Inmunologically active proteins on a T-cell: T-cell receptor, CD-4, CD-28, PD-1 and CTLA-4 and a calcium channel. Cancer Immunotherapy
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Research presented at the International Association for the Study of Lung Cancer 2023 World Conference has shown that first-line immunotherapy with nivolumab plus ipilimumab gives rise to durable survival benefits in a significant proportion of patients with advanced non-small-cell lung cancer (NSCLC).

The 6-year update of the CheckMate 227 trial, presented by Solange Peters from Lausanne University Hospital in Switzerland, is the longest follow-up across first line immunotherapy trials in metastatic NSCLC and represents a pivotal moment in the management of this disease.

“For the first time in lung cancer, we start to see a plateau in the curve of survival,” Peters tells Inside Precision Medicine. “Suddenly, after a bit more than five years, you see these [survival] curves becoming really flat meaning that at some point you stop losing patients from the disease, which for lung cancer was unbelievable.”

CheckMate 227 included 1739 patients with stage IV or recurrent NSCLC and no known mutations in EGFR or ALK. Patients with tumor PD-L1 expression of 1% or greater (n=1189) were randomly assigned to be treated with first line nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy. Those with tumor PD-L1 expression below 1% (n=550) were given nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy.

Previously published data from the trial showed that two years of treatment with first line nivolumab and ipilimumab resulted in a significant and sustained survival advantage over chemotherapy. This led to approval of the regimen in PD-L1-positive (≥1% expression) patients in the USA, Canada, and South Korea, and in patients with any level of PD-L1 in Japan and Argentina.

The current analysis, with at least six years and one month of follow-up, revealed that nivolumab, a PD1 inhibitor, plus ipilimumab, which targets CTLA-4, continued to provide significant overall survival (OS) benefit versus chemotherapy regardless of PD-L1. Specifically, the 6-year OS rate among patients with PD-L1 at or above 1% was 22% in the dual immunotherapy arm compared with 13% in the chemotherapy arm.

For those with PD-L1 below 1%, the corresponding 6-year OS rates were 16% and 5%.

Peters says the fact that around 20% of patients were alive at 6 years was unimaginable in the past and the study shows that when you target CTLA-4 you create an immune response that lasts far beyond the original treatment duration.

Similar benefits were observed for other outcomes such as progression-free survival and duration of response and Peters notes that responders with substantial tumor burden reduction had considerably better OS with nivolumab plus ipilimumab than with chemotherapy. For example, the 6-year OS rate was 59% among the 52 patients with PD-L1 at or above 1% and tumor shrinkage of 80% or more who received nivolumab plus ipilmumab whereas it was 19% among the 31 patients with tumor shrinkage of 30–50%. In the group with PD-L1 expression below 1% (n=13 and 12, respectively), the corresponding 6-year OS rates were 77% and 42%.

Better baseline health-related quality of life (QoL) was also associated with improved OS at 6 years, regardless of the treatment received. At 6 years, the OS rate was 23% among participants with a high (above median) QoL and 17% among those with a low QoL who received dual immunotherapy. For those given chemotherapy, the rates were 15% and 5%, respectively.

Although this finding is “probably intuitive,” Peters notes that showing it in the trial will help doctors anticipate the outcomes of their patients. Indeed, both the QoL and tumor burden will allow the clinicians to “accompany the patients in their journey slightly more adequately,” by anticipating the treatment benefit and adjusting their tone and how they support the patients accordingly.

The data will also ultimately improve precision medicine for patients with advanced NSCLC as more studies identify biomarkers that predict which patients will have these durable outcomes. Peters believes her team now have a duty to continue the follow-up of the surviving CheckMate 227 participants to understand more about them and to confirm whether the plateau really is a plateau.

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