Durvalumab New Standard in Stage III Unresectable Lung Cancer

Pam Harrison

September 26, 2018

TORONTO — For the first time in decades, an improvement in overall survival (OS) has been demonstrated in patients with locally advanced stage III unresectable non–small cell lung cancer (NSCLC). It was seen with the addition of durvalumab (Imfinzi, AstraZeneca), an immune checkpoint inhibitor, following concurrent radiotherapy and chemotherapy.

The new OS data come from an updated analysis of the PACIFIC trial, presented here at the 19th World Conference on Lung Cancer (WCLC) and simultaneously published online in the New England Journal of Medicine.

"This is a disease that we approach with curative intent, and we treat these patients with the combined modality of radiation therapy and chemotherapy, most effectively given in a concurrent fashion," explained lead author Scott Antonia, MD, Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

With this approach, "we cure between 15% to 30% of patients," he told delegates here.

"But we've not been able to make any inroads towards improving outcomes for these patients for some time," he added.

"This is the first study in many years to demonstrate a survival advantage in this patient population, and results support the regimen [we used], which is the combined modality of concurrent radiation and chemotherapy followed by durvalumab for 1 year," Antonia concluded.

This is the new standard of care for the treatment of patients with this [stage of] disease. Dr Scott Antonia

"This is the new standard of care for the treatment of patients with this [stage of] disease, and we are in all likelihood increasing the cure rate in these patients," he concluded

Commenting on the study, press conference moderator Francis Shepherd, MD, honorary chair of WCLC 2018, noted that the patient population studied in PACIFIC represents an enormous number of cancers around the world in which the standard of care for decades has been chemotherapy and radiotherapy given together.

"We've not been able to move that bar for many years," she said.

For the first time, we may have been able to change the cure rate. Dr Francis Shepherd

"So it's very exciting that we have these investigators tell us that for the first time, we may have been able to change the cure rate for stage III lung cancer in what is an enormous subset of patients with this disease," Shepherd emphasized.

Study Details

PACIFIC involved a total of 709 patients with locally advanced, stage III, unresectable NSCLC. All of the patients underwent concurrent chemotherapy and radiotherapy and then showed no evidence of disease progression.

They were then randomly allocated to receive durvalumab (n = 473), given intravenously at a dose of 10 mg/kg of body weight, or placebo (n = 236) every 2 weeks for up to 12 months.

The coprimary endpoints of the study were progression-free survival (PFS) and OS; secondary endpoints were time to distant metastasis and safety.

Initial results from the PACIFIC study, reported a year ago, showed an 11.2-month improvement in PFS favoring the immune checkpoint inhibitor over placebo.

Now, with a longer median follow-up of 25.2 months, Antonia and colleagues were able to report on OS data for the first time.

"Median overall survival has not yet been reached for the durvalumab group while it is 28.7 months for the placebo group with a hazard ratio [HR] of 0.68 favoring durvalumab," Antonia reported. This shows a 32% improvement in OS for patients who received additional durvalumab, he added.

The 2-year landmark survival rate was 66.3% for patients who received additional durvalumab compared to 55.6% for those who received placebo, Antonia noted.

"Updated PFS data indicate there is no difference from our previous report where there remains a greater than 11-month improvement in median PFS in favor of durvalumab," he pointed out.

The survival advantage attributed to the addition of durvalumab was seen in all subsets of patients and was apparent in both the PFS and OS data.

Importantly, patients who were nonsmokers also benefited from durvalumab.

As Antonia explained to Medscape Medical News, it is known that patients with stage IV lung cancer who have never smoked have less of a chance of responding to immunotherapy.

"However, this chance is not zero by any means, and never-smokers should still be treated with immunotherapy, as nonsmokers clearly derive benefit from this therapy," he emphasized.

Median time to distant metastases also favored durvalumab at 28.3 months vs 16.2 months for placebo.

"We saw no new safety issues with these new data," Antonio added.

Serious adverse events occurred in 29.1% of patients who received additional durvalumab compared with 23.1% of control patients who received placebo.

Importantly, although the frequency of pneumonitis of all grades was higher in the durvalumab arm, rates of pneumonitis of grade 3 and higher were low, at only 3%, and no deaths occurred owing to this particular toxicity, he noted.

One problem with the new data was pointed out by discussant Everett Vokes, MD, University of Chicago, Illinois. The one cautionary observation in PACIFIC regards OS among durvalumab recipients who had no expression of programmed cell death–1 or levels of less than 1%, he said.

In this group of patients, OS was slightly compromised (HR, 1.36) compared with control patients who received placebo, Vokes observed.

"This was not statistically significant, but it gives us some cause for reflection and work to be done in the future," Vokes suggested.

Antonia was in agreement with Vokes and suggested that patients with programmed cell death–ligand-1 expression levels of less than 1% did not derive benefit from durvalumab in the trial.

Dr Antonia reports having received advisory board fees from AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, CBMG, Boehringer-Ingelheim, Memgen and FLX Bio. Dr Shepherd reports having received honoraria from Bristol-Myers Squibb, Eli Lilly, AstraZeneca, Roche, Genentech, Merck, Novartis, and Pfizer and owns stock in Eli Lilly and AstraZeneca. Dr Vokes reports having received support from Genentech.

19th World Conference on Lung Cancer (WCLC). Abstract PL02.01, presented September 25, 2018.

N Eng J Med. Published online September 25, 2018. Full text


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