Quest Continues to Turn NSCLC Into Chronic Disease

Nirav S. Dhruva, MD

A better understanding of the molecular characteristics of non—small cell lung cancer (NSCLC) has led to improved outcomes for patients with the disease, said Nirav S. Dhruva, MD. However, more research is needed to understand resistance mechanisms and determine which PD-L1 expression test is best suited for each patient.

“Arguably the biggest advance we've made in NSCLC over the past few years has been in our ability to learn more about tumors and their characteristics,” said Dhruva. “[Now] we can better tailor treatments to patients, and as such, we [are seeing] better toxicity profiles, better efficacy, and ultimately, [we’re helping] patients live longer.”

Through improved understanding of changes in NSCLC cells that help them proliferate in the body, several targeted therapies for alterations such as EGFR, ALK, and ROS1 have emerged in the paradigm, leading to improved survival outcomes. Beyond these agents, immunotherapy has become a mainstay in the frontline setting.

“In many situations now, we're using upfront immunotherapy with chemotherapy or upfront immunotherapy alone,” said Dhruva. “Therefore, the big question now is, ‘As we have moved up the immunotherapy to the first-line [setting] in many patients, what do we do in the second-line?’”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Dhruva, an adjunct assistant professor at University of North Carolina (UNC) Rex Healthcare, highlighted key advances made in NSCLC, the importance of PD-L1 expression testing, and ongoing efforts to bridge the gap between community and academic centers in lung cancer care.

OncLive: How has the treatment of NSCLC changed over the past 5 years?

Dhruva: It started with [us targeting] EGFR, but now [we also look for] ALK and ROS1 [alterations]. It seems like day by day, newer molecular targets [are emerging]. We also have immunotherapy. What was once very simple in lung cancer has now become very complex.

Which agents or trials have had the greatest impact on the treatment landscape?

We, of course, have the EGFR- and ALK-targeted drugs that were initially approved; they really have changed what a lung cancer [diagnosis means for patients]. Lung cancer has evolved from a limited-survival disease to one where [patients] can live sometimes for years.

What has been exciting, is that we're now seeing newer agents in the space and we're starting to learn how resistance occurs and how to overcome that. I believe that drug development is just going to continue and hopefully, we'll be able to figure out these resistance mechanisms. [Hopefully, with this knowledge, lung cancer] will become a chronic disease for many patients rather than a life-limiting illness.

How is immunotherapy being used in this space to improve patient outcomes?

Immunotherapy has definitely become much more of an upfront modality that we use often; it has really changed the landscape. Before, we only used chemotherapy in the first-line setting, which was then followed by immunotherapy.

There are a lot of exciting data for many different agents. Some of the more interesting [data to read out] are with the combinations. [For example, some of the CheckMate trials looking at nivolumab (Opdivo) and ipilimumab (Yervoy) are particularly interesting. [We still have a lot to learn about the] different testing available for PD-L1 and how to determine which test is most appropriate in each situation.

Could you expand on the importance of PD-L1 testing in lung cancer? What are some questions that still need to be answered?

All of us in the community are trying to figure out which PD-L1 assay we should be using. Oftentimes, we're using an assay that is very drug-specific for the patient in whom we're trying to use the agent. A bigger question that us, as community physicians, are trying to understand is, “As we try to become more uniform in practice with academic centers, what are the best PD-L1 tests and how do we get a little more homogeneity across the board with this testing?” It seems to be very variable with different drugs.

You moderated one of the Peer Exchange panels of this State of the Science Summit™. What questions were discussed?

I really wanted to leave it informal for our physicians in the room, which consisted of many community oncologists. [I wanted our audience to have the opportunity to] really pick the panel's brains for insight regarding practical day-to-day questions that they're running into. We wanted to leave it as open as possible so that we could start a dialogue and hopefully help clear up some of the questions that they probably have had for quite some time, but just did not have the forum to ask all of these wonderful experts.

Some of the questions centered on different PD-L1 assays, different genomic assays for which we’d send lung tumor specimens—whether it's an academic platform, or something like FoundationOne, or some other next-generation sequencing tests. We also discussed the role of blood-based biomarker testing and how this equates with tissue testing. I believe that's a very relevant question, and there's a fair amount of variability that happens in practice. It’s nice to see what [other physicians] are doing in academic centers and the limitations [that come with] each approach.

Based on your own experience, do you tend to use tissue-based or blood-based assays?

I've always tried to get tissue-based testing because I believe it is the most reliable. However, I do believe there are certain situations where blood-based testing may be appropriate. For example, if it's unsafe [for a patient] to get a biopsy or if the patient is not willing to get it, [they should have a blood-based test].

I wonder if we'll start using more blood-based testing in the future, as we try to understand resistance mechanisms. There’s going to be a feasibility issue of what a patient will endure as far as repeat biopsies. If we can get better at some of the blood-based testing, maybe that will help us better understand mechanisms of resistance [in a less invasive way].

What is the biggest challenge faced in the field?

A couple of the key challenges faced in the field have to do with just bridging the gap between the community and the academic centers, as well as understanding the logistics of treating patients in the community who might have a little less in terms of resources or access to clinical trials.

[Other challenges include figuring out how] to standardize our practices—from local community centers to those with academic affiliation to the tertiary medical centers—and how to make our treatments more uniform, which I believe will ultimately help our patients.

What are some ongoing efforts being designed to bridge that gap?

At Rex Healthcare, we have a huge relationship with UNC. We're part of a very robust clinical trial group and we have our own clinical trial program, which is nice, but there are many areas that might not have that access. However, we have a very strong working relationship with our UNC colleagues, so it's very easy to bounce off ideas with them as far as recent advances go, [and understanding] how those advances make a difference in the day-to-day treatment of patients. In some communities where people are a little more isolated, it's a little harder to bridge that gap. [In those cases], programs like this are great for that.

In order to continue to making progress in this field, where should future research focus?

It should continue to focus on the tumor and the individual characteristics of tumors equating to people. Why is it that some [tumors] behave differently than others? Also, [we need more research dedicated to] understanding resistance. As we're getting better and better at choosing that first target and that first line of therapy, the real questions become, "Well, what do we do in the second-line setting? How about the third-line setting?"

[Answering those] questions will help us enable patients to live longer. We’re making some huge advances as far as what our first go-to approach is, but that's where the complexities lie. We use many of these agents upfront and then we're kind of scratching our heads like, "OK, what do we use further down the road?"