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Combination Therapies and Resistance-Based Approaches Reshape EGFR Care
Mya Tran, PharmD, BCOP, offers insights for navigating the complex treatment landscape for non-small cell lung cancer.
In an interview with Pharmacy Times® at the HOPA 2025 Annual Meeting, Mya Tran, PharmD, BCOP, precision oncology–thoracic clinical oncology pharmacist from Indiana University Health Simon Cancer Center highlighted recent advancements in EGFR treatments, including third-generation Tyrosine kinase inhibitors (TKIs), combination therapies like amivantamab (Rybrevant; Johnson & Johnson) with chemotherapies, and novel therapies targeting HER3 and TROP2. She also emphasized gaps in clinical guidelines, the importance of toxicity management, and the need for supportive care and shared decision-making in real-world settings.
Pharmacy Times: Why has the treatment landscape for EGFR-mutant non-small cell lung cancer (NSCLC) become so complex in recent years, particularly for patients with classically activating mutations like exon 19 deletion and L858R?
Mya Tran, PharmD, BCOP: I think within the last 2 to 3 years, we have seen some very promising and exciting data in the world of EGFR treatments—not only in first-line therapies, but also in subsequent-line therapies. For example, in first-line therapy, we’ve come a really long way—from first-generation TKIs to second-generation TKIs. We’ve been pretty settled with third-generation TKIs for a while now, and now we have combination therapies coming out, such as osimertinib [Tagrisso; AstraZeneca Pharmaceuticals LP] in combination with chemotherapy, and even non-chemo combination options like bispecific amivantamab in combination with Lazertinib [Lazcluze; Janssen Biotech, Inc].
In the subsequent-line settings, we now have the approval of chemotherapy in combination with amivantamab. We can still use chemotherapy alone, and we can also use treatment strategies personalized based on resistance mechanisms. There are also some novel therapies coming out, including those that can target HER3—such as patritumab deruxtecan [Daiichi Sankyo and Merck & Co]—or that target other pathways, like datopotamab deruxtecan [Datroway; AstraZeneca] for TROP2.
So, the landscape has become very, very complex—but it’s also very exciting, because we now have a lot more options to offer our patients.
Pharmacy Times: How have clinical guidelines evolved for patients with unresectable EGFR-mutant NSCLC, and where do we still see gaps in the data?
Tran: So, I think within the U.S., the guidelines—namely the ASCO Living Guidelines and the NCCN Guidelines—have done a phenomenal job at keeping everything very up to date with all the new approvals and emerging data. But one thing you notice when looking at these guidelines is that they give you a list of therapies to choose from—they don’t necessarily tell you how to pick the best option for your specific patient. And that’s because there are still gaps in the guidelines—gaps that are driven by the limitations of the data.
For example, I think there are 3 main gaps I can point out. First, we need to further personalize treatment strategies for our EGFR-positive cancer patients. Not all patients will need combination therapy, so we need to identify who will benefit from monotherapy—so they’re not exposed to the additional side effects of combination treatment—and who truly needs that combination approach based on their disease characteristics.
Second, there’s still the unanswered question of whether aggressive upfront treatment is always better than a sequential or stepped strategy. For example, we don’t yet know if starting with osimertinib plus chemotherapy is better than starting with osimertinib alone and adding chemotherapy later. The same goes for amivantamab combinations. Is it better to start early or reserve it for later? We just don’t know yet.
And third, part of the gap is driven by how fast the treatment landscape is evolving. We now have novel therapies that target HER3 and TROP2, and we’re also able to personalize treatment based on resistance mechanisms in patients receiving frontline anti-EGFR therapy. But by the time we get data from randomized controlled trials, those results can already be outdated and may not reflect what’s actually happening in real-world practice.
So, there’s a real need for more pragmatic trials—studies that can adapt to the pace of change and help guide treatment decisions in real time.
Pharmacy Times: With newer combination regimens, how should clinicians approach frontline treatment selection in metastatic EGFR-mutant NSCLC?
Tran: Yes, so, based on different criteria, I think there are 3 main factors that can really help clinicians select the best frontline treatment option.
The first is patient factors. This includes their clinical characteristics and genomic profile. For example, patients who present with a high disease burden—such as de novo brain metastases or liver metastases—may benefit from a more aggressive treatment approach, assuming they can tolerate it. Similarly, patients with certain genomic features, like baseline TP53 or RB1 mutations, or those with specific EGFR exon 20 insertions, tend not to respond as well to monotherapy. For those patients, we might want to consider starting with combination therapy upfront instead.
The second factor is patient preference, which has become increasingly important. Different treatment regimens come with different toxicity profiles, so it’s essential to have a thorough conversation with the patient. Ask what they’re comfortable with and what their goals are. I’ve had patients say, “I just want a pill I can take at home—do I have to go into the infusion center?” For some, that level of commitment is a lot, so it’s important to consider their lifestyle and priorities when making treatment decisions.
The third factor is the level of support the clinician has in their practice setting. I work in an academic institution where we’re fortunate to have strong support systems, but I know many of my colleagues in community settings don’t have the same resources. The good thing is that, with all the new and complex options we now have, clinicians can tailor the treatment plan based on what fits best for the patient and what works best for the practice setting.
Pharmacy Times: What are the most promising treatment options following progression on osimertinib?
Tran: So, in terms of treatment options moving forward, I would say the most promising—and the one with the most robust data—is amivantamab in combination with chemotherapy. That regimen already has FDA approval, and we have randomized controlled trial data supporting its efficacy. So, I think that should be the regimen of choice if it’s appropriate for the patient. Of course, amivantamab isn’t suitable for everyone.
There’s also a new drug on the horizon, patritumab deruxtecan, which targets HER3 in EGFR-mutated lung cancer. We’ve seen some very promising data in patients who have progressed on osimertinib, and it also shows good CNS penetration—which is important, since brain metastases are unfortunately common in EGFR-mutant non–small cell lung cancer.
Another treatment strategy I’ve seen used in the clinic, though it’s not yet backed by strong data, is adding chemotherapy on top of osimertinib for patients without brain metastases or with only local, small progression. We’re still waiting for randomized controlled trials to clarify the benefit of this approach, but it’s being used quite frequently.
There’s also growing interest in personalized treatment strategies based on resistance mechanisms. As someone who works in precision genomics for solid tumors—especially lung—I’m particularly interested in this area. We sometimes see resistance mechanisms like ALK [anaplastic lymphoma kinase] fusions, RET fusions, or BRAF mutations emerge. In those cases, there have been anecdotal reports and small case series showing that adding a targeted therapy to osimertinib can be beneficial. Many patients like this approach because it allows them to delay or avoid chemotherapy.
And we do have relatively robust data supporting MEK [mitogen-activated extracellular signal-regulated kinase] inhibitors in patients who develop MEK-related resistance to EGFR therapies. So hopefully, in the near future, we’ll have more clinical trials that can help guide us in using these more tailored, mechanism-driven strategies.
Pharmacy Times: What considerations should pharmacists and providers keep in mind when managing these newer agents in terms of toxicity, monitoring, or patient education?
Tran: Yes, so whenever we target EGFR, there are certain toxicities that are quite characteristic of that pathway—particularly involving the skin and nails. You’ll often see things like rashes, nail bed changes, and weakening of the nails. Sometimes patients even develop painful blisters around the nails, which can be quite uncomfortable.
On the GI [gastrointestinal] side, it’s not so much nausea or vomiting that we see, but diarrhea can be a significant side effect with anti-EGFR therapies. Traditionally, we recommend prophylactic measures to help mitigate these effects. For example, using sunscreen when going outside, wearing protective clothing, applying non-alcohol–based moisturizers regularly—all of those are important.
But one thing I want to emphasize is that toxicities can worsen with combination therapies, especially when we’re doubling down on EGFR targeting, like with amivantamab. That’s when we start to see a real exacerbation of those typical EGFR-related toxicities. Fortunately, there are trials designed specifically to address this. The COCOON trial [NCT06120140], which released updated data just two or three weeks ago, introduced a helpful prophylactic regimen. It includes doxycycline twice daily for the first 12 weeks, a gentle cleansing routine, alcohol-free lotion, and chlorhexidine nail soaks twice daily.
These measures have shown promise in reducing dermatologic toxicity for patients. But of course, it’s a lot to manage. So, it's really important that we counsel patients upfront, give them plenty of resources, and follow them closely—especially during the first few months of therapy, when side effects tend to be more severe. This is where having strong clinic support—pharmacists and nurses—makes a huge difference in helping patients stay on therapy and get through it successfully.
Another issue, particularly with bispecific agents like amivantamab, is the risk of infusion reactions. Right now, we’re still using the IV formulation, and that’s where we see the highest risk. Hopefully, the subcutaneous version, which has a much lower reaction rate, will get approved soon—but we’re not there yet.
In the meantime, we’ve seen from trials that pre-medicating with dexamethasone—8 mg twice a day for the two days prior to infusion, along with 10 mg IV on the day of infusion—can significantly reduce the risk of reactions.
My hope is that these strategies become more widely incorporated into clinical practice, so that our patients don’t have to suffer through these preventable side effects or feel discouraged from continuing therapy.
