generally manageable with supportive care, dose interruptions and dose reductions as needed. Additional translational analyses are ongoing to clarify which pts received clinical benefit. Clinical trial information: NCT03579316. [Table: see text]

Background: Adavosertib (AZD1775; AD), a highly selective inhibitor of WEE1 kinase, regulates S and G2/M cell-cycle checkpoints. This study (NCT03333824; Part B) assessed the effect of doses of AD on the QT interval in patients (pts) with advanced solid tumors. Methods: After a 7-14-day washout from prior short-term AD exposure, pts received AD 225 mg bid (five doses; combi therapy MTD/RP2D) on days 13 at 12-h intervals, under fasted conditions: 2 h pre-dose to 2 h post-dose. Pts underwent digital electrocardiogram (dECG) on day −1 (time-matched baseline), and dECG and pharmacokinetic (PK) sampling before AD administration and up to 12 h post-dose on days 1 and 3. Antiemetic(s) were given (1 mg granisetron ± 4 mg dexamethasone) on day −1 (baseline), and 30 min prior to AD (days 1-3). Pts had their final PK/dECG assessments on day 4, 24 h post-dose. Corrected QT interval by Fridericia (QTcF) outliers following dosing were defined as values >450 ms or increases from baseline >30 ms. Results: Of 33 enrolled pts (median age, 60.0 years, range 41-83; F:M, 18:15), 21 (64%) received AD (Part B of the study). There was no significant relationship between ΔQTcF (vs baseline) and AD concentration. The slope of the linear relationship between ΔQTcF and AD concentration was not statistically significant (P=0.27), with the 95% CI of the slope (−0.003978, 0.01351) incl 0. Model predictions of ΔQTcF at the geometric mean of AD Cmax were, on day 1 (712.8 nM) and day 3 (1462 nM), −2.4 ms (90% CI −5.9, 1.1) and −0.8 ms (90% CI −5.1, 3.6), respectively. The largest mean difference in ΔQTcF was 7.3 ms, 3 h post-dose, on day 3. On day 1, two pts had an increase in QTcF >30 ms, and one of these (who took mirtazapine) had increases in QTcF >30 ms on day 3. No QTcF >450 ms or increase in QTcF >60 ms was observed. On day 1 and day 3, there were no apparent effects of AD on mean QRS, mean PR interval or heart rate (mean change was within ± 10 bpm). Geometric mean AUC0-12 and Cmax of AD on day 1 were 4940 nM·h and 712.8 nM, respectively, vs 10810 nM·h and 1462 nM on day 3. Cmin on day 3 was 410.4 nM. Geometric least-squares mean ratios (90% CI) of AD on day 3 vs day 1 for AUC0-12 and Cmax were 231% (200, 266) and 207% (170, 251), respectively; accumulation of AD over the dosing period was ~2.3 for AUC0-12 and ~2.1 for Cmax. Median tmax of AD was 3.0 h (range 1.0-6.0) on day 1 and 2.5 h (range 1.0-3.1) on day 3. Intra-subject variability was low (5% for AUC0-12 and 9% for Cmax) on day 3. AEs were reported by 16 (76%) patients, most commonly diarrhea, nausea (each 7 [33%] pts) and vomiting (5 [24%] pts). Eleven (52%) pts had treatment-related AEs (2 [10%] pts with grade ≥3). Conclusions: No significant relationship was found between ΔQTcF and AD concentration. Modeling showed that AD does not have a clinically important effect on QT prolongation. Accumulation over the dosing period was approximately twofold, concordant with results from prior studies at this AD dose. No new safety concerns were reported. Citation Format: Mats Någård, Mei-Lin Ah-See, Karen So, James Strauss, Trisha Wise-Draper, Howard Safran, Ding Wang, Laura Nadeau, William Edenfield, Lionel D. Lewis, Dinko Rekić, Corina Dota, Lone Ottesen, Yan Li, Ganesh Mugundu. Adavosertib (AZD1775) does not prolong QT interval in patients with advanced solid tumors: A Phase I open-label study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 591.

5002 Background: PRCC is the most common type of non-clear cell RCC, accounting for 10–15% of renal malignancies. As a subset of PRCC cases are MET-driven, MET inhibition may be an appropriate targeted treatment approach. In a single-arm Phase II study, savolitinib (AZD6094, HMPL‐504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in pts with MET-driven PRCC (Choueiri et al. JCO 2017). The Phase III SAVOIR study (NCT03091192) further assessed savolitinib vs standard of care sunitinib in pts with MET-driven PRCC. Methods: In this open-label (sponsor blinded), randomized study, pts with centrally confirmed MET-driven ( MET and/or HGF amplification, chromosome 7 gain and/or MET kinase domain mutations), metastatic PRCC were randomized to savolitinib 600 mg once daily (QD), or sunitinib 50 mg QD 4 weeks on / 2 weeks off. Primary objective was progression-free survival (PFS; RECIST 1.1 by blinded independent central review). Secondary objectives included overall survival (OS), objective response rate (ORR), and safety and tolerability. Results: After external data on predicted PFS with sunitinib in pts with MET-driven disease became available, study enrollment was closed. At data cutoff (Aug 2019), only 60 of the planned 180 pts were randomized (savolitinib n = 33; sunitinib n = 27). Most had chromosome 7 gain (savolitinib 91%; sunitinib 96%) and no prior therapy (savolitinib 85%; sunitinib 93%). PFS, OS, and ORR were numerically improved with savolitinib vs sunitinib (Table). CTCAE grade ≥3 adverse events (AEs) were reported in 42% and 81% of pts; dose modifications were related to AEs in 30% and 74% of pts with savolitinib and sunitinib respectively. After discontinuation, 36% of all savolitinib and 19% of all sunitinib pts received subsequent anticancer therapy. Conclusions: Although pt numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy and an improved safety profile vs sunitinib, with fewer grade ≥3 AEs and fewer dose modifications required. Sunitinib performance was poorer than expected based on external retrospective data. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted. Clinical trial information: NCT03091192 . [Table: see text]

e19321 Background: PRCC accounts for 10–15% of RCCs, but there are limited biomarker-based data to inform targeted treatment. Treatments for patients (pts) with advanced/metastatic PRCC include those approved for clear cell RCC such as sunitinib or everolimus, however their activity in PRCC can be limited. A subset of PRCCs are MET-driven, and it has been suggested that this may be a negative prognostic factor, although the role of MET activation in advanced/metastatic disease is unclear. We explored the prevalance of MET status in pts with advanced/metastatic PRCC treated with targeted therapies and impact on clinical outcomes. Methods: This large, international, retrospective, observational study included pts with previously treated, locally advanced/metastatic PRCC. MET status was determined retrospectively by NGS of archival tissue. MET-driven disease was defined as MET and/or HGF amplification, chromosome 7 gain (requiring > 30% tumor content) and/or MET kinase domain mutations. Study objectives included progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS) by MET status. Results: 305/308 pts (International Metastatic RCC Database Consortium, n = 72; The Asan Genito-Urinary Cancer Center, n = 40; Groupe Français d’Etude des Tumeurs Uro-Génitales, n = 196) received first-line (1L) treatment; sunitinib was most common (68%). 214 (69%) pts received 2L therapy; everolimus was most common (20%). Of 179 pts with valid NGS results, 38%, 49% and 13% had MET-driven, MET-independent (ind) tumors and chromosome 7 ploidy unevaluable, respectively. Baseline demographics were mostly balanced among groups. In sunitinib-treated pts, PFS and TTF were numerically longer in pts with MET-driven tumors vs pts with MET-ind tumors, but OS was similar (Table). In everolimus-treated pts, PFS and TTF were similar for both MET groups; however the sample size was small. Conclusions: MET alterations are frequent in advanced/metastatic PRCC and have potential to impact PFS and TTF, although our results show limited effect on OS. These data show that MET-driven tumours may not predict for poorer outcome vs MET-ind tumours and there is a need for suitable therapies for MET-driven PRCC. [Table: see text]

Foretinib is a multikinase inhibitor that inhibits multiple receptor tyrosine kinases, including MET and VEGFR, with the potential for treatment of solid tumors. Hepatocellular carcinoma (HCC) pathogenesis is associated with overexpression of MET, and physiologic changes in the livers of HCC patients may decrease CYP3A isozyme-mediated metabolism of foretinib. A population pharmacokinetic model of foretinib was developed to explore the effect of tumor type, formulation, and other covariates. Data from 1 HCC study in Asia and 3 non-HCC studies in the United States with varying foretinib regimens and formulations were used for analysis. A 2-compartment model with a linear first-order absorption and elimination and lag time in absorption adequately described foretinib pharmacokinetics in 132 advanced non-HCC and HCC patients and identified an effect of formulations on bioavailability. The bisphosphate salt capsules and freebase tablets had a relative bioavailability 37% and 20% higher, respectively, than the solution formulation. HCC patients had ≈19.6% lower mean clearance (70.14 L/h), ≈16% lower mean volume of distribution (1725.6 L), and higher dose-normalized exposure compared with non-HCC patients. This could be a result of differences in metabolism in HCC patients, body weight, or activity of CYP3A isozymes between Asian and Western cancer patients.

This study was designed to evaluate the safety, pharmacokinetics, and clinical activity of pazopanib combined with paclitaxel to determine the recommended phase II dose in the first-line setting in patients with advanced solid tumors. Patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated regimen (MTR) of once daily pazopanib plus paclitaxel administered every 3 weeks at four dose levels (DL1-4). Safety, pharmacokinetics, pharmacogenetics, and disease assessments were performed. Twenty-eight patients received treatment. One patient at DL1 had dose-limiting toxicity (DLT) of elevated hepatic enzymes. After pazopanib discontinuation, liver enzyme concentrations remained high until a concurrent medication, simvastatin, was discontinued. This patient had the defective CYP2C8*3*3 genotype. At DL2, 1 patient had DLT of elevated hepatic enzymes with rash and 1 patient had DLT of rash. The MTR was paclitaxel 150 mg/m2 plus pazopanib 800 mg. The most common toxicities were alopecia, fatigue, hypertension, nausea, diarrhea, dysgeusia, neutropenia, myalgia, hair color changes, and peripheral neuropathy. Coadministration of pazopanib and paclitaxel resulted in a 38% increase in systemic exposure to paclitaxel, relative to administration of paclitaxel alone, at the MTR. Of the 28 patients treated with the combination, 10 achieved a partial response and 10 achieved stable disease of ≥12 weeks. Pazopanib 800 mg daily plus paclitaxel 150 mg/m2 every 3 weeks was the recommended phase II dose, with a manageable safety profile, and with clinical activity in both melanoma and non–small cell lung cancer that suggest further evaluation of this combination is warranted. Mol Cancer Ther; 14(2); 461–9. ©2014 AACR.

Purpose: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma patients. Experimental Design: In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30–60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival. Results: The MTD of foretinib was established as 30 mg every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified mRECIST, the objective response rate was 22.9%, the disease stabilization rate 82.9%, and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS. Conclusions: Foretinib demonstrated promising antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib. Clin Cancer Res; 23(10); 2405–13. ©2016 AACR.

After EGFR T790M, the second most common driver of acquired resistance to EGFR-TKIs in pts with EGFR-mutant NSCLC is MET-amplification. MET-amplification is seen in 5-30% of pts with resistance across various case series’. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent and highly selective MET-TKI. Preliminary findings from the expansion phase of the open-label, multi-center, Phase I TATTON study (NCT02143466) demonstrated acceptable safety and preliminary anti-tumor activity with savolitinib plus osimertinib in pts with EGFR-mutant NSCLC. Here we report updated interim data from this expansion phase in pts with EGFR-mutant, T790M negative, MET-amplified NSCLC who had progressed on prior first/second-generation EGFR-TKI. Pts included in this analysis were treated with osimertinib 80 mg QD plus savolitinib 600 mg QD and met the following inclusion criteria: ≥18 years; confirmed EGFR-mutant T790M negative, locally advanced or metastatic NSCLC; progressed on ≥1 prior first/second-generation EGFR-TKI (no prior third-generation EGFR-TKIs allowed); WHO performance status 0-1. Pts were initially enrolled based on local testing for MET-positive status (NGS, FISH [MET gene copy ≥5 or MET/CEP7 ratio ≥2], or immunohistochemistry [+3 in ≥50% of tumor cells]). Primary objective was safety and tolerability; secondary objectives included assessment of anti-tumor activity (RECIST v1.1). At data cut-off (Feb 2018), 46 pts had received study treatment. Median age was 59 years (range 41-92), 31 (67%) pts were female, and 37 (80%) were Asian. The most common (≥20%) all-causality adverse events (AEs) were nausea (n=17, 37%), diarrhea (n=14, 30%), fatigue (n=13, 28%), decreased appetite (n=13, 28%), pyrexia (n=12, 26%), and vomiting (n=10, 22%). Serious AEs were reported in 17 (37%) pts. Treatment-related AEs were reported in 42 (91%) pts and were classified as CTCAE grade ≥3 in 20 (43%) pts. Sixteen (35%) pts had an AE leading to discontinuation of study treatment. Two (4%) pts died due to an AE (n=1 acute kidney injury considered possibly related to savolitinib; n=1 pneumonia considered unrelated to study treatment). Objective response rate was 52% (n=24 all partial responses, confirmed after 4 weeks). Median duration of response was 7.1 months. Savolitinib plus osimertinib had an acceptable safety profile and demonstrated preliminary anti-tumor activity. These findings warrant further investigation of this combination in pts with EGFR-mutant, T790M negative, MET-amplified NSCLC who progressed on prior first/second-generation EGFR-TKI treatment. Citation Format: Helena Yu, Myung-Ju Ahn, Sang-We Kim, Byoung Chul Cho, Lecia Sequist, Sergey Orlov, Lone H. Ottesen, Remy B. Verheijen, Anders Mellemgaard, Jonathan Wessen, Ji-Youn Han. TATTON Phase Ib expansion cohort: Osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-amplified NSCLC after progression on prior first/second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) [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 CT032.

Background: Preclinical data suggest that adavosertib (AZD1775), a highly selective Wee1 inhibitor, enhances the antitumor effect of PARP inhibitors such as olaparib. The dose-escalation part of this Phase Ib study (NCT02511795) investigated the safety and tolerability of adavosertib plus olaparib in patients (pts) with refractory solid tumors to determine a maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Methods: Pts received adavosertib (QD or BID) for 3 consecutive days with 4 days off treatment (3/4), or 5 consecutive days with 2 days off (5/2), plus olaparib (BID) for 14 or 21 days of a 21-day cycle (Table). The MTD was the highest dose at which 7 days, gr 3 thrombocytopenia with gr ≥2 bleeding, non-hematologic gr ≥3 AEs (excluding nausea, vomiting or diarrhea that responds to supportive care), liver function gr ≥3 AEs lasting >48 hours or changes consistent with Hy’s Law, or any other toxicity that disrupted dosing for >7 days. Results: 119 pts were treated (84 female; median age 59; most common primary tumor sites: ovary [21%], breast [16%], lung [12.6%]) (Table). The most common gr ≥3 AEs were anemia (n=28, 23.5%), neutropenia (n=26, 21.8%), and thrombocytopenia (n=20, 16.8%) (all grouped terms). The most common DLTs were thrombocytopenia (n=4) and neutropenia (n=4); two pts experienced both. There were 4 SAEs with an outcome of death, 1 was treatment related. ORR for the total population, cohort 4.2 and cohort 7.4 was 11.1%, 30.8% and 0%, respectively. DCR was 55.7%, 76.9% and 53.8%, respectively. PK and biomarker data will be presented. Conclusions: Treatment with adavosertib plus olaparib showed antitumor activity, mostly at the MTD/RP2D for the BID schedule, which was determined to be adavosertib 175 mg (3/4) for 2/3 weeks plus olaparib 200 mg BID. The RP2D for QD schedule was adavosertib 200 mg (3/4) for 2/3 weeks plus olaparib 200 mg BID. Summary of study cohortsCohortAdavosertib doseOlaparib doseAdavosertib schedule, daysOlaparib schedule, daysPatients, n (evaluable,* n)Patients with a DLT, n (%)Grade ≥3 AEs,† n (%)ORR, n (%)DCR, n (%)1125 mg BID (3/4)100 mg BID1–3/8–101–143 (2)01 (33.3)03 (100)2150 mg BID (3/4)100 mg BID1–3/8–101–144 (4)02 (50)1 (25)2 (50)3.1175 mg BID (3/4)100 mg BID1–3/8–101–144 (2)03 (75)03 (75)3.2150 mg BID (3/4)200 mg BID1–3/8–101–147 (5)04 (57.1)1 (14.3)5 (71.4)4.1175 mg BID (3/4)200 mg BID1–3/8–101–147 (7)04 (57.1)1 (14.3)4 (57.1)4.2175 mg BID (3/4)200 mg BID1–3/8–101–2114 (11)1 (9.1)9 (64.3)4 (30.8)10 (76.9)4.3175 mg BID (3/4)200 mg BID1–3/8–10/15–171–2114 (11)2 (18.2)13 (92.9)1 (7.7)7 (50)5175 mg BID (3/4)300 mg BID1–3/8–101–145 (5)1 (20.0)3 (60.0)2 (50)4 (100)6.1250 mg QD (5/2)200 mg BID1–5/8–121–217 (4)2 (50.0)6 (85.7)1 (20)1 (16.7)6.2200 mg QD (5/2)200 mg BID1–5/8–121–217 (5)2 (40.0)4 (57.1)01 (14.3)7.1250 mg QD (3/4)200 mg BID1–3/8–101–2116 (14)2 (14.3)12 (75)010 (62.5)7.2250 mg QD (3/4)200 mg BID1–3/8–10/15–171–214 (4)1 (25.0)3 (75)1 (25)3 (75)7.3300 mg QD (3/4)200 mg BID1–3/8–101–213 (3)1 (33.3)2 (66.7)007.4200 mg QD (3/4)200 mg BID1–3/8–101–2113 (12)1 (8.3)3 (23.1)07 (53.8)8.1200 mg QD (3/4)300 mg BID1–3/8–101–2111 (9)1 (11.1)4 (36.4)04 (40)*Evaluable patients received >75% of the planned dose of adavosertib and olaparib; †Common Terminology Criteria for Adverse Events. DCR, disease control rate; ORR, objective response rate Citation Format: Erika Hamilton, Gerald S. Falchook, Judy S. Wang, Siqing Fu, Amit Oza, So Karen, Esteban Rodrigo Imedio, Sanjeev Kumar, Lone Ottesen, Ganesh M. Mugundu, Juliann Chmielecki, Suzanne Jones, David R. Spigel, Bob T. Li. Phase Ib study of adavosertib in combination with olaparib in patients with refractory solid tumors: Dose escalation [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 CT025.

TPS1112 Background: TNBC comprises ≈15% of invasive breast cancer cases and alterations in BRCA1/ 2 are associated with ≈5% of all BCs. Ola (a poly ADP-ribose polymerase inhibitor [PARPi]) is approved for treating pts with HER2-negative metastatic BC with a germline BRCA mutation (g BRCAm), demonstrating an improvement in progression-free survival (PFS). Alterations in other non- BRCA1/2 homologous recombination repair (HRR)-related genes (non- BRCA HRRm) may also confer sensitivity to Ola therapy in pts with TNBC. Ola, AZD1775 (a WEE1 checkpoint inhibitor) and AZD6738 (an ataxia telangiectasia and Rad3-related protein inhibitor) target DNA damage repair and cell cycle regulation. Preclinical studies in TNBC models show synergistic antitumor effects of Ola+AZD1775 and Ola+AZD6738, vs Ola monotherapy supporting the clinical evaluation of these combinations. Methods: VIOLETTE is a global, multicenter, open-label, phase II study (NCT03330847) randomising 1:1:1 450 pts with advanced TNBC to 3 treatment arms: 1) Ola 200 mg bid daily + AZD1775 150 mg bid D1-3, D8-10 q21, 2) Ola 300 mg bid daily + AZD6738 160 mg qd D1-7 q28, or 3) Ola 300 mg bid daily q28. All pts will be stratified by prior platinum exposure. Each treatment arm of ≈150 pts will be comprised of 3 biomarker strata of ≈50 pts each (A: BRCAm; B: non- BRCA HRRm; C: non-HRRm). Centralized tumor molecular testing will be deployed to detect mutation(s) in 15 HRR genes. Eligible pts will have received 1-2 prior lines of chemotherapy for metastatic disease, including an anthracycline or taxane. Exclusion criteria include prior PARPi therapy. The primary endpoint is PFS (each combination vs Ola alone) assessed by blinded, independent central review (RECIST v1.1). Secondary endpoints are objective response rate, duration of response, change in tumor size, and overall survival for comparisons between combinations and for each combination vs Ola alone; drug exposure; and safety and tolerability. The first prespecified futility analysis in Stratum C has met the recruitment target and will be assessed by unblinded review April 2019. Clinical trial information: NCT03330847.

Introduction: This randomized open-label phase II study evaluated the efficacy, safety, and tolerability of pazopanib in combination with pemetrexed compared with the standard cisplatin/pemetrexed doublet in patients with previously untreated, advanced, nonsquamous non–small-cell lung cancer. Methods: Patients were randomized (2:1 ratio) to receive pemetrexed 500 mg/m 2 intravenously once every 3 weeks plus either oral pazopanib 800 mg daily or cisplatin 75 mg/m 2 intravenously once every 3 weeks up to six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. The primary endpoint was progression-free survival (PFS). Results: The study was terminated after 106 of 150 patients were randomized due to a higher incidence of adverse events leading to withdrawal from the study and severe and fatal adverse events in the pazopanib/pemetrexed arm than in the cisplatin/pemetrexed arm. At the time enrolment was discontinued, there were three fatal adverse events in the pazopanib/pemetrexed arm, including ileus, tumor embolism, and bronchopneumonia/sepsis. Treatment with pazopanib/pemetrexed was discontinued resulting in more PFS data censored for patients in the pazopanib/pemetrexed arm than those in the cisplatin/pemetrexed arm. There was no statistically significant difference between the pazopanib/pemetrexed and cisplatin/pemetrexed arms for PFS (median PFS, 25.0 versus 22.9 weeks, respectively; hazard ratio=0.75; 95% confidence interval, 0.43%–1.28%; p = 0.26) or objective response rate (23% versus 34%, respectively; 95% confidence interval, –30.6% to 7.2%; p = 0.21). Conclusion: The combination of pazopanib/pemetrexed in first-line treatment of non–small-cell lung cancer showed some antitumor activity but had unacceptable levels of toxicity.

Purpose: Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. Experimental Design: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. Results: Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0–24)] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose–proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. Conclusions: In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)–approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day. Clin Cancer Res; 19(13); 3631–9. ©2013 AACR.

TPS1116Background: Invasive BC is diagnosed in > 255,000 pts in the US annually, and TNBC comprises ≈15% of cases. Alterations in BRCA1/2 are associated with ≈5% of all BCs. Ola (a poly ADP-ribose ...

Purpose Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. Patients and Methods Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. Conclusion Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.

Introduction We sought to define the maximum tolerated dose (MTD) and evaluate the safety, pharmacokinetics, and preliminary clinical activity of pazopanib plus pemetrexed in patients with solid tumors. Methods This dose-escalation study used a standard 3 + 3 design to evaluate once daily pazopanib (400–800 mg) plus pemetrexed (400–500 mg/m2 on Day 1 of each 21-day cycle). Eight additional patients were enrolled into an expansion cohort. Results Twenty-five patients were enrolled. Pazopanib 800 mg plus pemetrexed 500 mg/m2 was the MTD. The most common adverse events at all dose levels included fatigue, neutropenia, diarrhea, and thrombocytopenia. The frequencies of non-hematologic adverse events were consistent with those of the individual agents. The rates of all-grade and Grade 4 hematologic toxicities (reversible neutropenia with median duration of 4 days) were higher with the combination regimen than with either monotherapy. Exploratory analyses revealed no association between the plasma levels of 3 biomarkers of vitamin B12 metabolism (cystathionine, homocysteine, and methylmalonic acid) and the risk of Grade 4 neutropenia and Grade 3 febrile neutropenia. Of 20 patients evaluated for efficacy, 2 (10 %) had a partial response. Pazopanib did not affect pemetrexed clearance, but increased pemetrexed maximal concentration by 22 %. In exploratory pharmacogenetic analyses, allelic variants of the VEGFA gene demonstrated weak correlation with development of severe neutropenia. Conclusions Concomitant administration of pazopanib 800 mg once daily plus pemetrexed 500 mg/m2 once every 21 days is feasible, albeit associated with a high frequency of brief, reversible neutropenia. Preliminary activity was observed in non-small-cell lung cancer.

Introduction As angiogenic pathways have become important targets for inhibition of tumor growth, we examined the concept of dual pathway blockade by small-molecule tyrosine kinase inhibitors targeting vascular endothelial and epidermal growth factor receptors. Methods Escalating doses of pazopanib (400–800 mg once daily [QD]) plus erlotinib (100–150 mg QD) doses were evaluated in cohorts of 3–6 adults with advanced solid tumors. Twelve additional patients were enrolled in an expansion cohort to confirm the maximum tolerated dose (MTD). Results The MTD, defined during assessment of 20 patients, was pazopanib 600 mg plus erlotinib 150 mg. Two dose-limiting toxicities, rash and elevated liver enzymes, occurred at pazopanib 800 mg and erlotinib 150 mg. Overall, 30 % and 27 % of patients required dose interruption of pazopanib or erlotinib, respectively; 15 % of patients required a dose reduction of erlotinib to manage toxicities. The most common adverse events in patients treated with any dose regimen of pazopanib plus erlotinib (N = 33) were diarrhea, rash, nausea, and decreased appetite. The adverse-event profile of the combination did not appear to differ from that of each compound administered alone. Coadministration of pazopanib 600 mg QD and erlotinib 150 mg QD did not consistently affect the pharmacokinetics of either compound relative to that observed for either compound administered alone. Of 26 patients evaluated for efficacy, 3 (12 %; all non-small-cell lung cancer) had partial response and 10 (38 %) had stable disease. Conclusions Concomitant administration of pazopanib 600 mg and erlotinib 150 mg is feasible, with a manageable toxicity profile. These results support further clinical development of the pazopanib-erlotinib combination.

Purpose Patients with early-stage, resectable, non–small-cell lung cancer (NSCLC) are at risk for recurrent disease, and 5-year survival rates do not exceed 75%. Angiogenesis inhibitors have shown clinical activity in patients with late-stage NSCLC, raising the possibility that targeting the vascular endothelial growth factor pathway in earlier-stage disease may be beneficial. This proof-of-concept study examined safety and efficacy of short-term, preoperative pazopanib monotherapy in patients with operable stage I/II NSCLC. Patients and Methods Patients scheduled for resection received oral pazopanib 800 mg/d for 2 to 6 weeks preoperatively. Tumor response was measured by high-resolution computed tomography, permitting estimation of change in tumor volume and diameter. Gene-expression profiling was performed on 77 pre- and post-treatment lung samples from 34 patients. Results Of 35 patients enrolled, 33 (94%) had clinical stage I NSCLC and two (6%) had clinical stage II NSCLC. Median treatment duration was 16 days (range, 3 to 29 days). Thirty patients (86%) achieved tumor-volume reduction after pazopanib treatment. Two patients achieved tumor-volume reduction ≥ 50%, and three patients had partial response according to Response Evaluation Criteria in Solid Tumors. Pazopanib was generally well tolerated. The most common adverse events included grade 2 hypertension, diarrhea, and fatigue. One patient developed pulmonary embolism 11 days after surgery. Several pazopanib target genes and other angiogenic factors were dysregulated post-treatment. Conclusion Short-duration pazopanib was generally well tolerated and demonstrated single-agent activity in patients with early-stage NSCLC. Several target genes were dysregulated after pazopanib treatment, validating target-specific response and indicating a persistent pazopanib effect on lung cancer tissue. Further clinical evaluation of pazopanib in NSCLC is planned.

There is an unmet need for pharmacodynamic and predictive biomarkers for antiangiogenic agents. Recent studies have shown that soluble vascular endothelial growth factor receptor 2 (sVEGFR2), VEGF, and several other soluble factors may be modulated by VEGF pathway inhibitors. We conducted a broad profiling of cytokine and angiogenic factors (CAF) to investigate the relationship between baseline CAF levels, CAF changes during treatment, and tumor shrinkage in early-stage non–small cell lung cancer (NSCLC) patients treated with pazopanib, an oral angiogenesis inhibitor targeting VEGFR, platelet-derived growth factor receptor, and c-kit. Plasma samples were collected before treatment and on the last day of therapy from 33 patients with early-stage NSCLC participating in a single-arm phase II trial. Levels of 31 CAFs were measured by suspension bead multiplex assays or ELISA and correlated with change in tumor volume. Pazopanib therapy was associated with significant changes of eight CAFs; sVEGFR2 showed the largest decrease, whereas placental growth factor underwent the largest increase. Increases were also observed in stromal cell–derived factor-1α, IP-10, cutaneous T-cell–attracting chemokine, monokine induced by IFN-γ, tumor necrosis factor–related apoptosis-inducing ligand, and IFN-α. Posttreatment changes in plasma sVEGFR2 and interleukin (IL)-4 significantly correlated with tumor shrinkage. Baseline levels of 11 CAFs significantly correlated with tumor shrinkage, with IL-12 showing the strongest association. Using multivariate classification, a baseline CAF signature consisting of hepatocyte growth factor and IL-12 was associated with tumor response to pazopanib and identified responding patients with 81% accuracy. These data suggest that CAF profiling may be useful for identifying patients likely to benefit from pazopanib, and merit further investigation in clinical trials. Cancer Res; 70(6); 2171–9

4108 Background: Hepatocyte growth factor (HGF)/MET signalling plays a pivotal role in tumor cell proliferation, migration and invasion in HCC and circulating levels of HGF correlate with poor prognosis. This phase I/II trial (MET111645) evaluated foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR, as first-line therapy in Asian advanced-HCC patients. Methods: Asian patients with measurable, unresectable/metastatic HCC, no prior sorafenib or other multi-kinase inhibitors, ECOG PS 0-1, adequate organ function and Child-Pugh grade A were recruited. The phase I was a standard 3+3 dose escalation design with a phase II cohort expansion. The primary endpoint was safety and tolerability at the maximum tolerated dose (MTD) and the secondary endpoints included antitumor activity (objective response rate [ORR], disease stabilization rate [DSR; confirmed CR/PR or SD for at least 12 weeks], and time to progression [TTP] evaluated by central review according to modified RECIST), and overall survival (OS) at the MTD, plus pharmacokinetics (PK). Results: Thirteen patients were enrolled in phase I. Two dose-limiting toxicities (DLT) (renal failure, proteinuria) were observed at 45 mg once daily (QD) but no DLTs were observed at 30 mg QD. Thus, the MTD was determined to be 30 mg QD. A further 32 patients were enrolled at the MTD, for a study total of 39 patients treated at 30 mg QD. The most common AEs, independent of causality,were hypertension (36%), decreased appetite (23%), and pyrexia (21%). The most common SAEs were hepatic encephalopathy (10%) and ascites (8%). Two patients discontinued foretinib due to AEs. No dose reductions were reported. Thirty-eight patients were evaluable for efficacy. The ORR was 24% (95% CI 11-40), DSR 79% (95% CI; 63-90), and the median TTP was 4.2 months (95% CI 2.7-7.5). Mature OS data will be presented. Mean steady-state exposures (AUC/Cmax) were comparable after administration of foretinib at 30 and 45 mg. Conclusions: Foretinib has an acceptable safety, tolerability, and PK profile in an Asian HCC population. It has demonstrated promising antitumor activity that warrants further testing in a randomized setting.

355 Background: Foretinib is an oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations and/or amplifications in MET have been described in patients (pts) with papillary renal cell carcinoma (PRC). The aim of this study was to evaluate the efficacy and safety of 2 dosing regimens of single agent foretinib bisphosphate (foretinib) in pts with PRC and to explore modulation of plasma proteins indicative of target inhibition. Methods: Pts were enrolled in 2 cohorts with different dosing schedules of foretinib: 240 mg/day on days 1–5 of every 14 days (intermittent arm) or 80 mg/day (daily dosing arm). The primary endpoint was overall response rate (ORR) targeting an ORR of at least 25%. Pts were stratified based on status of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, chromosome 7 gain or none of these). Plasma markers reflecting potential target effects of MET and VEGFR inhibition were also analyzed. Results: Overall, 74 pts were enrolled with 37 in each dosing cohort. ORR was 13.5%, progression-free survival 9.3 months, 1 year overall survival (OS) was 70% and median OS was not reached. The median duration of response was 18.5 months. Of 68 pts with adequate tumor assessment data available, 50 experienced some reduction in the sum of the longest tumor diameters (SLD) ranging from −2% to −75%. The most frequent grade 3/4 adverse events related to foretinib were fatigue (6.8%), hypertension (50%), and diarrhea (6.8%). A high rate of non-fatal pulmonary embolism was observed (11%). There were no significant differences in efficacy or safety between the two cohorts. In both arms, plasma sMET and VEGF increased and sVEGFR2 decreased after 2 cycles indicating target inhibition, but these changes were not associated with response or PFS. Outcomes based on molecular characterization are presented separately at this meeting. Conclusions: In the largest clinical trial devoted to papillary RCC, foretinib demonstrated anti-tumor activity in patients with PRC, modulation of several target indicator plasma proteins, and a manageable toxicity profile.

372 Background: Activating mutations and/or amplifications in MET have been described in patients (pts) with papillary renal cell carcinoma (PRC). Foretinib, an oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors, was evaluated in a phase 2 study in pts with PRC. An important objective of this study was to evaluate whether activation of the MET receptor pathway by mutation, amplification, or gain of chromosome 7 was predictive for or correlated with clinical outcomes. Methods: Pts were stratified based on status of MET pathway activation. Blood samples were collected at screening for determination of germline MET mutational status. Archival tumor tissue samples were obtained for the analysis of somatic MET mutation, amplification of the MET locus (7q31), and gain of chromosome 7 using standardized assays. Results: A total of 74 pts were enrolled on the trial (37 each in intermittent and daily dosing arms); overall efficacy and safety data are reported separately at this meeting. Sixty-seven pts were evaluable for both mutation status and response. 5/10 pts (50%) with a germline MET mutation experienced a PR, while 5 pts (50%) had SD as their best response, including 4 pts who demonstrated tumor SLD reductions of > 10%, but did not achieve PR by RECIST 1.0. Responses were also seen in pts without germline MET mutation. However, the presence of a germline MET mutation was highly predictive of a response as only 5/57 pts (9%) without a mutation experienced a PR. Other measures of MET pathway activation did not appear to correlate with activity with only 1/5 pts (20%) with somatic MET mutation having a PR; furthermore, in the absence of a concomitant MET mutation, no responses were seen in patients with MET amplification (n=2) and only 1/18 (5%) pts with a gain of chromosome 7 experienced a PR. Conclusions: The presence of germline MET mutations correlated strongly with activity of the MET inhibitor foretinib in pts with PRC. These data provide early proof of principle that MET may be a valid therapeutic target in a subset of patients with PRC.

e21084 Background: Eltrombopag is a novel, oral thrombopoietin receptor (TPO-R; MPL) agonist that interacts with the TPO-R on bone marrow progenitors to stimulate megakaryocyte production, thus inc...

Abstract 2409 Poster Board II-386 Background: Eltrombopag (Promacta®) is a novel, oral thrombopoietin receptor (TpoR) agonist that interacts with the TpoR on bone marrow progenitors to stimulate megakaryocyte production, thus increasing platelet counts in thrombocytopenic patients. The effects of eltrombopag on the proliferation of solid tumor cell lines and the expression of thrombopoietin receptor (MPL, TpoR) on patient tumors is of interest given that chemotherapy can cause thrombocytopenia. Materials and methods: Proliferation was measured by Cell Titer Glo assay on 3 ovarian (OVCAR3, OVCAR4, SKOV3), 4 lung (A549, NCI-H226, NCI-H510, NCI-H460) and 3 breast (BT-474, MCF7, HCC1937) cancer cell lines from the ATCC treated with 0.01 – 100 ug/mL eltrombopag. Quantitative RT-PCR (qRT-PCR) for MPL expression was performed on the tumor cell lines and on 40 tumor samples, each from subjects with ovarian, lung or breast cancer. Microarray analysis for MPL mRNA expression was examined from 118 subjects with breast cancer and 29 with non-small cell lung cancer (NSCLC). Microarray data was normalized using robust multiarray average (RMA) and relative mRNA expression was determined. To determine expression of TpoR protein, western blot analyses was performed on some of the tumor cell lines. Results: Eltrombopag induced an inhibition of proliferation on all of the ovarian, lung and breast solid tumor cell lines tested. The IC50 ranged from 3.7 to 49.7 ug/mL (see table below). The Cmax of ITP patients treated with 75 mg eltrombopag is 11.4 ug/mL, demonstrating that these concentrations are clinically achievable. There was no enhancement of proliferation at any concentration of eltrombopag, consistent with the very low or undetectable level of MPL expression on samples of tumors from patients with these diseases. MPL was expressed at very low or undetectable levels in these tumor cell lines with the exception of the lung cancer line, NCI-H510. However, western blot analyses showed no detectable TpoR protein expression regardless of the higher levels of MPL mRNA in NCI-H510 cells. Erythropoietin receptor (EPOR) mRNA was expressed at low-to-moderate levels, while ERBB2 and IGF1R were expressed at higher levels in these cell lines. Microarray analysis showed undetectable MPL mRNA levels in all 118 samples from patients with breast cancer and 52% of the NSCLC samples, the remaining NSCLC samples expressed low levels of MPL. In contrast, EPOR was expressed in 75–100% of the breast cancer, and NSCLC samples. ERBB2 was expressed in 97–100% of the samples and IGF1R was expressed in 54–100% of the samples. When 40 other tumor samples each from subjects with ovarian, lung and breast cancer were examined by qRT-PCR, MPL mRNA levels were also very low or undetectable. EPOR, ERBB2, and IGF1R expression levels varied according to tumor type, but were greater than MPL levels. Conclusions: In summary, similar to its effects on leukemia and lymphoma cell lines, all of the nine lung, ovarian, breast or prostate tumor cell lines demonstrated decreased proliferation in response to eltrombopag. The undetectable or very low levels of expression of MPL mRNA in tumors of patients with lung, ovarian, breast or prostate cancer supports the proliferation results. Disclosures: Erickson-Miller: GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties, Research Funding. Kirchner:GlaxoSmithKline: Employment. Pillarisetti:GSK: Employment, Equity Ownership, Patents & Royalties. Ottesen:GSK: Employment, Equity Ownership. Mostafa Kamel:GSK: Employment, Equity Ownership. Liu:GSK: Employment, Equity Ownership. Martin:GSK: Employment, Equity Ownership. Messam:GSK: Employment, Equity Ownership.

7557 Background: Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR and c-kit. The present phase II open-label trial (NCT00367679; VEG105290) was designed to determine the clinical/...

7568 Background: Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR and c-kit. In a single-arm phase II trial (NCT00367679; VEG105290), patients received pazopanib 800 mg QD for 2–6 weeks before scheduled surgery. Tumor volume measurements were performed using high resolution CT images before and after treatment. An exploratory analysis was planned to describe the modulation of C/AFs during pazopanib treatment and identify potential predictive plasma markers. Methods: Plasma samples were collected pre- treatment and on the last day of pazopanib dosing. Levels of 52 C/AFs were measured by suspension bead multiplex assays (BioRad) or ELISA. Results were correlated with change in tumor volume. Statistical analyses included Wilcoxon tests and Pearson correlation tests. Results: 19 paired samples have been analyzed. Pazopanib treatment was associated with a significant modulation of 13 C/AFs, including a decrease in soluble VEGFR-2 (p

Background Numerous efficacious chemotherapy regimens may cause thrombocytopenia. Thrombopoietin receptor (TPO-R) agonists, such as eltrombopag, represent a novel approach for the treatment of chemotherapy-induced thrombocytopenia. The TPO-R MPL is expressed on megakaryocytes and megakaryocyte precursors, although little is known about its expression on other tissues. Methods Breast, lung, and ovarian tumor samples were analyzed for MPL expression by microarray and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and for TPO-R protein expression by immunohistochemistry (IHC). Cell line proliferation assays were used to analyze the in vitro effect of eltrombopag on breast, lung, and ovarian tumor cell proliferation. The lung carcinoma cell lines were also analyzed for TPO-R protein expression by Western blot. Results MPL mRNA was not detectable in 118 breast tumors and was detectable at only very low levels in 48% of 29 lung tumors studied by microarray analysis. By qRT-PCR, low but detectable levels of MPL mRNA were detectable in some normal (14-43%) and malignant (3-17%) breast, lung, and ovarian tissues. A comparison of MPL to EPOR, ERBB2, and IGF1R mRNA demonstrates that MPL mRNA levels were far lower than those of EPOR and ERBB2 mRNA in the same tissues. IHC analysis showed negligible TPO-R protein expression in tumor tissues, confirming mRNA analysis. Culture of breast, lung, and ovarian carcinoma cell lines showed no increase, and in fact, showed a decrease in proliferation following incubation with eltrombopag. Western blot analyses revealed no detectable TPO-R protein expression in the lung carcinoma cell lines. Conclusions Multiple analyses of breast, lung, and ovarian tumor samples and/or cell lines show no evidence of MPL mRNA or TPO-R protein expression. Eltrombopag does not stimulate growth of breast, lung, or ovarian tumor cell lines at doses likely to exert their actions on megakaryocytes and megakaryocyte precursors.