Tara Elisabeth Seery

Phase 2 study of MK-2206, an allosteric inhibitor of AKT, as second-line therapy for advanced gastric and gastroesophageal junction cancer: A SWOG cooperative group trial (S1005)

The AKT inhibitor MK‐2206 at a dose of 60 mg every other day was evaluated in gastric/gastroesophageal junction cancers.

Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial

Importance KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer. Objective To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed. Design, Setting, and Participants SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases. Interventions Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle. Main Outcomes and Measures The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival. Results There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients). Conclusions and Relevance Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX. Trial Registration clinicaltrials.gov Identifier: NCT01658943

HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

Magnetic resonance imaging following treatment of advanced hepatocellular carcinoma with sorafenib

Hepatocellular carcinomas are highly vascular tumors, showing progressive hypervascularity by the process of neoangiogenesis. Tumor angiogenesis is critical for tumor growth as well as metastatic spread therefore, imaging and quantification of tumor neo-angiogenesis is essential for monitoring response to targeted therapies and predicting disease progression. Sorafenib is a molecular targeting agent used for treating hypervascular tumors. This drug is now the standard of care in treatment of patients with advanced hepatocellular carcinoma. Due to its anti-angiogenic and anti-proliferative actions, imaging findings following treatment with Sorafenib are quite distinct when compared to conventional chemotherapeutic agents. Liver MRI is a widely adopted imaging modality for assessing treatment response in hepatocellular carcinoma and imaging features may reflect pathophysiological changes within the tumor. In this mini-review, we will discuss MRI findings after Sorafenib treatment in hepatocellular carcinoma and review the feasibility of MRI as an early biomarker in differentiating responders from non-responders after treatment with molecular targeting agents.

Composite liver tumors: a radiologic-pathologic correlation

Bi-phenotypic neoplasm refers to tumors derived from a common cancer stem cell with unique capability to differentiate histologically into two distinct tumor types. Bi-phenotypic hepatocellular carcinoma-cholangiocarcinoma (HCC-CC), although a rare tumor, is important for clinicians to recognize, since treatment options targeting both elements of the tumor are crucial. Imaging findings of bi-phenotypic HCC-CC are not specific and include features of both HCC and CC. A combination of imaging and immuno-histochemical analysis is usually needed to make the diagnosis.

Abstract CT120: Axitinib safety and pharmacokinetics in Child-Pugh A and Child-Pugh B patients with advanced hepatocellular cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Introduction: Hepatobiliary excretion is the major elimination pathway for axitinib, an oral, potent, selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, approved for second-line treatment of advanced renal cell carcinoma. A formal hepatic impairment (HI) study was previously conducted in subjects with Child-Pugh A (CPA) and Child-Pugh B (CPB) disease but who were otherwise healthy to evaluate the effect of mild and moderate HI on the pharmacokinetics (PK) of axitinib following a single 5 mg oral dose. The safety and PK of axitinib were further evaluated in CPA and CPB patients (pts) with advanced hepatocellular carcinoma (HCC) following continuous multiple axitinib dosing. Methods: Two study portions (randomized double-blind portion of axitinib versus placebo, and non-randomized portion) were conducted in parallel in pts with advanced HCC after failure of one prior antiangiogenic therapy. In the non-randomized portion, the effect of HI on safety and PK were evaluated in HCC CPA (starting dose: 5 mg twice a day [BID]) and CPB (Score 7, starting dose: 2 mg BID) pts. This was also intended to identify the recommended starting dose of axitinib in HCC CPB pts. Serial PK samples up to 8 hour postdose were collected at steady state (Cycle 1 Day 15). Results: Data from 15 CPA and 7 CPB pts were available for safety analysis. Most pts were male (n = 17) and Asian (n = 21). Overall, the most frequently reported all-causality treatment emergent adverse events (TEAE) in all, CPA and CPB pts were fatigue (63.6%, 80% and 28.6%), decreased appetite (54.5%, 46.7% and 71.4%), diarrhea (45.5%, 60% and 14.3%), hypertension (45.5%, 46.7% and 42.9%), and palmar-plantar erythrodysesthesia syndrome (45.5%, 53.3% and 28.6%). Overall, the most frequently reported Grade ≥3 TEAEs in all, CPA and CPB pts were hypertension (27.3%, 26.7% and 28.6%), fatigue (18.2%, 20% and 14.3%) and hyponatraemia (18.2%, 6.7% and 42.9%). One out of 6 evaluable CPB pts treated with 2 mg BID experienced Cycle 1 dose limiting toxicity (proteinuria; >3.5 g/24 hours). PK samples were collected from 12 CPA and 7 CPB pts (AUC0-24 and CL/F reported for 8 CPA and 6 CPB pts, respectively). In CPA and CPB pts, the geometric mean (geometric% coefficient of variance [CV]) values for axitinib AUC0-24 were 311 (63) and 316 (118) ng.hr/mL, respectively. The geometric mean (geometric% CV) values for axitinib CL/F were 32.2 (63) and 12.7 (118) L/hour, respectively, indicating that axitinib CL/F is decreased with increasing HI. Conclusions: The safety profile of axitinib in HCC CPA and CPB pts in this study was consistent with the known safety profile of axitinib. Axitinib plasma exposures were comparable in CPB pts receiving 2 mg BID axitinib and CPA pts receiving 5 mg BID axitinib. These data are in agreement with the previous single-dose HI study and further support that 2 mg BID is an appropriate axitinib starting dose for CPB pts with HCC. Citation Format: Yoon-Koo Kang, Tara E. Seery, Mina Kato, Debasis Chakrabarti, Olga Valota, Ying Chen, Jie Tang, Yazdi K. Pithavala, Masatoshi Kudo. Axitinib safety and pharmacokinetics in Child-Pugh A and Child-Pugh B patients with advanced hepatocellular cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT120. doi:10.1158/1538-7445.AM2015-CT120