Patient-Centered Discussions Will Be Critical to Navigate Treatment Selection in EGFR+ NSCLC

Isabel Preeshagul, DO, MBS

Selecting the optimal treatment approach, both in the first line setting and following progression on frontline regimens, requires shared decision-making as well as careful consideration of patient comorbidities and treatment tolerability, according to Isabel Preeshagul, DO, MBS. She added that expanded upfront treatment options for patients with EGFR-mutated non-small cell lung cancer (NSCLC) based on positive results from the phase 3 FLAURA2 (NCT04035486) and MARIPOSA (NCT04487080) trials offer greater flexibility for such patient-centered care.

“We certainly have options, but there is no [one] right approach; the correct answer is to do what feels right for your patient and what meets their lifestyle and expectations,” Preeshagul said in an interview with OncLive® regarding a recent State of the Science Summit™ on lung cancer, which she chaired.

In the interview, Preeshagul outlined key considerations for frontline treatment selection for patients with EGFR-mutated NSCLC, emphasized the importance of shared treatment decision-making in both the first- and second-line settings, and how the lack of head-to-head comparisons complicates the recommendation of perioperative vs neoadjuvant approaches.

Preeshagul, who is a thoracic medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in Montvale, New Jersey, also discussed efforts to expand the treatment arsenal for patients with extensive- or limited-stage small cell lung cancer in a concurrent interview.

OncLive: How have recent data from the FLAURA2 and MARIPOSA trials expanded frontline treatment options for patients with EGFR-mutated NSCLC?

Preeshagul: As of late, we have a plethora of options for patients with stage IV NSCLC harboring an EGFR exon 19 deletion [or] exon 20 L858R mutation. For these patients, a couple years ago I would have told you that osimertinib [Tagrisso] is the go-to drug. It’s shown efficacy over erlotinib [Tarceva] and gefitinib [Iressa], and there’s excellent central nervous system [CNS] penetration. Now in the frontline setting, we have osimertinib, and data from the FLAURA2 trial which evaluated combining osimertinib with chemotherapy. Then we have data from the MARIPOSA trial, which [investigated] amivantamab-vmjw [Rybrevant] plus lazertinib [vs osimertinib or lazertinib monotherapy] in the frontline setting.

How do you select between the 3 treatment options in the frontline setting?

It requires a discussion. You need to sit down with your patients and their caregivers and talk to them about these 3 options. Talk to them realistically about toxicity and tolerability, what the [dosing] schedule looks like, and what [they can] expect. If you have a patient who is elderly, has a lot of comorbidities, has underlying cytopenias, or is not interested in intravenous [IV] chemotherapy, osimertinib plus chemotherapy or amivantamab plus lazertinib may not be the best option, as they require infusions. [Instead], osimertinib with a pill alone may be the best choice.

However, if you have a patient with an EGFR exon 21 alteration with brain metastases, there is a subset analysis in FLAURA2 [showing] that perhaps there was a signal for those patients. Interpretation of the data still needs to come down to what’s important to and works for the patient.

Regarding amivantamab plus lazertinib, this [regimen] is not a walk in the park [according to] the MARIPOSA data. We gave it in the clinical trial, I have yet to give it as the standard of care [SOC], but it’s difficult. With amivantamab you have the risk of infusion reactions early on. We see them and know how to handle them, but it can be terrifying for a patient. [Additionally, patients still have to receive] IV infusions every 2 weeks after they’re done with the loading dose. Lazertinib is a pill, and that’s great, but it’s taken in addition to amivantamab, so you [are contending with] the toxicity of both. Then you worry about the toxicity of rash or diarrhea. [Patients also] have to remember to take a pill. It can be a lot.

[Overall], I’m excited that we have options, and I’m excited that we can have these in-depth discussions. However, in the end, it falls on the patient [to know what is best for them], and that is just with SOC options. We also have clinical trials [evaluating potential regimens for] patients in the frontline setting.

What key data inform second-line treatment selection?

For patients who have progressed on frontline osimertinib, we have the phase 3 PAPILLON trial [NCT04538664] looking at amivantamab plus chemotherapy in this setting. We also have the phase 3 MARIPOSA-2 study [NCT04988295] evaluating amivantamab and chemotherapy with or without lazertinib. [Once again,] it’s up to your patient.

In addition to these options, we have clinical trials evaluating whether patients have known resistance alterations to progression on osimertinib. [For example,] have they had histologic transformation to squamous cell carcinoma or small cell carcinoma? Do they have known resistance mutations such as a C797S alteration or MET amplification, and is it better to target that resistance pathway?

What are the major takeaways from the phase 3 LAURA study (NCT03521154) of consolidation osimertinib following chemoradiation? For which patients might you hesitate to recommend this regimen?

LAURA [evaluated] concurrent chemotherapy and radiation in patients with unresectable stage III disease harboring EGFR alterations. Following concurrent chemotherapy and radiation, they were started on osimertinib, which continued indefinitely. At the 2024 ASCO plenary session, there was a standing ovation for this presentation. We are very happy to see the benefit here, but it gave me pause. When you’re trying to treat someone with curative intent, [having to take] osimertinib for life in that setting is a difficult pill to swallow. We’re talking about taking chemotherapy every single day for the rest of your life, as long as you can tolerate it.

Although there is an advantage [to taking it], and there certainly is, it’s not toxicity free. A patient has to worry about cytopenias, rash, and diarrhea, as well as long-term toxicity and cardiac issues. We need to figure out a way to determine if there’s a patient who we could de-escalate treatment for, or a way to determine if a patient does not need treatment for life. Could circulating tumor DNA [help] or is there another marker that would let us know and give us a glimmer of hope that a patient may not need osimertinib for life? That is something I take into consideration when I’m starting my patients on this drug. It is a commitment, and they need to understand that.

For patients with mutations other than EGFR such as ROS1 rearrangements, what are some of the key limitations and toxicity concerns observed with currently available agents?

[Treatments] have expanded to include TRK inhibitors [such as] entrectinib [Rozlytrek] or repotrectinib [Augtyro]. With TRK inhibitors, we worry about the TRK-associated adverse effects [AEs], which include a lot of dizziness and neuropathy, which you might not think is a big deal, but grade 1/2 dizziness can be awful and [potentially] life-altering. Patients can’t drive, can’t walk down the hallway every time they get up. [Patients who have] neuropathy [often] can’t feel the floor anymore. Maybe their cancer is in check, but their quality of life is [not high].

What’s nice about the data from the phase 1/2 ARROS-1 study [NCT05118789] evaluating [the ROS1 inhibitor] NVL-520 is that it has less of these off-target and TRK-related AEs. It also may have better CNS efficacy, but that is yet to be determined. [​​NVL-520] is not FDA approved yet, so it’s still in [early] clinical trial [evaluation]. However, I hope that this may be moved into the frontline setting, given its better tolerability and its efficacy.

How does the ongoing debate surrounding perioperative vs neoadjuvant therapy reflect current challenges in determining which patients benefit most from post-surgical treatment?

This is one of the hottest debates right now because there are a lot of data with induction therapy or neoadjuvant therapy based on the CheckMate studies. There are also these newer kids on the block, which include perioperative therapy. However, none [of these approaches] have truly been compared head-to-head, and we still don’t know who benefits most from perioperative therapy. We know that benefit [is conferred by] administering treatment before [surgery]. Everyone has bought into neoadjuvant therapy, but who needs treatment after their tumor has been resected is yet to be defined. All the trials [assessing either approach] are trying to highlight a different aspect [of treatment].

However, until we have a true comparison, we’re not going to know who benefits. [Additionally], it’s difficult to explain to patients that they’re going to need more treatment for at least a year after they’ve had their tumor resected and [achieved] a response. It would be nice to say, ‘you need this treatment’, and [explain the reasons why] we know they’re going to benefit [from it]. Until we have that, it’s going to be a tough sell, and it’s difficult to know who should receive that kind of treatment.