• Respiratory Cancers
• Cancer
• Pulmonary Guidelines Genomics

• Respiratory Cancers
• Cancer
• Pulmonary Guidelines
• Oncology Genomics
• Oncology

During the past 50 years, substantial progress has been made in the treatment of the most common type of lung cancer, non–small cell lung cancer (NSCLC).

Heather Wakelee, MD, Stanford University, Stanford, California, USA, reviewed adjuvant therapy in NSCLC. A meta-analysis of >1300 patients enrolled in 8 clinical trials published in 1995 generated enthusiasm for the use of cisplatin in the adjuvant setting, reporting a 5% survival benefit at 5 years that did not quite achieve significance (p=0.08) [Non–small Cell Lung Cancer Collaborative Group BMJ 1995]. After disappointing outcomes obtained with adjuvant cisplatin-based regimens from multiple randomized Phase 3 trials, the International Adjuvant Lung Cancer Trial [IALT] (n=1867) found a 4% 5-year survival benefit to adjuvant cisplatin (p<0.03) [Arriagada R et al. N Engl J Med 2004]. The long-term follow-up of IALT in 2009 was disappointing in that the HR for overall survival (OS) was no longer significant (p=0.10), but the benefit on disease-free survival persisted (p=0.02) [Arriagada R et al. J Clin Oncol 2010]. Later adjuvant chemotherapy trials in which a doublet of cisplatin and vinorelbine was used maintained their survival benefits even with long-term follow-up. One such trial was the Adjuvant Navelbine International Trialist Association [ANITA], which reported an OS HR of 0.80 (p=0.017) [Douillard JY et al. Lancet Oncol 2006].

The Lung Adjuvant Cisplatin Evaluation [LACE] meta-analysis included 4584 patients from the 5 largest post-1995, randomized, adjuvant cisplatin–based trials, and it found an absolute survival benefit of 5.4% at 5 years (HR, 0.89; p=0.005) in favor of chemotherapy [Pignon JP et al. J Clin Oncol 2008]. The survival benefit in LACE was stage dependent: a significant benefit was observed for stages II and III, with no benefit for stage IA and a borderline benefit for stage IB. The larger-updated NSCLC Collaborative Group meta-analysis produced results concordant with those of LACE [Arriagada R et al. Lancet 2010]. Patients with stage IB NSCLC with tumor size ≥4 cm did appear likely to benefit from adjuvant chemotherapy, according to subanalyses of 2 trials.

The strongest evidence for adjuvant chemotherapy in NSCLC is with cisplatin and vinorelbine, but other cisplatin doublets have known efficacy [Kreuter M et al. Ann Oncol 2013]. Carboplatin is also used as adjuvant therapy despite the lack of randomized Phase 3 data to support it.

Predictive markers of chemotherapy sensitivity remain elusive. Prospective adjuvant trials are assessing the usefulness of ERCC1–RRM1, ERCC1–TS, ERCC1–epidermal growth factor receptor (EGFR) mutation, and BRCA1–RAP80 as biomarkers.

Targeted agents (ie, erlotinib and gefitinib) as adjuvant therapy for patients with EGFR-activating mutations or anaplastic lymphoma kinase translocations are under investigation, and they are awaiting a trial with positive outcomes.

In discussing the treatment of locally advanced stage III NSCLC throughout the past 50 years, combined-modality regimens for inoperable stage III NSCLC have almost tripled the median survival, said Karen Kelly, MD, University of California Davis, Sacramento, California, USA.

Stage III NSCLC patients are a heterogeneous population with distinct clinical subsets, making management challenging, she said. Radiation therapy has been the backbone for more than 50 years. Concurrent chemotherapy and radiation has been the standard of care for fit patients since the early 1990s, doubling the 2-year survival rate compared with thoracic radiotherapy alone [Dillman RO et al. N Engl J Med 1990]. Later, daily cisplatin with radiotherapy was associated with significantly improved survival over radiation alone, although at a cost of severe nausea and/or vomiting in >25% of patients [Schaake-Koning C et al. N Engl J Med 1992]. Concurrent cyclic chemotherapy (mitomycin, vindensine, and cisplatin) was superior to sequential chemotherapy on 5-year OS (16% vs 9%: p=0.03998) in a study conducted by the West Japan Lung Cancer Group [Furuse K et al. J Clin Oncol 1999]. In the United States, a similar trial by the Radiation Therapy Oncology Group also showed a survival advantage for the concurrent regimen compared to sequential therapy [Curran WJ et al. J Natl Cancer Inst 2011]. The survival advantage appears to be the result of local regional control, said Dr. Kelly, but is associated with more esophagitis [Auperin A et al. J Clin Oncol 2010].

Induction or consolidation chemotherapy has failed to show survival benefits over standard chemoradiation, but the role of consolidation therapy may depend on the chemotherapy regimen used during concurrent chemoradiotherapy, she said.

Exploiting the immune system is a promising approach to therapy in NSCLC. Tecemotide is a mucin 1 antigen-specific vaccine that induces a T-cell response; it failed to improve OS in a Phase 3 randomized study, but in the large subset of patients who received concurrent chemoradiation, the vaccine was associated with a significant 22% improvement in OS (p=0.016) [Butts C et al. Lancet Oncol 2014; Butts C et al. J Clin Oncol 2005].

Integration of novel cytotoxic and targeted agents into chemoradiotherapy, and the use of higher doses and alternative schedules of radiotherapy, has yet to be proven successful.

Martin J. Edelman, MD, University of Mexico, Albuquerque, New Mexico, USA, spoke about progress in the treatment of advanced NSCLC, noting that the value of treatment for essentially all fit patients with advanced disease is now well established in terms of significant improvement in both the quantity and quality of life. By 1990, consensus had emerged that platinum-based therapy was superior to best supportive care for patients with good performance status. Newer agents with single activity in NSCLC (i.e., vinorelbine, paclitaxel, docetaxel, gemcitabine, and irinotecan) in combination with cisplatin later proved superior to cisplatin alone on OS.

The equivalence of platinum doublet regimens was established in randomized, cooperative group studies, and it offered physicians a choice of regimens based on toxicity, scheduling considerations, and cost. There has been no advantage demonstrated from combining new agents, with the goal of avoiding platinum agents.

In patients with activating mutations of the EGFR, an EGFR tyrosine kinase inhibitor (TKI) has demonstrated superior progression-free survival over chemotherapy, but it provides no OS advantage because of crossover effects [Wu YL et al. Lancet Oncol 2014; Mitsudomi T et al. J Clin Oncol 2012; Rosell R et al. Lancet Oncol 2012; Yang J C-H et al. J Clin Oncol 2012; Zhou C et al. J Clin Oncol 2012; Zhou C et al. Lancet Oncol 2011; Maemondo M et al. N Engl J Med 2010; Mitsudomi T et al. Lancet Oncol 2010]. By 1 year, about half of patients treated with an EGFR TKI will need to move on to other therapy because of resistance, said Dr. Edelman. New agents have been designed against the mutated receptor, and they have shown significant activity in this setting with less toxicity (Table 1).

The advent of immunotherapy has been the most dramatic change in the treatment of advanced NSCLC in the past 2 years. Anti-PD-1 and anti-PD-L-1 antibodies have demonstrated activity, some with response rates that exceed 30%, in heavily pretreated patients [Brahmer JR et al. N Engl J Med 2012; Topalian SL et al. N Engl J Med 2012].

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