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New Standard Takes Shape in Unresectable Stage III NSCLC

Vince Calio
Published: Saturday, Nov 10, 2018

Nasser Hanna, MD
Nasser Hanna, MD
Most patients with unresectable stage III non–small cell lung cancer (NSCLC) should receive consolidation immunotherapy in light of 2 studies that show improved overall survival (OS) outcomes with anti–PD-1/PD-L1 treatment, according to Nasser Hanna, MD.

Nevertheless, signals emerging from these findings indicate that patients who are not candidates for chemoradiation, those with poor performance status scores or substantial weight loss, poor lung capacity, or interstitial lung disease should not undergo the additional therapy.

Those were among the key points that Hanna made during a presentation at the 13th Annual New York Lung Cancers Symposium that Physicians’ Education Resource (PER®), held November 10 in New York City. He is the Tom and Julie Wood Family Foundation Professor of Lung Cancer Clinical Research at The Indiana University School of Medicine in Indianapolis.

In February, durvalumab (Imfinzi) became the first treatment to gain FDA approval for patients with unresectable NSCLC with the goal of reducing the risk of cancer progression. The PD-L1 inhibitor is indicated for patients whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

The approval was based on progression-free survival (PFS) results from the phase III PACIFIC trial in which 713 patients who had achieved responses or stable disease after platinum-based chemoradiation were randomized 2:1 to receive either durvalumab or placebo.

Patients in the durvalumab arm had a PFS of 16.8 months (95% CI, 13.0-18.1) versus 5.6 months (95% CI, 4.6-7.8) for those who received placebo. The PFS for the durvalumab arm at 18 months was 44.2% (95% CI, 37.7%-50.5%) versus 27.0% (95% CI, 19.212139%-34.5%) for the placebo arm. Durvalumab therapy reduced the risk of progression or death by 48% (stratified HR, 0.52; 95% CI, 0.42-0.65; 2-sided P <.001).1

After a median follow-up of 25.2 months, the median OS among patients in the intention-to-treat population who had received durvalumab was not reached (NR; 95% CI, 34.7 months-NR) compared with 28.7 months (95% CI, 22.9-NR) for those in the placebo arm. That translated into a 32% reduction in the risk of death (HR, 0.68; 99.73% CI, 0.47-0.997; 2-sided P = .0025).2 Findings were reported simultaneously at the 2018 World Conference on Lung Cancer and in the New England Journal of Medicine.

“The message that was delivered at the World Lung Conference in Toronto was that there was indeed an overall survival difference favoring durvalumab, and this is no small task,” said Hanna. “We have failed for 20 years to really move the bar in terms of overall treatment beyond concurrent chemoradiation, so the PACIFIC trial was a very big deal. It was not only statistically significant, but it was clinically significant because it favored durvalumab and a new standard of care, and the FDA has approved this in patients with stage III NSCLC.”

Hanna and colleagues conducted a study concurrently with the PACIFIC trial, HCRN LUN-14-179 (NCT02343952), a single-arm, multicenter phase II trial to evaluate pembrolizumab (Keytruda) consolidation after chemoradiation in patients with unresectable stage III NSCLC. Patients received 1 of 3 chemotherapy regimens: cisplatin plus etoposide, carboplatin plus paclitaxel, or cisplatin plus pemetrexed (Alimta). Radiation was administered at 59.4 to 66.6 Gy. Those who responded or achieved stable disease went on to receive pembrolizumab at 200 mg every 3 weeks for up to 12 months.

The study population consisted of 59 men and 33 women, 95% of whom were former (77.2%) for current (17.4%) smokers. About 60% of the patients had stage IIIA disease. Among 54 patients with known PD-L1 expression status, 11 tested negative, 11 exhibited 1% to 49% expression, and 31 had expression values >50%.

The OS rate with pembrolizumab in this smaller phase II trial was 81.3% at 12 months and 61.5% at 24 months, while the median OS was not reached. Although a smaller patient population, Hanna noted similarities in the data. “The overall survival curve is nearly identical to the overall survival curve of the durvalumab arm of the PACIFIC trial. The follow-up time was similar and the median time to metastatic disease or death is very similar to each other,” he said.

In the HCRN LUN-14-179 study, the most common adverse event (all grades) was fatigue (47.3%), followed by cough (25.8%), and dyspnea (21.5%). The most common grade 3 adverse events were dyspnea (5.4%), fatigue (4.3%), and diarrhea (4.3%). No grade 4-5 adverse events occurred.

Roughly 17.2% of patients developed the immune-related adverse event pneumonitis, consisting of 10.8% grade 2, 4.3% grade 3, and 1.1% each for grade 4 and grade 5. The median interval to grade ≥2 pneumonitis was 8.4 weeks, and in three-fourths of cases, pneumonitis occurred within the first 12 weeks of pembrolizumab treatment.


  1. Antonia SJ, Villegas A, Daniel D; et al; for the PACIFIC Investigators. 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. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC [published online September 25, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1809697.
  3. Durm G, Althouse S, Sadiq A, et al. Updated results of a phase II trial of concurrent chemoradiation with consolidation pembrolizumab in patients with unresectable stage III NSCLC. Presented at: 2018 World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada.

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