The international phase 3 PACIFIC trial was the first study to demonstrate a survival advantage in this setting, supporting the use of chemoradiotherapy followed by the PD-L1 immunotherapy durvalumab (Imfinzi) as the standard of care for stage III NSCLC, said Scott J. Antonia, MD, PhD, Director, Center for Cancer Immunotherapy, Duke Cancer Institute, Durham, NC, at the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium.
“Five, six, or seven years ago as the data were emerging that anti–PD-1 or PD-L1 had very significant clinical impact on advanced NSCLC, we and others began to think about how we could move this into earlier stages,” Dr Antonia said.
Some of the ongoing research is assessing anti–PD-1 or anti–PD-L1 therapy in the neoadjuvant and adjuvant settings for patients with resectable stage I to III NSCLC and in combination with stereotactic body radiation therapy in patients with unresectable stage I to II disease. Although outcomes data are awaited for these approaches, recent data show the value of anti–PD-1 consolidation after chemoradiation in stage III NSCLC.
Approximately 25% to 30% of patients with NSCLC have locally advanced disease at the time of diagnosis. The current standard of care for patients with unresectable stage III NSCLC has been platinum-based chemotherapy with concurrent radiation. However, the median progression-free survival (PFS) with this approach is approximately 8 months, and the 5-year overall survival (OS) rate is only 15% to 30%.
“Knowing that anti–PD-1 has a different mechanism of action, and having independent activity in advanced disease, we thought that it would be at least additive in terms of ultimate clinical impact if we gave it in the consolidated setting after chemoradiation,” Dr Antonia said. “But we also hypothesized that synergy was possible.”
This hypothesis was based on the observation that many NSCLC tumors have an insufficient number of T-cells. Radiation can release tumor antigens and induce immunogenic cell death by increasing the number of tumor-reactive T-cells that, when they infiltrate the tumor microenvironment, induce secretion of inflammatory cytokines, such as gamma interferon, which is a potent inducer of PD-L1 for the immune checkpoint protein. “So it was necessary for us to achieve that synergy that we hypothesized to combine radiation with anti–PD-1 or anti–PD-L1,” Dr Antonia emphasized.
The PACIFIC clinical trial randomized patients with unresectable NSCLC to the PD-L1 inhibitor durvalumab after chemoradiation (N = 473) or to placebo (N = 236).
At a median follow-up of 25.2 months, durvalumab significantly improved OS compared with placebo (stratified hazard ratio [HR], 0.68), with a median survival not reached with durvalumab versus 28.7 months with placebo. Durvalumab improved OS in all the prespecified subgroups.
The median PFS was also extended in the durvalumab arm versus placebo (17.2 vs 5.6 months, respectively; stratified HR, 0.51).
Of note, nonsmokers, who normally do not respond as well to immunotherapy as do smokers, responded equally as well as smokers.
“Nonsmoking patients, both stage IIIa and IIIb, as well as those with squamous and nonsquamous histologies, benefited from durvalumab,” Dr Antonia observed. “At least in terms of PFS, patients with EGFR mutations also had at least an indication of a benefit but [there were] nowhere near enough patients in this study to draw any firm conclusions about OS.”
Overall, 37% of the patients had sufficient tissue to assess PD-L1 expression before chemoradiotherapy. A prespecified analysis of PD-L1 expression using a 25% cutoff value was planned, and a PD-L1 expression cutoff value of 1% was part of an unplanned post-hoc analysis. PD-L1 status was not available for approximately 25% of the patients.
In patients with PD-L1 ≥1%, the OS favored durvalumab, Dr Antonia said, but in those with PD-L1 expression <1%, the OS favored placebo.
The median time to distant metastasis was 28.3 months in the durvalumab arm versus 16.2 months in the placebo arm (HR, 0.53; 95% confidence interval, 0.41-0.68). The incidence of new lesions was 22.5% in the durvalumab arm versus 33.8% with placebo.
Durvalumab was well-tolerated: 30.5% of patients in the durvalumab arm and 26.1% in the placebo arm had grade 3 or 4 adverse events; adverse events leading to discontinuation were 15.4% and 9.8%, respectively. Any-grade pneumonitis was 33.9% in the durvalumab group and 24.8% in the placebo group, but there was no difference in death caused by pneumonitis.
An ongoing clinical trial is integrating anti–CTLA-4 therapy with chemoradiation, followed by nivolumab, in patients with locally advanced unresectable stage III NSCLC in the first-line setting. In explaining the rationale, Dr Antonia said that “it makes sense to us that if ipilimumab [Yervoy] were around when tumor antigens were being released and presented to T-cells in the lymphoid compartment, then we could produce additional synergy.”