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    <recommendedItem id="20100101_19_357"
                     title="Targeted Therapy Disappoints in Recurrent Brain Tumors (CME/CE)"
                     score="0.011"
                     href="http://www.medpagetoday.com/HematologyOncology/BrainCancer/tb/18237?impressionId=1265736423024"
                     
      &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_276"
                     title="ASCO GI: Antibody Slows Metastatic Colon Cancer"
                     score="0.004"
                     href="http://www.medpagetoday.com/MeetingCoverage/ASCOGI/tb/18134?impressionId=1265736423024"
                     
      ORLANDO  --  Patients with nonmutated colorectal tumors had significant improvement in progression-free survival (PFS) when the monoclonal antibody panitumumab (Vectibix) was added to conventional chemotherapy, data from two randomized clinical trials showed.&lt;br&gt;
&lt;br&gt;When used in first-line therapy for metastatic cancer, the antibody-chemotherapy combination was associated with a 20% improvement in the hazard ratio for progression compared with chemotherapy alone. In the second-line metastatic setting, the combination improved the hazard ratio by 27%.&lt;br&gt;
&lt;br&gt;Separate analyses of the trials showed that the addition of panitumumab to chemotherapy did not improve PFS in patients whose tumors had K-ras mutations.&lt;br&gt;
&lt;br&gt;Overall survival was similar between treatment arms in both trials, according to presentations here at the Gastrointestinal Cancers Symposium.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;&quot;The results of these two studies are consistent in that they demonstrate a benefit from the addition of panitumumab among patients with wild-type K-ras tumors,&quot; Salvatore Siena, MD, of Ospedale Niguarda Ca&apos;Granda in Milan, Italy, said in an interview. &quot;The results also are consistent with what we know about the role of K-ras in colorectal cancer.&quot;&lt;/p&gt;
&lt;p&gt;&quot;The addition of panitumumab to the chemotherapy regimens used in the studies was well tolerated, as no unexpected toxicity was observed,&quot; he added.&lt;/p&gt;
&lt;p&gt;Panitumumab is a fully human monoclonal antibody against epidermal growth factor receptor (EGFR). The agent is approved for treatment of chemotherapy-refractory metastatic colorectal cancer.&lt;/p&gt;
&lt;p&gt;The two clinical trials initially were designed to evaluate panitumumab in all patients, irrespective of K-ras status. Following reports about the adverse effect of K-ras mutations on therapeutic outcomes in colorectal cancer, the trials&apos; protocols were amended to test the hypothesis that adding panitumumab to chemotherapy would improve PFS in patients with wild-type K-ras status.&lt;/p&gt;
&lt;p&gt;The trial of first-line metastatic therapy compared panitumumab plus 5-FU/leucovorin/oxaliplatin (Eloxatin) chemotherapy versus chemotherapy (FOLFOX) alone. The open-label, randomized trial involved 1,183 patients enrolled at centers in Canada, South America, Europe, South Africa, and Australia.&lt;/p&gt;
&lt;p&gt;The primary endpoint was PFS, and secondary endpoints included overall survival, overall response rate, time to response, duration of response, and safety. The protocol excluded patients with prior chemotherapy for metastatic colorectal cancer or prior EGFR inhibitor therapy.&lt;/p&gt;
&lt;p&gt;Tissue samples were collected for biomarker assessment, but EGFR and K-ras status assessment were not required at entry. Siena said K-ras status was ascertained in 93% of the patients and showed that 60% of both treatment arms had wild-type K-ras tumors.&lt;/p&gt;
&lt;p&gt;In the primary analysis involving patients with wild-type K-ras tumors, the addition of panitumumab to FOLFOX was associated with a PFS of 9.6 months compared with 8.0 months for patients treated with chemotherapy alone (HR 0.80, 95% CI 0.66 to 0.97, &lt;em&gt;P&lt;/em&gt;=0.02). Addition of the antibody was associated with a trend toward improved overall survival (23.9 months versus 19.7 months, &lt;em&gt;P&lt;/em&gt;=0.07) and overall response rate (55% versus 48%, &lt;em&gt;P&lt;/em&gt;=0.07).&lt;/p&gt;
&lt;p&gt;Patients with mutant-type K-ras tumors fared better with chemotherapy alone, which led to a median PFS of 8.8 months versus 7.3 months for chemotherapy plus panitumumab (&lt;em&gt;P&lt;/em&gt;=0.02).&lt;/p&gt;
&lt;p&gt;Similar results emerged from the study of second-line therapy for metastatic cancer, reported by Marc Peeters, MD, of University Hospital Ghent in Belgium.&lt;/p&gt;
&lt;p&gt;The trial involved 1,186 patients who had previously received chemotherapy for metastatic colorectal cancer enrolled at centers in the U.S., Europe, Asia, and Australia. As in the study of first-line therapy, about 60% of the patients had wild-type K-ras tumors.&lt;/p&gt;
&lt;p&gt;The trial compared FOLFIRI chemotherapy (5-FU/leucovorin/irinotecan [Camptosar]) alone versus FOLFIRI plus panitumumab.&lt;/p&gt;
&lt;p&gt;Among patients with wild-type K-ras tumors, the addition of panitumumab was associated with a median PFS of 5.9 months versus 3.9 months for chemotherapy alone (HR 0.73, 95% CI 0.59 to 0.90, &lt;em&gt;P&lt;/em&gt;=0.004).&lt;/p&gt;
&lt;p&gt;Median overall survival was 14.5 months with the monoclonal antibody and 12.5 months without, a difference that did not reach statistical significance. The overall response rate was significantly higher in the panitumumab arm (35% versus 10%, &lt;em&gt;P&lt;/em&gt;=0.001).&lt;/p&gt;
&lt;p&gt;As in the first-line study, patients with mutant K-ras tumors did not benefit from the addition of panitumumab, which was associated with a median PFS of 5.0 months versus 4.9 months with chemotherapy alone. Overall survival was 11.8 months with panitumumab and 11.1 months without it, a nonsignificant difference.&lt;/p&gt;
&lt;p&gt;The panitumumab regimen was generally well tolerated in both studies. The principal difference in adverse events was an excess of skin toxicity with panitumumab, a recognized side effect of the monoclonal antibody.&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;Both studies were supported by Amgen.&lt;/p&gt;&lt;p&gt;One or more investigators in the studies disclosed relatinships with Amgen, Merck Serono, Roche, Baxter International, Merck &amp;amp; Co., Roche, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, ImClone Slystems, sanofi-aventis, and Pfizer.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_6_760"
                     title="ASCO: Higher Cranial Radiation Dose No Help in Brain Metastasis Prevention"
                     score="-0.005"
                     href="