ctDNA Testing Gains Ground in NSCLC With the Potential to Further Guide Treatment Decisions

Wade Iams, MD, MSCI

Liquid biopsies are critical in understanding oncogenic drivers and resistance mechanisms in patients with non–small cell lung cancer (NSCLC), said Wade Iams, MD, MSCI, who added that although clinical utility has yet to established, circulating tumor DNA (ctDNA) testing has the potential to inform treatment escalation and de-escalation strategies.

“Primarily, the current standard-of-care use [of liquid biopsies] is at the time of diagnosis, particularly if tissue is insufficient for testing, and for the identification of specific acquired resistance mutations. On the horizon, [we have] minimal residual disease [MRD] monitoring and are looking at treatment efficacy end points with ctDNA in patients with NSCLC,” said Iams in an interview with OncLive® during an Institutional Perspectives in Cancer (IPC) webinar on lung cancer.

Iams also highlighted that with novel targeted therapies for KRAS G12C–mutated and EGFR exon 20 insertion–positive subgroups, as well as the novel immunotherapeutic combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for PD-L1–positive disease, the role of liquid biopsies has grown significantly in the paradigm.

During the interview, Iams, chair of the IPC meeting, and an assistant professor of medicine at Vanderbilt-Ingram Cancer Center of Vanderbilt University Medical Center, discussed the current state of clinical validity and utility with ctDNA testing in NSCLC, updates with targeted therapy and immunotherapy in NSCLC, and the need to address remaining challenges in small cell lung cancer (SCLC).

OncLive^®: How is liquid biopsy shifting the paradigm of NSCLC? What could the tool add to the treatment selection process?

Iams: My hope is that liquid biopsies can add to radiographic monitoring of patients with cancer. [Liquid biopsy] does provide additional and novel information, both in terms of mechanisms of resistance and specific oncogenes that can drive these malignancies. We have opportunities to escalate or de-escalate therapies based on the presence or absence of tumor DNA. That is yet to be proven in terms of clinical utility in prospective trials, but that is my hope. 

How could the field utilize MRD monitoring and ctDNA testing to guide treatment?

One of the avenues on the horizon is MRD monitoring, particularly after patients have completed curative-intent therapy, [such as] concurrent chemoradiation in the case of patients with stage III unresectable NSCLC or after surgical resection in NSCLC. These patients often have high rates of relapse, so we have a lot to learn about using liquid biopsies to detect residual disease and determine who needs adjuvant therapy.

When it comes to patients with stage IV NSCLC, monitoring early treatment efficacy sooner than every 2- or 3-month imaging—which is the shortest interval we typically use in patients with stage IV NSCLC—[is needed]. We have opportunities to monitor the treatment effect, [but] we need to prove that changing treatment based on those liquid biopsy findings can improve outcomes.

What is the difference between clinical validity and clinical utility? What is needed to establish clinical utility with ctDNA testing?

Most folks are most familiar with clinical validity, [which is] how representative a specific measurement is of what we are trying to capture in terms of information. This [includes measures] like sensitivity, specificity, and positive and negative predictive values of a variety of clinical measurements that we obtain, like lab value, radiography, or physical exam findings. ctDNA has clinical validity in a variety of circumstances, more so than the way it is used in the clinic. That is because we know that in specific applications, ctDNA is representative of the NSCLC we are attempting to measure. It’s valid.

What we don’t know is the clinical utility [of ctDNA], meaning whether acting on that measurement improves patient outcomes. In cancer care, that means prolonging survival. We need to prove that the clinical utility of liquid biopsies is there, and specifically that acting on [the results] can improve survival.

What clinical trial opportunities are available to incorporate ctDNA?

Of the opportunities for prospective trials, there are 2 large entities in the field. We have our Cooperative Group and National Cancer Institute [NCI]–funded studies and our Pharma-funded studies. There are opportunities in both arenas for the integration of ctDNA into prospective trials. Both in the MRD and treatment-efficacy settings, liquid biopsies can be integrated to ask fundamental questions to improve patient outcomes. In the case of pharmaceutical companies sponsoring such a trial, they would have interest in their drug demonstrating the ability to be one of the early adopters of that paradigm in cancer care. In the case of the NCI, [clinical trials evaluating ctDNA could] ask fundamental questions as well about how liquid biopsy can affect [cancer care] from a treatment-agnostic standpoint.

During the IPC meeting, Tejas Patil, MD, of the University of Colorado Medicine, discussed updates with targeted therapy in NSCLC. Do you anticipate targeted therapy options will remain monotherapies or move into combination regimens?

First and foremost, [we have seen] some new opportunities for patients who have not had targeted therapies, including patients with KRAS G12C–mutated NSCLC and EGFR exon 20 insertion–positive disease. The other big takeaway is thinking about the mechanisms that these drugs are acting on and getting some anticipation of mechanisms of resistance. Currently, the applications that Dr Patil discussed are [for] monotherapy, but understanding the mechanisms of action and acquired resistance informs the likelihood of monotherapy remaining the standard of care or whether combination therapies will supplant monotherapy. 

There are a variety of combinations being evaluated and moving into the first-line setting. Those are the 2 components on the horizon for these agents.

Christine Bestvina, MD, of the University of Chicago Medicine, showcased the continued efficacy of nivolumab plus ipilimumab in NSCLC. How has that combination evolved from research to now being utilized clinically?

The durability of response with the nivolumab and ipilimumab combination in NSCLC is particularly compelling. It is a bit late to the treatment paradigm compared with our platinum-doublet plus pembrolizumab [(Keytruda) regimen]. However, [nivolumab/ipilimumab] continues to have a role for a subgroup of patients, particularly those with brain metastases or individuals who are particularly chemotherapy averse.

The FDA approval is for patients with PD-L1 [expression of] 1% or greater. That is where Dr Bestvina also touched on the CheckMate 9LA [NCT03215706] regimen of 2 cycles of platinum-doublet chemotherapy plus nivolumab and ipilimumab, which is a minimal-chemotherapy regimen for patients with PD-L1 [expression] of less than 1%.

What is your anticipation for neoadjuvant immunotherapy in NSCLC?

Where the data stand with neoadjuvant immunotherapy is that the trials have demonstrated compelling pathologic complete responses [pCR]. The scientific rationale is such that, with the tumor antigen present at the initial introduction of a checkpoint inhibitor, we may have maximal clinical benefit. That is very interesting. We need to see longer-term overall survival [OS] benefit, but in surgically resectable patients, that is going to take years to play out and to decipher that true survival benefit over time. So far, we have very impressive pCR rates in patients with breast cancer, so [pCR] has been demonstrated to be a valid surrogate end point and representative of OS. We are hopeful [to see] similar things in NSCLC.

Finally, Jason Porter, MD, of the West Cancer Center, highlighted updates in SCLC, such as the introduction of lurbinectedin (Zepzelca) as a second-line therapy in extensive-stage (ES) disease. What other updates have been significant in SCLC, and what other challenges are attempting to be addressed with ongoing research?

We had progress with a 2-to-3-month improvement in median OS with the introduction of checkpoint inhibitors in patients with ES-SCLC. However, the challenge is two-fold. A 2-to-3-month improvement in OS is not nearly enough for such a severe disease. SCLC remains very difficult to treat at the time of relapse. A better understanding of the fundamental biologies and emerging paradigms of the 4 SCLC subtypes can help inform therapeutic development in the future.

Particularly among patients with ES-SCLC or stage IV SCLC, it is now standard of care if there is not an absolute contraindication to include a checkpoint inhibitor with the initial treatment as it does improve the median OS. That has been replicated in 2 large phase 3 randomized-controlled trials with platinum-etoposide and atezolizumab [Tecentriq] or durvalumab [Imfinzi]. The use of checkpoint inhibitors is being evaluated in the adjuvant setting for patients with limited-stage SCLC. We don’t know yet whether that can help us improve cures, which [is a word] we are always very cautious to use in patients with SCLC. However, there is a subset of patients with limited-stage SCLC who we can cure. We hope that the use of checkpoint inhibitors in the adjuvant setting can increase [the rates of cure].

The most important recent development to be aware of for patients with relapsed SCLC is the introduction of lurbinectedin, which is a cytotoxic chemotherapy that inhibits transcription for patients with relapsed SCLC. That drug is FDA approved and [is included] in the National Comprehensive Cancer Network guidelines for platinum-sensitive and platinum-resistant disease. That is the biggest novel development.

On the horizon, we have the identification of 4 unique SCLC subtypes defined based on transcription-factor profiles. As we are able to allocate therapies among those subgroups, we will find other interesting insights for patients with relapsed SCLC.