Long-Term Survival Benefit With PD-1 Monotherapy Correlated With High PD-L1 Expression in Advanced NSCLC

Despite being a standard of care in the treatment of patients with advanced non–small cell lung cancer (NSCLC), not all patients experience responses with PD-1 monotherapy. Accordingly, the assessment of PD-L1 expression levels in this population may provide new insight into long-term survival outcomes with PD-1 monotherapy, addressing the need for improved identification of patients who are most likely to benefit from this treatment option, according to Biagio Ricciuti, MD.

Findings from an analysis of 2 independent cohorts of patients with advanced NSCLC and a PD-L1 tumor proportion score (TPS) of 50% or greater who received a PD-1 inhibitor were presented at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer. The data confirmed that PD-1 monotherapy produces a meaningful long-term survival benefit in patients with advanced NSCLC and a PD-L1 TPS of 90% or greater.

Further correlative analysis revealed that patients with a very high PD-L1 TPS may have a lower prevalence of STK11/SMARCA4 mutations and increased CD8-positive/PD-1–positive T cells, suggesting a more favorable genomic and immunophenotypic profile.

“These long-term outcomes suggest that PD-1 monotherapy can [serve as] a reasonable treatment for patients with very high PD-1 expression levels of 90% to 100% vs chemoimmunotherapy, because it can potentially spare the added toxicity of the chemotherapy backbone,” said Ricciuti who is a thoracic medical oncologist and staff scientist II in the Department of Medicine at Dana-Farber Cancer Institute in Boston, Massachusetts.

In an interview with OncLive^®, Ricciuti discussed the need to improve the identification of patients with advanced NSCLC that benefit most from immune checkpoint inhibition, the relationship between PD-L1 expression and long-term survival with anti–PD-1 monotherapy identified in this analysis, and how these findings might influence future immunotherapy clinical trial designs in NSCLC.

OncLive: What was the rationale for evaluating survival outcomes with PD-1 monotherapy according to PD-L1 expression level in patients with advanced NSCLC and a PD-L1 TPS of 50% or higher?

Ricciuti: Checkpoint blockade has improved clinical outcomes in patients with NSCLC and is currently a first-line treatment option for a large fraction of our patients. Despite their improvement of survival, only a fraction of these patients will respond to these treatments—even when the PD-L1 expression is greater than 50%. In this patient population, pembrolizumab [Keytruda] monotherapy is approved as a standard of care, and responses to this therapy are seen in [approximately] 45% of patients. In this study, we set out to understand which patients are more likely to benefit from PD-1 monotherapy among those that have PD-L1 expression levels of 50% or greater. We are [also] trying to improve [outcomes] by identifying potential vulnerabilities that can be exploited [through] combination strategies.

Please describe the patient population included in this analysis.

In this study, we included 2 different cohorts of patients. The first cohort [included] patients who were enrolled in the phase 3, randomized EMPOWER-Lung-1 trial [NCT03088540], which compared first-line cemiplimab-rwlc [Libtayo] alone vs chemotherapy in treatment-naive patients with metastatic NSCLC [and a PD-L1 expression level of 50% or greater]. The second cohort served as a validation cohort, and [consisted of a] patient population derived from 4 academic centers in the United States. [These] treatment-naive patients with metastatic NSCLC were treated with first-line pembrolizumab and had a PD-L1 expression level of 50% or greater. [In summary], we had 2 independent cohorts in which we aimed to address this question.

What long-term survival outcomes from this study were presented at the IASLC 2023 World Conference on Lung Cancer?

Two years ago, our group and others reported the first results of these analyses, which [included] patients with PD-L1 expression of 50% vs 90 to 100% [who were] treated with pembrolizumab monotherapy. In that read-out, we did see that patients with a very high PD-L1 expression level had better clinical outcomes with first-line pembrolizumab vs those with a PD-L1 expression level of 50% to 10%. Still, we had no data on long-term outcomes in this patient population.

In this analysis, we looked at 3-year outcomes in the same patient population. We found that among patients treated with cemiplimab monotherapy in EMPOWER-Lung-1, those with PD-L1 expression of 50% to 89% had lower response rates as well as shorter progression-free survival [PFS] and overall survival [OS] vs those with PD-L1 expression of 90% to 100%. Interestingly, we didn't see a difference in terms of survival outcomes at 3 years between those patients with [low vs high] PD-L1 expression in the control cohort. In our validation cohort of patients with first-line pembrolizumab monotherapy, we confirmed that patients with a PD-L1 expression of 90% to 100% experienced a significant improvement in PFS after 3 years of follow-up compared with patients who have PD-L1 expression levels between 50% to 89%.

What do initial data from correlative analyses reveal about the relationship between PD-L1 expression and survival benefit with PD-1 monotherapy? Are any other analyses of genomic or immunophenotypic features planned for the future?

We [will continue to] conducte correlative analyses in this study, some of which [were] presented during this meeting. We know that these patients with high PD-L1 expression do better than those with [low expression], but we want to understand more about the genomics and immunophenotype of these tumors and see if there is any difference in those features between different NSCLC subtypes. Preliminary analysis is showing that tumors with a very high PD-L1 expression may be more likely to have a high density of CD8-positive PD-L1–positive T cells compared with those with a [lower] PD-L1 expression level.

Another [feature] that we are currently exploring is differences in the tumorigenic profile of these cancers. What we know so far is that tumors with a 50% to 10% level of PD-L1 expression may be more likely to harbor a concurrent mutation in STK11/SMARCA4, which has previously been associated with resistance to immunotherapy. This is another difference that may be present between these 2 types of NSCLC, but there's still work to be done in terms of understanding the differences and potential vulnerabilities that can be exploited to further build on these findings and improve outcomes in this patient population.

What are the clinical implications of this research?

We do not have randomized studies comparing PD-1 monotherapy and chemoimmunotherapy in patients with high PD-L1 expression levels, [although] there is a phase 3 study called INSIGNIA [NCT03793179] that will address this question. In the meantime, these data suggest that we [should consider] using PD-1 monotherapy in patients with an extremely high PD-L1 expression level.

Another implication is relative to how we interpret and design clinical trials. Right now, we don't necessarily use stratification measures to ensure that treatment arms are well balanced in terms of high PD-L1 expression levels. [Accordingly], we will need to employ appropriate strategies to make sure that [these] imbalances in [patients with] high PD-L1 expression are not responsible for differences between treatment outcomes in clinical trials. [Lastly, these results have] implications [for the use of] perioperative immunotherapy. We do not have strong biomarkers to [identify] patients that benefit from neoadjuvant or adjuvant immunotherapies. We may need to explore whether high PD-L1 expression may play a role in determining [which of] those patients are more likely to benefit from this treatment.

Was there any other research presented at this year’s meeting that you feel will be particularly influential in the lung cancer space?

It'd be extremely relevant for our community to learn about the phase 3 FLAURA2 trial [NCT04035486], which compared osimertinib [Tagrisso] monotherapy with the combination of osimertinib and chemotherapy. Over the past several years, [several] randomized phase 3 studies have tried to combine first-generation EGFR inhibitors with chemotherapy [with the goal of] improving clinical outcomes in this patient population. In general, there has been a benefit in progression-free survival with the addition of chemotherapy to EGFR inhibitors compared with EGFR inhibitors alone, suggesting that this could be a promising treatment strategy. [However,] longer follow-up did not necessarily [show an] overall survival benefit [with combination regimens] in these studies. Learning [that] the combination [osimertinib and chemotherapy] may further improve outcomes in this patient population is [highly] relevant.

Reference

Ricciuti B, Elkrief A, Lin J, et al. Three-year outcomes and correlative analyses in patients with non–small-cell lung cancer (NSCLC) and a very high PD-L1 tumor proportion score (TPS) ≥ 90% treated with first-line cemiplimab and pembrolizumab. Presented at: 2023 IASLC World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract OA14.04.