Expert Discusses Immunotherapy's Expanding Role in Lung Cancer Treatment

In the past few years, there has been a number of exciting advances in the treatment field of non-small cell lung cancer (NSCLC), especially regarding checkpoint inhibitors that target the PD-1 and PD-L1 pathways.

Most recently, a supplemental biologics license application for the checkpoint inhibitor Imfinzi (durvalumab) was granted a priority review designation by the FDA in October 2017 for the treatment of patients with stage 3, unresectable NSCLC.

The indication would be for patients whose disease has not progressed following platinum-based chemoradiation therapy. If approved, Imfinzi would join the ranks of the PD-1/PD-L1 checkpoint agents Opdivo (nivolumab), Keytruda (pembrolizumab) and Tecentriq (atezolizumab) in the NSCLC armamentarium.

The priority review of Imfinzi is based on the phase 3 PACIFIC trial, which showed a median progression-free survival (PFS) benefit of 11.2 months favoring the Imfinzi arm versus the placebo arm (16.8 vs 5.6 months). The 12-month PFS rate was 55.9 percent versus 35.3 percent, and the 18-month PFS rate was 44.2 percent versus 27.0 percent, favoring the Imfinzi arm. Overall survival (OS) data are not yet mature and were not included in the analysis.

Additionally, PACIFIC investigators found that the PFS benefit associated with Imfinzi was consistent across all prespecified subgroups, as defined according to patient demographic characteristics, baseline clinicopathologic features and response to previous treatment.

Moreover, the PFS benefit was found to be irrespective of PD-L1 expression prior to chemoradiotherapy. The HR was 0.59 for patients with a PD-L1 expression level less than 25 percent and the HR was 0.41 for patients with a PD-L1 expression level of at least 25 percent.

What is the current role of immunotherapy in lung cancer?

In an interview with CURE, Marina C. Garassino, M.D., medical consultant, Medical Oncology Division, Fondazione IRCCS Istituto Nazionale dei Tumori, discussed the evolving paradigm of immunotherapy in NSCLC, with a specific focus on Imfinzi and the role of combination therapy.In the last three years, there was a big change in the paradigm of cancer care with immunotherapy. With the advance of immunotherapy now, we’ve changed the paradigm in several points of disease in patients with NSCLC, starting from stage 3 disease—which is the big novelty of this year with the PACIFIC trial. We also have several new drugs for the first-line treatment, in particular for patients with PD-L1 expression. The survival of patients treated with Keytruda presented [at the IASLC 18th World Conference on Lung Cancer], was 30 months. Before it was about 17 months, so it really has radically changed the treatment of NSCLC.

What is the role of combination therapy in NSCLC?

Can you share your insight on the pivotal findings from the PACIFIC trial and how they will impact clinical practice?

We also have several drugs in the second-line treatment of patients with NSCLC. We have Opdivo for all comers, Keytruda for patients with PD-L1 more than 1 percent, and Tecentriq for all comers. Several other trials are starting in the neoadjuvant setting and the adjuvant setting. We would really like to increase the number of patients still alive, and the promise is in combinations. In the future, treatment will be based on the immune phenotype, and we have at least three phenotypes right now: inflamed, immune excluded and immune desert. According to the three phenotypes, we will be able to combine the first generation of immune checkpoint inhibitors with several other agents. Some of them could be an IDO inhibitor, but we also have TM3, GITR, and, again, chemotherapy. Chemotherapy can be a very important thing to add to the immune checkpoint inhibitors because it attacks the immune cycle of cancer. Therefore, we have several possibilities to increase the response rate, PFS, and OS. The PACIFIC trial is a very important trial because it covers a huge unmet need for NSCLC, which is stage 3 locally advanced disease. The patients who are considered resectable were randomized to receive either Imfinzi or placebo. The PFS was clearly in favor of patients who received the chemoradiation, and after chemoradiation they received Imfinzi. There was an increase of more than 11 months PFS in treating patients with Imfinzi for up to one year.

Could immunotherapy be used for patients with driver mutations?

There are still several points that must be covered. First, PACIFIC has two coprimary endpoints— one was PFS and the other was OS. We only have data for PFS right now. We do not know if we [should] do a sequential treatment with chemoradiation if we can reproduce the same effect of the concurrent chemoradiation. But, [more than 11] months of PFS in stage 3 NSCLC is something really important. Also, what we know from the data is that we are able to prevent distant metastases in this kind of disease—which are quite frequent. This study is really interesting and will be practice changing. This is a very interesting story. If we look to the subgroup analysis of all randomized clinical trials, there is no clear benefit in never-smokers or EGFR-mutated patients. Therefore, it is difficult to say whether it is better to treat these patients with immunotherapy or chemotherapy. We have just a few data coming from the ATLANTIC trial with Imfinzi. In the ATLANTIC trial, patients with EGFR and ALK translocation were selectively treated with Imfinzi at the standard dose every two weeks. In ALK-translocated patients there was no benefit, but in EGFR-mutated patients, who were PD-L1-positive — more than 25 percent — there was a good PFS and a very good OS. I am going to present the results of the expanded access in Italy with Opdivo, where there is some benefit in EGFR-mutated patients.

My personal opinion is that immunotherapy is not the best treatment for these kinds of patients because they have a low mutational burden, but we do not know clearly about the further lines.