Atezolizumab Shines in Long-term POPLAR Findings

Anti PD-L1 immunotherapy with atezolizumab (Tecentriq) was strongly superior to docetaxel in locally advanced or metastatic non—small cell lung cancer (NSCLC), according to 3-year survival findings from the phase II POPLAR study.

The results were not specific to PD-L1 expression, which means the search must continue for biomarkers to improve targeting with this drug, investigators said at the 2018 European Lung Cancer Congress in Geneva, Switzerland.

“Nearly 1 in 5 patients treated with atezolizumab was alive at 3 years. This places atezolizumab among the drugs with the highest landmark overall survival [OS] in previously treated lung cancer patients,” said lead author Julien Mazières, MD, PhD, of Toulouse University Hospital, Toulouse, France.

OS was significantly higher with atezolizumab at 2 and 3 years compared with docetaxel. Investigators said 32.2% of patients in the atezolizumab arm (n = 144) were alive at 2 years compared with 16.6% in the docetaxel cohort (n = 143; P = .0027). At 3 years, 18.7% of patients on atezolizumab were alive versus 10% in the docetaxel group (P =.0419).

Investigators said the long-term OS benefit with atezolizumab was observed in both squamous and non-squamous histologies, and occurred regardless of PD-L1 expression level. “Even patients with PD-L1 expression in less than 1% of tumor cells and less than 1% of immune cells had a promising rate of long-term survival,” investigators said in a release.

In the analysis by PD-L1 expression, the 3-year OS rate for patients with high tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression was 37.5% for atezolizumab versus 14.9% for chemotherapy (P = .0724). Patient numbers were balanced (24 vs 23, respectively).

For those with low-to-high PD-L1 expression, the 3-year OS rate for atezolizumab was 18.0% versus 11.0% for docetaxel (P = .1759). For those with no PD-L1 expression, the 3-year OS rate was 20.5% versus 6.8% (P = .0693), respectively.

In the nonsquamous subgroup analysis, the 3-year OS rate was 23.3% for atezolizumab versus 12.4% for docetaxel (P = .0585). The respective numbers for patients with squamous NSCLC were 9.4% and 5.2% (P = .4603).

“The fact that all subgroups of patients benefitted to a similar degree is good in the sense that atezolizumab can be tried in all advanced NSCLC patients,” Mazières said. “On the other hand, it means that we cannot predict which patients are most likely to live for 3 years. We need to find biomarkers to help us identify the long-term survivors with the drug.”

The 3-year findings from POPLAR represented the longest follow-up reported to date with anti-PD-L1 immunotherapy in patients with previously treated, advanced NSCLC. Patients (n = 287) were recruited from 61 sites across 13 countries and randomly assigned to 1200 mg of atezolizumab or 75 mg/m2 of docetaxel every 3 weeks.

The overall response rate was 15% in the intent-to-treat populations of both treatment groups, but median duration of response 3 times longer with atezolizumab (22.3 vs 7.2 months).

Patients assigned to atezolizumab experienced fewer adverse events (AEs) than for docetaxel, and Mazières said the milder tolerability profile of atezolizumab means patients can stay on it for several years.

“Some of my patients who were in the atezolizumab treatment group are now long-term survivors with lung cancer,” he said. “They are not cured, but they have survived, have a good quality of life, and have returned to work.”

Solange Peters, MD, PhD, head of medical oncology for the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, noted in a statement that the findings for atezolizumab were consistent with 3- and 5-year survival results for anti-PD-L1 antibodies pembrolizumab (Keytruda) and nivolumab (Opdivo). She noted that these immunotherapies have dramatically improved survival chances for patients with NSCLC.

Peters said there is now a strong argument that immunotherapy should be offered to patients with advanced NSCLC. She added that researchers should focus on developing ways to identify patients who would not benefit from these agents to help overcome the high cost of immunotherapy treatment.

Based on the POPLAR results, PD-L1 has been shown not to be an effective biomarker for screening purposes in advanced NSCLC. Peters said that, ultimately, it may take a combination of many biomarkers, “including tumor mutation burden,” to identify patients who would not benefit from immunotherapy.

Future trials can accomplish the task of testing new biomarkers for these agents, she said. “These trials should be conducted in patients with similar characteristics to the long-term survivors in the phase I and II trials with atezolizumab, pembrolizumab, and nivolumab,” she said. “So, the first step will be to describe these patients in terms of demographics, smoking history, tumor mutation burden, expression of immune genes, and PD-L1 expression.”

Mazières J, Park K, Lewanski C, et al. 3-year survival and duration of response in randomized phase II study of atezolizumab (atezo) vs docetaxel (doc) in 2L+ NSCLC (POPLAR). Presented at: the 2018 European Lung Cancer Conference; April 11-14; Geneva, Switzerland. Abstract 136PD.

<<< 2018 European Lung Cancer Congress

“These latest results are exciting because unlike the previous 2 trials, POPLAR was a large randomized trial and provides convincing proof that long-term survival now exists in lung cancer,” she said.