Nivolumab/Ipilimumab Combo Active in SCLC With High Tumor Burden

Matthew D. Hellmann, MD

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) induced an objective response rate (ORR) of 46% in patients with recurrent small cell lung cancer (SCLC) with high tumor mutation burden (TMB), according to an exploratory analysis from the phase I/II CheckMate-032 study. The ORR was 21% with nivolumab monotherapy.

In patients with medium and low levels of TMB treated with the combination, the ORR was 16% and 22%, respectively. The ORR was 7% and 5%, respectively, among patients in these populations receiving single-agent nivolumab.

Among patients with high TMB, the 1-year overall survival (OS) rate was 62% with the combination and 35% with single-agent nivolumab. This compared to 1-year OS rates of 20% and 26%, and 23% and 22%, with the combination and monotherapy in patients with medium and low levels of TMB, respectively.

“These exploratory TMB data from CheckMate-032 are the first to show the potential of using mutation burden to predict response in some patients with the combination of two [immuno-oncology] agents,” study investigator Matthew D. Hellmann, MD, Memorial Sloan Kettering Cancer Center, said in a press release. “Further investigation is warranted to explore the application of this marker across lung cancers, and in the setting of both immuno-oncology combination and monotherapy.”

Data from CheckMate-032 are being presented at the International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer (WCLC), taking place this week in Yokohama, Japan.

SCLC accounts for 10% to 15% of all lung cancers. Five-year survival rates tend to be lower than in non—small cell lung cancer because SCLC is more aggressive and often goes undetected until the cancer is at an advanced stage. Globally, the 5-year survival rate ranges from 20% to 40% for stage I SCLC and drops to just 1% for stage IV disease.

CheckMate-032 is an ongoing, open-label, phase I/II trial evaluating the safety and efficacy of 3 mg/kg of nivolumab monotherapy or 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab in advanced or metastatic solid tumors. Treatment is delivered every 3 weeks for 4 cycles or until disease progression or unacceptable toxicity. The trial includes both PD-L1 expressors and non-expressors.

The primary endpoint was ORR assessed by a blinded independent central review. Secondary objectives included safety, OS, progression-free survival (PFS), and duration of response. Biomarker analysis was an exploratory objective. Investigators did not present any new safety data in this analysis.

Overall, in the pooled intent-to-treat (ITT) population (n = 401), the ORR was 11% with nivolumab alone and 22% with the combination. Among the ITT population, 211 (53%) patients had an evaluable TMB result for these analyses and were divided into subgroups of high, medium, and low levels of TMB.

One-year PFS was 30% in patients with high TMB levels who received the combination. The 1-year PFS rates with the combination were 8% in patients with medium TMB levels and 6% for those with low TMB levels. With single-agent nivolumab, the 1-year PFS rates were 21% and 3% for patients with high and medium TMB, respectively. PFS was not evaluable in patients with low TMB.

“Assessing the effect of TMB on treatment outcomes has been an important part of our ongoing translational medicine research,” Nick Botwood, MD, development lead, thoracic cancers, Bristol-Myers Squibb, the manufacturer of nivolumab and ipilimumab, said in a statement. “Based on these exploratory data from CheckMate-032 in previously treated small cell lung cancer, and the growing scientific evidence for this biomarker, we continue to investigate TMB to understand its relevance as a marker to potentially predict outcomes with immunotherapy.”

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