Liquid Biopsy HIC Proteomic Testing May Aid in NSCLC Treatment Decision-Making

David Oubre, MD

Performing blood-based host immune classifier (HIC) proteomic testing in patients with non–small cell lung cancer (NSCLC) may reveal clinically meaningful information to aid oncologists in deciding to treatment with immunotherapy, irrespective of PD-L1, according to results from the INSIGHT study (NCT03289780).¹

According to the study investigators, data from INSIGHT signal that patients with HIC cold NSCLC tumors will not benefit from treatment with immune checkpoint inhibitors (ICIs) alone, regardless of their PD-L1 expression.

“The data for patients who had HIC cold tumors and were treated with monotherapy alone were shockingly poor. That is to say that patients who received immunotherapy alone and had a HIC cold score, their median overall survival was less than 3 months. It’s quite astounding in today’s landscape that there is that subset of patients. We all know those patients exist, but it can be used well in that setting to possibly decide not to treat that group of patients with immunotherapy by itself. In that situation, you could feel better about adding chemotherapy or deciding not to treat the patient at all,” David Oubre, MD, a medical oncologist and founder of the Pontchartrain Cancer Center in Louisiana, told Targeted Oncology ™, in an interview.

INSIGHT is a prospective, observational registry study, which is analyzing data from up to 3570 patients with NSCLC at any stage and any treatment line who were treated at 35 different sites in the United States. The prespecified interim analysis took place after 1-year of follow-up when 2000 patients were enrolled.

From the interim analysis, investigators shared overall survival (OS) data. The investigators compared 284 patients treated in the front-line setting with ICI-based regimens, and patients treated with all frontline therapies (n = 877). Patients were stratified by HIC type and treatment type.

Among patients treated with ICI-based therapies, the median OS was not reached (NR; 95% CI, 15.4-NR) in the HIC hot population compared with 5 months (95% CI, 2.9-6.4) in the HIC cold population (HR 0.38; 95% CI, 0.27-0.53; P <.0001). In patients treated with ICI monotherapy, the median OS was 16.8 months in the HIC hot group vs 2.8 months in the HIC cold group (HR 0.36; 95% CI, 0.22-0.58; P <.0001). Finally, in patients who received ICI therapy and chemotherapy, the median OS was not reached in the HIC hot population vs 6.4 months in the HIC cold group (HR 0.41; 95% CI, 0.26-0.67; P =.0003).

In the interview, Oubre discussed the use of liquid biopsy to identify prognostic and predictive biomarkers in patients with NSCLC. He also explained the results and implications of the INSIGHT study.

TARGETED ONCOLOGY: What is the current role of liquid biopsies in the non–small cell lung cancer space?

Oubre: We still prefer to do solid tissue biopsies, if we can. But there are some situations where

we would go for a blood-based or liquid biopsy. It is less invasive to get a blood test, and it might be less expensive. We also may do a liquid biopsy if we have an inadequate tumor sample, and lot of times, folks are using endobronchial ultrasound to get biopsies. Sometimes the tumor samples aren't as good as the traditional biopsies. In that situation, if we don't have access to a nice piece of tissue then a blood-based biopsy can really give us some good information. We also may use it in a situation where you are measuring ctDNA of a tissue, and you may measure it over time to see if it goes up or down based on your treatment. That is done more commonly in other diseases right now, but it's coming in lung cancer.

What are the key markers that can be detected in the blood?

Most of the biomarkers can be detected in the blood. Some examples are EGFR, ALK, ROS1, BRAF, and KRAS G12C. Some other biomarkers that can be found with a blood-based biopsy are MT, NTRK, and the RET oncogene. The one that’s not available as much in the blood is PD-L1, which is very important. PD-L1 is probably the most common biomarker we use. But we can get a test called tumor mutational burden, which will allow us to potential decide if a patient is a candidate for immunotherapy.

When do you think it is appropriate to do a tissue biopsy over a liquid biopsy?

I think it’s still the standard of care. The sensitivity or the ability to detect the abnormality is higher with tissue, and you get the PD-L1 as well. It is still better to have a tissue biopsy, in my opinion. But sometimes it's just not feasible. We still try to get the tissue biopsies when we can, but we would use the liquid biopsies in some situations.

Can you discuss some of the biomarker-driven therapies that are available for NSCLC?

There are a lot. Each one of those markers that I mentioned has at least 1 drug that goes with it. For instance, in EGFR mutations, there are, I believe, 5 targeted therapies that are available. There is osimertinib [Tagrisso], afatinib [Gilotrif]and 3 others. Gefitinib [Iressa] has been around the longest.

For ALK1, there's, I think 4 or 5 ceritinib [Zykadia] is one of them, and alectinib [Alecensa] another. RAS mutations has sotorasib [Lumakras], but only for the KRAS G12C mutation.

There's probably 25 total, biomarker-driven medications that are available for NSCLC, and that's not even counting the PD-L1 drugs, such as pembrolizumab [Keytruda], and nivolumab [Opdivo], and others. It's quite a large list, and it's nice to be able to have several choices for the common mutations, and at least 1 choice for the uncommon mutations. This gives us a lot of opportunity to treat cancer in ways that we didn't have before that will allow patients to avoid chemotherapy, and very often with drugs that are less toxic, and perhaps more effective.

You were an investigator in a study that assessed liquid biopsy in patients with advanced-stage NSCLC who were treated in a real-word setting. Can discuss the background of this study?

What we were talking about in this study is something different. We were not measuring a mutation, per se. What we were talking about measuring is a prognostic marker or a predictive marker to try and find out if patients can be predicted to either be responsive to a treatment or not. Bioethics testing has been available for some time, and if we can predict if a patient was either hot or cold on that test, we could tell if they were more or less likely to respond to chemotherapy. We could take some patients and be able to tell them, for instance, that they may have a year or more expected survival.

For other patients, because they look, we can do treatments on them, but the outcomes are not good based on the type of tumor that you have. Sometimes that'll help a patient decide whether they want to want to take treatment. The question for this trial was how did the tests predict a patient responding to immunotherapy?

Can you explain the findings?

The study showed that response to immunotherapy could also be predicted by the test. What we got was the level of the host immune factor would either be hot or cold. If a patient was HIC hot, then the average survival of a patient getting immunotherapy was not reached in the study. I think that 15.4 months was the minimum. We knew that it was going to be at least 15.4 months, but the number wasn't reached. Whereas in patients who were HIC cold, the average survival was 5 months. We're talking about a difference of almost a year in patients who are HIC hot and HIC cold. It was very predictive of survival, which is the ultimate outcome in these patients.

Some of the subset analyses question whether the type of treatment mattered, whether the patients were getting immunotherapy alone or immunotherapy with chemotherapy. It found that in each situation, the predictive value of the test was still present. For a patient getting immunotherapy alone, if they were HIC hot, their expected survival was well over a year. Whereas if a patient who was HIC cold received monotherapy, the expected survival was only 3 months. In patients treated with chemotherapy and immunotherapy, there was a similar prediction for whether the patient was hot or cold. The whole point of the test is to identify the value of the treatment for the patient. It's a prognostic and predictive model for the use of the therapy. It makes it easier for a doctor or a patient to either strongly or less strongly recommended treatment.

What do these results imply about the use of immune checkpoint inhibitors in NSCLC?

These results give us a mechanism for trying to figure out who's likely to respond. We are often trying to give our patients a sense of whether the medicine is likely to work, and maybe there is benefit in just treating everybody and seeing what happens. But if you want to be a little bit more scientific and helpful to the patients, it's nice to be able to explain to them that they have a tumor that's very risky or they have a tumor that is likely to respond to therapy. It gives us a lot more information that we don't otherwise have by simply getting the standard biomarkers as we discussed earlier.

The data for patients who had HIC cold tumors and were treated with monotherapy alone were shockingly poor. That is to say that for patients who received immunotherapy alone and had a HIC cold score, their median overall survival was less than 3 months. It’s quite astounding in today’s landscape that there is that subset of patients. We all know those patients exist, but it can be used well in that setting to possibly decide not to treat that group of patients with immunotherapy by itself. In that situation, you could feel better about adding chemotherapy or deciding not to treat the patient at all.

Do you think your research is consistent with or additive to information reported from clinical trials?

I think that this adds to it. It's consistent with what we knew before, which was that the chemotherapy patients who were HIC hot, were likely to have a better outcome than those who were HIC cold. It's justification for getting that test for the information to help and selection of treatment,but it's the first time it's been looked at immunotherapy. We now know that the results apply just as well for immunotherapy-based treatments, whether it's alone or with chemotherapy.

_REFERENCE:

_{Rich P, Mitchell RB, Schaefer E, et al. Real-world performance of blood-based proteomic profiling in first-line immunotherapy treatment in advanced stage non-small cell lung cancer. J Immunother Cancer. 2021;9(10):e002989. doi:10.1136/jitc-2021-002989.}