CHICAGO—Nivolumab, a PD-1 inhibitor, was approved by the Food and Drug Administration in March for treatment of squamous cell non-small cell lung cancer (SC-NSCLC), which accounts for approximately 15 percent of all lung cancers. But does it work in non-squamous NSCLC in patients with advanced disease that progressed after platinum-based chemotherapy, and does it work better than the current second-line standard of care, docetaxel?
According to the Phase III CheckMate 057 trial, the answer is yes, data for which were presented here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA109).
The trial included 582 patients with advanced non-squamous non-small cell lung cancer randomly assigned to nivolumab or docetaxel.
Lead author Luis Paz-Ares, MD, PhD, Professor of Medicine and Chair of the Department of Oncology at Hospital Universitario Virgen Del Rocio in Spain, reported a 19.2 percent response rate for 292 patients receiving immunotherapy versus 12.4 percent for 290 patients receiving docetaxel, and a superior duration of response—17.1 months for immunotherapy versus 5.6 months for docetaxel.
Median overall survival was 12.2 months for nivolumab versus 9.4 months for docetaxel, and the one-year overall survival rate was 51 percent for nivolumab versus 39 percent for docetaxel.
Paz-Ares said 4.9 percent of patients stopped nivolumab due to toxic side effects versus 14.9 percent of patients on docetaxel.
“Nivolumab appears to be more potent against this most common lung cancer, but it is important to note that it is also far easier on patients compared with docetaxel,” Paz-Ares said. The number of patients having grade 3/4 adverse events was 10.5 percent for the immunotherapy versus 53.7 percent for docetaxel.
Nivolumab is a fully humanized IgG4 PD-1 immune checkpoint inhibitor antibody, and tumor levels of the ligand to PD-1, PD-L1, appear to influence response to the drug. A subgroup of patients with PD-L1 levels of one percent or higher in their tumors had a median survival with nivolumab greater than 17 months, versus nine months for docetaxel.
And while patients who received nivolumab had a reduction in risk of death of 27 percent compared with docetaxel patients, the subgroup of patients with high PD-L1 levels had a 41 to 60 percent reduction in risk of death, which was not observed in cases of low or undetectable PD-L1, he said.
Paz-Ares said nivolumab demonstrated efficacy and safety in an earlier Phase III trial, which compared nivolumab with docetaxel in patients with advanced squamous NSCLC.
The nivolumab dose in that trial and the trial reported here was 3 mg/kg every two weeks, and the docetaxel dose was 75 mgm2 every three weeks.
Grade 3/5 drug-related adverse events occurred in 10.5 percent (30 of 287) of nivolumab patients versus 53.7 percent (144 of 268) of docetaxel patients. There were no deaths in the nivolumab arm of the study, versus one in the docetaxel arm.
After discontinuation, 42.1 percent of nivolumab patients and 49.7 percent of docetaxel patients received subsequent systemic therapy.
Roy Herbst Asks: Is This Truly Checkmate?
The Discussant for the CheckMate 057 trial was Roy S. Herbst, MD, PhD, Professor of Medicine and Pharmacology and Chief of Medical Oncology and Director of the Thoracic Oncology Program at Yale School of Medicine.
“Is this truly ‘checkmate’ for NSCLC, or do we still have a lot of work to do on our endgame?” he asked provocatively in his first slide.
Cutting to the chase, his conclusion slides declared, “YES! Nivolumab is the new standard of care for previously treated non-squamous NSCLC. This is a positive, randomized Phase III trial that sets a new treatment standard,” he said.
There are still questions to be resolved, though of course: “Should this PD-L1 biomarker assay be used for patient selection? No, not yet,” he said. “It is an intriguing possibility, but for now it is only hypothesis generating. The biomarker was not prospectively stratified here, and data are incomplete, since 22 percent of patients had no measurement in the trial.”
Some issues with biomarkers in general, he noted, are the heterogeneity of multiple tumors and multiple passes within a tumor; the interval between biopsy and treatment; primary versus metastatic disease; antibody and staining conditions.
Herbst said that while higher PD-L1 levels were associated with improved response and survival, in this trial even the nivolumab patients with PD-L1 tumor levels less than one percent had activity at least equal to docetaxel, and with less toxicity.
“If a patient has a less than one percent tumor level of PD-L1, do we still give nivolumab?” he asked.
Herbst called for future studies with nivolumab to explore its potential benefit in a greater number of patients—in front-line therapy, in the adjuvant setting in earlier-stage disease, in small-cell lung cancer, and in ALK and EGFR mutants.
Considered Impossible Until Recently
“Even five years ago, an effective immunotherapy for lung cancer was considered impossible. Today we have such a treatment, and it surpasses the standard therapy both in terms of efficacy and patient quality of life,” said ASCO designated expert Gregory A. Masters, MD, Associate Professor of Medicine at Thomas Jefferson University, who was invited by ASCO to comment at a news conference on progress in cancer immunotherapy.
Luis Paz-Ares, MD, elaborates on his remarks in a podcast interview with Peter Goodwin on the iPad edition of this issue. Lynn Schuchter, MD, Chief of Hematology/Oncology at Abramson Cancer Center of the University of Pennsylvania and the moderator of the news conference at which the study was discussed, added her comments about the scope for using this form of checkpoint inhibition as a target in lung cancer.