Summary
Findings from the 3-year follow-up of the phase III CheckMate-227 Part 1 trial demonstrate that first-line nivolumab plus ipilimumab offers sustained improvements in overall survival (OS) for patients with metastatic non-small cell lung cancer (NSCLC). Data was presented during an oral presentation at the ASCO 2020 Annual Meeting (Abstract 9500).
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Original Article
Survival Benefit of Nivolumab + Ipilimumab in NSCLC
Oncology Times
By Catlin Nalley
Findings from the 3-year follow-up of the phase III CheckMate-227 Part 1 trial demonstrate that first-line nivolumab plus ipilimumab offers sustained improvements in overall survival (OS) for patients with metastatic non-small cell lung cancer (NSCLC). Data was presented during an oral presentation at the ASCO 2020 Annual Meeting (Abstract 9500).
“Non-small cell lung cancer is a complex and aggressive disease, and despite recent treatment advances, patients remain in need of additional options that may provide a long-lasting survival benefit,” said CheckMate-227 study investigator Suresh S. Ramalingam, MD, Deputy Director, Winship Cancer Institute of Emory University, in a statement.
“The 3-year outcomes from CheckMate-227 show evidence of sustained survival gains with nivolumab plus ipilimumab in the first-line treatment of non-small cell lung cancer,” he continued. “The data reaffirm the established scientific rationale that dual inhibition of PD-1 and CTLA-4 has the potential to deliver deep and durable responses for certain patients.”
Methods & Results
CheckMate-227 is a multi-part, open-label, phase III trial evaluating nivolumab-based regimens compared to platinum-doublet chemotherapy among patients with first-line advanced NSCLC across non-squamous and squamous tumor histologies.
Researchers randomized (1:1:1) patients with stage IV, recurrent NSCLC and PD-L1 ≥1 percent (n=1189) to receive nivolumab (3 mg/kg Q2W) plus ipilimumab (1 mg/kg Q6W), nivolumab (240 mg Q2W) alone, or chemotherapy. Patients with PD-L1 < 1 percent (n=550) were randomized to nivolumab and ipilimumab; nivolumab (360 mg Q3W) plus chemotherapy; or chemotherapy.
The primary endpoint was OS in patients with PD-L1 ≥1 percent. The investigators also conducted an exploratory analysis of OS in patients by response status (CR/PR, SD, PD) at 6 months.
“We designed this trial to compare this regimen to chemotherapy for metastatic NSCLC patients,” explained Ramalingam. “We are also interested in finding out whether the patient's PD-L1 expression would be relevant to treatment decisions. Therefore, we included both patients with high and low PD-L1 expression, defined as greater than 1 percent or less than 1 percent.”
With a median follow-up of more than 3 years (43.1 months), nivolumab plus ipilimumab continued to show a survival benefit among patients whose tumors expressed PD-L1 ≥1 percent, when compared to chemotherapy (HR: 0.79; 95% CI: 0.67 to 0.93).
In this population, 3-year OS rates were 33 percent for nivolumab plus ipilimumab versus 22 percent for chemotherapy alone. The researchers also reported that this combination delayed disease progression or death for this patient population, with a 3-year progression-free survival (PFS) of 18 percent compared to 4 percent with chemotherapy alone.
The researchers also conducted an exploratory landmark analysis of OS by response status and found 70 percent of patients whose tumors expressed PD-L1 ≥1 percent and who had a complete or partial response by 6 months to the nivolumab plus ipilimumab combination were alive 3 years later, compared to 39 percent of those treated with chemotherapy.
In the exploratory analysis of patients whose tumors expressed PD-L1 <1 percent, nivolumab plus ipilimumab showed 3-year OS rates of 34 percent versus 15 percent for chemotherapy alone (HR: 0.64; 95% CI: 0.51 to 0.81), according to the study authors.
Another important aspect of immunotherapy is the toxicity profile. “What we are reporting in this analysis is that even with the longer-term follow-up, no new safety signals were observed,” noted Ramalingam. “We also note that the autoimmune toxicities of interest happened primarily in the first 6 months and once patients got through that there was a very minimal incidence of newer toxicities.
“Therefore, among patients who are benefiting it's possible, even if they develop an autoimmune toxicity, to manage them with appropriate supportive care and continue forward with treatment,” he added.
Clinical Implications
With these findings, Ramalingam and his fellow researchers, contend that “the combination of nivolumab plus ipilimumab is an evidence-based approach to first-line treatment of NSCLC.”
The current treatment approach for patients with PD-L1 expression greater than 50 percent is pembrolizumab monotherapy, according to Ramalingam. For patients with PD-L1 expression less than 50 percent, it is chemotherapy with a checkpoint inhibitor.
“Based on the CheckMate-227 results, I would make the case that, at least for patients with low PDL-1 expression, the combination of nivolumab and ipilimumab could be a chemotherapy-free option, with the advantage of providing durable long-term benefits compared to chemotherapy plus immunotherapy,” Ramalingam told Oncology Times.
The benefits of this combination are now being explored in other settings as well. “For example, we plan to do a trial in earlier stages of NSCLC,” he said. “We're also interested in trying to identify biomarkers that could help us even more specifically narrow down, which patients should receive the combination.
“And, lastly, there's also another study that's going to be reported at ASCO evaluating the use of chemotherapy in combination with nivolumab and ipilimumab for frontline treatment of NSCLC,” he concluded. “Understanding if there is a specific subset of patients who could benefit from receiving chemotherapy alongside this combination is going to be another important question for the field moving forward.”
Catlin Nalley is a contributing writer.