Immumotherapy in first line treatment of NSCLC?
During the last decade, improvements in cancer biology and immune system knowledge led to a significant prolongation in overall survival for patients with metastatic non-small cell lung cancer (NSCLC). It is well established that immune system plays a critical role in destroying cancer cells. Tumor cells, however, use different strategies to avoid recognition by the immune system, including “immune checkpoint” activation. Programmed death-1 (PD-1) immune checkpoint pathways have been the one most extensively studied. Several agents interfering with the PD-1 axes have been evaluated in clinical trials. Since these drugs directly target the patient’s immune system, they have the potential for utility across multiple tumor types, including lung cancer. The PD-1 receptor is expressed on activated T-cells, and the key ligands for this receptor are programmed death-ligands 1 (PD-L1) and 2 (PD-L2). PD-L1 is up-regulated in many tumors and high levels of expression (³50%) have been observed in approximately 30% of NSCLC. This overexpression helps tumor to evade immune responses. Binding of PD-L1 or PD-L2 to PD-1 receptors inhibits T-cell activation reducing antitumor immune responses. Therefore, PD-1 represents a logical target for cancer immunotherapy. At the present time, in first-line setting, immunotherapy as single agent or in combination with chemotherapy is the standard of care in PD-L1 expressing patients, target therapy is recommended in oncogene addicted and the proportion of patients still candidate for exclusive chemotherapy is gradually decreasing. Agents targeting PD-1 or PD-L1, such as pembrolizumab, nivolumab or atezolizumab, are now approved in clinical practice in first or in second-line setting. Results from several randomized clinical trials comparing immunotherapy as single agent or in combination with chemotherapy versus chemotherapy alone are rising the question on what is the best first-line treatment and whether platinum-based chemotherapy could be avoided in our patients. Three phase III studies compared immunotherapy as single agent versus platinum-based chemotherapy. The Keynote 024 study compared pembrolizumab monotherapy versus platinum-based doublets in NSCLC patients with high PD-L1 expression. The study demonstrated that pembrolizumab is superior to chemotherapy by doubling median overall survival (OS: 30.0 versus 14.2 months, p=0.002). Similar results were obtained in the Keynote 042 trial, a phase III study comparing pembrolizumab versus chemotherapy in patients with at least 1% of PD-L1 expression. This study, including a large percentage of patients with PD-L1 expression ≥ 50%, confirmed the superiority of pembrolizumab versus chemotherapy in terms of OS (20.0 versus 12.2 months, p=0.003). In contrast, the Checkmate 026 study, comparing nivolumab versus chemotherapy in patients with at least 1% of PD-L1 expression, showed no OS difference in both arms even in the subgroup of patients with PD-L1 expression ≥ 50%. Importantly, both Keynote 042 and Checkmate 026 showed no survival improvement in patients with low levels of PD-L1 expression (1-49%). Four different phase III trials, two in non-squamous (Keynote 189 and IMPOWER 150) and two in squamous histology (Keynote 407 and IMPOWER 131), compared standard chemotherapy plus a checkpoint inhibitor versus chemotherapy alone. The Keynote 189, evaluating pembrolizumab plus chemotherapy versus chemotherapy alone, showed a significant improvement in OS when pembrolizumab was added to chemotherapy in all patient subgroups, irrespective of PD-L1 expression. Interestingly, the OS Hazard Ratio (HR) was better than the HR obtained in studies with pembrolizumab monotherapy, suggesting that combination of immunotherapy and chemotherapy could be superior to chemotherapy alone even in patients with high levels of PD-L1 expression, with the cost of increased toxicity. The IMPOWER 150, a large 3 arms study (atezolizumab plus carboplatin-paclitaxel: Arm A; or atezolizumab carboplatin-paclitaxel-bevacizumab: Arm B; or carboplatin-paclitaxel-bevacizumab: Arm C), demonstrated a significant survival improvement for arm B versus C but not in arm A versus arm C, at least in at the initial survival analysis. The Keynote 407 compared pembrolizumab plus carboplatin-taxol (paclitaxel or nab-paclitaxel) versus the same chemotherapy regimens in patients with squamous histology. Similarly to Keynote 189, addition of pembrolizumab to chemotherapy yielded in a OS improvement in patients receiving immunotherapy, irrespective of PD-L1 expression. The IMPOWER 131 was a 3 arms study comparing atezolizumab plus carboplatin-paclitaxel (Arm A) or atezolizumab plus carboplatin-nab-paclitaxel (Arm B) versus carboplatin-nab-paclitaxel as initial therapy in patients with squamous histology. Although arm B was superior to arm C in terms of progression-free-survival (PFS), the first interim analysis showed that OS improvement was confined to individuals with PD-L1 expression ≥ 50%. Finally, of particular interest are the preliminary data from the PD-L1 negative cohort included in the Checkmate 227 study. In this trial, PD-L1 negative patients were randomized to nivolumab plus ipilimumab versus platinum-based chemotherapy versus platinum-based chemotherapy plus nivolumab. In patients with high Tumor Mutational Burden (high-TMB), defined as patients with ≥ 10 mutations/Mb, PFS at 12 months was almost 5 times higher with nivolumab-ipilimumab and 3 times higher with chemotherapy plus nivolumab than in individuals treated with chemotherapy alone. In patients with low TMB no difference in PFS was observed in the three arms. Overall these data support TMB and a relevant biomarker for refining selection of patients candidate to immunotherapy. Overall, all available data demonstrated that immunotherapy is the new standard of care as initial therapy in patients with NSCLC irrespective of histology. Current evidence support usage of immunotherapy single agent only in PD-L1 ≥ 50%. For patients with low or no PD-L1 expression immunotherapy plus chemotherapy is superior to chemotherapy alone. Combination of PD-L1 expression and TMB could better define in which patients chemotherapy can be avoided and in which patients immunotherapy is not effective.