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PRIORITY PRESS - 35th Congress of the European Society of Medical Oncology

Milan, Italy / October 8-12, 2010

Lung cancer is responsible for 1.3 million deaths/year worldwide, more than melanoma and breast, colon, liver and kidney cancer combined. Approximately 85% of these patients have non-small-cell lung cancer (NSCLC). Recent developments include bevacizumab, a biologic agent targeting vascular endothelial growth factor and inhibiting tumour angiogenesis. Pivotal phase III trials E4599 and AVAiL showed that bevacizumab-based therapy followed by bevacizumab as a single agent until disease progression significantly improved clinical outcomes, compared with chemotherapy alone, in patients with advanced non-squamous NSCLC. Both trials met their primary end points: overall survival (OS) in E4599 (HR 0.79, P=0.003) and progression-free survival (PFS) in AVAiL (HR 0.75, P=0.003 and HR 0.82, P=0.03 for 7.5 mg/kg and 15 mg/kg, respectively). However, AVAiL did not demonstrate an improvement in OS.

Yet as Dr. Lucio Crinò, University Hospital of Perugia, Italy, reminded delegates here at ESMO, not all NSCLCs are the same. In Europe and North America, around 10% to15% of affected patients carry mutations in the epidermal growth factor receptor (EGFR) and a higher proportion in East Asian patients of 30% to 40%. When these patients are treated with the specific EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib, significantly longer PFS is observed compared with standard chemotherapy. Direct evidence for such an effect came from the landmark IPASS (Iressa Pan-Asia Study), explained Dr. Crinò, in which a clear separation was observed in the efficacy of gefitinib therapy according to EGFR mutation status. Since then, prospective studies in patients carrying EGFR mutations, notably the practice-changing NEJ002 study (N Engl J Med 2010;362:2380-8), have confirmed this finding. The results of the OPTIMAL study, presented here at ESMO by Prof. Caicun Zhou, Shanghai Pulmonary Hospital, China, now suggest that similar improvements in PFS are obtained with erlotinib in chemotherapy-naive patients.

Based on available evidence, Prof. Michael Cullen, Queen Elizabeth Hospital, Birmingham, UK, told delegates, “You cannot escape from the conclusion that a new biological variety of NSCLC has been identified for which there is a specific treatment, and the treatment works.” He explained that EGFR mutations not only define the cancer but are also “responsible for the malignant phenotype of the cancer cells.” First-line treatment with an EGFR TKI “can be used to reverse this malignant phenotype in around 70% of patients,” but since around 30% of patients never receive second-line therapy, Prof. Cullen told delegates that the “inescapable” conclusion must be that “patients with advanced NSCLC should, wherever possible, receive the best treatment first.”

IPASS and Other Study Findings

The importance of appropriate first-line treatment was highlighted during the presidential session led by Prof. Chih-Hsin James Yang, National Taiwan University Hospital, Taipei, who showed that the final OS results from IPASS revealed no difference between first-line treatment arms (HR 0.90; 95% CI, 0.79-1.02; P=0.109). According to Prof. Yang, substantial crossover in the prescription of second-line treatment might have acted as a confounder in this analysis and diluted the effect of gefitinib on this secondary outcome, making PFS a more appropriate measure of treatment outcome in these patients.

The finding that median OS was almost twice as long in mutation-positive than -negative patients (21.6 vs 11.2 months and 21.9 vs. 12.7 months in the TKI and carboplatin/paclitaxel arms, respectively) confirms the separation of NSCLC into 2 groups according to mutation status, explained Prof. Yang.

Dr. Jean-Charles Soria, Institut de Cancérologie Gustave Roussy, Villejuif, France, discussed the clinical implications of the IPASS results, including the suggestion that EGFR mutation acts as a positive prognostic factor in NSCLC. He reminded delegates that, despite the similarity observed in OS, front-line gefitinib offers greater symptom improvement, better quality of life, superior PFS and oral availability—echoing the call for “best treatment first” from Prof. Cullen and others.

The possibility of effective, targeted treatment is dependent upon mutation testing. Based upon experiences in Japan, Dr. Tetsuya Mitudomi, Aichi Cancer Center Hospital, Nagoya, showed that the adoption rate of EGFR mutation testing has increased rapidly since approval of health insurance coverage in 2007. Furthermore, decisions on testing should not be based on clinical criteria such as smoking status (non-smokers), delegates heard. For instance, a study of 679 Japanese patients described by Dr. Mitudomi found that a substantial proportion of smokers (50% of women and 30% of men with adenocarcinoma) carried EGFR mutations.

Presentations here in Milan thus provided hope for targeted therapy in NSCLC according to EGFR mutation status. To achieve this goal, it was argued that mutation testing should not be restricted on the basis of clinical criteria in patients with advanced disease and that mutation-positive patients should receive EGFR TKIs such as gefitinib as first-line therapy.

ATAC: 10 Years On

Prof. John Forbes, University of Newcastle, Australia, presented results of a 10-year follow-up analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial here at ESMO. He told delegates that “anastrozole is clearly significantly superior to tamoxifen” in terms of disease-free survival, breast cancer recurrence and development of contralateral breast cancer in patients with hormone receptor-positive breast cancer.

The trial, which compared the aromatase inhibitor (AI) anastrozole 1 mg/day with tamoxifen 20 mg/day, alone or in combination, as primary adjuvant therapy in women with localized invasive breast cancer, began in 1996. Following treatment discontinuation after 5 years, blinded clinic-based follow-up has now continued for at least 10 years (median follow-up 120 months). In this rare opportunity to assess the ongoing effects of breast cancer treatment over such a long follow-up period, Prof. Forbes showed strong statistical evidence that superiority of the AI was not only sustained but also displayed continued improvement for important outcome measures at least 5 years after completion of treatment.

Disease-free survival remained superior in anastrozole- vs. tamoxifen-treated patients at 10 years (HR 0.86, P=0.03). Analysis of time to recurrence of breast cancer revealed a “striking carryover effect” in which the 2.7% absolute difference between anastrozole and tamoxifen at 5 years increased to 4.3% at 10 years. Further statistical support for this effect was provided in the form of a smoothed hazard plot, showing that the event rate with tamoxifen remained higher than with the AI after completion of treatment. Also, there was no statistical heterogeneity across subgroups and no evidence of reduced efficacy in node-negative patients (“quite the opposite,” remarked Prof. Forbes).

The effect was even stronger for the time to distant recurrence, which Prof. Forbes indicated was likely to reflect breast cancer deaths. In this case, the absolute difference between anastrozole and tamoxifen at 10 years (2.6%) was double that observed at 5 years (1.3%). Deaths after recurrence, which are largely breast cancer deaths, were reduced by 13% (HR 0.87, P=0.09). Although this effect was not statistically significant, Prof. Forbes argued that the wealth of supporting information on the effects of AIs nevertheless supported a real, clinically significant reduction that was unlikely to be based on chance.

The effect of anastrozole on the occurrence of contralateral breast cancer “clearly suggests that an AI may be effective in primary prevention of breast cancer,” argued Prof. Forbes. Pointing out that the effect of tamoxifen on contralateral breast cancer was the key factor behind the primary prevention trials for that agent, he highlighted the finding that the absolute difference at 10 years (1.7%) with anastrozole was twice that observed at 5 years (0.8%). In terms of safety, Prof. Forbes reported, “After 5 years of treatment, there is no excess fracture rate and no new morbidity or mortality concerns.”

Follow-up of patients from the ATAC trial will now be continued in the LATTE (Long-term Anastrozole vs Tamoxifen Treatment Effects) study. This study will extend the analysis to 15 years, making it potentially the longest study in breast cancer to demonstrate continued efficacy and safety.