Researchers have identified a potential predictive marker for survival in cases of metastatic colorectal cancer (mCRC) treated with bevacizumab (Avastin), suggesting that patients who have the appropriate biomarker could experience a greater benefit when given the drug, whereas others who do not express the biomarker could be spared from receiving unnecessary therapy.

Bevacizumab is approved by the FDA to treat mCRC when given in combination with a standard chemotherapy regimen of ironotecan, 5-fluorouracil, and leucovorin as a firstor second-line therapy. Although clinical trials in patients with mCRC have shown an improvement in survival, no proven predictive markers have yet been identified to determine which patients may experience a greater survival benefit when given the therapy.

The drug works by targeting and blocking VEGF-A, a protein associated with angiogenesis. Since VEGF-A is the product of one gene encoding multiple isoforms, researchers decided to focus on one splice variant of VEGF-A called VEGF165b that was shown to have antiangiogenesis properties. The hypothesis for the study was that patients with relatively low levels of VEGF165b would respond better measured by progression- free survival (PFS)&mdash;when treated with bevacizumab. Researchers posited that in patients with lower levels of VEGF165b, more of the drug might be able to block the angiogenesis-promoting form of protein VEGF165.

Researchers at the University of Bristol used 97 blinded tumor samples from a phase III trial in which patients with mCRC received the FOLFOX4 (oxaliplatin, leucovorin, and 5-fluorouracil) chemotherapy regimen with or without bevacizumab. Those tissue samples were assessed for VEGF165b and total VEGF by immunohistochemistry, and the ratio of the two levels was scored relative to normal tissue samples.

An unadjusted analysis of PFS showed that patients with lower VEGF165b:total VEGF ratios treated with the FOLFOX4 and bevacizumab regimen (n = 24) had a longer median PFS than those who received FOLFOX4 alone (n = 26; median, 8.0 months vs 5.2 months; P <.02). However, no beneficial effect on PFS was observed in patients with higher VEGF165b:total VEGF ratios when the combination regimen (n = 20) was compared with FOLFOX4 alone (n = 27; median, 5.9 months vs 6.3 months).

Although patients with a lower VEGF165b ratio achieved a higher median overall survival (OS) when given FOLFOX4 and bevacizumab (median, 13.6 months) compared with patients who received FOLFOX4 alone (median, 10.6 months), the results did not reach statistical significance. No difference in OS was observed in the higher VEGF165b ratio group when comparing the FOLFOX4 and bevacizumab regimen (median, 10.8 months) with FOLFOX4 alone (11.3 months).

&ldquo;Avastin has shown great potential for a minority of people with bowel cancer, but it&rsquo;s been impossible to predict who will benefit from the drug,&rdquo; said David O. Bates, PhD, lead researcher from the University of Bristol School of Physiology and Pharmacology and lead author of the study. &ldquo;We now need to look at cancer samples from a larger group of patients about to start taking Avastin and determine if the amount of VEGF165b can accurately identify those patients that will benefit, and so potentially open a new treatment option for some people with advanced bowel cancer.&rdquo;

Bates DO, Catalano PJ, Symonds KE, et al. Association between VEGF splice isoforms and progression- free survival in metastatic colorectal cancer patients treated with bevacizumab [published online ahead of print October 25, 2012].

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Researchers have identified a potential predictive marker for survival in cases of mCRC treated with bevacizumab (Avastin), suggesting that patients who have the appropriate biomarker could experience a greater benefit when given the drug.

Biomarker May Predict Response to Bevacizumab in mCRC

An analysis of the phase III AFFIRM trial showed that enzalutamide (Xtandi) significantly delayed the time to first skeletal-related event (SRE) and significantly improved pain and quality of life (QoL) compared with placebo in men with metastatic castrationresistant prostate cancer (mCRPC) who had received prior docetaxel.

Enzalutamide is an oral androgen receptor inhibitor that targets multiple steps on the androgen receptor pathway. Based on the results of the AFFIRM trial, the FDA recently approved enzalutamide to treat patients with mCRPC who were previously treated with docetaxel.

The AFFIRM trial included 1199 patients with progressive mCRPC who had received &le;2 regimens of docetaxel. Participants were randomized 1:1 to enzalutamide or placebo. Demographic characteristics were well balanced between the two treatment arms. Median age was 69 years. Median pain score was >4 in 28% of patients. Ninety percent had bone metastasis, and 43% had received bisphosphonates. Overall results of the AFFIRM study showed that enzalutamide prolonged survival and risk of death versus placebo. Median survival was 18.4 months with enzalutamide versus 13.6 months with placebo, representing a 37% reduction in risk of death.

At the 2012 ESMO Congress, Karim Fizazi, MD, Institut Gustav Roussy, Villejuif, France, reported a subanalysis of AFFIRM focused on the effect of enzalutamide versus placebo on SRE, pain, and QoL. The subanalysis showed that enzalutamide significantly delayed time to first SRE: a median of 16.7 months with enzalutamide versus 13.3 months with placebo, representing a 31% reduction in risk of SRE (

The distribution of first SRE showed a generally favorable effect of enzalutamide, with fewer patients experiencing radiation to the bone (20% for enzalutamide versus 25% for placebo) and spinal cord compression (6% vs 8%), but about 4% in each group experiencing pathological fracture.

Pain was assessed by three methods: Brief Pain Inventory Short Form (BPI-SF, baseline and week 13); self-reported pain diaries at baseline and weekly, including analgesic use and worst pain for 7-day period; and Functional Assessment of Cancer TherapyProstate (FACT-P) questionnaire at baseline and week 13.

On the BPI-SF, enzalutamide reduced pain severity; patients taking enzalutamide improved pain scores by 7.5%, while those on placebo had worsening pain by 23% (P <.001).

Pain diaries showed pain progression in 28% taking enzalutamide versus 39% of placebo patients (

= .0018). Palliation (ie, >30% reduction in mean pain score at week 13 vs baseline without a >30% increase in analgesic use) was achieved in 45% of the enzalutamide arm versus 7% of the placebo arm (

On the FACT-P, the median for time to pain progression had not yet been reached in the enzalutamide arm versus 13.8 months in the placebo arm, representing a risk reduction of 44% (

= .0004). The total QoL score on the FACT-P showed that QoL was dramatically improved in patients taking enzalutamide: 43% had improvement in QoL versus 18% in the placebo arm. Significant improvements were seen in all QoL domains for enzalutamide compared with placebo (P <.001 for all except social/family, which was significant at

Formal discussant of this trial, Eleni Efstathiou, MD, PhD, MD Anderson Cancer Center, Houston, Texas, commended the authors for including QoL and pain alleviation in their analysis of AFFIRM. However, she urged caution when considering the positive results of the subanalysis.

&ldquo;Although enzalutamide clearly reduced the risk of SRE, improved QoL and functionality, and relieved pain and delayed pain progression, there is no evidence in this trial that severe pain is reduced. Enzalutamide ameliorated bone metastasis in symptomatic men with CRPC. However, we cannot declare victory, given that severe pain-related events may not be altered,&rdquo; Efstathiou said. She added that better understanding of the mechanisms involved in bone metastasis could move the field forward.

Fizazi K, Scher HI, Saad F, et al. Impact of enzalutamide, an androgen receptor signaling inhibitor, on time to first skeletal related event (SRE) and pain in the phase 3 AFFIRM study. Presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract 896O.

An analysis of the phase III AFFIRM trial showed that enzalutamide significantly delayed the time to first skeletal-related event and significantly improved pain and quality of life  compared with placebo in men with mCRPC who had received prior docetaxel.

January 2013 | Targeted Therapies in Oncology

Biomarker May Predict Response to Bevacizumab in mCRC

Enzalutamide Delays First SRE, Improves Pain and QoL in Patients With Metastatic Prostate Cancer