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BARCELONA – First-line treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) led to a longer duration of overall survival (OS) versus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC), independent of the PD-L1 expression level, according to a secondary analysis of the CheckMate 227 trial.

Among patients with a PD-L1 expression level of ≥1%, the median OS duration was 17.1 months (95% CI 15.0-20.1) with nivolumab plus ipilimumab versus 14.9 months (95% CI 12.7-16.7) with chemotherapy (P=0.007), according to Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

The 2-year OS rates were 40.0% with the immunotherapy combination and 32.8% with chemotherapy, she reported at the European Society for Medical Oncology (ESMO) annual meeting and simultaneously in the New England Journal of Medicine.

In addition, the median duration of response was 23.2 months with nivolumab plus ipilimumab versus 6.2 months with chemotherapy.

Also, patients with a PD-L1 expression level <1% saw OS benefits, with a median duration of 17.2 months (95% CI 12.8-22.0) with the immunotherapy combination versus 12.2 months (95% CI 9.2-14.3) with chemotherapy.

"The bottom line is this: We have a new option for unselected patients with advanced NSCLC," Peters told 番茄社区app. "For years, we have given these patients chemotherapy; we don't like to do this and the patients don't like it either. This trial show that ipilimumab and nivolumab is a a good option. We saw that it met the primary endpoint for OS, and even the patients with negative PD-L1 expression did well. We also saw that the duration of response was greater with the combination."

Other CheckMate 227 results were reported at the 2018 American Association for Cancer Research meeting, including a progression-free survival rate at 12 months in patients with high tumor mutational burden (TMB) of 42.6% with versus 13.2% with chemotherapy. However, in July 2019, nivolumab developer Bristol-Myers Squibb reported that first-line nivolumab plus chemotherapy versus chemotherapy alone among NSCLC patients regardless of PD-L1 status.

Peters suggested that patients who did not have high levels of PD-L1 benefited from the combination because the immunotherapy agents upregulated production of PD-L1, which brought the disease into the target area for nivolumab. "We are exposing these patients to a regimen that allows them to have a good quality of life, without the side effects of chemotherapy and maybe 4 or 5 years of survival," Peters told 番茄社区app.

"It is incredible that we are here to talk about multiple options for treatment of advanced NSCLC," said Marina Garassino, MD, of the Istituto Nazionale dei Tumori in Milan. "The population of this study represents most of the patients that we see in our clinics."

Just 5 years ago, immunotherapy was considered second-line treatment, but has advanced to first-line in that short time period, she noted. "We now have three [advanced NSCLC treatment] options: We can treat patients with a single immunotherapy agent; we can treat our patients with chemotherapy and immunotherapy; and now we have the possibility of treating them with immunotherapy and immunotherapy in a chemotherapy-sparing regimen," Garassino said.

However, she stressed that it's still necessary to perform PD-L1 testing, despite the fact that CheckMate 227 demonstrated that the combination therapy was effective in all groups of patients "because we still need to work out who are the right patients to be treated with each of these regimens. We need to discuss these options with our patients."

In the , chemotherapy-naïve patients with stage IV or recurrent NSCLC and a PD-L1 expression level of ≥1% were randomized 1:1:1 to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy.

Patients who had PD-L1 <1% were randomly assigned 1:1:1 to receive the immunotherapy combination, nivolumab plus chemotherapy, or chemotherapy alone.

Peters and colleagues reported that 32.8% of patients who received the immunotherapy combination experienced grade 3 or 4 treatment-related adverse events (TRAEs) versus 36.0% of the patients who chemotherapy.

But serious TRAEs of any grade were more common with the immunotherapy combination than with chemotherapy (24.5% vs 13.9%), as were TRAEs leading to discontinuation (18.1% vs 9.1%). The most common select TRAEs of any grade with a potential immunologic cause in the immunotherapy combination group were skin reactions (34.0%) and endocrine events (23.8%).

Treatment-related deaths occurred in eight patients in the immunotherapy combination group and in six patients in the chemotherapy.

"The adverse events that were associated with nivolumab plus ipilimumab and chemotherapy according to PD-L1 expression level were similar to the adverse events in the overall population...were consistent with those in previous trials, and the incidence did not increase with longer follow-up," the authors wrote.

The CheckMate 227 investigators noted that "Further understanding of the role of the [TMB], if any, as a biomarker, is warranted before the integration of this factor into clinical practice." Studies presented at the 2019 World Conference on Lung Cancer indicated that TMB was not ready for widespread dissemination as a marker of key outcomes in NSCLC.

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