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Marina C. Garassino, MD, discusses the evolving paradigm of immunotherapy in NSCLC, with a specific focus on durvalumab and the role of combination therapy.
Marina Chiara Garassino, MD
The treatment landscape of non—small cell lung cancer (NSCLC) has had a number of encouraging findings in the last 3 years, particularly with checkpoint inhibitors that target the PD-1/PD-L1 pathway.
Most recently, a supplemental biologics license application for the checkpoint inhibitor durvalumab (Imfinzi) was granted a priority review designation by the FDA in October 2017 for the treatment of patients with stage III, unresectable NSCLC.
The indication would be for patients whose disease has not progressed following platinum-based chemoradiation therapy. If approved, durvalumab would join the ranks of the PD-1/PD-L1 checkpoint agents nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq) in the NSCLC armamentarium.
The priority review of durvalumab is based on the phase III PACIFIC trial, which showed a median progression-free survival (PFS) benefit of 11.2 months favoring the durvalumab arm versus the placebo arm (16.8 vs 5.6 months; HR, 0.52; 95% CI, 0.42-0.65; P <.001). The 12-month PFS rate was 55.9% versus 35.3%, and the 18-month PFS rate was 44.2% versus 27.0%, favoring the durvalumab 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 durvalumab 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 (95% CI, 0.43-0.82) for patients with a PD-L1 expression level <25% and the HR was 0.41 (95% CI, 0.26-0.65) for patients with a PD-L1 expression level ≥25%.
In an interview with OncLive, Marina C. Garassino, MD, medical consultant, Medical Oncology Division, Fondazione IRCCS Istituto Nazionale dei Tumori, discussed the evolving paradigm of immunotherapy in NSCLC, with a specific focus on durvalumab and the role of combination therapy.Garassino: In the last 3 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 III 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 pembrolizumab (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.
We also have several drugs in the second-line treatment of patients with NSCLC. We have nivolumab for all comers, pembrolizumab for patients with PD-L1 more than 1%, and atezolizumab (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 3 phenotypes right now: inflamed, immune excluded, and immune desert. According to the 3 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 III locally advanced disease. The patients who are considered resectable were randomized to receive either durvalumab or placebo. The PFS was clearly in favor of patients who received the chemoradiation, and after chemoradiation they received durvalumab. There was an increase of more than 11 months PFS in treating patients with durvalumab for up to 1 year.
There are still several points that must be covered. First, PACIFIC has 2 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 III 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 durvalumab. In the ATLANTIC trial, patients with EGFR and ALK translocation were selectively treated with durvalumab at the standard dose every 2 weeks. In ALK-translocated patients there was no benefit, but in EGFR-mutated patients, who were PD-L1-positive—more than 25%—there was a good PFS and a very good OS. I am going to present the results of the expanded access in Italy with nivolumab, 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.
Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer [published online September 8, 2017]. N Engl J Med. doi: 10.1056/NEJMoa1709937.