Immunotherapy- the biological rationale

The immune system uses the same mechanisms to defend us against cancer cells that they do against infections.

The genomic instability of tumor cells, due to the accumulation of genetic alterations over time, favors the development of immunogenic clones, which are recognized by the cells of the immune system. Dendritic cells and antigen-presenting cells, in turn, stimulate the CD8+ T cells, which activate the mechanisms normally used to eliminate viruses and bacteria. The consequence is the cancer cell death.

To prevent tissue damage due to prolonged activation of immune system, pathways that modulate and shut down the immune response were selected during evolution. Among these, the PD-1/PD-L1 checkpoint inhibits immune system cells’ activation and is used by cancer cells to escape the immune system.

Drugs that inhibit the PD-1 checkpoint destroy these inhibitory pathways and restore the antitumor activity of T cells.

Currently, two PD-1 inhibitors (nivolumab and pembrolizumab) and one PD-L1 inhibitor (atezolizumab) have been approved by the Italian regulatory body (AIFA) for the treatment of patients with non-small cell lung cancer.

Effectiveness of immunotherapy drugs

First-line therapy for patients with PD-L1≥50%

Pembrolizumab is a humanized IgG4 antibody that inhibits PD-1. Its effectiveness was evaluated in the phase 3 study, KEYNOTE-024, designed for patients who have never undergone previous chemotherapy treatments. 305 patients with advanced stage non-small cell lung cancer and PD-L1 overexpression (PD-L1 ≥ 50%) were randomized between pembrolizumab or platinum-based chemotherapy. The study demonstrated the clear advantage of pembrolizumab against 1st line chemotherapy, with significant increase in progression-free survival, overall survival and objective response rates.

Another PD-1 inhibitor, nivolumab, was evaluated in patients who had not undergone any chemotherapy treatment in the CheckMate 026 study. The study compared nivolumab with platinum-based 1st-line chemotherapy in patients with PD-L1 expression ≥ 1%. Unlike what was observed in the KEYNOTE 024 study, there were no significant differences in terms of progression-free survival or overall survival in the two treatment arms. The different groups of patients (PD-L1 overexpression >50% in KEYNOTE-024 and PD-L1≥ 1% in the CheckMate 026 study) influenced the results of the two studies.

Today, based on the KEYNOTE-024 study, pembrolizumab represents first-line therapy in patients with PD-L1 expression ≥ 50%.

Therefore, PD-L1 is a marker to look for on biopsy performed at the time of diagnosis. It is information that must be acquired before deciding on the patient’s therapeutic strategy.

If you want to know the side effects of pembrolizumab, go to the side effects page.

Second-line therapy for lung cancer

In addition to second-line chemotherapy, following failure of first-line treatment, for patients who have not yet received immunotherapy in their first-line treatment, Nivolumab, Pembrolizumab and Atezolizumab represent a therapeutic choice for patients with non-small cell lung cancer, in progression to first line chemotherapy.

Also, in 2nd-line, the registration process for the two drugs were different.

The efficacy of nivolumab was evaluated in two studies, one designed for patients diagnosed with squamous cell carcinoma, the CheckMate 017 study, and the other for patients with lung adenocarcinoma, the CheckMate 057 study. In these studies, patients were not enrolled based on their PD-L1 expression, as both PD-L1-expressing and non-PD-L1-expressing patients were included. In both studies, the efficacy of nivolumab was compared with that of docetaxel, which represented standard line chemotherapy. In patients with squamous cell carcinoma, nivolumab doubled the percentage of objective responses, increased progression-free survival and overall survival. Even in patients with adenocarcinoma, nivolumab prolonged overall survival, although the advantage in terms of percentage of objective responses and progression-free survival was observed mainly in patients with PD-L1 expression.

The results of these studies led to the registration of nivolumab in 2nd- and 3rd-lines, both in patients diagnosed with squamous cell carcinoma of the lung and in those with a diagnosis of adenocarcinoma. Since the studies did not involve the enrollment of patients on the basis of PD-L1 expression and benefit of nivolumab was observed regardless of it, nivolumab can also be prescribed for patients negative for PD-L1.

The efficacy of pembrolizumab in 2nd-line was evaluated in the KEYNOTE-010 study, a phase III study, which enrolled patients with PD-L1 expression of at least 1%. The study was designed to compare the efficacy of pembrolizumab with the standard second-line chemotherapy, docetaxel. Pembrolizumab causes a significant increase in the overall survival. Based on these results, pembrolizumab has been approved for the treatment of patients with PD-L1 ≥ 1% after chemotherapy failure. Unlike nivolumab, it is indicated from 2nd line onwards only.

Atezolizumab is a PD-L1 inhibitor. The drug’s effectiveness was first evaluated in the phase II study, POPLAR, which demonstrated an advantage for atezolizumab over a chemotherapeutic treatment with docetaxel, in terms of overall survival, in patients who have undergone previous chemotherapy in first line. These results were subsequently confirmed in a phase III study (OAK) conducted in 194 centers in 31 countries. In the OAK study, 1225 patients with metastatic non-small cell lung cancer, progressing after one or two previous lines of chemotherapy were randomized to receive either atezolizumab or docetaxel. The PD-L1 expression was not requested to enroll in the study. The results showed a significant increase in overall survival for patients treated with atezolizumab, independent of PD-L1 expression. On the basis of these results, in July 2018, atezolizumab was registered in Italy for patients with non-small cell lung cancer, who have previously undergone chemotherapy in first line.

To date, there are no studies comparing nivolumab, pembrolizumab and atezolizumab in terms of efficacy and side effects. Therefore, all three drugs represent valid therapeutic alternatives.

If you would like to learn more about the side effects, go to Side Effects.