Clinical Trial End Points and Genomic Profiling Represent Key Sectors of the Evolving NSCLC Landscape

Sid Devarakonda, MD

Sid Devarakonda, MD, a thoracic medical oncologist at Swedish Cancer Institute in Seattle, Washington, highlights the role of surgery for patients with non–small cell lung cancer (NSCLC) and approaches for treating patients with metastatic disease in an interview with OncLive® following a State of the Science Summit™ which he co-chaired. Devarakonda also expanded on the significance of overall survival (OS) data when evaluating a treatment for efficacy and noted the potential value of additional end points including pathologic complete response (pCR) and event-free survival (EFS).

“Some of these are very valuable end points to get trials done and report them in a timely manner, as well as to make sure that drugs reach patients in a timely manner,” he said. “pCR has been a very good surrogate for EFS. We know that when most recurrences happen in patients, they happen in the first 1 to 2 years. A short exposure to immunotherapy with an EFS benefit that leads into year 2 and year 3 will very likely transfer into an OS benefit. Context matters for an end point.”

Devarakonda also further delved into the importance of genomic profiling for personalized treatment and the challenges that community oncologists face in staying updated on advancements in treatment protocols. He provided additional insights on navigating neoadjuvant vs adjuvant immunotherapy approaches in NSCLC in another interview.

OncLive: How important is the OS primary end point when looking at data on immunotherapies in NSCLC?

Devarakonda: You could take the very gold standard traditional approach and say OS data is what matters and needs to be shown at the end of the day as more drugs [emerge] in the market, and as you’re incorporating them into your clinical practice; I still stand by that and I’m a bit old school when it comes to it. However, we have an understanding of pCR [and our] understanding of EFS is also evolving in the context of immunotherapy.

How could the role of surgery potentially evolve with the emergence of new agents?

I have struggled with wrapping my head around the question of resectability. [With] resectability, sometimes I think even if a patient had metastatic disease, a surgeon could cut [all tumors] out. It’s not just a question of can you take [all of the disease] out—the big question is can we get a complete resection and will that complete resection lead to improved survival? That’s what we’re trying to understand in this space. It’s a definition that we have to redefine compared with the conventional way in which we have defined resectability.

Going forward, many patients who were previously considered [to have] unresectable disease because of nodal disease or poor biology, [perhaps could undergo treatment] with neoadjuvant chemoimmunotherapy [and] we could change that; we could make it so more patients are likely to benefit from a resection. Our understanding of this space is evolving and the role of surgery is going to evolve as well.

What are some approaches to ensure that patients with metastatic disease are getting the most appropriate treatment given the pathology of their disease?

An analogy I heard in training and used multiple times since then is that you don’t treat breast cancer without knowing if it’s estrogen receptor–, HER2–, or progesterone receptor–positive, so genomic profiling should be the standard. [Similarly], you cannot treat lung cancer without knowing what you’re treating from a genomic perspective, especially adenocarcinomas, and I would make a case even for all NSCLCs; although for small cell lung cancer [SCLC] we are not there yet. We know that there are transcriptional subtypes in SCLC, but as of today, there is no big clinical implication for that with approved treatments.

The ideal way to treat patients and identify treatment regimens is genotype dependent. The more important factor when it comes to patients with non-oncogene driven [disease] that is targetable is which immunotherapy regimen do you reach for—there are a lot of data out there [on] PD-L1, chemotherapy, PD-1, and CTLA-4. We all have our own experiences and level of comfort and the regimen that you’re familiar with, especially when it comes to the nuances and toxicities, is valuable for the patient. The choice of systemic therapy for non-oncogene driven tumors where there is a target is very different and physician dependent. However, there are many reasonable options now to pick from.

Finally, the one thing that trumps everything else is how patients are doing in general; performance status is still a very good predictor [of outcomes]. If somebody can handle chemotherapy or not, what their comorbidities are, and what their functional reserve looks like plays a major factor in picking regimens, especially chemoimmunotherapy.

How can community oncologists keep up with the latest data and treatments available?

It is getting more challenging with so many trials coming out. Being a thoracic oncologist only, I struggle to keep up despite having good conferences. There are many ways in which you can keep up now, but it’s a challenge. [But] you cannot try to fit a patient into a theoretical framework all the time; you must look at patient-specific factors and understand your data rather than seeing which flowchart they will fall into.

We need to see what it is that patients want from their treatments. What is it that you want for them? How comfortable are you with a certain regimen? There are so many factors that influence a treatment choice. Some are very straightforward, and others require more thought from you and the patient and shared decision-making.