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

In an interview with&nbsp;<em>Targeted Oncology</em>, 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 non&ndash;small cell lung cancer.

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 likeEGFRandALKalterations 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 withBRAF-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 withBRAF-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 withEGFRandHER2-positive disease (P<.01).BRAFV600E 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 harboringBRAFmutations had an increased benefit from ICB therapy compared with other NSCLC subgroups. The investigators suggested that clinical trials look into ICB therapy more closely forBRAF-mutant disease.

In an interview withTargeted 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 classicEGFRandALKalterations have been associated with poor outcomes. More recently, we have data previously published showing that tumors that harborSTK11or 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 classicEGFRandALKalterations 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 withRETfusions. These drivers have become more and more frequent and our question is, do these drivers behave like classicEGFRandALKalterations or do they have different patterns of response to immune checkpoint blockade.

What we did is leverage 2 different independent cohorts of oncogene-driven lung cancers totaling over 1000 patients. One cohort is from MD Anderson Cancer Center and the other is from the Flatiron Database that we're calling the CGDB cohort. What we observed is thatHER2andEGFRexon 20 mutations are associated with poor outcomes, like low response rates and short PFS, similar to the classicEGFRalterations. But, on the other hand, patients with tumors that harborBRAFmutations, both V600E and non-V600E, showed better outcomes. There were high response rates in the order of 60%. I know that this is limited by a small sample size for the objective response analysis, but there was still a prolonged PFS ranging from 7.4 months in the MD Anderson Cancer Center cohort to 9.5 months in the CGDB cohort.

The other question that we looked into was if there were differences in the patterns of TMB and PD-L1 expression across these distinct molecular groups and for that we leveraged the Foundation Medicine database with over 3500 patients with oncogene-driven NSCLC that had been profiled for both PD-L1 and TMB. We found distinct patterns of TMB and PD-L1 expression across these groups. Starting with PD-L1 expression, theBRAFV600E—harboring tumors had a higher PD-L1 expression compared with the other groups analyzed. For TMB, we showed that theBRAFnon-V600E and the tumors-harboringBRAF non-V600E or KRASmutations both had higher TMB compared with the other drivers that we analyzed.

TARGETED ONCOLOGY: Why do you expect patients withBRAFmutations experience more benefit from immunotherapy than others?

Negrao: That's not fully understood right now. There are a couple of hypotheses from data that have been recently published. One of them suggests thatBRAFmutations are associated with increased PD-L1 expression, and this is determined by an increase in immune-stimulating cytokines in the tumor environment. That would be one possibility. The other one is thatBRAFmutations themselves are more frequently associated with the production of neoepitopes, so they might be more immunogenic and more readily recognized by the immune system. Those are the 2 hypotheses that we have data for, but these have to be further evaluated in translational and clinical research.

TARGETED ONCOLOGY: Are there any next steps with this research?

Negrao: For these oncogenic drivers that are more resistant to immunotherapy, I think that targeted therapies are still the best approach. For classicEGFR, we have osimertinib (Tagrisso) and other compounds that are being developed. There's even a question of whether there's a benefit in combining these regimens with chemotherapy in the frontline setting. This is one path that I see moving forward.

But, with immune-based approaches, we still need to have a better understanding of why these mutations are associated with resistance. There is preclinical work that's being done in our group to address these issues and also translational work with actual patient tumor samples that's looking into this. I believe future work will answer these questions.

As for theBRAFgroup, the clinical data in the melanoma setting that has been presented suggest that combination strategies with BRAF plus or minus a MEK inhibitor, in combination with a PD-1/PD-L1 inhibitor is an interesting approach. It has shown high response rates and also prolonged PFS, which I think warrants further evaluation in the NSCLC setting. But this is mostly focused in the V600E setting where we have data supporting the use of tyrosine kinase inhibitors (TKIs).

In the non-V600E group, we have data from our group, which we presented at the ASCO Annual Meeting this year, showing that non-V600E mutations might be sensitive to combinations of MEK plus or minus BRAF inhibitors. There is some rationale there not only to test TKI combinations for this population but even potentially combine them with immune checkpoint blockade in the future. Our research, which shows the benefit that these mutations might derive from TKIs, is expected to be published in the near future.


Negrao M, Skoulidis F, Montesion M, et al. BRAF Mutations Are Associated with Increased Benefit from PD1/PDL1 Blockade Compared with Other Oncogenic Drivers in Non-Small Cell Lung Cancer. Presented in: Proceedings of the 2019 World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract MA03.05.