[Interview] Transforming lung cancer care: Insights from Dr. Sanjay Popat at KSMO 2024

The Korean Society of Medical Oncology (KSMO) 2024 conference, themed "From Insights to Impact – Defeating Cancer Together," brought together leading oncologists and researchers to discuss the latest advancements in cancer treatment for a two-day run at COEX in Seoul from Thursday to Friday.

Various sessions highlighted recent advancements and the future direction of cancer care.

Notably, Dr. Sanjay Popat from the Royal Marsden Hospital, U.K., delivered a plenary speech titled “Rapidly expanding treatment options in lung cancer,” highlighting the remarkable progress in lung cancer treatment over the past two decades.

Dr. Popat's presentation outlined how advances in genomics, medicinal chemistry, immunology, and public health have transformed lung cancer from a uniformly devastating diagnosis into a diverse range of diseases, some now manageable as chronic conditions.

He also emphasized the impact of targeted therapies, immune checkpoint inhibitors, and the routine genotyping of multiple genes for optimal treatment decision-making.

Korea Biomedical Review interviewed Dr. Popat to share his insights on the latest advancements in lung cancer care, from genomic testing to immunotherapy and the promising future of liquid biopsies.

Question: You mentioned lung cancer is now seen as a diverse range of diseases. How has this new understanding impacted treatment strategies?

Answer: Lung cancer is now viewed as a diverse group of diseases. With non-small cell lung cancer, we should be giving a genomic diagnosis rather than just calling it NSCLC. If we know the precise molecular aberration driving the disease, we can give the right drug to that patient.

A great example of this progress is that the median survival was less than a year before we had any genotyping. Suppose we find an ALK-positive patient and give them lorlatinib, the first-line treatment. In that case, data shows that a patient has a 65 percent probability of being cancer-free for five years. This is a remarkable transformation.

We are able to give the right drug to the right patient and prevent the wrong drug from being given.

Q: How critical is genomics in lung cancer treatment today?

A: Genomics is critical. We went from doing single-gene mutation testing in 2004 to now, when we need to genotype at least eight genes in the front-line setting to determine the right strategy and drugs for our patients.

We're talking about comprehensive genomic analysis because some genetic alterations are hard to detect.

So not only do we have to do comprehensive molecular testing, but we've got to use the proper form of molecular testing in the lab to ensure we're not getting false negatives and that we're getting true positives.

Q: While kinase inhibitors have been a game-changer for patients with druggable mutations, you mentioned some tumors lack such targets. What are the challenges in expanding the scope of immunotherapy and kinase inhibitors to non-targetable mutations?

A: Kinase inhibitors have been transformative for patients with druggable mutations. They allow us to precisely target specific molecular aberrations, often resulting in better outcomes and quality of life than traditional chemotherapy.

However, it's important to note that some tumors still lack such targets. For these patients, immunotherapy has become standard. If a patient has a PD-L1 expression (TPS) of more than 50 percent, we see a reasonable proportion of cancer-free patients five years after starting immunotherapy.

However, if the PD-L1 level is below 50 percent or negative, the proportion of patients who derive meaningful benefit from immunotherapy is relatively low.

We're still working to advance our understanding of immunotherapy, enhance the activity of these drugs, and get them to the right patients.

Numerous ongoing trials are looking at different combinations of new immunotherapy drugs for patients with metastatic lung cancer.

Q: With the rise of circulating tumor DNA (ctDNA) analysis, how do you see this impacting routine clinical care in the future?

A: ctDNA testing is incredibly important for accurately identifying a patient's mutational signature. It's easy because it involves a simple blood draw.

From various data sources, we often read identical genotypes if we use ctDNA in conjunction with tissue next-generation sequencing (NGS).

Interestingly, 25 percent of the time, ctDNA picks up genotypes that tissue misses, and 25 percent of the time, tissue picks up things that ctDNA doesn't.

ctDNA does have some limitations. Patients don't often shed ctDNA if they have small-volume disease or early-stage disease, and it can sometimes be quite difficult to interpret the ctDNA because of the nature of the genotype identified. However, if ctDNA does identify a drug target, it's immediately treatable.

In the U.K., we've been piloting a "Liquid First" strategy. When a patient presents to the respiratory clinic with a CT scan that looks like stage four lung cancer, a blood draw is taken immediately for ctDNA NGS.

Our initial experience has shown that it's dramatically changing patient outcomes. While we had the tissue diagnosis in parallel when the pathologist told me it was adenocarcinoma, I already got a report from the liquid biopsy telling me that the patient had, for example, a MET exon 14 insertion so that I could start the patient on treatment much quicker.

Q: What are the cost implications of liquid biopsies?

A: Cost is a consideration, but we're doing an economic health exercise in England to determine the costs. If you've done a ctDNA test and tested for all your genes and find that the patient is, for example, RET fusion-positive, you can start that patient on a first-line RET inhibitor straight away.

You don't need to send the tissue for NGS, so you only pay for your NGS once.

We need to do the health economic evaluation, but I'm optimistic that it is economically viable to implement a liquid-first-based strategy because finding what you're looking for already saves many of the costs of tissue NGS.

Q: What about the low sensitivity issue with ctDNA testing?

A: This depends on what sort of technology you're using and your mutation frequency. For example, in Korea, where 60 percent of the population is EGFR mutation-positive, you may not need a ctDNA NGS. You can get away with an EGFR ctDNA test, which costs a couple hundred dollars rather than a couple thousand dollars for an NGS assay.

The critical issue is whether you've got an informative result. Not everybody sheds ctDNA. Your probability of shedding ctDNA is higher if you have a more proliferative tumor and stage 4 disease.

If you have a tumor with a very low-volume disease, then there's not much point in doing ctDNA because your probability of an informative result is very low.

It's about case selection.

Q: How do you see CT screening and AI playing a role in early lung cancer detection?

A: CT screening has changed the face of the patients we see. In areas where it has been implemented, we're seeing huge shifts in the number of stage 1 patients diagnosed and a reduction in the number of patients with stage 4 disease.

However, screening in government systems is primarily based on tobacco exposure. We need to work out better ways of identifying people at risk, which isn't just based on tobacco exposure. This is particularly important for women who have never smoked.

AI is also critical for diagnostics. The number of scans we do in routine clinical care is increasing rapidly, especially as we implement CT screening.

But we're not employing radiologists that can meet such demands at the same rate. AI tools are very good at flagging abnormalities. I see the future as AI-assisted CT screen reporting, with AI doing the triaging and humans looking at the flagged cases in more detail.

Q: You mentioned that for some patients, responses to immunotherapy may be "durable and perhaps lifelong.” Are we nearing a point where certain lung cancer subtypes can be effectively "cured," or do you foresee these therapies extending life without full remission for most patients?

A: "Cure" is a dangerous word for oncologists. However, we're seeing remarkable progress. Nearly one in 10 patients who started with metastatic lung cancer and had two years of immunotherapy has never relapsed three years after stopping treatment.

So, five years from the point of starting, they remain progression-free.

That's about as optimistic as I can get. Before the immune checkpoint inhibitor era, that percentage was zero. Not a single patient got that far. And here we are at 10 percent. That's pretty remarkable progress.