Nivolumab Considered Practice Changing in Refractory, Advanced Nonsquamous NSCLC

Nivolumab Considered Practice Changing in Refractory, Advanced Nonsquamous NSCLC

Having recently been approved for second-line treatment of squamous non–small cell lung cancer (NSCLC), nivolumab demonstrated a significant overall survival (OS) benefit for patients with nonsquamous (NSQ) NSCLC based on data from the CheckMate 057 trial (Abstract LBA109) reported during “Immunotherapy for Every Patient: Check Your Enthusiasm,” on Saturday, May 30. “Checkmate 057 is the second phase III trial to demonstrate superior survival of nivolumab over docetaxel in advanced NSCLC,” said Luis Paz-Ares, MD, PhD, of the Hospital Universitario Virgen Del Rocio, Spain.

Dr. Luis Paz-Ares

CheckMate 057 was a phase III, randomized study conducted in patients with advanced NSQ NSCLC for whom platinum-based doublet chemotherapy had failed. Patients were randomly assigned to receive the PD-1 immune checkpoint inhibitor nivolumab at a dose of 3 mg/kg every 2 weeks (292 patients) or docetaxel at a dose of 75 mg/m2 every 3 weeks (290 patients) until disease progression or discontinuation because of toxicity or other reasons. “The confirmed prespecified boundary for overall survival was crossed, and an Independent Data Monitoring Committee was unanimous in declaring superiority in OS for nivolumab versus docetaxel,” Dr. Paz-Ares said.

As the primary endpoint, median OS was significantly higher for the nivolumab group: 12.2 months versus 9.4 months for the docetaxel group (hazard ratio [HR] 0.73, 95% CI [0.59, 0.89]; p = 0.0015). Patients receiving nivolumab were, therefore, at a 27% reduced risk for death. One-year OS was 51% for the nivolumab group compared to 39% for the docetaxel group.  Survival benefits were seen for all subgroups of patients, except those whose tumors had EGFR mutations.

Objective response rate (ORR) was also significantly higher for patients receiving nivolumab: 19% for the nivolumab group versus 12% for the docetaxel group (p = 0.0246). There were no significant differences in progression-free survival (PFS).

Moreover, “patients with PD-L1–positive tumors have a huge magnitude of benefit, and PD-L1 expression was a predictor of response,” Dr. Paz-Ares said.

In an analysis correlating PD-L1 staining with OS, median OS for nivolumab was 17.2 months, 18.2 months, and 19.4 months for patients with tumors having 1% or higher, 5% or higher, and 10% or higher of cells staining positive for PD-L1, respectively, compared with 9.0 months, 8.1 months, and 8.0 months for treatment with docetaxel. Median OS for patients with tumors having less than 1%, less than 5%, and less than 10% of cells staining for PD-L1 was similar for nivolumab (range 9.7 to 10.4 months) and docetaxel (10.1 to 10.3 months). The values of 1%, 5%, and 10% were predefined cut-points for PD-L1 expression.

Adverse events of any grade occurred in 69% of patients receiving nivolumab and 88% of patients receiving docetaxel; grade 3-5 adverse events occurred in 10% of patients in the nivolumab group and 54% of those in the doce-taxel group.

Dr. Roy S. Herbst

Discussant Roy S. Herbst, MD, PhD, of Yale Comprehensive Cancer Center, indicated that the study was practice changing. Dr. Herbst asked, “Is this truly checkmate, or do we still have a bit of work to do on our endgame?”

Dr. Herbst pointed to the delayed effects of immunotherapy and indicated that the survival curves for patients on nivolumab were “very impressive.”

Although the biomarker data showed significant outcomes for patients expressing any level of PD-L1, PD-L1 expression was determined using archival specimens and was not available for all patients. Despite the fact that these studies are hypothesis generating, Dr. Herbst commented that more work is needed before PD-L1 expression is used to determine treatment in the second-line setting and that patients were not prospectively stratified. Dr. Herbst noted that the field is now grappling with multiple biomarkers associated with different immunotherapy drugs. “It will be important to reconcile this in the future,” he said.

Based on data from CheckMate 057, Dr. Herbst considers nivolumab the new standard of care for patients with previously treated NSQ NSCLC. 

“This is a positive randomized phase III trial with the primary endpoint for all comers,” Dr. Herbst said. “There is a particularly long benefit in a select population of patients, and nivolumab is significantly less toxic.” However, he said that the PD-L1 biomarker should not yet be used for patient selection.

He further noted that although positivity for the PD-L1 biomarker does improve ORR, PFS, and OS with nivolumab, even the group with less than 1% expression appeared to have at least equal activity to that of docetaxel with less toxicity.

Concluding his discussion on CheckMate 057, Dr. Herbst indicated that future studies are warranted to benefit a greater number of patients—as front-line therapy, in the adjuvant setting, in tumors with ALK and EGFR mutations, and in small cell lung cancer.

Watch the session: Visit the ASCO Virtual Meeting website.