Looking for results in non-small-cell lung cancer: is bio-chemotherapy the right answer?

Keywords::

• Bio-chemotherapy
• Non-small-cell lung cancer
• Overall survival
• Progression-free survival

Non-small-cell lung cancer (NSCLC) is one of the major causes of cancer-related deaths, and treating patients with advanced disease can be a hard task, as NSCLC is incurable in this stage1.

The current standard of care for advanced NSCLC is based on systemic anti-neoplastic treatment, which can be constituted of chemotherapy or an inhibitor of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). It should be remembered that anti-neoplastic treatment has a palliative role in advanced NSCLC, and the main goals are the prolongation of progression-free survival (PFS) and overall survival (OS), as well as preventing or delaying cancer-related complications. In this setting, the achievement of an objective response has been commonly seen as a surrogate end-point for PFS and OS2–5, and the most active regimens are usually preferred in chemotherapy-naïve patients. First-line chemotherapy is commonly represented by a regimen containing a platinum derivate (cisplatin or carboplatin) and a third-generation drug6, while EGFR can be targeted through reversible tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, or through irreversible inhibitors, like the recently approved afatinib. Additionally, the monoclonal antibody bevacizumab, directed against the vascular endothelial growth factor (VEGF), has been employed in combination with platinum-based chemotherapy (carboplatin–paclitaxel or cisplatin–gemcitabine); the inclusion of bevacizumab in first-line chemotherapy has achieved good results in terms of response rate (RR) and survival7.

It is known that, sooner or later, patients affected by advanced NSCLC are destined to experience progressive disease despite receiving first-line treatment; in such circumstances, further therapy can be taken into consideration, considering that the aim of a second-line treatment is still represented by survival prolongation and symptom control8. The second line is usually characterized by lower outcomes in terms of RR and survival benefit compared to the first line; additionally, pre-treated patients progressing after previous treatment may suffer from a significant worsening of clinical conditions, hence being unable to receive further drugs9. For these reasons, clinical oncologists are often called to select the patients who will most likely benefit from further treatment. The available drugs approved for second line in advanced NSCLC include two chemotherapeutical agents (docetaxel and pemetrexed), and an EGFR-TKI (erlotinib). Recently acquired data suggest that chemotherapy might be more effective than targeted therapy in previously treated patients who are unselected for specific molecular targets10, although the reported results raised some concern; to date, the question of which treatment modality (chemotherapy or EGFR–TKI) is more appropriate in clinical practice in the second line remains unanswered11.

Since achievements of both chemotherapy and targeted drugs in pre-treated patients are limited, especially in comparison with the first line, increasing efforts are being made in order to improve results in terms of response and survival. An appealing option for previously treated patients could be represented by a combination including a single chemotherapeutical agent and a targeted agent, based on the assumption that this approach might result in improved response and survival, similar to that observed with bevacizumab-containing regimens in the first line.

Recently, Li et al. have presented a meta-analysis of 14 randomized controlled trials addressing this specific issue. The authors selected seven randomized phase II and seven randomized phase III trials comparing standard second-line chemotherapy (docetaxel or pemetrexed) in combination with a targeted agent versus chemotherapy alone (or chemotherapy plus placebo); targeted drugs included agents which are already employed in clinical practice (aflibercept, bevacizumab, cetuximab, erlotinib, vandetanib), as well as investigational agents (enzastaurin, ganetespib, matuzumab, nintedanib, selumetinib).

Taken together, these trials gathered 6922 patients.

The analysis of the global population indicated that combined bio-chemotherapy was associated with improved median PFS over chemotherapy alone (HR = 0.83; 95% CI, 0.78–0.87; P = 0.000), while no significant difference in terms of median OS was observed (HR = 0.95; 95% CI, 0.90–1.01; P = 0.081). Sub-group analyses indicated that bio-chemotherapy resulted in improved PFS in the trials employing docetaxel as a chemotherapeutical agent, and in trials employing vandetanib or nintedanib. Notably, non-squamous histology was associated with both PFS and OS benefit in targeted drug-containing arms. Both RR and disease control rate (DCR) were improved in the arms including chemotherapy and a targeted drug (P = 0.000 each). The price of combination treatment was a significantly higher incidence of grade 3–4 adverse events (AEs); in particular, higher frequencies of diarrhea (P = 0.000), neutropenia (P = 0.000) and thrombocytopenia (P = 0.001) were reported12.

These results suggest that, in spite of improved RR and PFS, the combination of biotherapy and chemotherapy in the second line for advanced NSCLC should be avoided in unselected patients, as the increased toxicity does not translate into survival improvement. The failure in translating PFS benefit into prolonged OS is a quite common result when new investigational agents or regimens are evaluated in oncology. It has been theorized that PFS could represent an inadequate surrogate end-point for OS for several reasons: it is possible that the time of occurrence of progressive disease in patients with an initial low burden of disease might not be sufficient to affect the time to death of these patients; in addition, a PFS difference that is considered statistically significant for the purpose of a clinical trial might not result into detectable OS differences; moreover, it has been hypothesized that continued exposure to some biological drugs may lead to the development of a more aggressive phenotype after progression13.

In conclusion, the choice of the optimal therapy for previously treated NSCLC patients is still challenging, and requires a wise balance between the expected benefits and the costs that each patient may be called to pay. Nevertheless, an approach involving bio-chemotherapy should not be completely disbanded, as patients harboring specific mutations might gain significant benefit. The increasing development of specific biomarker-driven agents, and the effort that is being made in order to determine which patients can gain the most significant benefits from currently available treatments, constitute an appealing direction of translational and clinical research, and could lead to a real ‘tailored’ approach for each patient; this approach could include chemotherapy, a selective biological agent, or both, according to the specific case. In this context, it is advised to conduct current and future research in lung cancer with a particular focus on molecular bio-markers and on the specificity of different sub-populations of patients.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

C.G., E.R., and F.G. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

Acknowledgments

The authors wish to express their gratitude to Dr. Giulia Barletta, Dr. Federica Biello, and Dr. Maria Giovanna Dal Bello for their support.