Evaluating the Top EGFR+ NSCLC Treatment Combinations

The authors.

The landscape of therapies for EGFR- mutated metastatic non–small cell lung cancer (NSCLC) is continuously evolving and advancing. Experts gathered for an Around the Practice® program hosted by CancerNetwork® and discussed the top agents in the space, with one of the most prevalent being osimertinib (Tagrisso) as evaluated in the phase 3 FLAURA2 trial (NCT04035486). Specifically, they compared the regimen from FLAURA2—osimertinib plus chemotherapy—with the regimen from the phase 3 MARIPOSA trial (NCT04487080)—amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze).

The panel was moderated by Samuel Rosner, MD, an assistant professor of medicine at the University of Maryland Cancer Center in Baltimore, and Laura Alder, MD, an assistant professor of medicine at Duke Cancer Center in Durham, North Carolina. They were joined by fellow experts Najeff Waseem, MD, a medical oncologist/hematologist at Maryland Oncology Hematology in Columbia, and Sarah Sagorsky, PA-C, a solid tumor advanced practice practitioner at the Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins Medicine in Baltimore, Maryland.

Regimen Preferences

Rosner / Has combination therapy with either osimertinib plus chemotherapy or amivantamab plus lazertinib become the preferred standard-of-care regimen for patients whom you see with newly diagnosed EGFR-mutated disease?

Waseem / Compared with osimertinib monotherapy, we know that both combinations are better, certainly for progression-free survival [PFS], and with the vast majority of patients who come to us, we want to be aggressive. With most other cancers, we use our strongest sauce first; it tends to be best for overall outcomes, and this is no different. There are subtleties between which combination [to use], but…thinking about the combinations over osimertinib monotherapy, the only population I would leave it out [for] is the [older population with frailty]. If you’re worried about infusion or people who don’t want to come in for infusions and just want to be on a pill monotherapy, then that’s a situation where I think about osimertinib alone, but I still have the conversation.

Sagorsky / We don’t have a preferred regimen in the frontline setting for our patients. Several factors are taken into consideration prior to selecting a first-line regimen. Whether it be single-agent osimertinib, osimertinib plus chemotherapy, or amivantamab plus lazertinib, the treatment recommendations are tailored to each individual patient’s clinical characteristics and their next-generation sequencing. Single-agent osimertinib is preferred for patients who have a small burden of disease; they may have central nervous system [CNS] metastasis but are asymptomatic from it. Patients who have multiple medical comorbidities may not tolerate chemotherapy, and it appeals to those who value quality of life with the convenience of an oral agent.

Alder / I agree…. It’s patient dependent. I also tend to discuss with them. It’s vital to talk about the different options and portray the risks and the benefits of each one, [like] the [adverse] effect profile. Considering the patient themselves, any high-risk features—you mentioned CNS involvement—that point us toward combination therapy, in addition to coalterations and mutations in the genomic panel. Making sure that we find the best match for the patient in front of us, utilizing a variety of different factors, both tumor biology and patient dependent as well, [is important].

Rosner / Who might you consider osimertinib monotherapy for as opposed to combination strategies…? Are there any patient demographic or genomic data that you take into account?

Waseem / If you have comutations and if you’re worried about MET, those are different discussions, but if you have a run-of-the-mill EGFR mutation, you think that there are no resistance mechanisms that you’re worried about. In my case, I like to talk about all the data. We have a well-read population of patients, so I talk about the data with each patient. My job is like trying to help them choose from a menu of things. [With] older patients [with frailty]—people with comorbidities [who] you’re worried about [with] infusion therapy or the risk of adverse effects—before we had a lot of the osimertinib data and all that stuff, we only had 1 choice, which was chemotherapy. We found a way to make it work, and not every 80-year-old [patient] is the same. I don’t think there’s an age cutoff. It’s people’s willingness to be aggressive, as Dr Alder mentioned, and trying to tailor specifically not only to disease biology but also to what people’s preferences are.

What ends up becoming a reality, unfortunately, is that a lot of patients, by the time the second line comes around, can’t get a second-line therapy. If people are debating whether we try to be aggressive up front, sometimes I’ll start the chemotherapy and the osimertinib, knowing that we have the osimertinib backbone. If they don’t do well, then we stop the chemotherapy earlier. If they do well, then maybe we can get through 4 cycles of the full doses and they can feel better about the fact that they took the most aggressive approach. There’s not a one-size-fits-all approach. The nice part about having good data and 3 different choices is that nobody can hold you to any 1 of them.

Evaluating Time and Financial Toxicities

Alder / Can you describe the additional time and financial burdens associated with some of these combination regimens?

Rosner / I have some patients who say, “If it will keep my cancer away longer, then that’s the end of the discussion.” For a lot of patients, these time toxicity and financial burdens are...the primary drivers of their decision-making. With osimertinib, usually I do a 2-week follow-up after [treatment], whether that’s telemedicine or in person. We check laboratory [results]. Some patients are tolerating it well. I can start spacing visits quickly, especially if they’re asymptomatic. We eventually get to a point where we’re doing...follow-ups [every 3 months] with scans and laboratory [results]. That’s quite freeing. These are young patients who have families, so being able to forget that I exist for a while is helpful emotionally. The trade-off, of course, if you are considering some of these combination options, is not only increased visits. In the case of FLAURA2, they’re coming every 3 weeks; ideally, they’re staying on the maintenance pemetrexed. That continues every 3 weeks, and then the amivantamab, which has more frequent visits up front—weekly, followed by biweekly after that, and indefinite as well. That is a time toxicity. Our infusion center doesn’t work as smoothly as we would like it to, and those days can add up. On top of that, there are risks that patients will have more urgent care visits. They have to come back more urgently for the adverse effects associated with both therapies.

Alder / What has been your experience in deciding past 5 cycles of continuing the pemetrexed, and what [does] that conversation look like with the patient?

Rosner / With most patients, hopefully, I did a decent job of explaining that’s the goal and that is how the trial was. They’re not surprised when we’re continuing every 3 weeks. Pemetrexed does tend to be better tolerated in terms of chemotherapy, though some patients do require some dose reduction, and I’m quick to do that, particularly if we’re watching renal function or any cumulative toxicity that can happen.

The other thing is that osimertinib is driving the majority of that benefit, so if we do need to stop or temporarily...pausetherapy, I’m quick to do that and can provide reassurance to patients. Finally, you can also get a little creative again, knowing that osimertinib is driving the benefit. I have, once or twice, spaced out the pemetrexed dosing a little bit to [once every 4] weeks. Again, it’s not data driven, just more trying to provide that freedom for patients as well. There are a lot of different ways to do it.

The one thing I’ll say is that of course we try [to] keep them on maintenance pemetrexed; there are some data from FLAURA2 that the longer patients stayed on, there was a trend toward PFS benefit, albeit that’s tough because there’s some selection bias in that, but that does drive some of my thinking in terms of wanting to continue. We also know that in the non-EGFR space, continuing that maintenance pemetrexed sometimes has some increased benefit as well.

Evaluating Toxicity Profiles

Alder / When discussing combination therapy with patients, which toxicities do you find most important to highlight, and which ones do you emphasize when you’re talking about the 2 different combinations?

Sagorsky / We have discussions with our patients about the potential toxicities that they may encounter on therapy. With the combination of osimertinib and chemotherapy, patients are going to have fatigue. It’s going to impact their quality of life. With the cytotoxic chemotherapy, they’re going to have pancytopenia requiring frequent laboratory draws, [gastrointestinal] adverse effects, nausea, and vomiting; diarrhea is also a possibility. When adding osimertinib to it, we discuss dermatologic toxicity, such as rash and paronychia. What I will share with patients is that although there is a laundry list of toxicities that could potentially occur, the supportive care regimens have come a long way as well. Ideally, if we intervene early, these patients tend to have manageable toxicities. Dose reductions [and things like that] can help mitigate some of these toxicities. When discussing amivantamab plus lazertinib, we talk about infusion-related reactions. That’s a No. 1 priority to talk about the logistics of giving it and the length of infusion time for the amivantamab.

The biggest differentiation is the importance of the [venous thromboembolism] prophylaxis. For the first 4 months, they need to be on anticoagulation. The major thing that we’ve experienced is skin-related toxicities, so paronychia [and] rash. And I’ve had a decent amount of patients who have had stomatitis who have required some [intravenous] fluids and supportive care, like [dexamethasone] mouthwash for the mucositis and stomatitis the patients are experiencing.

Waseem / Skin toxicities are certainly very jarring for patients, so the use of prophylaxis, doxycycline, and things like that can be difficult, even with the osimertinib. Nail changes are not trivial, but we have come a long way in terms of our comfort level with managing chemotherapy adverse effects, [such as] nausea and cytopenias. Our practice is a little interesting. We make sure everybody has some antibiotics at home because we don’t have urgent care, so they can call in with fevers. We make sure that at least they have something if they can’t get into a hospital.

With any chemotherapy regimen, we give them—it’s an interesting practice—but we give a fluoroquinolone because, a lot of times, what is more likely with our patients is they call in [that] they’re febrile. You’re not sure [whether] they’re neutropenic, and they do not want to go to the emergency [department]. You want to at least have some recourse if they’re otherwise stable.

Sagorsky / One thing we haven’t touched on…is that the adverse effects from the amivantamab plus lazertinib tend to improve after the first couple of months on therapy. Sometimes, that is a discussion point from a quality-of-life standpoint for the patients.