Testing, Clinical Trial Enrollment Challenges Recognized During Lung Cancer Awareness Month

David M. Waterhouse, MD, MPH

It wasn’t long ago that the prognosis for patients with lung cancer was dismal, with little hope for patients. However, the advances in immunotherapies and targeted therapies have paved the way for promising outcomes not only in patients with lung cancer but many other cancer types that have followed suit based on the positive findings for these therapies in the lung cancer space.

The addition of immunotherapy and targeted therapies has prompted a greater need for genomic testing so that appropriate treatments can be selected for each patient. The data that can be collected today to inform treatment decisions has transformed the field, but there remains significant challenges to implementing testing for all patients. At this time, not all physicians are testing their patients uniformly, therefore not optimizing treatment with the latest immunotherapeutic and targeted approaches that have become available for select lung cancer sub-populations.

One question of debate in this space now is whether liquid biopsies can be of use among patients with lung cancer. Liquid biopsies pose an alternative solution to situations when there is not enough tissue for standard tissue-based next-generation sequencing (NGS). However, more work needs to be done for liquid biopsy to move even further in the lung cancer landscape, at which time the National Comprehensive Cancer Network (NCCN) guidelines and others are expected to include these assays more regularly.

In an interview with Targeted Oncology, David M. Waterhouse, MD, MPH, medical oncologist and hematologist, OHC (Oncology Hematology Care) and The US Oncology Network, discussed the evolving role of genomic testing and related challenges in the lung cancer treatment paradigm as immunotherapies and targeted therapies continue to expand the field. He also shared a message with fellow oncologists in the lung cancer arena as we recognize all of these important advances during Lung Cancer Awareness Month.

TARGETED ONCOLOGY: What advances have you found most exciting over the last few years for the treatment of patients with lung cancer?

Waterhouse: I think immunotherapies have changed lung cancer and the image of lung cancer more than any of the other treatments. Up until about 2015, when thePD-L1 inhibitors first received their approvals, patients and their providers largely viewed lung cancer as a terminal disease with little or no hope. Immunotherapy certainly gave patients hope, and I think that, to me, it is probably the biggest change.

We just reported out the 5-year survival statistics from the original lung cancer immunotherapies, and we know that probably somewhere near 15% will be alive. Now, that's way too few. We can do way better than that, and in fact, we are doing better. Now the immunotherapies are being used in the first line treatment of lung cancer patients, so expect those numbers to get better. Overall, immunotherapy changed the field.

If you look at targeted therapies, I think the biggest change is occurring right now. We know that targeted therapies have been around for a while. ALK-positive patients, ROS1-positive patients, EGFR-positive patients, but we added to that list in the last year, MET-positive patients, RET-positive patients, NTRK-positive patients and soon KRAS positive patients. We hit the tipping point for testing, so I think that the biggest topic in biomarker testing right now is methodology of testing and is everybody getting tested. One of the sad parts that we're learning is that not everybody gets testing, and even for those who get the testing, the testing is coming back too late to actually inform the decision. Moreover, even when you have the testing, not every doctor is acting appropriately on the testing results. There is a big gap between who gets tested and making sure that the right patient gets the right drug at the right time.

I think we're right on that fringe now of understanding that this is a very big issue and needs a solution. There are some very big projects that are ongoing.

Oddly enough, for the longest time lung cancer was the “redheaded stepchild” of cancer. Nobody wanted to take care of people with lung cancer. It wasn't important, it wasn’t fair to patients and research in this field wasn’t favored. Now the people who do lung cancer are the cool people. We have shown the rest of the world now how to treat these patients who were largely abandoned. It wasn't that long ago that we were arguing should we even treat them, never-mind what is the most appropriate front-line, second-line, third-line setting, etc.

We're also seeing biomarker driven adjuvant therapy for EGFR-positive patients. That's brand new as of this year, and those results were very impressive in that population. We're seeing in stage III, the results of the PACIFIC trial and the use of radiation plus chemotherapy, followed by immunotherapy maintenance therapy has been very positive. We saw that duration of therapy counts. I'm proud of our paper looking at 1-year versus continuous immunotherapy in those patients in second line. We are simply doing a better job of managing lung cancer.

TARGETED ONCOLOGY: Could you elaborate more on the need for genomic testing and how we can improve upon their current use?

Waterhouse: There's no doubt about it that genomic testing has changed the management of lung cancer. One of my partner's once joked that he gave more cisplatin in tumor board than he did in real life. Doctors do much more testing at tumor board than they do in real life. We're not as good at as we all claim we are, so the first step is that we must make sure that every patient gets the appropriate testing at the appropriate time. Until recently, we used to do what we call “hotspot testing,” but there's too many tests now. I think that every patient should have NGS testing, and the only argument now is whether liquid biopsies are going to be a reasonable substitute for tissue NGS.

That is a hot topic that is being argued. I don't think anybody knows the right answer. I think a lot of doctors are doing tissue testing, but if there's not sufficient tissue, they’ll send the liquid biopsy. We're going to have to come up with better standardized testing algorithms, but the fact that we're discussing it is a victory. The fact that we recognize we need it is a victory. I think we're going to see NCCN guidelines again pushing further that every patient gets tested prior to first line decisions. I think that's appropriate, but we need to do a better job at it. We need better turnaround time for testing. And, of course, COVID-19 has only made that worse.

TARGETED ONCOLOGY: What other advances are you seeing in the field right now that you're most excited for?

Waterhouse: I think you started right at the very beginning: screening. We're doing a better job screening for lung cancer. We now know there are patient populations that should get screenings, and health care systems are starting to learn how to identify those patients and how to use informatic tricks to pick them out. It would be great if all lung cancers were caught early, and they didn't have to get to me. The sad part is I see the patients with advanced disease. Lung cancer screening has been shown to decrease cause-specific mortality, which is the measure of an effective screening test.

Now you've been diagnosed: adjuvant therapy. As we mentioned before, EGFR-positive patients can benefit. Patients with resected stage IB through IIIA will benefit from having EGFR-directed adjuvant therapy. These are the first studies to show that this kind of targeted approach to adjuvant therapy is effective. We still don't know what to do with the inoperable stage III patient with an actionable EGFR mutation. Should they get targeted therapy instead of immunotherapy following chemo/XRT? Maybe the answer is yes, but we don't know that yet, so that's a gap.

As we go into advanced diseases, as I mentioned, we need to make sure every patient gets tested and that results are available for the provider, so that every provider correctlty uses those results to benefit their patient. I think that we're now understanding there's gaps in that approach. The drugs are also simply better. We've got better targeted agents than we used to have, so we're getting there.

TARGETED ONCOLOGY: What advice would you like to share with community oncologists treating patients with lung cancer?

Waterhouse: The first thing is, make sure everybody's tested for the actionable biomarkers. Also, let's not forget the advances in immunotherapy. We now have frontline immunotherapy alone for patients with PD-L1 greater than 50%, and now with the combination of ipilimumab (Yervoy) and nivolumab (Opdivo), we could treat anybody with a PD-L1 of 1% or higher with an immunotherapy, not chemotherapy.

Think about that! No chemotherapy in the frontline. Did we imagine that 5 years ago? No. I think the first thing is every patient needs to be tested, and those testing results need to inform that first treatment, which means for the doctor, you should sit on your hands and wait for those results. There's going to be a few patients who must be treated, but that's not the majority. We get antsy. Our patients get antsy. Everybody wants to get treatment right away, but you need to explain to your patient why it's in their best interest to wait.

TARGETED ONCOLOGY: What message would you like to share with fellow oncologists in the lung cancer field as we recognize all these advances during Lung Cancer Awareness Month?

Waterhouse: Put your patients on a clinical trial. Every eligible patient should be on a clinical trial. Every single patient. The NCCN says that we only put about 3% of our patients on clinical trials, which is a sad statistic. On every NCCN guideline, they always say the best treatment is the clinical trial, so put them on the trial. If you don't have a trial, get a trial. If you don't have a trial, find me, and I'll find you a trial. It's in your patient’s best interest. It's in society's best interest. It is the right thing to do.