For this month and next month, Dr Christy Russell and I will be covering some of the data from this year’s American Society of Clinical Oncology^® (ASCO) meeting. In this edition, I will review for you a number of the presentations and posters concerning hematologic malignancies, gastrointestinal (GI) cancers, lung cancer and head & neck cancers. In August, Dr Russell will cover breast cancer, genitourinary (GU) cancers, and other areas.

Presentations from the Lung Cancer Sessions

There were 5 presentations in the lung section that I believe are worth reviewing.

Abstract 8007: Molecular and clinical predictors of outcome for cetuximab in non-small cell lung cancer (NSCLC): Data from the FLEX study by Dr Ken O’Byrne, et al

As you may recall, the FLEX study was presented at ASCO last year. FLEX is a phase III randomized trial in first-line therapy of advanced non-small cell lung cancer (NSCLC) randomizing patients to cisplatin-vinorelbine with or without cetuximab. The FLEX study demonstrated an increase in both OS and 1-year survival in all histologic subgroups with the addition of cetuximab to cisplatin-vinorelbine (CT). This examination of molecular and clinical predictors included KRAS mutational status and epidermal growth factor receptor (EGFR) gene copy number, which were well balanced in both treatment arms. The authors also looked at the predictive value of any degree of cetuximab-related rash on outcome. Satisfactory tissue samples for biomarker analysis were available from 35% of the FLEX trial patients. Nineteen percent of the patients with satisfactory tissue samples in the FLEX trial were KRAS mutated, and 81% were KRAS-wild type (wt) in both arms of the study. Survival curves were over-lapping for KRAS-wt and KRAS-mutant in both arms of the study. While there was a small numerically better OS in the KRAS-wt group compared to the KRAS-mutant group in each arm, these differences did not approach statistical significance. Progression-free survival by KRAS mutation status also showed no statistical difference between the 2 treatment arms. The hazard ratios for response rate by KRAS mutation were also non-significant. Twenty-five percent of the study population had tissue samples satisfactory for EGFR gene copy number testing by FISH. Approximately 37% were FISH-positive and 63% FISH-negative in both treatment arms of the study. Once again, the OS curves for FISH-positive versus FISH-negative in both treatment arms overlap with no significant differences. Neither PFS nor response rate were significantly affected by FISH status in either treatment arm. The authors then, in a pre-planned analysis, examined the occurrence of an acne-like skin rash after the first cycle of therapy with CT + cetuximab, and its predictive value on outcome. Five hundred eighteen patients were included in this analysis. Forty-four percent had no evidence of rash. Grade 1 rash was seen in 33%, grade 2 rash in 18%, and grade 3 rash in 5%. The presence or absence of rash was not dependent on gender, histology, smoking status, stage or performance status. However, any degree of rash in the first cycle of therapy was associated with an OS of 15.0 months compared to an OS of 8.8 months for those patients without a rash. This was statistically significant with a P value of <.001 and a HR = 0.631. The intensity of the skin rash did not significantly impact on the OS results.

The authors concluded that:

1. Cetuximab added to standard chemotherapy improves the OS in first-line therapy for patients with NSCLC regardless of KRAS mutational status or EGFR gene copy number.
2. First-cycle rash is a clinical biomarker predictive of improved OS with cetuximab.

Abstract CRA8000: Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC) by Dr Chandra Belani, et al

Dr Belani presented the final results of a randomized phase III study in advanced NSCLC in this abstract. The initial results of this study had been presented 1 year ago by Dr Cuileanu. After 4 cycles of a standard first-line platinum-based chemotherapy regimen that did not include pemetrexed, patients who had shown non-progression were randomized in a 2:1 ratio to pemetrexed every 21 days or placebo. All patients received B12 and folic acid. Six hundred sixty patients were randomized. Progression-free survival was the primary endpoint. The 2 treatment arms were well balanced. Over 70% of patients had non-squamous histology, and 27% were never-smokers. Gemcitabine plus cisplatin/carboplatin and paclitaxel-carboplatin were the most common front-line regimens used in this trial. Median follow-up on this maintenance trial is now about 1 year. Approximately half the patients on the PEM arm completed 6 cycles, and 23% completed 10 cycles. Only 28% of patients on the placebo arm completed 6 cycles. Progression-free survival for the PEM arm is 4 months versus 2 months for the placebo arm. The P value is <.00001. In the non-squamous patients, the PFS was 4.4 months versus 1.8 months. There was no difference in PFS among the patients with squamous cell carcinoma between PEM versus placebo. Overall survival in the intent-to-treat (ITT) population demonstrated a statistically significant improvement with PEM at 13.4 months versus 10.6 months for placebo. The P value was .012. Once again, this significant OS improvement was seen only in the histologic groups with non-squamous histology (15.5 months vs 10.3 months). The disease control rate during this maintenance trial was 49% for PEM versus 29% for the placebo. Grade 3-4 adverse events were ≤5% for the PEM arm for both hematologic and non-hematologic events.

The post-study systemic therapies evaluation showed that 67% of the patients who received placebo received post-study systemic agents compared to only 52% of the patients treated with PEM.

Abstract 8001: SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following non-progression with first-line platinum-based chemotherapy in patients with advanced NSCLC by Dr Frederic Cappuzzo, et al

In this trial, 1949 patients were initially registered for platinum-based front-line chemotherapy and tissue sampling. Eight hundred eight-nine non-progressing patients were then randomized in a 1:1 ratio to erlotinib or placebo maintenance until PD. Primary endpoints included PFS in all patients, and PFS in those patients who were EGFR-positive by immunohistochemistry (IHC). Patients were stratified by EGFR status, stage, performance status, smoking history, front-line chemotherapy regimen and geographic region. The 2 arms were well balanced with approximately 45% of patients having adenocarcinoma and 40% having squamous cell carcinoma. The primary endpoint of PFS in all patients was met with a HR of 0.71 and a P value of <.0001. Progression-free survival at 12 weeks was 53% for erlotinib versus 40% for placebo. At 24 weeks, the PFS was 31% versus 17%. The PFS percentages in the EGFR-positive groups were similar and also statistically significant. During the maintenance phase, 11.9% of patients on the erlotinib arm experienced either a PR or CR versus 5.4% on the placebo arm. Disease control rates during the maintenance phase were 60.6% versus 50.8% with a P value of .0035. Although patients with adenocarcinoma seemed to benefit more, the forest plot demonstrated that the HR for squamous cell patients was also <1.0 and within the confidence interval. Benefit from erlotinib was greatest for never smokers and somewhat less for former smokers, but even current smokers derived significant benefit.

Overall survival data is not mature as yet. Epidermal growth factor receptor mutation analysis was performed in 50% of patients. In those patients with a documented EGFR mutation, the HR for PFS benefit from erlotinib versus placebo was 0.10 and the P value was <.0001. Rash was seen in 60% of patients treated with erlotinib. Fifty-five percent of erlotinib treated patients received post-study systemic treatment compared to 64% of the placebo treated patients.

Abstract LBA8002: A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) by Dr Vincent Miller, et al

In this trial, 1160 patients were treated with 4 cycles of first-line platinum-based therapy. Seven hundred sixty-eight non-progressing patients were randomized in a 1:1 ratio to receive bevacizumab-erlotinib or bevacizumab-placebo until PD. Progression-free survival was the primary endpoint. Median follow-up at the time of the presentation was 8.3 months. Seven hundred forty-three patients were evaluable for response. Treatment arms were well balanced. Eighty-one percent of patients had adenocarcinoma. Progression-free survival was significantly in favor of the bevacizumab-erlotinib arm with a HR of 0.722 and a P value of .0012. Progression-free survival equaled 4.76 months for bevacizumab-erlotinib versus 3.75 months for bevacizumab-placebo. Progression-free survival at 6 months was 67.7% for bevacizumab-erlotinib and 53.4% for bevacizumab-placebo. Never smokers derived significantly more benefit than did current or former smokers. Post-study systemic therapy did vary significantly between arms. Grade 3-4 adverse events were more common in the bevacizumab-erlotinib arm at 44.1% versus 30.4% in the bevacizumab-placebo arm. Rash and diarrhea were the most common grade 3-4 events. There were also twice as many grade 5 events in the bevacizumab-erlotinib arm (8 events versus 4 events). Pulmonary hemorrhage and gastrointestinal (GI) perforation were rare.

Abstract CRA8003: Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZODIAC) by Dr Roy Herbst, et al

Vandetanib is an oral tyrosine kinase inhibitor (TKI) with potential to inhibit vascular endothelial growth factor receptor (VEGFR)–2, VEGFR3, RET and EGFR at a dose of 100 mg per day. A previous trial documented safety and efficacy of vandetanib plus docetaxel. A similar trial, ZEAL, combining vandetanib with pemetrexed was also presented at ASCO. In the ZODIAC trial, 1391 patients with disease failure after first-line platinum based therapy were randomized in a 1:1 ratio to docetaxel 75 mg/m² plus vandetanib 100mg/day (D-V) versus docetaxel 75 mg/m² plus placebo (D-P). Progression-free survival was the primary endpoint. Twenty-five percent were non-smokers. Twenty-five percent of patients had squamous cell carcinoma. Only 3% had received bevacizumab in the front-line. Median follow-up at data cut-off was 12.8 months. Fifty-eight percent to 60% of the patients had died at the time of data cut-off. Objective response rate was significantly better for the D-V arm at 17% versus 10% for the D-P arm with a 2 sided P value of .001. Progression-free survival curves separated early and stayed separated throughout the follow-up period favoring the D-V arm with a HR = 0.79 and a P value <.001. Progression-free survival for D-V is 4.0 months compared to 3.2 months for D-P. The PFS benefit was similar in all histologic types. Overall survival difference was not significant at 10.6 months versus 10.0 months with a P value of .196. Overall survival for females was greater than for males, but even for females there was no significant difference in OS between the 2 treatment arms. The OS at 12 months in the D-V arm was 44.7% versus 41.2% for the D-P arm which was again not statistically significant.

Dr Herbst made a strong effort to point out that there was a statistically significant difference in the time to deterioration in symptoms in favor of the D-V arm. The only adverse events significantly increased in the D-V arm were rash, neutropenia, diarrhea and hypertension, but nausea, vomiting and anemia were less frequent. There was no increase in bleeding or thrombotic events, and prolongation of the QTc interval was seen in <2% of patients treated with D-V.

OncoFacts™ Editor:

James Epstein, MD

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