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    <recommendedItem id="20100101_19_357"
                     title="Targeted Therapy Disappoints in Recurrent Brain Tumors (CME/CE)"
                     score="0.009"
                     href="http://www.medpagetoday.com/HematologyOncology/BrainCancer/tb/18237?impressionId=1265774514014"
                     
      &lt;p&gt;High hopes for treating recurrent glioblastoma with the novel, targeted antiangiogenic enzastaurin have been diminished by disappointing phase III results.&lt;/p&gt;
&lt;p&gt;The study failed its primary endpoint with a median progression-free survival of 1.5 months compared with 1.6 months on conventional lomustine (CeeNu, &lt;em&gt;P&lt;/em&gt;=0.08).&lt;/p&gt;
&lt;p&gt;Nor were there any other significant benefits, despite generally good tolerability, Wolfgang Wick, MD, of the University of Heidelberg, Germany, and colleagues reported online in the &lt;em&gt;Journal of Clinical Oncology&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;In an earlier &lt;a href=&quot;http://www.medpagetoday.com/HematologyOncology/BrainCancer/1062&quot; mce_href=&quot;http://www.medpagetoday.com/HematologyOncology/BrainCancer/1062&quot; target=&quot;_blank&quot;&gt;phase II study&lt;/a&gt;, the drug shrank tumors in 22% of heavily pretreated patients with recurrent glioblastoma, a heavily vascular cancer and one of the toughest to treat.&lt;/p&gt;
&lt;p&gt;The experimental agent is a potent and selective inhibitor of protein kinase C-beta, which mediates the most important regulator of vessel growth in glioma.&lt;/p&gt;
&lt;p&gt;Even so, jumping directly into a phase III study before the final results of a phase II study might have been premature, even with a strong preclinical rationale, the authors and an accompanying editorial said.&lt;/p&gt;
&lt;p&gt;Evanthia Galanis, MD, DSc, and Jan C. Buckner, MD, both of the Mayo Clinic in Rochester, Minn., wrote in an editorial that response rate &quot;can be particularly misleading as an indicator of antitumor activity of antiangiogenic agents.&quot;&lt;/p&gt;
&lt;p&gt;Reduced vascular permeability can appear as improvement on enhanced MRI, without true antitumor effect, the editorialists noted. Nor does response rate correlate well with progression-free or overall survival in this type of cancer, they wrote.&lt;/p&gt;
&lt;p&gt;Still, they cautioned, these negative phase III results aren&apos;t the final word on the drug whose modest activity was comparable to standard treatment  --  and with satisfactory tolerability.&lt;/p&gt;
&lt;p&gt;&quot;It would therefore still be worth incorporating enzastaurin in rationally designed combinatorial regimens, especially if based on a strong mechanistic rationale or preclinical demonstration of synergistic activity,&quot; Galanis and Buckner wrote.&lt;/p&gt;
&lt;p&gt;The study randomized patients with World Health Organization grade 4 glioblastoma to receive six-week cycles of open-label enzastaurin 500 mg/d (1,125-mg loading dose on day one) or lomustine (100 to 130 mg/m&lt;sup&gt;2&lt;/sup&gt; on day one).&lt;/p&gt;
&lt;p&gt;It was stopped at the planned interim futility analysis after enrollment of 266 patients.&lt;/p&gt;
&lt;p&gt;The researchers had powered the study for a 45% improvement in median progression-free survival, but found it actually tended to be 28% better with lomustine (HR 1.28, 95% CI 0.97 to 1.70).&lt;/p&gt;
&lt;p&gt;Six-month progression-free survival rates were 11.1% with the experimental treatment, compared with 19.0% among controls (&lt;em&gt;P&lt;/em&gt;=0.13).&lt;/p&gt;
&lt;p&gt;Overall survival, too, was similar at 6.6 and 7.1 months, respectively (HR 1.20, &lt;em&gt;P&lt;/em&gt;=0.25). Objective response rate showed no differences either (&lt;em&gt;P&lt;/em&gt;=0.501).&lt;/p&gt;
&lt;p&gt;Patient-reported time to deterioration  --  measured on the Functional Assessment of Cancer Therapy&amp;#8211;Brain questionnaire  --  was 2.27 months with enzastaurin compared with 2.33 months for lomustine (&lt;em&gt;P&lt;/em&gt;=0.54).&lt;/p&gt;
&lt;p&gt;Results likewise were similar between the groups for physical and functional well-being and for brain tumor&amp;#8211;specific concerns (&lt;em&gt;P&lt;/em&gt;&amp;gt;0.05).&lt;/p&gt;
&lt;p&gt;Adverse event rates were not different between groups, although more were drug-related in the lomustine group (62% versus 44%, &lt;em&gt;P&lt;/em&gt;=0.008).&lt;/p&gt;
&lt;p&gt;Enzastaurin did have the advantage of less hematologic toxicity overall (&lt;em&gt;P&lt;/em&gt;&amp;#8804;0.001), and specifically for grade 3 to 4 adverse events (one versus 46 events, &lt;em&gt;P&lt;/em&gt;&amp;#8804;0.001).&lt;/p&gt;
&lt;p&gt;Study deaths in the enzastaurin group totaled 11, including four due to adverse events and one drug-related; while the four deaths in lomustine-treated patients were disease-related.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was supported by Eli Lilly, including writing and editorial support.&lt;/p&gt;&lt;p&gt;Wick and co-authors reported financial conflicts of interest with Eli Lilly, including employment and stock ownership for some.&lt;/p&gt;&lt;p&gt;Co-authors also reported financial conflicts of interest with Merck, Genentech, Enzon, Schering-Plough, and AstraZeneca.&lt;/p&gt;&lt;p&gt;Galanis reported conflicts of interest with Merck, Bristol-Myers Squibb, Gradalis, Genetech, and Bayer Pharmaceuticals.&lt;/p&gt;&lt;p&gt;Buckner reported conflicts of interest with Merck Serono, Genentech, Excelixis, Bayer Pharmaceuticals, Bristol-Myers Squibb, and Anti-Sense Pharma.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_174"
                     title="AACR-IASLC: MicroRNA Linked to SCLC Response (CME/CE)"
                     score="-0.004"
                     href="http://www.medpagetoday.com/MeetingCoverage/AACR-IASLC/tb/18008?impressionId=1265774514014"
                     
      &lt;p&gt;CORONADO, Calif.  --  Tiny genetic segments may give a big tip-off to platinum chemoresistance in patients with small cell lung cancer, researchers said.&lt;/p&gt;
&lt;p&gt;Three microRNAs were linked to de novo chemoresistance in a small study led by Glen J. Weiss, MD, of Scottsdale Healthcare and the Translational Genomics Research Institute (TGen), both in Scottsdale, Ariz.&lt;/p&gt;
&lt;p&gt;He presented the results here at the Joint Conference on Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.&lt;/p&gt;
&lt;p&gt;Further validation would be needed before denying any patient chemotherapy based on the findings, cautioned Tyler Jacks, PhD, of the Massachusetts Institute of Technology and president of the AACR.&lt;/p&gt;
&lt;p&gt;However, &quot;biomarkers of this sort will be useful in diagnosing patients and applying relevant therapies  --  in this instance perhaps applying novel therapies, given the belief that the conventional therapies will be of no value to these individuals,&quot; he said as discussant on the study at a press conference.&lt;/p&gt;
&lt;p&gt;Weiss agreed.&lt;/p&gt;
&lt;p&gt;&quot;This is early stage,&quot; he said in an interview. &quot;But hopefully down the road it will have implications for treating patients with small cell [lung cancer].&quot;&lt;/p&gt;
&lt;p&gt;Non-small cell lung cancer has been a success story for personalized treatment.&lt;/p&gt;
&lt;p&gt;It was revolutionized by discovery of epidermal growth factor receptor (EGFR) mutations as both a prognostic factor and treatment target for the EGFR tyrosine kinase inhibitors.&lt;/p&gt;
&lt;p&gt;But for small cell lung cancer, the standard treatment is platinum-based chemotherapy with only two real options in first-line treatment, the researchers said.&lt;/p&gt;
&lt;p&gt;Worse, 15% to 30% of small cell tumors are intrinsically resistant to platinum chemotherapy and never respond.&lt;/p&gt;
&lt;p&gt;&quot;[Small cell] lung cancer patients haven&apos;t had a real advance in 15 years or more for chemotherapy,&quot; Weiss told &lt;em&gt;MedPage Today&lt;/em&gt;. &quot;What we&apos;re trying to do is identify the group that doesn&apos;t respond to standard therapy so that we can identify new treatments for them up front instead of treating everyone the same.&quot;&lt;/p&gt;
&lt;p&gt;Among the genetic possibilities for these efforts, microRNA  --  RNA molecules of around 20 nucleotides in length  --  are a good option, Weiss explained.&lt;/p&gt;
&lt;p&gt;They regulate gene expression like messenger RNA but are smaller and more stable across a variety of fluid and tissue types, he said.&lt;/p&gt;
&lt;p&gt;In the study, the researchers analyzed diagnostic tumor samples from 34 patients with small cell lung cancer.&lt;/p&gt;
&lt;p&gt;Among them, 19% had de novo chemoresistance marked by progressive disease. Most had had a partial or complete response to chemotherapy (61.9% and 9.5%, respectively).&lt;/p&gt;
&lt;p&gt;After extraction of total RNA, microRNA profiling revealed 16 top candidates for association with progressive disease.&lt;/p&gt;
&lt;p&gt;The 28 samples with sufficient RNA for further testing showed three microRNAs linked to chemoresistance that were validated by quantitative real-time PCR: &lt;ul&gt; &lt;li&gt;miR-92a-2* with a &lt;em&gt;P&lt;/em&gt;-value of 0.010&lt;/li&gt; &lt;li&gt;miR-147 with a &lt;em&gt;P&lt;/em&gt;-value of 0.018&lt;/li&gt; &lt;li&gt;miR-574-5p with a &lt;em&gt;P&lt;/em&gt;-value of 0.039&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;Many of the patients had comorbidities at baseline, including 47.1% with hypertension and 32% with emphysema or chronic obstructive pulmonary disease. But these did not predict chemotherapy response.&lt;/p&gt;
&lt;p&gt;The next step is to validate the biomarkers in an independent cohort of small cell lung cancer patients, the researchers concluded.&lt;/p&gt;
&lt;p&gt;Then studies will need to determine what does work in these chemoresistant patients, Weiss said.&lt;/p&gt;
&lt;p&gt;&quot;We&apos;ve learned that if we&apos;re going to make the next hurdle and if we&apos;re going to better treat this disease, we need more personalized care,&quot; agreed Roy Herbst, MD, PhD, of M.D. Anderson Cancer Center in Houston.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was supported by the American Cancer Society-Sylvia Chase Pilot Grant, IBIS Foundation of Arizona, and the TGen Foundation.&lt;/p&gt;&lt;p&gt;Weiss reported recieving lab support from TGen Foundation and Scottsdale Healthcare Foundation as well as being party to provisional patents related to microRNAs in lung cancer.&lt;/p&gt;&lt;p&gt;Jacks provided no information on conflicts of interest.&lt;/p&gt;&lt;p&gt;Herbst has reported financial relationships with Genentech, Lilly, Amgen, and AstraZeneca. &lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
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