Imaging and clinical correlates with regorafenib in metastatic colorectal cancer.

In colorectal cancer (CRC), imaging is important in determining tumor stage, selecting treatment strategies, and in assessing response to therapy. However, some challenges remain with established imaging techniques, such as computed tomography, and with some commonly used response criteria, such as Response Evaluation Criteria in Solid Tumors, which measures change in size of several target lesions instead of change in tumor morphology or metabolic function. In addition, these assessments are not typically conducted until after 8 weeks of treatment, meaning that potential non-responders are often not identified in a timely manner. Regorafenib, an oral tyrosine kinase inhibitor indicated for the treatment of metastatic CRC, blocks the activity of several protein kinases involved in angiogenesis, oncogenesis, metastasis, and tumor immunity. Timely differentiation of regorafenib responders from non-responders using appropriate imaging techniques that recognize not only changes in tumor size but also changes in tumor density or vasculature, may reduce unnecessary drug-related toxicity in patients who are unlikely to respond to treatment. This review discusses the latest developments in computed tomography, magnetic resonance imaging, and positron emission tomography tumor imaging modalities, and how these aid in identifying patients with metastatic CRC who are responders or non-responders to regorafenib treatment.

Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313.

PURPOSE: Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC). MATERIALS AND METHODS: Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS). RESULTS: PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm. CONCLUSION: Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.

A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105.

RET fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with RET fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%-17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion-positive NSCLC), and 67% (95% CI, 30%-93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-KIF5B-RET-containing cancers. Novel approaches to targeting KIF5B-RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.This article is highlighted in the In This Issue feature, p. 305.

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.

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.

Current Options for Third-Line Treatment of Metastatic Colorectal Cancer.

Until recently, treatment options for patients with metastatic colorectal cancer (CRC) were limited to chemotherapy, vascular endothelial growth factor­targeted therapy, and, for patients with RAS-wild type tumors, epidermal growth factor receptor­targeted therapy. For patients with disease progression after treatment, newer agents are now available: the multitargeted tyrosine kinase inhibitor regorafenib and the cytotoxic combination of trifluridine and tipiracil (TAS-102). Both regorafenib and trifluridine/tipiracil have demonstrated significant improvements in overall survival in patients with refractory metastatic CRC. Durable responses exceeding a year have been reported with regorafenib. The agents differ in their safety profiles. Regorafenib is associated with hand-foot skin reaction and fatigue, primarily in the first cycle. Alternative dosing strategies appear to improve the tolerability of regorafenib, and randomized dosing studies are underway to define the optimal strategy. Trifluridine/tipiracil is associated primarily with myelosuppression. Sequencing of these agents can be guided by patient characteristics, such as comorbidities and adverse reactions to previous treatments. Patients with a poor performance status are not likely to benefit from regorafenib. Ongoing studies are further defining the role of regorafenib and trifluridine/tipiracil in the treatment of metastatic CRC.

Durable response using regorafenib in an elderly patient with metastatic colorectal cancer: case report.

Regorafenib, an oral multikinase inhibitor, was approved in September 2012 by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer. Since this time, however, few case reports outlining real-world usage have been published in the literature. Here, we detail the clinical history of an elderly woman with KRAS wild-type colon cancer who received regorafenib after prior treatment with other agents. We show that by employing dose modification strategies to address adverse events, this patient was able to remain on therapy for 11 months and achieve stable disease.

Identification and characterization of RET fusions in advanced colorectal cancer.

There is an unmet clinical need for molecularly directed therapies available for metastatic colorectal cancer. Comprehensive genomic profiling has the potential to identify actionable genomic alterations in colorectal cancer. Through comprehensive genomic profiling we prospectively identified 6 RET fusion kinases, including two novel fusions of CCDC6-RET and NCOA4-RET, in metastatic colorectal cancer (CRC) patients. RET fusion kinases represent a novel class of oncogenic driver in CRC and occurred at a 0.2% frequency without concurrent driver mutations, including KRAS, NRAS, BRAF, PIK3CA or other fusion tyrosine kinases. Multiple RET kinase inhibitors were cytotoxic to RET fusion kinase positive cancer cells and not RET fusion kinase negative CRC cells. The presence of a RET fusion kinase may identify a subset of metastatic CRC patients with a high response rate to RET kinase inhibition. This is the first characterization of RET fusions in CRC patients and highlights the therapeutic significance of prospective comprehensive genomic profiling in advanced CRC.

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).

BACKGROUND: The AKT inhibitor MK-2206 at a dose of 60 mg every other day was evaluated in gastric/gastroesophageal junction cancers. METHODS: Patients who had progressed after first-line treatment were eligible. Pertinent eligibility criteria included adequate organ function, a fasting serum glucose level ≤ 150 mg/dL, and less than grade 2 malabsorption or chronic diarrhea. MK-2206 was given orally (60 evaluable patients required). The primary endpoint was overall survival, and a median survival of 6.5 months (power, 89%; significance level, 0.07) was considered encouraging for further investigation. RESULTS: Seventy patients were included in the final analyses. The median age was 59.8 years (range, 30.4-86.7 years); 70% were male, 89% were white, and 7% were Asian. There were 2 deaths possibly related to the study drug (cardiac arrest and respiratory failure). Grade 4 adverse events included hyperglycemia, anemia, and lung infection (1 each). Grade 3 adverse events occurred in < 5% of patients except for fatigue (6%). Other adverse events (all grades) included anemia (17%), anorexia (30%), diarrhea (26%), fatigue (50%), hyperglycemia (30%), nausea (40%), vomiting (22%), dry skin (19%), maculopapular rash (30%), and acneiform rash (13%). The response rate was 1%, the median progression-free survival was 1.8 months (95% confidence interval, 1.7-1.8 months), and the median overall survival was 5.1 months (95% confidence interval, 3.7-9.4 months) CONCLUSIONS: MK-2206 as second-line therapy was well tolerated by an unselected group of patients with gastric/gastroesophageal junction cancers, but it did not have sufficient activity (response rate, 1%; overall survival, 5.1 months) to warrant further testing in this population.

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.

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.

Role of primary tumor resection among chemotherapy-treated patients with synchronous stage IV colorectal cancer: a survival analysis.

INTRODUCTION: The benefit of an operation to remove the primary tumor among patients with synchronous stage IV colorectal cancer is controversial. This study analyzed the survival benefits associated with primary tumor resection among chemotherapy-treated stage IV colorectal cancer patients. METHODS: The study analyzed 11,716 chemotherapy-treated stage IV colorectal cancer patients in the California Cancer Registry between 1996 and 2007, with follow-up through 2009. Patients were stratified into operation and non-operation groups. Estimates of median overall and colorectal cancer-specific survival were generated. RESULTS: Patients undergoing operation compared to those who are not had higher median overall and colorectal cancer-specific survival, 21 versus 10 months (p < 0.0001) and 22 versus 12 months (p < 0.0001), respectively. Patients who were offered surgery but refused had decreased median overall and colorectal cancer-specific survival when compared to patients who underwent resection, 8 versus 21 months (p < 0.001) and 7 versus 22 months (p < 0.001), respectively. In multivariate regression models, patients who underwent resection of primary tumor had improved overall (hazard ratio (HR), 0.42; 95% confidence interval (CI) 0.40-0.44, p < 0.0001) and colorectal cancer-specific survival (HR, 0.43; 95% CI, 0.41-0.45; p < 0.0001). CONCLUSION: Primary tumor resection is associated with improved survival among stage IV chemotherapy-treated colorectal cancer patients.

Mortality risk after preoperative versus postoperative chemotherapy and radiotherapy in lymph node-positive rectal cancer.

INTRODUCTION: Persistent lymph node-positive disease after preoperative radiotherapy for rectal cancer is associated with adverse outcomes. We quantified mortality risks of persistent pathologic lymph nodes in lymph node-positive rectal cancer patients treated with preoperative versus postoperative chemoradiation. METHODS: This was a retrospective population-based analysis of 2,038 patients with stage III rectal cancer diagnosed 1994-2005 with follow-up through 2007 using data from the California Cancer Registry. Survival estimates were generated using the Kaplan-Meier method. Multivariate cancer-specific and overall mortality analyses were performed using Cox proportional hazard ratios with adjustment for age, gender, race/ethnicity, tumor grade, T stage, N stage, socioeconomic status, and time period (1994-1997, 1998-2001, and 2002-2005). RESULTS: Overall survival was higher among lymph node-positive patients receiving postoperative chemoradiation compared to lymph node-positive patients receiving preoperative chemoradiation (median overall survival = 87 versus 62 months, P = 0.0002). In adjusted analyses, patients with persistent lymph node-positive disease after preoperative chemoradiation treatment had increased overall (HR = 1.69; 95 % CI, 1.42-2.01) and CRC-specific (HR = 1.78; 95 % CI, 1.44-2.19) mortality risk compared to lymph node-positive disease after postoperative chemoradiation treatment. CONCLUSIONS: Stage III rectal cancer patients with persistent pathologic lymph nodes after preoperative chemoradiation represent a high-risk group, with higher mortality than those treated with postoperative chemoradiation.

Temozolomide in malignant gliomas: current use and future targets.

Temozolomide (TMZ) is an oral alkylating agent that is regarded as a tolerable and effective drug. When combined with radiotherapy in patients with newly diagnosed glioblastoma, survival is significantly prolonged. This finding has led to widespread use of TMZ for patients with this disease. We summarize developing concerns regarding the use of TMZ, imaging of malignant gliomas, and the pharmacology of TMZ-mechanism of action, scheduling and strategies for overcoming resistance.