Oncology PulsePoint: ASCO Updates Targeted Therapy for Stage IV NSCLC

The American Society of Clinical Oncology (ASCO) Living Guideline, version 2026.3.0, expands targeted treatment options for patients with stage IV non–small cell lung cancer (NSCLC) harboring EGFR, HER2, ROS1, NRG1, and other driver alterations. Andrew Li, PharmD, BCOP, oncology pharmacist at Providence Regional Cancer Partnership in Everett, Washington, highlights major changes for patients with classical EGFR mutations, including combination regimens that improve survival but carry greater toxicity and treatment burden. He also examines barriers to real-world implementation, including oral therapy access, financial approval, infusion requirements, and uncertainty about treating older or medically frail patients.

Pharmacy Times: What are the most significant changes in the Therapy for Stage IV Non–Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, 2026.3.0, and how might they impact clinical practice

Andrew Li, PharmD, BCOP: This guideline is particularly interesting because it highlights several new treatments for different mutations, along with impactful changes involving classical EGFR mutations, which are among the most common alterations in non–small cell lung cancer (NSCLC).

I will begin with several updates involving less common alterations. For EGFR exon 20 insertion mutations, sunvozertinib emerged as an option following disease progression on platinum-based chemotherapy based on findings from the WU-KONG1 trial. For patients with acquired MET amplification during treatment with an EGFR tyrosine kinase inhibitor (TKI), findings from the SAVANNAH, INSIGHT 2, and SACHI trials showed that tepotinib or savolitinib may be added to osimertinib.

For HER2 exon 20 insertion mutations, zongertinib, evaluated in the Beamion LUNG-1 trial, and sevabertinib, evaluated in the SOHO-01 trial, emerged as additional options alongside trastuzumab deruxtecan. For ROS1 alterations, repotrectinib and taletrectinib gained support as first-line and subsequent-line treatment options based on findings from the TRIDENT-1 and TRUST-I and TRUST-II trials, respectively. For NRG1 fusion–positive disease, zenocutuzumab, an IgG bispecific antibody targeting HER2 and HER3, demonstrated activity in the eNRGy trial.

The guideline also includes significant changes for classical EGFR mutations, including exon 19 deletions and exon 21 L858R substitutions. These alterations account for approximately 30% to 40% of targetable mutations among patients with NSCLC. Therefore, recommendations in this setting may have a substantial effect on clinical practice.

In the first-line setting, findings from the FLAURA2 trial demonstrated an overall survival benefit with osimertinib plus platinum-based chemotherapy compared with osimertinib alone. Similarly, the MARIPOSA trial demonstrated an overall survival benefit with amivantamab plus lazertinib compared with osimertinib alone. However, the guideline notes that these combinations are associated with greater toxicity and treatment burden, including longer infusion times. Osimertinib monotherapy remains an appropriate option for patients with poor performance status or those who may be unable to tolerate more intensive combination regimens.

Following disease progression on osimertinib, the MARIPOSA-2 trial demonstrated that amivantamab plus chemotherapy improved progression-free survival compared with chemotherapy alone. Findings from the COMPEL trial also supported adding chemotherapy to osimertinib after disease progression rather than switching to chemotherapy alone. This approach may represent a less intensive option for certain patients.

Finally, findings from the TROPION-Lung01 trial supported datopotamab deruxtecan, a TROP2-directed antibody-drug conjugate, as an option for patients whose disease progresses following treatment with osimertinib and chemotherapy.

Pharmacy Times: From a pharmacy perspective, what unique considerations should clinicians be aware of when implementing this update (i.e., operational and access challenges, rare/delayed toxicity management, step-up dosing, and patient populations where this is especially relevant or potentially controversial)?

Li: The introduction of these agents has created several challenges and barriers. First, many of the treatments I mentioned are oral anticancer agents, which are often difficult to access because of cost and insurance authorization requirements. Coordinating the timely delivery of oral medications with intravenous (IV) therapy can also be challenging, particularly when the treatments must be initiated concurrently.

Additionally, patients receiving oral therapy alone may have fewer opportunities for follow-up compared with those who regularly visit the clinic for IV treatment. These challenges are not unique to the treatments discussed here; they apply broadly to patients receiving oral anticancer therapies.

Another significant concern is the adverse events associated with these agents and combinations, particularly regimens containing amivantamab. These combinations are associated with high rates of certain adverse events. In the MARIPOSA trial, all-grade infusion-related reactions occurred in 65% of patients receiving amivantamab plus lazertinib, with severe reactions reported in 6%. All-grade venous thromboembolism occurred in 40% of patients, with severe events reported in 11%.

In the MARIPOSA-2 trial, which evaluated amivantamab plus platinum-based chemotherapy, all-grade rash occurred in 72% of patients, with grade 3 or higher rash reported in 11%. Similarly, infusion-related reactions occurred in 59% of patients, with severe reactions reported in 5.4%. These adverse-event rates raise important questions about which patients can tolerate these combinations. One concern is that these phase 3 trials excluded patients with poor performance status. In clinical practice, many patients with cancer are older, frail, or have multiple comorbidities, creating uncertainty about the most appropriate treatment for these populations.

For patients receiving osimertinib, clinicians may hesitate to switch to combination therapy because osimertinib is generally well tolerated. Although the trials demonstrated improved survival with combination regimens, that benefit must be weighed against the increased toxicity and treatment burden. Determining which patients can tolerate these adverse events while still benefiting from intensified therapy remains a significant clinical challenge.

Pharmacy Times: How do these updates align or conflict with what you’re currently seeing in real-world practice?

Li: I have not yet seen widespread use of these combinations and newer agents in clinical practice. Even when therapies are well supported by guidelines, their adoption tends to fluctuate. Some clinicians quickly incorporate guideline-supported regimens into practice, whereas others proceed with greater caution. Currently, there appears to be more hesitation, likely because of a disconnect between understanding a regimen’s efficacy and knowing how to manage its adverse events effectively.

The introduction of ipilimumab offers a useful comparison. When ipilimumab, one of the first immune checkpoint inhibitors, became available around 2014, it improved survival but also caused potentially severe immune-related adverse events. Clinicians initially had limited experience managing these toxicities, creating uncertainty despite the treatment’s demonstrated clinical benefits. Some clinicians temporarily moved away from using ipilimumab because of this lack of understanding.

Over time, new protocols were developed, and clinicians gained a more refined understanding of how to prevent and manage immune-related adverse events. As confidence in toxicity management increased, ipilimumab was gradually incorporated more broadly into the treatment toolkit.

We may be experiencing a similar phase with newer combination regimens, particularly those containing amivantamab. Although these combinations have demonstrated survival benefits, clinicians are still learning how to manage their adverse events effectively. Bridging this knowledge gap may help clinical practice become more closely aligned with guideline recommendations. Importantly, the guidelines acknowledge the adverse-event burden associated with these regimens and emphasize that toxicity should be considered when evaluating treatment options.

Pharmacy Times: What is your key takeaway for pharmacists?

Li: As I mentioned, the current challenge is bridging the gap between understanding these regimens’ efficacy and managing their adverse events. Pharmacists can play a key role in closing that gap by reducing the impact of adverse events and increasing clinicians’ confidence in using these treatments.

For example, prophylactic anticoagulation is recommended during the first 4 months of treatment with amivantamab plus lazertinib. Datopotamab deruxtecan, the TROP2-directed antibody-drug conjugate discussed previously, can frequently cause oral mucositis, stomatitis, and unique ocular surface toxicities. Several prophylactic strategies are available to help prevent these adverse events. Pharmacists can ensure that patients use steroid-containing mouthwash correctly and coordinate appropriate examinations with optometrists or ophthalmologists to monitor for ocular toxicities.

The COCOON trial demonstrated that a prophylactic dermatologic management strategy reduced the incidence of dermatologic adverse events associated with amivantamab by 44%. The SKIPPirr trial evaluated different corticosteroid schedules and found that administering oral dexamethasone twice daily for 2 days before treatment and again on the morning of treatment reduced infusion-related reactions by 66%.

These findings provide valuable clinical insights that pharmacists can share with the care team. Applying these supportive care strategies can help patients tolerate and remain on optimal therapy. Therefore, pharmacists’ knowledge can improve not only treatment tolerability but also clinical outcomes and potentially survival.