Metastatic NSCLC: New Findings, New Avenues to Explore

Article extracted from the ESMO 2014 onsite newspaper.

It is not surprising, therefore, that research into ways to improve patient outcome continues apace. Metastatic disease is particularly challenging. Metastases are often already established at diagnosis, and patients with metastatic non-small-cell lung cancer (NSCLC) generally survive less than 1 year. We have all seen the rise and fall of promising new treatment strategies and new anticancer drugs in lung cancer, as this disease is often drug-resistant upfront or rapidly develops drug resistance. Not only do we want effective new therapies for our patients, or combinations of existing therapies, we also need reliable biomarkers to better personalise anticancer treatment in lung cancer. These issues were discussed in presentations, including 3 late-breaking abstracts, at yesterday’s Proffered Paper Session on NSCLC, Metastatic 1.

A small phase III non-inferiority trial demonstrating comparable activity of pemetrexed/cisplatin and docetaxel/cisplatin doublet chemotherapy in the first-line treatment of stage IV non-squamous NSCLC was presented by Dr Young-Chul Kim from Chonnam National University Hwasun Hospital, Hwasun Gun, Korea. Among 149 patients, median progression-free survival (PFS) was 4.7 months with pemetrexed/cisplatin and 4.6 months with docetaxel/cisplatin. However, pemetrexed/cisplatin had a better safety profile, with less severe (febrile) neutropenia compared with docetaxel/cisplatin.

A clue as to which patients most benefit from cisplatin/pemetrexed chemotherapy was provided by Dr Myung-Ju Ahn from Sungkyunkwan University School of Medicine, Seoul, Korea. Dr Ahn presented some supporting evidence that thymidylate synthase (TS) expression may be a useful biomarker for predicting outcome in the second-line treatment of metastatic NSCLC. Among 315 patients with advanced non-squamous NSCLC, TS-negativity by immunohistochemistry was significantly associated with higher response rates (38% versus 21%; p=0.007 for interaction) and improved PFS (6.4 versus 5.5 months; p=0.013 for interaction) in patients receiving pemetrexed/cisplatin as compared with gemcitabine/cisplatin. Although there was no between-treatment difference in overall survival (OS) with regard to TS expression, TS-negativity was an independent, favourable prognostic factor for OS (hazard ratio [HR] 0.64; 95% confidence intervals 0.45–0.90).

Another biomarker, folate receptor (FR) overexpression, may be useful for therapy selection for certain groups of patients with NSCLC. From a phase II trial in 199 patients with FR-expressing NSCLC, Dr Nasser Hanna from Indiana University, Indianapolis, IN, USA, presented results showing that adding the FR-targeted drug vintafolide to docetaxel second-line significantly improved OS compared with docetaxel alone in a subgroup of patients with adenocarcinoma (HR 0.51; p=0.0147). However, no benefit of vintafolide was seen in the overall patient group.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are an established part of treatment for patients with EGFR-mutated NSCLC and two trials provided more detailed insight into the role of these agents.

A phase II, open-label, single-arm study, suggested that continuation of erlotinib after disease progression (PD) was feasible and active, according to Professor Keunchil Park from Sungkyunkwan University School of Medicine, Seoul, Korea. Of the 207 patients treated, 150 had PD (RECIST v1.1) at data cut-off and 81 patients continued erlotinib post PD at the investigator’s discretion. The median PFS at PD (PFS1) was 10.8 months overall and 11 months in patients with exon 19 deletion/L858 mutations. Patients who continued erlotinib had a post-PD PFS of 3.7 months. As outlined by the presenter, identifying those patients most likely to benefit from this approach is the next hurdle.

Data from the largest prospective, randomised phase III trial comparing the reversible EGFR TKI erlotinib with the irreversible EGFR TKI afatinib in relapsed/refractory squamous cell NSCLC (LUX-LUNG 8) showed afatinib to have only marginal efficacy benefits over erlotinib. According to Dr Glenwood Goss from the University of Ottawa, ON, Canada, 669 patients failing first-line platinum-based chemotherapy received either afatinib or erlotinib. Significant benefits for afatinib over erlotinib were seen in median PFS (2.4 months versus 1.9 months; p=0.043) and disease control rates (45.7% versus 36.8%; p=0.02). Treatment-related grade ≥3 diarrhoea and stomatitis were more common with afatinib than erlotinib. Overall, the small benefit of afatinib as compared with erlotinib is not clinically relevant and associated with an increase in diarrhoea and stomatitis.

The small benefit of afatinib compared with erlotinib in relapsed/refractory squamous cell NSCLC is not clinically relevant

What are the conclusions from these presentations? Immunohistochemical expression of TS (pemetrexed) and folate receptor (vintafolide) are promising new biomarkers to individualise second-line treatment of metastatic NSCLC. Pemetrexed/cisplatin will remain the standard first-line treatment over large parts of Europe, given the superiority against cisplatin/gemcitabine seen in the large Scagliotti trial¹ and the favourable safety profile of pemetrexed.

Pemetrexed/cisplatin will remain the standard first-line treatment for advanced NSCLC over large parts of Europe

We can also say that to all intents and purposes, afatinib and erlotinib are equally efficacious in the treatment of EGFR-mutated NSCLC. Finally, progress in lung cancer will come from improved patient selection for molecularly targeted treatment, realising that chemotherapy may also be targeted if we can identify the right biomarkers. Slowly but surely we are making progress in this aggressive disease. 

Reference

Scagliotti GV et al. J Clin Oncol 2008;26:3543-51