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Experts Calls for More Research on Predictive Biomarkers for Immunotherapy Treatment in NSCLC

Nichole Tucker
Published Online:4:20 PM, Thu October 10, 2019
Marcelo Vailati Negrao, MD
Marcelo Vailati Negrao, MD
The introduction of PD-L1/PD-L1 blockade has revolutionized the treatment of non–small cell lung cancer (NSCLC), said Marcelo Vailati Negrao, MD, during a presentation at the 2019 World Conference on Lung Cancer. However, he noted that only a small portion of patients currently benefit from it. In order to increase the proportion of patients that benefit, more predictive biomarkers are needed to guide patient selection.
 
The current predictive biomarkers for immunotherapy treatment are PD-L1 and tumor mutation burden (TMB). It is also known that patients with certain mutations like EGFR and ALK alterations have poorer outcomes to immunotherapy treatment, and those with other driver mutations may have distinct patterns of response, according to emerging research, although further research is needed.
 
This knowledge led investigators at MD Anderson Cancer Center (MDACC) to determine if oncogene-driven NSCLCs have distinct patterns of PD-L1 expression or TMB and distinct outcomes from immune checkpoint blockade (ICB) therapy.
 
The study was divided into 2 independent retrospective cohorts, one of which was the MDACC cohort and the other was from the Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-CGDB). Investigators assessed the difference in clinical outcomes by comparing specific molecular subtypes of NSCLC.
 
The results show that patients with BRAF-mutant NSCLC found in the MDACC group had the most significant response (P <.01) to ICB and had a longer progression-free survival (PFS) (P <.01). There was also a significant difference in PD-L1 expression compared with other NSCLC subtypes.

The FH-CGDB cohort showed similar results with BRAF-mutant patients showing a longer PFS and overall survival (OS) rate to ICB alone in a real-world analysis. Additionally, TMB and PD-L1 expression (tumor score ≥1% and ≥50%) were higher in this subset of patients compared with those with EGFR and HER2-positive disease (P <.01). BRAF V600E mutations were also identified in this cohort and such patients had a lower TMB (5.9 vs 13.7 mutations/Megabase; P <.01) and higher PD-L1 expression (≥1%: 72% vs 61%; ≥50%: 42% vs 32%) compared with non-V600E patients.

This study signaled that patients harboring BRAF mutations had an increased benefit from ICB therapy compared with other NSCLC subgroups. The investigators suggested that clinical trials look into ICB therapy more closely for BRAF-mutant disease.

In an interview with Targeted Oncology, Negrao, assistant professor, The University of Texas MD Anderson Cancer Center, reviewed data from the study of response to ICB therapy in patients with oncogene-driven NSCLC.

TARGETED ONCOLOGY: Historically, what subgroups of patients with NSCLC have the best outcomes to PD-L1 inhibition?

Negrao: This is where the field stands. We know that immune checkpoint blockade has revolutionized the treatment of NSCLC but as single agents, these drugs have provided benefits for a minority of the patients. Currently, the biggest data that we have in terms of predictive biomarkers are PD-L1 expression and TMB. Patients that have high PD-L1, high TMB, or a combination of both are the ones who've historically had the most benefit from immunotherapy.

We also know that patients who harbor oncogenic drivers such as classic EGFR and ALK alterations have been associated with poor outcomes. More recently, we have data previously published showing that tumors that harbor STK11 or KEAP1 alterations, have been associated with a more immune-depleted microenvironment, and they also have been associated with poor outcomes on immunotherapy.

This is the current landscape of the field of NSCLC in terms of benefit from immunotherapy.

TARGETED ONCOLOGY: How do you determine which subtypes will have poor outcomes?

Negrao:  You have immune markers and you have genomic markers. To detect these cancer gene mutations you can either achieve that through a focused next-generation sequencing panel or whole-exome sequencing. For the translocations, there are other methods as well, like immunohistochemistry, RNA-based methods, and blood assays  now can also detect these alterations. As for PD-L1 expression, that's usually performed through immunohistochemistry. Multiple antibodies have shown to be predictive of benefit from immunotherapy. The one that's most currently validated is the Dako 22C3 assay which has been validated for use with pembrolizumab (Keytruda). Those are the standards we usually assess in the clinic, and those are the methods that are more readily available in the clinic.

TARGETED ONCOLOGY: Can you discuss the background and results of your study?

Negrao:  With this setting in mind, what we set out to see was, knowing that classic EGFR and ALK alterations are associated with resistance to immunotherapy, how do other drivers behave themselves? This question comes from the fact that we are more frequently detecting new oncogenic drivers in NSCLC. For instance, there was a presentation on LOXO-292 in patients with RET fusions. These drivers have become more and more frequent and our question is, do these drivers behave like classic EGFR and ALK alterations or do they have different patterns of response to immune checkpoint blockade.


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