Building on the Momentum of the Durvalumab PACIFIC Trial in Stage III NSCLC

Naomi Fujioka, MD

While durvalumab (Imfinzi) has become standard of care for patients with unresectable stage III non—small cell lung cancer (NSCLC) who do not progress following platinum-based chemoradiation, investigators are continuing to evaluate the optimal timing and sequencing of immunotherapies, and to tease out subsets who will benefit most from these approaches, explained Naomi Fujioka, MD.

Data from the initial analysis of the PACIFIC trial showed a 48% reduction in the risk of progression or death versus placebo, leading to the February 2018 FDA approval of durvalumab for patients with locally advanced, unresectable disease who have not progressed following concurrent chemoradiotherapy.¹ In July 2019, the FDA updated the label for durvalumab to include 3-year overall survival (OS) data, which showed a 31% reduction in the risk of death versus placebo.²

"The PACIFIC trial [showed the benefit of giving] immunotherapy after chemoradiation. There are all kinds of ongoing studies that are trying to determine where immunotherapy fits in," said Fujioka. "There's one interesting trial being done right now where patients are being randomized to receive [concurrent] immunotherapy and chemoradiation, immunotherapy halfway through chemoradiation, or immunotherapy following chemoradiation, as in the PACIFIC trial."

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Fujioka, an assistant professor of medicine, Division of Hematology, Oncology, and Transplantation, at the University of Minnesota, discussed the clinical implications of the PACIFIC trial in NSCLC treatment and additional questions that are informing planned and ongoing trial designs in stage III disease.

OncLive: What is important to note about stage III NSCLC treatment?

Fujioka: The key takeaway is that the age of immunotherapy has arrived in stage III NSCLC. We still don't quite know what the role of PD-L1 is in this setting, but the survival outcomes from the PACIFIC trial are quite astonishing and have really given us hope, for the first time in a long time, for this group of patients. [Prior to the use of durvalumab], patients had an extremely high risk of recurrence [after chemoradiation]. The 5-year OS rate [ranges from] 15% to 30%, but in my experience, the recurrence rate is quite high. In the PACIFIC trial, the 3-year OS rate in the durvalumab arm was 66%, which is unheard of; it’s really a game-changer. [This trial has] brought an extremely important treatment option to patients with stage III lung cancer. It's very exciting.

Could you discuss the PACIFIC data and the questions that remain?

PACIFIC was a phase III, randomized trial that evaluated concurrent chemoradiation followed by 1 year of durvalumab or placebo. [OS] was vastly improved in the durvalumab arm compared with placebo; patients also tolerated the treatment pretty well. There were no new or unexpected safety signals with the addition of durvalumab, which is important because toxicity to the lungs with the use of a checkpoint inhibitor shortly after radiation had been a concern.

What remains to be seen is how any kind of treatment after chemoradiation applies to subsets of patients with lung cancer. For example, patients with EGFR mutations traditionally don't respond well to immunotherapy in the metastatic setting. Additional subsets include patients with bulky N2 or bulky N3 disease. There are all these different nuances that apply to staging in stage III NSCLC.

The PACIFIC trial enrolled a very heterogenous population; it would be nice to refine that data a little bit more. Hopefully, in the near future, we'll have more information. Many trials have tried to answer how to best treat patients with stage III NSCLC, but none of them—apart from PACIFIC—have been positive. PACIFIC was really the first time we saw a meaningful difference in patient outcomes.

Is there an optimal sequence of chemoradiotherapy and immunotherapy?

We really don't know. We don't know the optimal timing and sequencing of immunotherapy just yet, but over the next few years we'll get much more information about that.

Could you highlight the updated data from the phase III KEYNOTE-042 trial? What are the next steps for pembrolizumab (Keytruda) in this space?

Patients with locally advanced stage III cancers were included in the KEYNOTE-042 trial. However, it’s not entirely clear who these patients were. Did they have N3 disease? Many radiation oncologists would say these patients are too far advanced to feasibly undergo definitive doses of radiation. We know patients had to have good performance status in this trial, but maybe they were not fit enough for any kind of radiation to the lung. Those are questions that certainly could be answered in future studies. Because this was a small proportion of patients, we can’t definitively say whether pembrolizumab has a role in patients with stage III NSCLC who are not candidates for definitive chemoradiation.

References

1. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929 doi: 10.1056/NEJMoa1709937.
2. Gray J, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. J Clin Oncol. 2019;37(15 suppl; abstr 8526). doi: 10.1200/JCO.2019.37.15_suppl.8526.