ADAURA, Explosion of Targeted Agents Underscore Need for Molecular Testing in Lung Cancer

Rogerio C. Lilenbaum, MD

The data from the phase 3 ADAURA trial (NCT02511106) with adjuvant osimertinib (Tagrisso) are among the most significant to read out in the past year in the realm of non–small cell lung cancer (NSCLC), according to Rogerio C. Lilenbaum, MD, who added that this advance, along with other targeted agents such as sotorasib (Lumakras), selpercatinib (Retevmo), and pralsetinib (Gavreto), underscore the need for molecular testing to inform clinical decisions.

“I would encourage everyone to look at the data carefully and make a decision about how they want to approach ADAURA. In my view, this adds ammunition to the fact that every patient with a NSCLC histology of the nonsquamous type should have a molecular profile done, irrespective of stage,” Lilenbaum said. “This is an approach that we use, here, at MD Anderson, and it is now justified. In the past, it was justified because you wanted to have that information available for when you needed to act upon it. Now, the time to act is after surgery, so it is important to test every patient that may qualify for adjuvant therapy with an EGFR inhibitor.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on lung cancer, Lilenbaum, the director of the Banner MD Anderson Cancer Center, discussed the significance of recent approvals of targeted therapies spanning NSCLC subgroups and the new standard of care that has emerged in small cell lung cancer (SCLC).

OncLive®: What are some of the latest advances made with targeting EGFR in NSCLC?

Lilenbaum: We now have documented evidence that these agents are the standard first-line management for patients whose tumors harbor an EGFR sensitizing mutation. It appears that most, at least in the United States, have adopted osimertinib [Tagrisso] as their preferred agent, although it is important to realize that other agents are also very active in the same patient population. I do not believe that we have, at least at this point, definitive data to justify adding an EGFR inhibitor to chemotherapy. I personally still approach most of these patients with an EGFR inhibitor alone in the first-line management [of these patients].

It is also important to note that for patients who have tumors with EGFR sensitizing mutations, traditional checkpoint inhibitors do not seem to significantly [improve] outcomes. Therefore, at least when used as single agents, they should be avoided [in these patients]. It is an important management lesson that although it is relatively easy to use chemotherapy plus immunotherapy in the first-line management of patients with advanced NSCLC in general, that [approach] does not apply to patients who have EGFR sensitizing mutations. It is critical that we test for the mutation, and that we receive those results in a timely manner.

What are your thoughts on EGFR inhibition in the adjuvant setting?

In my view, the results of the phase 3 ADAURA trial are the most significant results that we have heard in lung cancer in the past 12 months. Any time that a treatment principle is tested and approved in the advanced setting, applied to earlier-stage disease, to the adjuvant setting, and leads to higher rates of cure, it is a significant watershed moment. It is important for everyone to make a decision about their views on the ADAURA trial. Personally, based on the results available so far—granted, these are not definitive or final results—I do offer adjuvant osimertinib to patients who have had definitive surgery and an EGFR-mutated tumor, and therefore, are candidates for this approach.

Not everyone feels the same way, and I respect that. However, this debate about EGFR inhibition in the adjuvant setting has been going on for too long, and a lot of it is about a degree of scientific purity that we do not hold ourselves to in other situations in oncology. We may very well be missing an opportunity to cure more patients with NSCLC who have EGFR mutations in the early stage.

Shifting to the stage III locally advanced setting, recently, a study was presented on concurrent chemoradiation and a checkpoint inhibitor. Do you believe that this approach could soon become the new standard of care, ousting what was shown in the phase 3 PACIFIC trial (NCT02125461)?

We have known since the release of the PACIFIC trial that concomitant approaches were being studied in [patients with] stage III disease. Now, we are beginning to see some results, and they may offer some advantages compared with the sequential or maintenance approach championed by the PACIFIC trial. Personally, I would like to see more data about the concomitant approach. The long-term results from the PACIFIC trial are impressive, with over 40% of patients with stage III disease alive after 5 years from diagnosis; this is unprecedented and [sets] a high bar for any other approach [under investigation] in [this population].

Looking at other targets in the metastatic setting, the FDA approved sotorasib for use in patients with NSCLC whose tumors harbor KRAS G12C mutations. What are your thoughts on this agent?

The pursuit of a targeted approach to tumors with KRAS mutations has been a long one, and for the first time, we now have an agent that has shown demonstrable benefit for patients who are previously treated. It is important to note that this [agent] is not approved for the first-line management of these patients, but for those in the second-line setting. I hope that it is only the beginning of a long road of discovery and innovation, with more effective KRAS inhibitors that may be utilized in diseases other than lung cancer. It is a very important moment for a molecular-based approach in solid tumors in general, and the approval in NSCLC is only the first step.

In terms of RET inhibition, we have selpercatinib and pralsetinib, which are very effective single agents. Do you believe they will soon be investigated in combination approaches?

It is an important testament to how much has been accomplished from a scientific perspective that we now have 2 very effective agents against a small subset of patients with NSCLC who harbor RET fusions. I am comfortable with using either of those agents in my own practice. Other approaches may be the subject of clinical trials in the future. However, we cannot lose sight of what this represents in the grand scheme of things, and how much progress has been made in identifying actionable mutations in this group of diseases that we call NSCLC. We will see some innovations in [this area], but right now, we have more than 1 option for patients with molecular changes in RET that did not exist just a few years ago.

In terms of other mutations, like MET exon 14 and HER2, have we been able to build on the advances seen in other tumor types?

We do have a standard first-line regimen for BRAF-mutated tumors, and that took a long time to become a recommendation as a first-line regimen as opposed to [a regimen for the] second-line [setting] and beyond. We also have very active drugs against MET alterations, including skipping mutations, and so I am very comfortable with a targeted approach in these patients, as well. When it comes to HER2 mutations, I have been more cautious about my approach, and I have not yet used targeted treatments in the first-line management of these patients.

Shifting to SCLC, what are some of the latest developments in this paradigm?

We now—for the first time in over 2 decades—have a new standard regimen for the treatment of patients with extensive-stage SCLC [ES-SCLC], which includes a checkpoint inhibitor, atezolizumab [Tecentriq], in addition to a standard backbone doublet regimen comprised of platinum and etoposide. This [approach] has demonstrated improved outcomes and represents the first time that a combination has prolonged survival in this patient population, which is exciting news.

In addition to the data that have been reported the atezolizumab, where might the findings observed with durvalumab (Imfinzi) fit in?

The data with durvalumab also corroborates the idea that adding a checkpoint inhibitor to a chemotherapy backbone prolongs survival and improves outcomes for patients with ES-SCLC. When you have 2 phase 3 randomized trials that essentially show the same results, you can consider that the addition of immunotherapy to chemotherapy in this patient population represents a new standard of care.

It has been said that these 2 regimens are essentially interchangeable. Would you agree with that?

Using atezolizumab or durvalumab in ES-SCLC is a clinician’s choice. I do not see significant differences in efficacy or toxicity between the 2 agents. [The decision lies in] the comfort level of the individual clinician. [We also need to take] into consideration patient factors, which may or may not play a role here, as well as institutional factors, depending on the availability of pathways, cost, and pharmacy changes.

In the second-line setting, lurbinectedin (Zepzelca) is now FDA approved. What is the clinical significance of this decision for the paradigm?

Having an approved agent in the second-line setting, after at least 2 decades, is a significant step forward. The data [with lurbinectedin] demonstrate benefit that is somewhat modest. However, every benefit that we have seen in SCLC is incremental. When we look at it sequentially, we sense that we are beginning to make a more substantial improvement in both survival and quality of life for these patients, so [lurbinectedin] is a nice option to have. [The agent] is also one that comes without a significant toxicity profile, which is important for patients with SCLC in the second-line setting.

Is there any ongoing or planned research in this disease that you wanted to highlight?

One important trial that was negative [looked at] the use of maintenance immunotherapy after first-line treatment of ES-SCLC. It is important to realize that these agents must be added to the regimen from the beginning, and not reserved for either second-line or maintenance treatment—that is not the best use for checkpoint inhibitors or other immunotherapy agents. We are also waiting to see how these agents contribute to better outcomes in [patients with] limited-stage SCLC when used with chemotherapy and radiation therapy.