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Nivolumab/Ipilimumab Combination Shows Benefit in First-Line Setting for NSCLC

Tony Berberabe, MPH
Published Online:5:00 PM, Mon November 11, 2019
Julie R. Brahmer, MD
Julie R. Brahmer, MD
Although the use of PD-1 and CTLA-4 pathway blockade in non–small cell lung cancer (NSCLC) has had mixed results in the past, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has demonstrated positive benefit in overall survival (OS) and adverse event (AE) profile compared with chemotherapy. Research suggests that anti–CTLA-4 helps induce T-cell responses and anti–PD-1 aids to restore anti-tumor T cell function.

“There has been benefit for this combination observed in renal cell carcinoma [NCT02231749] and melanoma [NCT01844505],” said Julie R. Brahmer, MD, director of the thoracic oncology program and professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. Brahmer discussed the rationale for the use of the nivolumab and ipilimumab combination in patients with NSCLC during the “Point-Counterpoint: New Data and Controversies on Immunotherapy Combinations in the First-Line Treatment of NSCLC” presentation at Society for Immunotherapy of Cancer’s 34th Annual Meeting & Pre-Conference Programs (SITC 2019).1

CheckMate 227 was the first large, phase III study that demonstrated that progression-free survival (PFS) was prolonged in patients with high tumor mutational burden (TMB). Patients with nonmetastatic NSCLC, with no EGFR mutations or known ALK alterations, were randomized based on their PD-L1 expression. Patients with PD-L1-positive disease received either the nivolumab and ipilimumab combination, single-agent nivolumab or chemotherapy. Patients with PD-L1-negative disease were randomized to receive either nivolumab and ipilimumab, chemotherapy or the combination of nivolumab and chemotherapy.

“This was the first study shown to demonstrate improved overall survival for the nivolumab and ipilimumab combination versus chemotherapy in patients who had PD-L1-positive disease with advanced NSCLC,” Brahmer said. The median overall survival in patients with tumor PD-L1 expression ≥1% was 17.1 months for patients who received the immuno-oncology (IO) combination compared with 14.9 months for patients receiving chemotherapy (HR, 0.79; 97.72% CI, 0.65-0.96; P = .007). The nivolumab and ipilimumab combination showed a 2-year overall survival of 40% compared with 33% for patients in the chemotherapy arm.

When single-agent nivolumab was added to the trial investigators reported that OS for nivolumab alone was 15.7 months. “We also see an improvement in [PFS] in patients treated with the nivolumab and ipilimumab combination compared with chemotherapy,” said Brahmer. Overall response rate and duration of response (DOR) also favored the IO combination arm compared with the nivolumab alone and chemotherapy arms (TABLE).

In patients with PD-L1 expression ≥50%, investigators reported a higher response rate in patients who received the IO combination compared with single-agent nivolumab and chemotherapy. PFS and OS also favored the IO combination arm, with a median OS of 21.2 months for the IO combination, 18.1 months for nivolumab alone and 14.0 months for chemotherapy. Median DOR for the IO combination, nivolumab and chemotherapy was 31.8, 17.5 and 5.8 months, respectively.

But what about patients with no PD-L1 expression?

“This is a huge unmet need,” said Brahmer. “There was an improvement in overall survival in patients with PD-L1 expression <1%, with median OS for the IO combination at 17.2 months compared with chemotherapy at 12.2 months. The IO combination does outperform the nivolumab and chemotherapy and chemotherapy alone arms with a median OS of 17.2, 15.2, and 12.2 months, respectively,” she said.

Further, Brahmer said that when looking at OS data for all randomized patients by PD-L1 expression and TMB status “we see that nivolumab and ipilimumab show an improvement in survival compared with chemotherapy, regardless of PD-L1 status.” Similarly, when looking at TMB, she noted an advantage of giving the IO combination regardless of TMB status.

Brahmer said that in general, AEs associated with the IO combination were not increased, compared with chemotherapy, “though there was an increased rate of discontinuation among patients in the IO combination arm because of treatment-related adverse events [TRAEs].” There was an 18% rate of discontinuation for patients who received the IO combination, 12% in patients who received nivolumab and 9% for patients who received chemotherapy.

Brahmer concluded, saying that the “nivolumab and ipilimumab combination is a viable treatment option for patients with NSCLC regardless of PD-L1 status, although the IO combination has a trend towards less [TRAEs] when compared with chemotherapy, but more [TRAEs] leading to treatment discontinuation.”

TABLE. Overall Response Rate and Duration of Response
Overall response rate (%)
  Nivolumab + ipilimumab (n = 142) Nivolumab (n = 109) Chemotherapy (n = 119)
Complete response 5.8 3.0 1.8
Partial response 30.1 24.5 28.2
Overall response 35.9 27.5 30.0
Duration of response (months)
  Nivolumab + ipilimumab (n = 142) Nivolumab (n = 109) Chemotherapy (n = 119)
Median duration of response 23.2 15.5 6.2
95% CI 15.2-32.2 12.7-23.5 5.6-7.4
CI indicates confidence interval.
1. Brahmer JR. Point-counterpoint: new data and controversies on immunotherapy combinations in the first-line treatment of NSCLC. Presented at: 34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019). November 7-10, 2019. National Harbor, Md.

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