Algorithm of the metastatic NSCLC treatment.

   Abstract

   We have approached the ceiling for chemotherapy in advanced NSCLC, median survival being 8-10 months in randomized phase 3 trials. Adding 3rd active agent to platinum doublet did not increase efficacy, but increased toxicity. Exception to this were Bevacizumab and Cetuximab,with these agents in lung adenocarcinomas the median overall survival (OS) reached 12 months. When gefitinib was tried in Asiatic population, in EGFR positive tumors for activating mutations on exons 19 and 21, response rate (RR) was over 70 %, progression free survival (PFS) 9-10 months and median OS was around 2 years. Optimal and Eurtac trials with Erlotinib demonstrated similar efficacy, Eurtac in Caucasian population, with benefit also for male patients, current or ex-smokers and even for non-adenocarcinomas. Exon 19 was the best EGFR mutations for PFS. Many patients on these trials crossed over or had further lines of treatments, thus OS did not significantly differ. Adverse events were mainly rash or diarrhea.

   In second-line therapy the efficacy of Pemetrexed, Docetaxel or Erlotinib is equal, but convenience and toxicity profile are better with Erlotinib, which can be administered even for years. As we loose patients, about 40 % for each next line of treatment, it is important to administer the best treatment each line. INTEREST trial demonstrated that we can give patients Docetaxel as a 3rd line treatment without a loss of benefit.

   Many questions are still unanswered for maintenance therapy, i.e. chemotherapy vs targeted one, which Rx for adenocarci- noma vs squamous cell cancer, for responders vs non-responders to first-line chemotherapy, PS (performance status) 2 patients etc. The most important is to discuss this option with the patients, who know they have, most of the time, only months to live and often they need a break from their treatments.

   New generation, oral, irreversible ErbB receptor family inhibitor Afatinib has a high potency and selectivity for EGFR, HER2 and HER4. LUX- LUNG 1 trial was randomized, phase 3 trial, where 585 patients were randomized 2:1 to 50 mg Afatinib daily + BSC vs Placebo+BSC, primary endpoint was OS. Patients had to receive 1-2 chemotherapy regimens and had to be on EGFR- TKIs for at least 3 months without disease progression. Median duration of prior EGFR-TKIs was 10.2 months, 45 % patients had PR/CR on prior EGFR-TKIs. Median PFS was 3.3 months on Afatinib, 1.1 months on Placebo, HR=0.38, p<0.0001. Median OS 11.7 vs 11 months on Placebo vs Afatinib, HR=1.001, p= 0.502, seventy nine percent of patients on placebo arm received further lines of treatments.

   Conclusion:

   We are entering an era of personalized medicine, where each line of treatment will be on the basis of the tumor analysis. Re-biopsy of the tumor will be in order to analyze for possible development of new mutation/resistance mutation, and thus enable individualized treatment strategies.