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42nd Annual Meeting of the American Society of Clinical Oncology

Atlanta, Georgia / June 2-6, 2006

Results from the ECOG 4599 trial on non-small cell lung cancer (NSCLC) presented here during the scientific sessions demonstrated that the addition of the monoclonal antibody (MAb) bevacizumab to carboplatin/paclitaxel (PCB) increased the response rate to 27.2% vs. 10% in the carboplatin/paclitaxel (PC) arm. Progression-free survival (PFS) as well as overall survival (OS) were also improved, to 6.4 months from 4.5 months and to 12.5 months from 10.2 months, respectively.

Biomarker Levels

A correlative laboratory study was also carried out for ECOG 4599, during which time researchers measured a variety of biomarkers, including endothelial leukocyte adhesion molecule-01 (E-selectin); intercellular adhesion molecule-1 (ICAM); vascular endothelial growth factor (VEGF) and another well-known angiogenic factor, b-FGF. “Our hypothesis was that the measurement of these factors would predict response and prognosis,” Dr. Afshin Dowlati, Assistant Professor of Medicine, Case Western Reserve University, Cleveland, Ohio, told delegates.

Baseline ICAM, E-selectin and b-FGF levels were available for 150 patients, while baseline VEGF levels were available for 113 patients. Low and high levels of each of these biomarkers were defined as equal to or less than the median (low) or greater than the median (high). Analyses indicated that there was a significant average decrease from baseline to week 7 in E-selectin levels in the combined sample (P<0.001) but the difference between the two treatment arms was not significant. Similarly, b-FGF levels decreased significantly from baseline to week 7 in the combined sample but the magnitude of the difference was again not significant between the two treatment arms. Further analysis revealed that low baseline levels of ICAM were associated with a significantly higher response rate at 32% for the combined sample compared with high baseline ICAM levels, where the response rate was only 14% (P=0.01 high vs. low).

Response rates in each of the treatment arms echoed those in the combined sample, such that patients with low baseline ICAM levels had a 40% response rate to PCB compared with 19.4% for those with high baseline ICAM levels. Response rates in the PC arm were 22.6% vs. 10.5% for those with low vs. high baseline ICAM levels, respectively. Importantly, researchers also observed that if patients started off with high VEGF levels, the addition of bevacizumab to PC increased the response rate to over 33% compared with only a 7.7% response rate in the PC-alone arm. “Thus, ICAM showed a significant association with best response in both PCB and PC groups,” Dr. Dowlati observed.

Baseline ICAM levels were also “highly significant” for predicting survival. At one year, 60% of patients with low ICAM baseline levels were still alive, compared with only 25% of those with high ICAM baseline levels. As for E-selectin, researchers found that if levels dropped by <5.35 ng/mL between baseline and week 7, the odds of surviving with no disease progression were significantly enhanced compared with those who experienced a greater decrease in E-selectin levels during the same treatment interlude. Indeed, a decrease of <5.35 ng/mL between baseline and week 7 translated into a 49% reduction in mortality with the addition of bevacizumab, whereas those who had a more substantial drop in E-selectin levels between baseline and week 7 derived no benefit in terms of PFS and OS with additional MAb therapy. Similarly, patients with low baseline ICAM levels of <260 ng/mL had a 53% improvement in PFS when the MAb was added to PC.

These two findings suggest that there is a substantial benefit to be gained by adding bevacizumab to PC in those with a decrease in E-selectin levels of <5.35 ng/mL from baseline to week 7, as well as those with low baseline ICAM levels of <260 ng/mL; however, there was no benefit with the MAb in patients with high baseline ICAM levels.

Targeting EGFR and VEGF

As discussed by investigators, the epidermal growth factor receptor (EGFR) and VEGF have both been identified as key molecular targets in a range of tumour types, including NSCLC. “Thus, combining drugs that target these molecules may confer additional clinical benefit,” reported investigators under lead author Dr. Louis Fehrenbacher, Medical Director of Oncology Clinical Trials Program, Kaiser Permanente Northern California, Vellejo. In a phase I/II trial, 120 patients with recurrent or refractory non-squamous NSCLC were randomized to one of three treatment arms: chemotherapy consisting of either docetaxel or pemetrexed alone; chemotherapy/bevacizumab; or bevacizumab/erlotinib.

At a median follow-up of between three and 4.8 months, the PFS rate at six months was 21.5% for the chemotherapy-alone arm, 30.5% for the bevacizumab/chemotherapy arm and 33.6% for the bevacizumab/erlotinib arm; at six months, 62.4%, 72.1% and 78.3% of patients, respectively, were still alive.

Ten out of 41 patients treated with chemotherapy alone discontinued study treatment due to an adverse event (AE), while over half experienced a serious AE. Discontinuation rates were similar for the bevacizumab/chemotherapy arm, where 10 patients out of 40 withdrew due to an AE. In contrast, only four patients out of 39 in the double MAb arm withdrew because of an AE. As expected, there was a greater incidence of rash and diarrhea in the double MAb arm compared with the other two cohorts but the incidence of neutropenia was similar for the chemotherapy-alone arm and the chemotherapy/bevacizumab arm. The overall incidence of neutropenia in the bevacizumab/erlotinib arm was approximately 10%.

“The bevacizumab/erlotinib combination may represent an alternative to chemotherapy-based treatments in relapsed NSCLC if these results can be confirmed in a fully powered phase III trial,” investigators concluded.

Limited-stage Small Cell Lung Cancer

Study findings presented by Dr. David Spigel, Associate Director of Clinical Research, Sarah Cannon Research Institute, Nashville, Tennessee, also suggest there may be a role for maintenance bevacizumab in the treatment of limited-stage small cell lung cancer (LS-SCLC). In an update of a phase II trial carried out by the Minnie Pearl Cancer Research Network, investigators reported results on 57 patients with LS-SCLC, 45 of whom received planned treatment with irinotecan/carboplatin and radiotherapy, and 41 of whom received planned treatment with irinotecan/carboplatin/radiotherapy followed by maintenance bevacizumab.

Treatment consisted of carboplatin given at an AUC 5 on day 1; irinotecan 50 mg/m2 on days 1 and 8 every 21 days for four cycles; and radiotherapy given at a dose of 1.8 Gy daily to a total dose of 61.2 Gy, beginning with the third cycle. “Patients were restaged after four cycles,” investigators reported, “and if there was no evidence of progressive disease, patients received bevacizumab 10 mg/kg intravenously every two weeks for a total of 10 doses or until progression.” Follow-up ranged from 14 to 28 months.

The overall response rate was 80% (CR and PR combined), while median survival was 17.5 months. Some 53% of patients were alive and had not progressed at one year. At two years, the PFS rate was 38%; at one year, 70% of patients were still alive, as were 29% at two years.

Dr. Spigel concluded, “Right now, it’s too early to know if bevacizumab adds anything to the maintenance setting in this disease. But what we did see is that treatment is very well tolerated in this setting and it provides a rationale for further study in both limited-stage and extensive-stage SCLC.”