David R. Spigel, MD, discusses the status of immunotherapy in locally advanced NSCLC and highlights recent milestones.
David Spigel, MD
It is estimated that one-quarter of patients with non—small cell lung cancer (NSCLC) will present with stage III disease at diagnosis, but the population rarely receives attention in the clinical trial space, says David R. Spigel, MD.
There have been no major advances in the treatment of stage III disease beyond chemoradiation in the last 30 years; however, recent successes with immunotherapy have indicated that is about to change.
The FDA approved durvalumab (Imfinzi) in February 2018 for the treatment of patients with locally advanced, unresectable stage III NSCLC who have not progressed following chemoradiotherapy. This approval was based on the PACIFIC trial, which compared durvalumab to placebo in this patient population.
In a presentation during the 2018 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer, Spigel, chief scientific officer at Sarah Cannon Research Institute, Tennessee Oncology, discussed the status of immunotherapy in locally advanced NSCLC and highlighted the recent milestone.
Historically, consolidation therapy has been the only choice for physicians treating their patients after progression on chemoradiation, but the data have not proven any benefit for this practice. This lack of treatment options led researchers to investigate the impact of immunotherapy in stage III disease.
The phase III results from the PACIFIC trial of durvalumab in this patient population were presented at the 2017 ESMO Congress and published in the New England Journal of Medicine.1,2 Investigators reported that the median progression-free survival (PFS) was 16.8 months with the PD-L1 inhibitor compared with 5.6 months for placebo (HR, 0.52; 95% CI, 0.42-0.65; P <.0001). Though the results showcasing the PFS benefit were released in September 2017, the FDA approval did not come until 2018.
“When the results came out, we were expecting the next day that the FDA would approve it. We waited a week, and then a month, and then a few months, and nothing happened,” said Spigel. “Then, the National Comprehensive Network said, ‘OK it is good enough for use,’ but nothing happened [with the FDA] until [February 2018].”
At 12 months, 55.9% of those in the durvalumab arm remained progression free compared with 35.3% of patients who received placebo. The overall response rate (ORR) following treatment was 28.4% and the complete response (CR) rate was 1.4% with durvalumab. This was in comparison with a 16.0% ORR and 0.5% CR rate in the placebo arm. The median age of patients in the study was 64 years, and Spigel pointed out that most were current or former smokers.
The delay in approval for durvalumab may have been due, in part, to the unreported overall survival (OS) benefit. However, Spigel explained that the PFS findings were a pivotal step in the march toward immunotherapy in stage III NSCLC.
“This was the sort of ‘aha’ take-home moment; durvalumab resulted in a substantial improvement in PFS, a coprimary endpoint,” said Spigel. “That means living without cancer recurring or progressing or dying from any other cause. The advantage here is substantial.”
One of the biggest concerns with immunotherapy in this population is the risk for adverse events (AEs), such as pneumonitis. There was a higher rate of side effects in the durvalumab population, but this was expected, said Spigel.
The most common AEs leading to discontinuation were pneumonitis or radiation pneumonitis, at 6.3% versus 4.3%, and pneumonia, at 1.1% versus 1.3%, for the durvalumab and placebo arms, respectively. Diarrhea, pneumonitis, rash, and pruritus were the most frequently observed AEs of any grade.
“I don’t think anything there should make us worrisome about embarking on immunotherapy in this setting,” Spigel said. “There is more to come.”
Other studies are looking at the role of immunotherapy in stage III disease, but some investigators are concerned about giving it with chemoradiation, so the trials are mostly small phase II efforts, Spigel explained.
“You have to have standardization about how radiation is delivered. You have to come to some agreement on what your endpoints are. It is hard to imagine another study like PACIFIC will get done,” he continued.
There is a vested interest in combinations with nivolumab (Opdivo) and ipilimumab (Yervoy), and IDO inhibitors with pembrolizumab (Keytruda) and nivolumab. Spigel said that these trials will be difficult to conduct going forward because not many in the community are convinced anything will show superiority compared with durvalumab.