Personalized Therapy, Surgical Staging, and Expanded Screening Guidelines Drive Progress in NSCLC

Isabel Preeshagul, DO, MBS

Expanding targeted therapy options in ALK- and EGFR-mutated non–small cell lung cancer (NSCLC) has complicated frontline decision-making, underscoring the importance of individualized treatment selection based on disease characteristics, toxicity profiles, and patient preferences, according to Isabel Preeshagul, DO, MBS.

“These are all good options, and we are simply happy to have them. However, we need to think about sequencing and what the next steps may be, because a lot goes into the decision-making process,” Preeshagul said in an interview with OncLive® following a State of the Science Summit™ on lung cancer, which she chaired.

In the interview, Preeshagul, who is a thoracic medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in Montvale, New Jersey, expanded on frontline treatment selection for ALK- and EGFR-mutated NSCLC, emphasized persistent disparities in lung cancer screening, and the need for rigorous mediastinal staging in early-stage disease to optimize outcomes.

In a concurrent interview, Preeshagul highlighted the significance of several regulatory milestones in small cell lung cancer and the need for further research to enhance the efficacy of current frontline regimens.

OncLive: How has the expanding arsenal of ALK and ROS1inhibitors influenced frontline treatment selection for patients with ALK-rearranged NSCLC?

Preeshagul: Years ago, we essentially only had crizotinib [Xalkori]. Over the past 5 to 10 years, we now have alectinib [Alecensa], brigatinib [Alunbrig], lorlatinib [Lorbrena], and ensartinib [Ensacove], all [of which] are approved in the frontline setting. Lorlatinib also has approval in the second-line setting for resistance alterations that can develop after frontline treatment.

We always want to [advise practitioners to] give their best drug first. These drugs have never been [compared] against each other—they're always [evaluated] against crizotinib as the comparator. We'll never really know for sure [which is best], but we do know that certain drugs may show a bit of a signal in specific areas or may be better tolerated in some scenarios. For example, we know lorlatinib has excellent central nervous system [CNS] penetration, so I may lean toward lorlatinib for patients with CNS metastases.

What are the current standard-of-care (SOC) approaches for the management of stage IV EGFR-mutant NSCLC, and how are emerging data challenging or potentially redefining these treatment paradigms?

As of late, there are now multiple ways we can treat patients with stage IV NSCLC harboring an EGFR exon 19 deletion or exon 21 L858R insertion [mutation]. One approach is with SOC upfront osimertinib [Tagrisso]. Another is with SOC chemotherapy plus osimertinib, based on the [data from the phase 3 FLAURA2 (​NCT04035486) trial]. We also recently saw new overall survival data emerge from [the phase 3] MARIPOSA [(NCT04487080) trial], evaluating frontline amivantamab-vmjw [Rybrevant] plus lazertinib [Lazcluze].

Once again, it comes down to having a discussion with the patient and reviewing all these regimens together. There are some data suggesting a possible survival advantage with amivantamab and lazertinib. Although those data may look promising, the regimen does not come without [associated] toxicities. It is important to talk to the patient, assess their comorbidities, and work as a team to make the best choice.

In the past, when we had a patient with frontline stage IV disease, I often said that the treatment discussion might take just a few minutes. Now, we need at least an hour, if not more, to walk through everything. More options mean more choices [for patients].

How have updates to lung cancer screening guidelines addressed previous limitations in identifying at-risk populations? What gaps in screening remain?

When lung cancer screening initially came out, the [U.S. Preventive Services Task Force (USPSTF)] guidelines were a little more stringent, and we realized that we were missing a lot of patients. We were missing patients who had a less extensive smoking history, and we were missing patients who were younger than 55 or 60 [years of age]. Because of that, the age range was broadened to start at 50 years to include those younger patients.

We also realized that we were missing certain ethnic groups who may have different smoking patterns than the [White patient] population. As a result, they were not meeting the criteria for screening. Because of this, the USPSTF adjusted the lung cancer screening guidelines to allow more patients to be captured. However, there is still work to be done in this space.

There are ways we can refine this approach, such as improving public awareness [about the availability of] lung cancer screening. Another question is what to do about patients with no history of smoking but a family history of lung cancer, or patients with no smoking history at all. We are noticing increasing rates of lung cancer in women and patients without a smoking history. We are still trying to figure out how best to handle these patients, how to guide them, and whether screening is needed. We don't know the answer to that yet.

What are the current considerations regarding the use of minimally invasive thoracic surgical techniques in early-stage NSCLC?

The main takeaway for me is the importance of mediastinal sampling and making sure that when you sample the mediastinum, you're sampling [across] the different stations needed to ensure appropriate staging.

The concern is always that if patients receive only a wedge resection or a minimally invasive approach, their mediastinum may not be sampled, and sometimes we miss node-positive disease. We know that local recurrence is a risk for patients with early-stage lung cancer, so we really want to ensure that we sample the mediastinum appropriately.