According to the latest update from CheckMate 227 Part 1, at 6 years’ minimum follow-up, nivolumab combined with ipilimumab continues to outperform chemotherapy up front for advanced non–small cell lung cancer in terms of overall survival. Dual immune checkpoint inhibition induced greater tumor shrinkage, and these deep responses strongly correlated with long-term OS benefit.

Based on the longest follow-up to date of CheckMate 227 Part 1, dual immune checkpoint inhibition (ICI) with nivolumab (Opdivo) and ipilimumab (Yervoy)—Bristol Myers Squibb drugs targeting PD-1 and CTLA4, respectively—shows robust efficacy and, in the long term, appears to be a winning first-line treatment strategy for advanced non–small cell lung cancer (NSCLC).

Part 1a of the phase III trial enrolled 1,189 patients with tumor PD-L1 levels of at least 1%, who were randomly assigned to receive nivolumab–ipilimumab (nivo–ipi), chemotherapy, or nivolumab alone. Another 550 patients in Part 1b, with tumor PD-L1 expression <1%, were given dual ICI, chemotherapy, or nivolumab plus chemotherapy. A landmark 5-year analysis was published earlier this year (J Clin Oncol 2023;41:1200–12), and the latest data were presented during the International Association for the Study of Lung Cancer's 2023 World Conference on Lung Cancer in Singapore, September 9–12.

Solange Peters, MD, PhD, of Lausanne University Hospital in Switzerland, reported that at 6 years’ minimum follow-up, overall survival (OS) rates were 22%, 15%, and 13% for the Part 1a cohort and 16%, 10%, and 5% for Part 1b. “Nivolumab plus ipilimumab is highly effective” up front for metastatic NSCLC, she said, “regardless of PD-L1 expression.”

Importantly, with nivo–ipi in either PD-L1 subgroup, “about half of the patients alive at 6 years were also progression-free,” remarked discussant Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston. “I think we've reached an inflection point where we can say that, for subsets of patients, we're altering this disease's natural history.”

Radiographically, “way more patients experienced substantial tumor shrinkage [80% or higher] with dual ICI than with chemotherapy” across both PD-L1 cohorts, Peters noted: 52 versus 12 in Part 1a, and 13 versus 1 in Part 1b. “These deep responses strongly correlated with durable OS benefit,” so tumor burden reduction could prove useful for clinicians “as another parameter to help predict patients’ probability of survival.”

“We need to better identify those most likely to survive long-term” with ICI, Skoulidis agreed. In this regard, “TMB's [tumor mutational burden] role has been somewhat controversial, but refined definitions of this biomarker may help.” For instance, HLA-corrected TMB takes into account loss of hetero­zygosity of HLA from conventional TMB (Ann Oncol 2020;31:902–11). Another recent concept revolves around measuring “persistent” TMB—mutations found in multiple copies per cell or in single-copy regions of the genome, and associated with ICI responsiveness (Nat Med 2023;29:440–9).

As well, sussing out which patients require CTLA4 blockade alongside anti–PD-1 therapy for durable benefit will be important. “A concordant message is emerging” from several studies, Skoulidis noted, including CheckMate 227, CheckMate 9LA, and POSEIDON, that “suggests an improved efficacy signal with regimens incorporating ipilimumab” for patients with STK11, KEAP1, and KRAS comutations. Such alterations being linked with poor prognosis, “long-term outcomes data from these molecularly defined groups would also be very interesting to see.”

Ultimately, well-informed treatment decisions warrant further basic research, Skoulidis said. Drug-tolerant persister cells, for instance—a known phenomenon with targeted therapy, enabling resistance—may be worth probing in the ICI context, in which resistant cells are poorly understood. Single-cell RNA sequencing has hinted at the existence of “immunotherapy persister” subpopulations that, by dint of stem-like, hybrid epithelial–mesenchymal features, can evade ICI (J Clin Invest 2021;131:e135038), but these phenotypes have yet to be confirmed in vivo.

“Tumor specimens from neoadjuvant or perioperative trials could provide unique insights too,” he added. “We know very little about the biology of ICI persister cells; this is an area that deserves more attention than it has received so far.” –Alissa Poh

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