Nir Peled MD, PhD, FCCP, Head of the Thoracic Cancer Unit, Thoracic Cancer Service, Davidoff Cancer Center, Petah Tikva, Israel
Onkologie 30. Juni 2016
“The importance of first-line and second-line targeted agents is obvious”
As the EGFR TKIs showed comparable PFS results in the big studies, toxicity is a selection criterion. Gefitinib, erlotinib and afatinib have similar toxicity profiles, but according to our daily experience, diarrhoea tends to occur more often with afatinib, as well as nail abnormalities, which can become a significant burden for many patients. We can control both diarrhoea and skin eruptions, but nail issues and paronychia are less well controlled; indeed, often they force us to decrease the afatinib doses. Patients can switch to another EGFR TKI if they are in need of increased tolerability. However, the LUX-Lung 7 trial, which was a direct comparison of afatinib and gefitinib, revealed a 27 % reduction in the risk of progression or death with afatinib over gefitinib . Another aspect is that a combined study analysis showed that patients with exon 19 abnormalities derive an OS benefit from afatinib treatment over chemotherapy , whereas the trials conducted with the other EGFR TKIs were not able to show OS improvement compared to chemotherapy in the first-line setting. This might also be a consideration.
In our daily practice, we take into account the type of mutation and the physical appearance of the patient. If the patient is an old lady with a body weight of 50 kg, afatinib would not be my first choice, but a young or middle-aged person with exon 19 mutation or other mutations can benefit from this treatment. Some of our patients also have HER2 aberrations, such as amplifications or mutations, on top of EGFR-activating mutations. These patients might experience an advantage due to the dual HER2 and EGFR blockade conferred by afatinib. Also, afatinib covers uncommon mutations, especially those in exon 18. Another consideration are brain metastases. Afatinib shows a favourable response rate of approximately 30 % with regard to brain lesions. I would consider afatinib for patients with brain metastases, rather than other EGFR TKIs. The other TKIs elicit brain responses too, but not as well as afatinib.
What about the second-line setting?
What are the current recommendations with respect to the management of brain metastasis?
If we observe responses of the extracranial lesions, and at the same time, cerebral progression, this means that the drug does not penetrate the blood-brain barrier well enough. In this situation, the administration of bevacizumab is an option, as well as radiation of the brain. An interesting phase II study yielded a median PFS of 16 months with first-line bevacizumab plus erlotinib in patients with advanced EGFR-mutation-positive NSCLC . Another phase II first-line trial showed a median PFS of 14.4 months with the combination of bevacizumab and gefitinib . These results exceed those obtained with any of the EGFR TKIs as a single agent. For the time being, this approach is based on phase II data only, but I hope it is going to be approved by the FDA soon. It is a very interesting option for many patients.
How is the role of re-biopsy currently defined?
What notable advances have recently been made in the field of molecular diagnostics?
A technology I expect to be implemented in many countries in the next 1 or 2 years is droplet digital PCR. This works via automated systems, requires a much smaller amount of tissue than the other methods, and is highly sensitive, highly specific, and has low cost. For the time being, liquid biopsy is only used at the time of progression. In the future, we might perform repeated liquid biopsies during monitoring and change therapy as soon as different clones occur, but this approach is still subject to research.
1 Park K et al., Afatinib versus gefitinib as first-line treatment of patients with EGFR mutationpositive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial : Lancet Volume 17, No. 5, p577–589, May 2016
2 Yang JC et al., Afatinib versus cisplatin-based chemotherapy for EGFR-mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015; 16: 141-151
3 Yang J et al., Osimertinib (AZD9291) in pretreated pts with T790M-positive advanced NSCLC: updated phase 1 (P1) and pooled phase 2 (P2) results. J Thorac Oncol 2016; 11(4 Suppl): S152-3
4 Ricciuti B et al., Osimertinib (AZD9291) and CNS response in two radiotherapy-naïve patients with EGFR-mutant and T790M-positive advanced non-small cell lung cancer. Clin Drug Investig 2016 May 13 [Epub ahead of print]
5 Tan DS et al., The International Association for the Study of Lung Cancer consensus statement on optimizing management of EGFR mutation positive non-small cell lung cancer: status in 2016. J Thorac Oncol 2016; 11(7): 946-963
6 Seto T et al., Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harboring EGFR mutations (JO25567): an open-label, randomized, multicenter, phase II study. Lancet Oncol 2014; 15(11): 1236-1244
7 Ichihara E et al., Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001. J Thorac Oncol 2015; 10(3): 486-491
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