The programmed death 1 (PD-1) immune-checkpoint-inhibitor-antibody nivolumab (Opdivo, Bristol-Myers Squibb) did not yield longer progression-free survival (PFS) than platinum-based chemotherapy when used as a first-line therapy in patients with untreated stage IV or recurrent non–small cell lung cancer (NSCLC), the open-label phase 3 CheckMate 026 trial now shows.
Furthermore, overall survival (OS) was similar between groups, report lead author David Carbone, MD, PhD, of the Ohio State University Comprehensive Cancer Center in Columbus, and colleagues in a study published online June 22 in the New England Journal of Medicine.
However, nivolumab had a favorable safety profile with no new or unexpected safety signals, the team also says.
Among NSCLC patients with a PD ligand 1 (PD-L1)–positive expression level of 5% or more, median PFS was 4.2 months in patients who received nivolumab vs 5.9 months for those treated with chemotherapy (hazard ratio [HR] for disease progression or death, 1.15; P = .25). The median OS was 14.4 months vs 13.2 months (HR for death, 1.02).
"The primary result was a surprise," Dr Carbone said in an interview with Medscape Medical News. "I fully expected there to be an improvement in progression-free survival," he explained, noting that there was "no difference in the patient population that we chose. We included anybody with any expression of the PD-L1 marker."
Earlier results with nivolumab in two phase 3 trials demonstrated significantly longer OS than was seen with docetaxel (Taxotere, Sanofi-Aventis) in patients with metastatic NSCLC who experienced disease progression during or after platinum-based chemotherapy. The OS advantage in patients treated with nivolumab was independent of PD-L1 expression level, although it was enhanced in patients with nonsquamous NSCLC with increasing PD-L1 expression.
These findings are in marked contrast to outcomes of the KEYNOTE-024 trial, in which the rival anti-PD-1 antibody pembrolizumab (Keytruda, Merck) was used as first-line treatment in patients with NSCLC with a PD-L1 expression level ≥50%, Dr Carbone and colleagues note. KEYNOTE-024 demonstrated a median PFS of 10.3 months for patients who received pembrolizumab compared to 6.0 months for patients who received chemotherapy, with response rates of 45% and 28%, respectively.
The reasons behind these different outcomes with two similar drugs "remain unclear and cannot be attributed to a single factor," the study authors say.
In an accompanying editorial, Edward B. Garon, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, suggests that the reason the efficacy of these similar drugs differed so greatly may be the result of "imprecise" patient selection.
"Could an effort to enhance the selection of patients fail on the basis of the inclusion of too broad a population, coupled with a PD-L1 assay that discriminates poorly at certain values? Absolutely, as is clearly shown in a trial of the PD-L1 inhibitor atezolizumab in patients with previously treated NSCLC in which atezolizumab was superior to chemotherapy," he writes.
The selection strategy in CheckMate 026 may have torpedoed the trial, he suggested. "Despite limitations, there is efficacy for first-line chemotherapy in non–small cell lung cancer," Dr Garon said in an email to Medscape Medical News. "A positive study based on a progression-free survival endpoint in first-line non–small cell lung cancer requires identification of a population with enhanced benefit from PD-1 inhibitors. The selection strategy in this study did not appear to sufficiently identify such a population," he said.
"Despite limitations, there is efficacy for first-line chemotherapy in non–small cell lung cancer," he added.
Noting that the KEYNOTE-024 trial used a different selection strategy and showed a benefit for pembrolizumab, Dr Garon recommended that "the successful strategy (assessing for PD-L1 using the 22C3 antibody) should be adopted by clinicians."
Many approaches are currently underway to improve outcomes, he noted.
"Ideally, ongoing phase 3 trials of combinations including inhibitors of PD-1 or PD-L1 in a broad population will improve outcomes," he told Medscape Medical News."Whether these phase 3 studies are positive or negative, it will be important to work to identify which patients are benefiting more from the addition of agents to a PD-1 or PD-L1 inhibitor."
In a statement, Martin J. Edelman, MD, chair of the Department of Hematology/Oncology at Fox Chase Cancer Center, in Philadelphia, Pennsylvania, reminded clinicians of the shortcomings of immunotherapy. "The message from this and other studies is that immunotherapy is active in a significant fraction of patients with advanced lung cancer. However, despite this, the majority of patients, even those identified with various biomarkers, do not benefit or benefit for only a short period of time."
To extend the benefits of immunotherapy, new agents and strategies that combine new drugs with chemotherapy and radiotherapy are also being evaluated, he pointed out.
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Baseline characteristics were balanced between the treatment groups. However, there were more women and more patients with a PD-L1 expression level of ≥50% in the nivolumab group than in the group receiving chemotherapy (32% vs 45% and 32% vs 47%, respectively).
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A total of 271 patients were allocated to receive nivolumab, administered intravenously at a dose of 3 mg/kg body weight once every 2 weeks; 270 patients were allocated to receive platinum-based chemotherapy once every 3 weeks for up to six cycles.
Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab, with 18% experiencing events of grade 3 or 4 severity. In the chemotherapy group, 92% of patients had treatment-related adverse events, with 51% experiencing events of grade 3 or 4 severity.
At the time of disease progression, determined in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 128 of 212 patients in the chemotherapy arm (60%) crossed over and received nivolumab as subsequent therapy.
Results from the study's exploratory biomarker analysis also demonstrated that tumor mutation burden may play a role in both response and PFS. It was conducted in 312 patients (58%) who underwent randomization. It showed that those with a high tumor-mutation burden did better with immunotherapy than with chemotherapy.
"This wasn't the primary endpoint, but it does need to be prospectively tested," Dr Carbone explained.
In patients with a high-mutation tumor burden, the response rate in those receiving nivolumab was higher than in those given chemotherapy (47% vs 28%), and PFS was longer (median, 9.7 vs 5.8 months; HR for disease progression or death, 0.62). In patients who had both a high tumor-mutation burden and a PD-L1 expression level ≥50%, the response rate to nivolumab jumped to 75%.
In the presence of just one of these two factors, however, response to nivolumab diminished significantly. The rate was 32% in patients who had a high-tumor burden only, and it was 34% in those with only a PD-L1 expression level of ≥50%. Without either of these factors, the response rate was 16%, the study authors say. They acknowledge that the comparison was not powered for statistical analysis.
However, Dr Carbone said these results "just add to the weight of evidence that molecular testing of blood cancer tumors should be done before any treatment. We should be looking for mutation burden, and expression of the PD-L1 marker should be part of the standard workup."
This kind of genetic testing is not readily available in community settings, he admitted, adding, "We need to educate community physicians to do testing and make more economical testing available right across the country."
Assessment of mutation quality to select mutations most responsive to therapy "will be the next thing to look at," he predicted. "It's not perfect, but it's better than just counting the number of mutations."
Dr Garon called the analysis "intriguing" but said that results are "akin to an algorithm developed today that predicts last season's World Series victory by the Cubs. Although potentially meritorious, its ability to pick this season's champion is unclear."