Opdivo/Yervoy Frontline Shows Promising Response in PD-L1-Positive Non-Small Cell Lung Cancer

Upfront treatment with the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) demonstrated an objective response rate (ORR) of 57 percent in patients with PD-L1-positive advanced non—small cell lung cancer (NSCLC), according to updated pooled findings from the phase lb CheckMate-012 study presented at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO), a gathering of 30,000 oncology professionals in Chicago.

In the three-arm study, patients received Opdivo alone or in combination with Yervoy every six weeks or every 12 weeks. Across the full population, which was not selected based on PD-L1 expression, single-agent Opdivo had an ORR of 23 percent. In the combination arms, the ORRs were 47 percent and 39 percent, respectively.

For the PD-L1 assessment, data were combined from the two combination arms. The 57 percent ORR was found in those with one percent or greater PD-L1 expression on cells. In those with 50 percent or greater PD-L1 expression, the ORR was 92 percent. In patients who tested PD-L1-negative, the ORR with the combination regimen was 15 percent.

"Opdivo plus Yervoy has promising activity, with response rates ranging from 39 percent to 47 percent. Median duration of response was not yet reached," said lead investigator Matthew Hellmann from Memorial Sloan Kettering Cancer Center. "Efficacy with Opdivo plus Yervoy is enhanced with increasing PD-L1 expression."

In the study, patients were randomized to receive Opdivo every 2 weeks alone or at the same schedule in combination with Yervoy. The primary endpoints of the study were ORR and 24-week progression-free survival (PFS). Secondary endpoints included overall survival (OS) and efficacy by PD-L1 expression.

In the 12-week and six-week arms, the median PFS were 8.1 and 3.9 months, respectively. In the single-agent Opdivo group, the median PFS was 3.6 months. The one-year OS rate was not reached in the 12-week arm, and was 69 percent and 73 percent in the six-week and single-agent arms, respectively.

In those with one percent or greater PD-L1 expression, median PFS were 8.1 and 10.6 months, in the 12-week and six-week arms, respectively. With single-agent Opdivo, median PFS was 3.5 months. The one-year OS rates were 90 percent, 83 percent and 79 percent and ORRs were 57 percent, 57 percent and 28 percent, for the 12-week, six-week and monotherapy arms, respectively.

In the pooled analysis, responses to frontline Opdivo and Yervoy varied based on smoking and Epidermal Growth Factor Receptor (EGFR) mutation status. The ORR in never smokers treated with the combination was 27 percent compared with 46 percent in current or former smokers. A similar trend was seen for single-agent Opdivo, at 9 percent and 27 percent, in never and current/former smokers, respectively.

For those with EGFR-mutant NSCLC in the combination arm, the ORR reached 50 percent. In EGFR wild-type tumors, the ORR was 41 percent. For single-agent Opdivo, ORRs were 14 percent and 30 percent, in EGFR mutated and wild-type tumors, respectively.

"These results must be interpreted with caution," warned Hellmann. "Of these four responders in the EGFR mutant group, one did not have classical exon 19 deletion or L858R EGFR activating mutations, three were former/current smokers and three had high PD-L1 expression levels."

All-grade adverse events (AEs) were similar across each arm, occurring in 82 percent, 72 percent and 71 percent of those in the 12-week, six-week and monotherapy arms, respectively. Grade 3/4 AEs were higher in the combination arms, at 37 percent and 33 percent for the 12-week and six-week schedules of Yervoy, respectively. In the single-agent arm, grade 3/4 AEs were experienced by 19 percent of patients. Grade 3/4 AEs led to treatment discontinuation for 5 percent, 8 percent and 10 percent of those in the 12-week, six-week and single-agent arms, respectively.

“The results from this study provide important insight into the combination immunotherapy with Opdivo and Yervoy, and supports the potential for this combination as a first-line treatment option for patients with advanced NSCLC,” Hellmann said in a press release. “We look forward to additional research of this combination in the first-line setting of patients with non-small cell lung cancer.”

Frontline treatment with the combination continues to be assessed in the phase 3 CheckMate-227 trial. For this four-arm study, platinum-doublet chemotherapy is being compared with Opdivo alone or in combination with Yervoy or platinum-doublet chemotherapy. The primary endpoint is OS, and the study plans to enroll 1,980 patients. The estimated primary completion date is January 2018.