NEWS FROM ESMO

This section of the newsletter will be dedicated to summaries of several important abstracts from the 33rd European Society for Medical Oncology (ESMO) Congress in Stockholm, Sweden on 12-16 September 2008. A special Clinical Update based on information presented at a Satellite Symposium during ESMO entitled “Responding to the Challenge of Advanced Melanoma” will conclude this portion of the newsletter.

Targeted Therapy Better Than Chemotherapy for NSCLC?

In Asia, a high proportion of non-smokers develop NSCLC with adenocarcinoma histology. Fifty to sixty percent of them have tumors with mutations in the epidermal growth factor receptor (EGFR) that are responsive to therapy with EGFR tyrosine kinase inhibitors (TKIs). Investigators designed a phase III randomized trial of 1,217 Asian non-smokers with stage IIIB/IV adenocarcinoma of the lung, chemo-naive, to receive oral gefitinib (Iressa™) (G) 250 mg daily or carboplatin + paclitaxel (C/P) chemotherapy. Primary endpoint was to assess non-inferiority of G vs C/P for PFS. Results: G demonstrated superior PFS compared with C/P (HR 0.74; p<0.001), exceeding the primary endpoint. Treatment effect was not constant over time, favoring C/P for the first 6 months and G for the remaining 16 months, probably driven by differences in PFS outcomes for patients with EGFR mutation M(+) and M(-) tumors. ORR was significantly higher with G than C/P (43% vs 32.2%, odds ratio [OR] 1.59; p=0.0001). QoL and tolerability profiles were significantly higher for G. PFS was longer for G than C/P in M(-) patients. The authors conclude that this study has demonstrated superior treatment outcomes for G over standard chemoRx as first-line treatment for this clinically selected population. They believe that gefitinib should be one of the standard first-line therapies for such patients.

Comment: Gefitinib and other EGFR TKIs are now considered as second-line therapy after failure of chemoRx, but in this special patient population they should be considered for use as initial treatment.

Mok T, et al. LBA2 Annals of Oncology 19 (Supplement 8) 2008.

A Promising New Option for Relapsed/Recurrent Ovarian Cancer

Trabectedin (Yondelis®) is a novel agent originally extracted from sea squirts and now prepared by a semi-synthetic process. A phase III study of a trabectedin (T) combined with pegylated liposomal doxorubicin (PLD) vs PLD alone in relapsed, recurrent ovarian cancer (OC) has demonstrated that the PLD + T combination is superior to PLD in both the primary endpoint PFS, and secondary endpoint of response rate (RR). The trial enrolled 672 patients whose disease progressed after response to first-line therapy. The patients’ median age was 57, and 64% had a platinum-free interval (PFI) > 6 months. Results: Median PFS for PLD + T was 7.3 months and for PLD 5.8 months (HR=0.79; p=0.019). For patients with a PFI > 6 months, the median PFS was 9.2 months for PLD + T vs 7.5 months for PLD alone (HR=0.73; p=0.017). RR for all patients: 28% vs 19% (p=0.008) and if PFI > 6 months: 35% vs 23%. Adverse events were manageable with appropriate monitoring.

This is one of the largest studies designed to establish clinical activity of a non-platinum doublet in second-line treatment of OC. Positive trials in recurrent OC are rare, so these results are quite encouraging.

Monk BJ, et al. LBA4 Annals of Oncology 19 (Supplement 8) 2008.

TKI Shows Activity in Head and Neck Cancer

Lapatinib (Tyverb®), an orally active dual tyrosine kinase inhibitor (EGFR and HER2) currently approved in the United States for treatment of advanced breast cancer, has demonstrated single-agent activity in another cancer, locally advanced squamous cell carcinoma of the head and neck (SCCHN). EGFR overexpression is found with high frequency in many cancers including H+N cancer and typically is associated with a more aggressive clinical course. A phase II study of therapy-naive SCCHN patients randomized participants to receive either lapatinib or placebo for 2 to 6 weeks prior to standard concurrent platinum-based chemoRx and radiation. Results showed an improved response rate (CR and PR) for patients given lapatinib of 86% vs 63% for placebo. A CR rate after receiving chemoradiation was seen in 28% in lapatinib arm vs only 7% in the placebo arm, suggesting lapatinib may enhance the effect of subsequent chemoradiation.

Del Campo JM, et al. Abstract 6880 Annals of Oncology 19 (Supplement 8) 2008.

Clinical Update From ESMO: Advanced Melanoma

This Clinical Update is based on information presented during a satellite symposium at the ESMO Congress on 14 September 2008 entitled, “Responding to the Challenge of Advanced Melanoma”. Jeffrey Weber, MD, PhD, from the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida discusses the topic “Enhancing the Anti-Melanoma Activity of T-cells by Targeting the CTLA-4 Receptors,” and this update features highlights from his presentation. The entire program may be viewed as a webcast at www.primeoncology.org.

Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) is a negative regulator of T-cell response and can exert a suppressive effect on the immune response against melanoma cells. Two human monoclonal antibodies directed against CTLA-4 have been studied in clinical trials: ipilimumab (an IgG1) which fixes complement and tremelimumab (an IgG2) which does not fix complement. The focus of this update will be ipilimumab (Bristol-Myers Squibb and Medarex).

Ipilimumab has been studied as monotherapy and in combination with vaccines, cytokines (IL-2), and chemotherapy. Significant antitumor activity has been seen in each of these treatment regimens. Side effects seen with inhibition of CTLA-4 are called immune-related adverse events (IRAEs) and are inflammatory in character. The most common of the IRAEs are rash, colitis, and hepatitis, and the occurrence of these events is generally associated with favorable anti-melanoma response. The timing of occurrence of antitumor responses is quite variable. It is important for clinicians to recognize the unique kinetics of response following ipilimumab administration. Indeed, some patients treated with ipilimumab may initially show disease progression followed by either prolonged stable disease or an objective response.

Currently, a phase III registration trial of ipilimumab for first line therapy of metastatic melanoma is ongoing. This trial will randomize 500 treatment naive patients to receive ipilimumab (10 mg/kg q 3 weeks x 4 cycles) + DTIC vs DTIC alone.

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