CheckMate -227: Immunotherapy Combination Demonstrates Improved Progression-Free Survival in People with a High Tumor Mutational Burden in Advanced Non-Small Cell Lung Cancer

The combination of nivolumab (Opdivo®) and ipilimumab (Yervoy®) has shown improved progression-free survival (PFS) compared with chemotherapy as a first-line treatment for people with a high tumor mutational burden (TMB) in advanced non-small cell lung cancer (NSCLC). Data from the CheckMate -227 trial is being reported by Matthew Hellmann, MD, of Memorial Sloan Kettering Cancer Center, at the AACR Annual Meeting 2018. This research is featured in the meeting’s press program, and findings are being presented in the Clinical Trials Plenary Session, “Immunotherapy Combinations: The New Frontier in Lung Cancer.” This data is being simultaneously published in the New England Journal of Medicine.

“This study demonstrates the efficacy of nivolumab plus ipilimumab immunotherapy as a first-line treatment for people with high-TMB NSCLC,” explained Dr. Hellmann. “This is the first phase III study to evaluate TMB, a measurement of the mutations carried by tumor cells, as a predictive biomarker for immunotherapy as a co-primary endpoint. The identification of a new biomarker for predicting who can benefit from this immunotherapy combination is encouraging and continues the progress we have made through precision medicine in treating people with lung cancer.”

Answering the Critical Question: Who Will Respond to Treatment?

Lung cancer is the greatest cause of cancer deaths worldwide. For people without a targetable oncogene, chemotherapy has long been the standard of care, but this treatment is characterized by its short duration of response and moderate toxicity. Checkpoint inhibitors, such as nivolumab, have recently emerged as a critical new treatment option for people with NSCLC. However, responses occur in only a minority of people with NSCLC, and biomarkers are needed to more effectively identify who is most likely to benefit from immunotherapy.

“In the CheckMate -227 trial, we applied the emerging data about TMB to validate this as a biomarker to predict who will best respond to this combination therapy,” explained Dr. Hellmann. “These results show that combination immunotherapy can be a new treatment option in the first-line setting and contribute to our ongoing effort to match people with the best therapies for them. For example, if combination immunotherapy is the best option for someone in the first-line setting, then it provides a potentially effective and durable option upfront, sparing the use of chemotherapy initially while saving an effective option with chemotherapy for the second line if needed.”

Method and Findings

Dr. Hellmann serves as the principal investigator for CheckMate -227, a large, open-label, randomized phase III trial of nivolumab, nivolumab plus ipilimumab, or nivolumab plus platinum-doublet chemotherapy (PT-DC) versus PT-DC alone in people with stage IV or recurrent NSCLC who had not received prior treatment. Data from the comparison between the immunotherapy combination and PT-DC are being reported. Co-primary endpoints of this study are PFS for nivolumab plus ipilimumab versus chemotherapy in people with a high TMB and overall survival for nivolumab plus ipilimumab versus chemotherapy in people with PD-L1 selected tumors. Data have showed that among people with newly diagnosed advanced NSCLC with a high TMB, those who received the immunotherapy combination had significantly improved PFS compared with people who received PT-DC, the standard-of-care chemotherapy, meeting one of the study’s co-primary endpoints.

A total of 299 people with a high TMB (ten mutations per megabase or higher) were randomized, and baseline characteristics were balanced between the immunotherapy combination and chemotherapy arms. PFS was significantly longer with nivolumab plus ipilimumab versus chemotherapy in people with a high TMB (hazard ratio 0.58, p=0.0002). PFS at one year was 43 percent versus 13 percent, respectively, and duration of response at one year was 68 percent versus 25 percent. The objective response rate among people with high-TMB NSCLC who were treated with nivolumab plus ipilimumab was higher compared with those treated with chemotherapy, 45.3 percent versus 26.9 percent. In addition, the combination therapy improved PFS compared with nivolumab alone in people with high-TMB, PD-L1-positive tumors, with one-year PFS at 42 percent for those treated with the combination therapy and 29 percent for those treated with the monotherapy.

Evolving Clinical Trial Design

Initial data from the CheckMate012 trial found that PD-L1 expression was associated with improved outcomes in people with NSCLC who were treated with nivolumab plus ipilimumab. For this reason, the CheckMate -227 trial was designed to examine the benefit of nivolumab plus ipilimumab versus chemotherapy in PD-L1 selected tumors. This co-endpoint remains ongoing.

In related work, Dr. Hellmann and colleagues published data in Cancer Cell on April 12 that highlights the critical importance of TMB as a predictive marker. This specific study examined the molecular features associated with response in people with NSCLC who were treated with the nivolumab plus ipilimumab combination. TMB was found to be strongly associated with benefit.

“The field of immunotherapy is evolving so rapidly, and we are learning more every day. As we continued to accrue data, it became clear that people with a high TMB who were treated with this combination demonstrated a significant benefit. Based on this and other emerging data about TMB as a biomarker, CheckMate -227 was amended to include the co-primary endpoint of nivolumab plus ipilimumab versus chemotherapy in a preselected group of people with high-TMB NSCLC,” explained Dr. Hellmann. “By understanding the genomic makeup of tumors and harnessing the power of precision medicine, we can identify predictive biomarkers, such as TMB, and help improve treatment options for people with cancer.”

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