Anti–programmed cell death protein 1 (PD-1) immunotherapy with nivolumab (Opdivo) extended survival in patients with the most common form of lung cancer—nonsquamous non–small cell lung cancer (NSCLC). Patients whose disease progressed on standard platinum doublet therapy who were treated with nivolumab lived an average of 3 months longer than those treated with docetaxel in this setting.¹

“Nivolumab is the first PD-1 inhibitor to significantly improve overall survival vs docetaxel in previously treated patients with advanced nonsquamous NSCLC. Nivolumab appears to be particularly active in patients with PD-1 ligand (PD-L1)–positive tumors. Nivolumab significantly improved response rates, with objective response rates as high as 36% in PD-L1 expressors. Overall survival approximately doubled with nivolumab vs docetaxel across the PD-L1–expressing continuum,” said Luis Paz-Ares, MD, PhD, Professor of Medicine at Hospital Universitario 12 de Octubre in Madrid.

Dr Paz-Ares emphasized that nivolumab is a “kinder, gentler” treatment compared with second-line docetaxel. He reported the results of the phase III CheckMate 057 trial at a press conference during the 2015 ASCO Annual Meeting.

Study Details

CheckMate 057 is the first phase III study to show that immunotherapy is active against nonsquamous NSCLC. Also presented at the Annual Meeting, a separate trial (CheckMate 017) found that nivolumab improved overall survival vs docetaxel in advanced squamous cell NSCLC.²

CheckMate 057 randomly assigned 582 patients with stage IIIB or IV advanced disease that progressed on previous platinum-based chemotherapy to treatment with nivolumab vs docetaxel. In addition, patients were allowed a prior tyrosine kinase inhibitor treatment in cases of EGFR mutation or ALK rearrangement. Patients were unselected for PD-L1 expression.

The study met the primary endpoint of overall survival. Median overall survival was 12.2 months for nivolumab vs 9.4 months for docetaxel. This represents a significant 27% decrease in the risk of death for patients who received nivolumab (P = .0015), Dr. Paz-Ares said. One-year overall survival was 51% for nivolumab-treated patients vs 39% for docetaxel recipients.

Objective response rates were improved from 12.4% with docetaxel to 19.2% with nivolumab (P = .0246). The duration of response was significantly longer with nivolumab (median, 17.2 vs 5.6 months). Median progression-free survival was not significantly different between treatment arms: 2.3 months with nivolumab vs 4.2 months with docetaxel. The 1-year progression-free survival rate was 19% vs 8%, respectively.

PD-L1 Expression

PD-L1 expression was measured using a validated Dako/Bristol-Myers Squibb automated immunohistochemistry assay. Cutoffs for PD-L1 expression were ≥ 1%, ≥ 5%, and ≥ 10%.

In the subgroup of patients with the highest level of PD-L1 expression (≥ 10% of cells), median overall survival with nivolumab was 19 months, compared with 8 months for those treated with docetaxel. Median overall survival was also substantially higher with nivolumab compared with docetaxel in those with PD-L1 ≥ 5% and ≥ 1%.

No difference in median overall survival was observed between the two treatment arms in those with low PD-L1 expression (< 10% of cells).

“These results suggest that PD-L1 expression is predictive of the survival benefit of nivolumab, with a huge benefit observed in those with positive expression: a 41% to 60% reduction in the risk of death, which was not found in patients with low or undetectable PD-L1 levels,” Dr. Paz-Ares noted.

“The survival benefit for nivolumab was huge compared to docetaxel in PD-L1–positive patients, with a median survival ranging from an unprecedented 17.2 months to 19.4 months, depending on level of expression,” Dr. Paz-Ares said.

Adverse Events

Treatment-related adverse events were much higher with docetaxel. Any treatment-related adverse event was experienced by 69% of the nivolumab group vs 88% of the docetaxel group. The rate of grade 3/4 adverse events was 10% in the nivolumab group vs 54% of the docetaxel group. Serious adverse events were reported in 7% vs 20%, respectively; the rate of grade 3/4 serious adverse events was 5% vs 18%, respectively.

Treatment-related discontinuations occurred in 5% of nivolumab recipients and 15% of docetaxel recipients.

PD-L1 expression may have limited usefulness as a biomarker to select patients who will benefit from nivolumab. Although PD-L1 expression predicted for survival benefit, some patients without PD-L1 still benefit from nivolumab, Dr. Paz-Ares noted.

Tanguy Y. Seiwert, MD, Assistant Professor of Medicine and Associate Program Leader for Head and Neck Cancer at the University of Chicago, suggested two additional potential biomarkers: “A high number of mutations and inflammation of the tumor as measured by a gene expression signature may be useful additional markers, particularly if used in conjunction with PD-L1 expression,” he said. “Just as buying more tickets in the lottery increases your chance of winning, having more mutations makes it more likely for the tumor to be recognized by the immune system.” 

Promising Results

“Nivolumab is an anti–PD-1 immunotherapy that takes the brakes off of the immune system and allows it to attack the tumor,” said press conference moderator Lynn Schuchter, MD, ASCO expert and Chief of Hematology/Oncology at Penn Medicine, Philadelphia.

“These results in a phase III lung cancer trial show improvement with immunotherapy compared with standard treatment and are promising,” she added.

Safety results were reassuring, Dr. Schuchter commented. “Toxicities can be immune-related, and immunotherapies have unique toxicities,” she continued. “In this study, the immune-related adverse events were less severe than those seen with ­chemotherapy.” ■

Disclosure: Dr. Paz-Ares has received honoraria from Roche/Genentech, Lilly, Pfizer, Boehringer-Ingelheim, Clovis Oncology, Bristol-Myers Squibb, and Merck, Sharp & Dohme. Dr. Seiwert has received honoraria from Amgen, Merck, Jounce Therapeutics, and Novartis. Dr. Schuchter reported no potential conflicts of interest.

References

1. Paz-Ares K, Horn L, Borghaei H, et al: Phase III randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract LBA109. Presented May 30, 2015.

2. Spigel DR, Reckamp KL, Rizvi NA, et al: A phase III study (CheckMate 017) of nivolumab (NIVO; anti-programmed death-1 [PD-1]) versus docetaxel (DOC) in previously treated advanced or metastatic squamous cell non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract 8009. Presented May 31, 2015.