WHAT CAN WE LEARN REGARDING IMMUNOTHERAPY FROM LUNG CANCER

Abstract

In the past, lung cancer has been considered to be a non-Immunogenic tumor and great effort with vaccination trials failed. However, some retrospective analyses of infiltrating immune cells in resected tumor specimens suggested a role of immunity also in this disease. Following the lead of melanoma where CTLA-4 inhibition gave the first evidence of the role of immune checkpoint inhibition, initial studies performed in small cell and non-small cell lung cancer (NSCLC) gave disappointing results. This changed with the introduction of inhibitors of the PD-1 and PD-L1 axis. Here large phase I trials in different cohorts of patients demonstrated a rapid and long lasting anti-tumor activity in a 15-20% of sometimes heavily pretreated patients with NSCLC. This was followed by phase III trials comparing PD-1 or PD-L1 inhibitors with the then standard second line therapy docetaxel. These trials demonstrated a superior outcome in terms of survival and toxicity and lead to the regulatory approval of nivolumab, pembrolizumab and atezolizumab for second line treatment of NSCLC. The fact the only a proportion of patient seem to have a strong benefit, the well implemented personalized treatment of oncogenic driver NSCLC, as well as the high costs of immunotherapy lead great efforts to identify predictive biomarkers. The initial focus was on the expression of PDL1 in tumor cells. Laboratory validation, retrospective and prospective clinical validation, and the approval of pembrolizumab for first line therapy in patient with NSCLC expressing PD-L1 in 50% or more of tumor cells has made PD-L1 immunohistochimstry to a - albeit imperfective - but routinely used test. Since, there is emerging data on the use of tumor mutation load and immune signatures as complementary predictive information. The major questions being answered by ongoing clinical trials in advanced NSCLC focus around the use of immunotherapy in first line, either alone in biomarker selected patients or in combination with CTLA-4 blockade or with chemotherapy. In stage III disease, trials are investigation the introduction of immune checkpoint inhibitors with or after chemoradiotherapy. The potential impact of adjuvant single agent immune checkpoint inhibition in resected NSCLC is being examined in phase III trials whereas in second line therapy the focus is on combinatorial treatments. There is a need for the academic community to address clinical questions on the duration of immune therapy and translational research questions on primary or acquired resistance to immunotherapy.