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Anti-PD-L1 Drug Boosts Survival in Stage III NSCLC

— New standard of care for patients with inoperable disease

Last Updated October 16, 2018
MedpageToday

TORONTO -- Patients with inoperable stage III non-small cell lung cancer (NSCLC) lived significantly longer if they received immunotherapy with durvalumab (Imfinzi) following standard chemoradiation therapy (CRT), new results from a placebo-controlled trial showed.

Although median survival had yet to be reached in the durvalumab arm, patients treated with the PD-L1 inhibitor had a statistically significant 32% lower risk of death versus placebo-treated patients after a median follow-up of 25.2 months. More patients in the durvalumab group remained alive at 12 and 24 months than in the placebo group, and the absolute difference increased from 12 to 24 months, reported Scott Antonia, MD, PhD, of the H. Lee Moffitt Cancer Center in Tampa, Florida, and colleagues, at the World Conference on Lung Cancer (WCLC).

The results were published simultaneously in the .

An updated analysis of progression-free survival (PFS) continued to show more than a three-fold difference in the median PFS in favor of durvalumab-treated patients, consistent with a previous report from the trial, known as PACIFIC.

"PACIFIC is the first study to show a survival advantage following chemoradiation therapy in this population," Antonia said. "Based on these findings, the PACIFIC regimen is the new standard of care for unresectable, stage III non-small cell lung cancer."

Invited WCLC discussant Edward Vokes, MD, of the University of Chicago, agreed with Antonia's assessment of the results.

"This is a positive trial; this is a new standard of care," said Vokes.

The trial also raised questions that need to be addressed to optimize therapy, he continued. Should patients with stage III NSCLC be tested for PD-L1 expression? Probably so, said Vokes, citing data from a subgroup analysis of PACIFIC showing an increased survival hazard for patients with PD-L1 expression <1%. Do the results apply to mutation-driven tumors? Probably so, he said. The optimal time to begin anti-PD-1 therapy and the optimal duration remain to be determined. Trials designed to provide some answers are ongoing.

Platinum-based CRT has formed the basis of care for patients with unresectable stage III NSCLC, which leads to 5-year survival of 15%-30%.

"Of course, we've been stuck with those numbers for decades," said Antonia. "We've not been able to make any inroads into improving outcomes for these patients."

Multiple studies of curative-intent systemic therapy following CRT failed to improve on the historical survival figures.

About a year ago, the initial planned interim analysis of PACIFIC showed almost a three-fold increase in median PFS from 5.6 months with placebo to 16.8 months with durvalumab. Antonia reported findings from the first interim analysis of overall survival (OS), performed in March 2018, after a median follow-up of 25.2 months.

PACIFIC involved 702 patients with stage IIIa/b NSCLC who had stable disease or response to platinum-based CRT. They were randomized 2:1 to 12 months of maintenance therapy with durvalumab or placebo. Eligibility criteria did not include PD-L1 expression status.

The analysis showed that placebo-treated patients had a median OS of 28.7 months, whereas the median survival had yet to be reached in the durvalumab arm. The difference translated into a statistically significant improvement in survival (HR 0.68, 95% CI 0.469-0.997, P=0.00251). The 12-month PFS was 83.1% with durvalumab and 75.3% with placebo, and the 24-month survival was 66.3% and 55.6% with durvalumab and placebo, respectively.

An extensive subgroup analysis showed a consistent survival advantage for treatment with durvalumab, said Antonia. The only exception, as noted by Vokes, applied to patients with <1% PD-L1 expression (N=148). The hazard ratio for the durvalumab arm versus placebo was 1.36, although not statistically significant (95% CI 0.79-2.34).

Updated analyses of other outcomes consistently favored durvalumab, including:

  • Median PFS: 17.2 versus 5.6 months
  • Median time to death or distant metastasis: 28.3 versus 16.2 months
  • Patients with new lesions: 22.5% versus 33.8%
  • Median time to second progression or death: 28.3 versus 17.1 months

An updated safety analysis showed no new safety issues with durvalumab as all-grade adverse events, grade 3/4 adverse events, serious adverse events, adverse events leading to discontinuation, and pneumonitis (an immune-related adverse event) occurred in a similar proportion of patients in each group, Antonia reported.

  • author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined 鶹ý in 2007.

Disclosures

The PACIFIC trial was supported by AstraZeneca.

Antonia disclosed relevant relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, Merck, CBMG, Boehringer Ingelheim, Memgen, and FLX Bio.

Primary Source

World Conference on Lung Cancer

Antonia SJ, et al “Overall survival with durvalumab versus placebo after chemoradiotherapy in stage III NSCLC: Updated results from PACIFIC” WCLC 2018; Abstract PL02-01.

Secondary Source

New England Journal of Medicine

Antonia SJ, et al “Overall survival with durvalumab after chemoradiotherapy in Stage III NSCLC” N Engl J Med 2018; DOI:10.1056/NEJMoa1809697.