By Matteo Giaj Levra, MD, and Silvia Novello MD, PhD
In September, the 2016 ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up of metastatic nonsmall cell lung cancer (NSCLC) were published. These guidelines outline many new recommendations updated from the 2014 version, following trends of innovation during the last 2 years in the field of thoracic oncology.
Without question, the big “revolution” and major change in this field is represented by immunotherapy: nivolumab, the PD-1 immune-checkpoint-inhibitor antibody, is now approved by the European Medicines Agency (EMA) after failure of first-line treatment for both squamous cell carcinoma (SCC) and non-squamous NSCLC. The results of the CheckMate 017 study showed a significant improvement in overall survival (OS) for patients with SCC treated with nivolumab (3 mg/kg every 2 weeks) compared with docetaxel (9.2 versus 6 months, HR 0.59, p < 0.001), together with a better toxicity profile.1 In non-squamous NSCLC, the results of CheckMate 057 study also showed a benefit for OS compared with docetaxel (12.2 versus 9.4 months, HR 0.73, p=0.002), despite a small excess of early progression and/or death in the nivolumab arm.2 A retrospective, unplanned analysis revealed an association between efficacy of nivolumab and PD-L1 tumor membrane expression, but nivolumab is approved in non-squamous NSCLC regardless of PD-L1 status.
Recently, the FDA and EMA also approved another anti-PD-1 antibody, pembrolizumab (2 mg/kg every 3 weeks), for the treatment of NSCLC regardless of histology after failure of first-line in patients with tumors expressing PD-L1.3
Immunotherapy is only one of the new components in the updated guidelines: oncogene-addicted tumors are the other side of the coin in metastatic NSCLC with the advent of new therapeutic approaches. For EGFR-mutant tumors that progress after first-line tyrosine kinase inhibitors (TKIs), the approval of osimertinib in patients with the exon 20 T790M resistance mutation has changed how we approach these patients and has raised the challenge of tumor re-biopsy at progression as well as the issue of tissue availability. In the new guidelines, liquid biopsy constitutes a new strategy for tumor genotyping, and is now an approved diagnostic approach to detect the resistance mutation and enable us prescribe the targeted drug.4,5 Without doubt, this is a major change for a disease where tissue is still the issue.
With a significant delay from the FDA approval, in the ALK-rearranged disease, crizotinib should be administered first-line according to the results of the PROFILE 1014 study, which showed a relevant benefit for progression-free survival (PFS) and overall response rate (ORR) compared with standard chemotherapy. 6 The advent of new anti-ALK agents such as ceritinib and alectinib will definitively change our treatment scenarios in the “ALK disease,” especially in patients with brain metastases. We eagerly await EMA approval for these second-generation agents.7,8
First-line treatment for the nononcogene addicted disease is still the province for chemotherapy, and the new guidelines consider a new targeted agent, necitumumab, for treatment-naive SCC; this has been approved in combination with cytotoxic agents. Necitumumab is an IgG1 human antibody against EGFR, which in combination showed a significant OS (11.5 versus 9.9 months, HR 0.84, p=0.01) and PFS improvement compared to the chemotherapy doublet alone. A retrospective analysis showed that tumors with positive EGFR expression by immunohistochemistry (IHC) benefited from triplet treatment, leading to the approval of necitumumab in this set of patients.9
Europe is extremely heterogeneous, and the diverse approval processes and country-based drug reimbursement systems make the management of advanced NSCLC even more complicated as new agents descend on the market. These new findings, however, underscore the critical need of generating updated common guidelines. ✦
1. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-135.
2. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627-1639.
3. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1- positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016; 387:1540–1550.
4. Douillard J-Y, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, singlearm study. Br J Cancer. 2014;110(1):55-62.
5. Oxnard GR, Thress KS, Alden RS, et al. 135O_ PR: Plasma genotyping for predicting benefit from osimertinib in patients (pts) with advanced NSCLC. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2016;11(4 Suppl):S154.
6. Solomon BJ, Mok T, Kim D-W, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167-2177.
7. Kim DW, Mehra R, Tan DS, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): Updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016; 17:452–463.
8. Ou S-HI, Ahn JS, De Petris L, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small- Cell Lung Cancer: A Phase II Global Study. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(7):661-668.
9. Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763-774.