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The Current and Future State of Immune Checkpoint Inhibitors in NSCLC
Volume 01
Issue 01

Brahmer Discusses Influence of 5-Year Nivolumab and Ipilimumab OS Data in Metastatic NSCLC


Julie R. Brahmer, MD, MSc, discusses how data from the CheckMate 227 trial may affect the treatment landscape for NSCLC and notes the quality-of-life outcomes reported with nivolumab and ipilimumab.

Julie R. Brahmer, MD, MSc

Julie R. Brahmer, MD, MSc

A 5-year analysis of the CheckMate 227 trial (NCT02477826) further supported the use of nivolumab (Opdivo) and ipilimumab (Yervoy) to treat metastatic non–small cell lung cancer (NSCLC) regardless of tumor PD-L1 expression level, according to Julie R. Brahmer, MD, MSc.

Data presented during the 2022 American Society of Clinical Oncology Annual Meeting showed a 5-year overall survival (OS) rate was 24% with the combination (n = 396) vs 14% with chemotherapy alone (n = 397) among patients with high PD-L1 expression (≥ 1%). For those with low PD-L1 expression (< 1%), the 5-year OS rates were 19% vs 7%, respectively, for nivolumab/ipilimumab (n = 187) vs chemotherapy (n = 186). At 5 years, the hazard ratio was 0.77 for OS.1

“Regardless of PD-L1 expression level, responses were maintained for greater than 5 years in more than 40% of those who responded [to treatment with nivolumab/ipilimumab]," Brahmer said. “The majority [of patients] remain treatment free for more than 3 years after treatment discontinuation.”

In an interview with OncologyLive®, Brahmer discussed how the data may affect the treatment landscape for NSCLC and the quality-of-life outcomes reported with nivolumab and ipilimumab. Brahmer is codirector of the Upper Aerodigestive Department and a professor of oncology at the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland. Brahmer is also the codirector of the Cancer Immunology Program and the director of thoracic oncology.

Please describe the rationale for investigating this drug combination and what sets it apart from different combinations in the space.

For CheckMate 227 we evaluated nivolumab and ipilimumab, which is a combination of checkpoint inhibitors. This is the first nonchemotherapy combination for patients with metastatic NSCLC in the first-line treatment setting.

For patients on this trial, they were treated up to 2 years and then [therapy was stopped] and followed thereafter. That’s where we get a lot of our long-term data. We know that this trial led to the approval of nivolumab and ipilimumab in patients with PD-L1–positive disease based on improvements in OS response rate and progression-free survival.

Also, it does have compendia listing for patients with PD-L1 negative disease. [Although] the trial was not statistically designed to answer this question, in patients [with PD-L1–negative disease] nivolumab and ipilimumab did trend [toward] improvements in OS in that patient subgroup.

What methodologies were leveraged in the 5-year analysis?

For the 5-year OS update, we also looked at treatment-free interval. This was defined as the time from the last dose of therapy to the subsequent systemic therapy or death.

This was a chance to look at this type of output in patients who stopped therapy and how long were they off their peak. When most [individuals] are on chemotherapy, they need to remain on some type of therapy, where patients on immunotherapy can stop treatment and not need any further therapy for a very long time. That was what we wanted to look at.

What were the top takeaways from the data shared at the 2022 ASCO meeting?

The data at ASCO this year were a 5-year [updated for] OS in patients with PD-L1–positive disease treated with nivolumab and ipilimumab. The 5-year OS [rate] was 24%; the hazard ratio remained 0.77 in patients with [PD-L1–]positive disease compared with chemotherapy where the 5-year OS [rate] was 14%. It was quite exciting to see that there seems to be a plateau from the 4-year survival to the 5-year survival.

The median overall survival is [approximately] 17 months in the nivolumab and ipilimumab arm compared with [approximately] 14.9 months in the chemotherapy arm for patients with PD-L1–positive disease. We are seeing a plateau for these patients. This is exciting, nearly almost a doubling of 5-year OS compared with chemotherapy and most of these [patients receiving] chemotherapy, at least some of them, go on to receive second-line immunotherapy.

We also showed a plateau of progression-free survival, and the median duration of response was over 2 years in the nivolumab and ipilimumab arm: 5-year duration of response of 28% in nivolumab and ipilimumab compared with only 3% in the chemotherapy arm. Again, [this] just shows the power of immunotherapy to control disease for quite some time.

In patients with PD-L1–negative disease, the 5-year OS [rate] in patients treated with nivolumab and ipilimumab was approximately 19%. Again, median survival [was] very similar to the PD-L1–positive [population] at 17.4 months. In the chemotherapy arm, the 5-year survival [rate] in the PD-L1–negative group was 75%; the hazard ratio remained quite significant at 0.65, but again, this [trial] was not designed to statistically compare the arms. From a clinical standpoint, this is important.

Progression-free survival was [approximately] 10% in the [PD-L1–negative] patient group treated with nivolumab and ipilimumab and again, an amazing [median] duration of response, 19.4 months, [was also reported, with] response at 5-years of approximately 21%. Very similar to PD-L1–positive disease.

I think these efficacy outcomes that we’re seeing at 5 years is amazing to report in patients with metastatic disease. We want to increase or that tail of the curve even further, but this is a great next step.

[In terms of] quality of life, we were able to show that patients had a very similar quality of life compared with the [general] US population. This again was great to be able to show. From a treatment status [perspective], for most patients, approximately 66%, who were treated with nivolumab and ipilimumab [who had] PD-L1–positive had not received subsequent therapy [at 5 years].

[For patients with] PD-L1–negative [disease] that was very similar for 5-year survivors [who received] nivolumab and ipilimumab; 64% of patients did not require any subsequent treatment. If you look at the treatment-free interval for 5-year survivors, patients who did not require further therapy beyond 3 years was approximately 66%. Again, [although] these numbers are relatively small, the percentage of patients [who] didn’t require further therapy beyond 3- ears, now they’re 5 years and beyond. It is pretty telling that this type of treatment can control their disease for a very long time.

[These data are] important for patients and [provide information clinicians] need to prescribe nivolumab and ipilimumab for this patient population. Obviously, we want to compare these [data] with chemotherapy and single-agent immunotherapy, or even the combination of nivolumab and ipilimumab with chemotherapy based on the CheckMate 9LA study [NCT03215706]. This is when we really need the 5-year survival [data] from these studies across the board.

What is the significance of these data for clinical practice?

[Going forward] we must think about long-term cancer survivorship programs in order to help these patients and figure out what’s the best way to follow them after they finish therapy. And [we must examine if] there are other issues that we need to be looking at long term.

Most of us are starting to use the word “cure.” But cure in patients with metastatic disease that they can do well for an extremely long time and may not ever have this cancer come back.

Again, that is completely different than where we were 5 years ago, when we were barely saying that word for patients with advanced disease. This is changing the outlook for patients; if they do well and have a great response, they can do well for a long period of time, even off therapy. You can’t tell me this does not affect someone's quality of life and change and improve hope for our patients.

For my colleagues, I would recommend considering nivolumab and ipilimumab as a treatment choice. We need to figure out how best to parse out who should receive what from single-agent immunotherapy, combination immunotherapy, and if we need chemotherapy at all. Over time, we will have studies and technology that gets us to that point.


Brahmer JR, Lee JS, Ciuleanu TE, et al Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): results from CheckMate 227. J Clin Oncol. 2022;40(suppl 17):9025. doi:10.1200/JCO.2022.40.17_suppl.LBA9025

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