Imaging Cadence, Radiation Timing, and Osimertinib Dosing Frame CNS Management Decisions in EGFR-Mutated NSCLC

The achievement of better systemic control in the management of EGFR-mutated non–small cell lung cancer (NSCLC) with brain metastases has moved critical decisions beyond which drug to start and toward when to image, when to radiate, and which member of the lung multidisciplinary team makes each call.

“Patients who have central nervous system [CNS] metastases seem to gain more benefit from the addition of chemotherapy than patients who don’t have CNS metastases, and that’s why [this strategy] may end up being preferred in the end for patients with CNS metastases,” Seema Nagpal, MD, said during a recent OncLive^® Scientific Interchange and Workshop, which she co-chaired.

Nagpal is a neuro-oncologist and a clinical professor and adult neurology clinical professor of neurosurgery at Stanford Cancer Institute in Palo Alto, California.

During the workshop, the faculty discussed 3 cases involving de novo brain metastases, CNS progression after 3.5 years of treatment with osimertinib (Tagrisso), and de novo leptomeningeal disease (LMD).

What are some considerations for frontline EGFR-mutated NSCLC treatment intensification when brain metastases are present?

The opening case involved a 59-year-old nonsmoking patient with an EGFR L858R mutation, a TP53 co-mutation, an ECOG performance status of 2, and multiple symptomatic bilateral metastases. Treatment decisions drew consensus from the panelists and included steroids, prompt radiation oncology referral, and stereotactic radiosurgery to dominant lesions rather than whole-brain radiation therapy. The use of osimertinib anchored these plans, and most experts favored adding platinum/pemetrexed per the phase 3 FLAURA2 trial (NCT04035486) findings, which showed that this strategy extended progression-free survival (PFS) vs osimertinib alone (HR, 0.62; 95% CI, 0.49-0.79; P < .001).¹

“I think of a reason not to escalate,” Laura Alder, MD, the workshop’s other co-chair, said. “When I escalate, it is [with the] FLAURA2 [regimen]. [However], amivantamab is toxic. If [the patient is] frail or if they have a poor ECOG performance status, that’s a reason not to escalate. I think of that more than reasons to escalate, especially with the documented overall survival [OS] benefit [with the FLAURA2 regimen]. That’s powerful.”

Alder is an assistant professor of medicine and a thoracic medical oncologist at Duke Cancer Institute in Durham, North Carolina.

The experts noted that amivantamab (Rybrevant) plus lazertinib (Lazcluze) should be reserved for select higher-risk patients per the phase 3 MARIPOSA trial (NCT04487080) findings. Mohamad Khasawneh, MD, noted that grade 3 or higher adverse effects [AEs] can occur at rates of approximately 60% to 70% with this regimen. He noted that AEs like rash, gastrointestinal toxicity, and anticoagulation make the regimen’s toxicity profile “prohibitive.”

Khasawneh is a hematologist and medical oncologist at Northwest Cancer Centers in Valparaiso, Indiana.

The panelists more sharply disagreed about brain metastasis imaging cadence. Nagpal argued in favor of imaging every 3 to 4 months in stage IV disease; Alder said that she scans asymptomatic patients annually. However, Matthew Gubens, MD, MS, FASCO, explained that many insurance companies often do not cover MRI surveillance at a frequency of every 6 months or even yearly.

Gubens is a professor of medicine and director of Thoracic Medical Oncology at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

Nagpal countered that late brain metastasis detection precludes the use of preoperative stereotactic radiosurgery, which phase 2 data suggest reduces the incidence of post-resection LMD.

What are the second-line, post-osimertinib treatment options for EGFR-mutated NSCLC?

The second case centered on a patient with CNS progression after approximately 3.5 years of osimertinib, with a cerebellar non-target lesion that Nagpal flagged would be considered early LMD until proven otherwise. Most panelists agreed that in this case, they would continue osimertinib and add chemotherapy per the phase 3 COMPEL trial (NCT04765059), in which the median PFS reached 8.4 months (95% CI, 5.7-11.8; n = 49) vs 4.4 months (95% CI, 3.5-5.6) with placebo plus chemotherapy (n = 49; HR, 0.43; 95% CI, 0.27-0.70).²

The panelists’ enthusiasm for newer agents was tempered. In the phase 3 MARIPOSA-2 trial (NCT04988295), amivantamab plus chemotherapy (n = 131) produced a median intracranial PFS of 12.5 months (95% CI, 10.8-not evaluable) vs 8.3 months (95% CI, 7.3-11.3) with chemotherapy alone (n = 263; HR, 0.55; 95% CI, 0.38-0.79).³ In the phase 2 TROPION-Lung05 study (NCT04484142), datopotamab deruxtecan (Dato-DXd; Datroway) yielded a 28% (95% CI, 17%-42%) overall response rate and a 5.4-month (95% CI, 3.1-7.0) median PFS in patients with baseline brain metastases (n = 53).⁴

Nagpal stated that she doesn’t find these data “as compelling” as the HER2-directed data in this setting. Meanwhile, Khasawneh described his preference for counseling patients around the use of the word “targeted” when referring to these therapies, saying, “I always like to give them a reality check that those are still chemotherapy-based treatments delivered in a different method.”

Gubens noted that Dato-DXd and sacituzumab tirumotecan share a payload, which likely means that they should not be used in sequence. Alder added that VEGF-targeted antibodies pseudo-normalize cerebral vasculature, so a T1 post-contrast MRI can look improved whereas T2 burden grows. She explained that ivonescimab (AK112) plus chemotherapy generated an intracranial PFS HR of 0.72 (95% CI, 0.55-0.94; P = .0172) when compared with placebo plus chemotherapy in patients without baseline brain metastases in the phase 3 HARMONi trial (NCT06396065), although this regimen did not confer a significant OS benefit, indicating that PFS benefit does not always equate to OS benefit over time.⁵

How should leptomeningeal disease in EGFR-mutated NSCLC be managed?

The final case involved a 52-year-old woman with de novo LMD, an opening pressure of 370 mm H₂O, and an EGFR L858R mutation. After cerebrospinal fluid drainage, Nagpal stated that she would start osimertinib and add chemotherapy if tolerated. When asked about pulse dosing, she endorsed it over a double dose, saying, “For some reason, the pulse dose seems to be better tolerated than the double dose.”

“The other thing that makes that [strategy] provocatively interesting is that it’s not an insurance fight,” Gubens added.

LMD incidence is rising as systemic disease control improves, Nagpal noted, saying that de novo presentations account for approximately 10% to 15% of cases. She and Gubens also explained that later-breakthrough LMD is more indolent and may respond to intensified osimertinib.

What unmet needs remain for patients with EGFR-mutated NSCLC?

The panelists converged on the importance of validated biomarkers, including MET amplification, TROP2 expression, and circulating tumor DNA kinetics. They also noted that regimen selection is currently informed by treatment toxicity profiles and logistics, although biology should play as large a role as possible. They advocated for payer-endorsed surveillance standards and CNS subgroups stratified by disease volume and lesion treatment status.

The designs of clinical trials investigating therapies for patients with EGFR-mutated NSCLC drew the sharpest criticism.

“These [trials] didn’t include [patients with] LMD, which is a big bummer, especially in the EGFR-mutated setting,” Alder said.

The experts concluded by agreeing that multidisciplinary communication protocols make medical oncologists mandatory stakeholders in neurosurgical decision-making, antibody-drug conjugate sequencing guidance is crucial as the treatment paradigm expands, and broadening intrathecal therapy access remains a priority in the field.

References

1. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
2. Peled N, Tufman A, Sequist LV, et al. COMPEL: osimertinib plus platinum-based chemotherapy in patients with EGFR-mutated advanced NSCLC and progression on first-line osimertinib. ESMO Open. Published online October 10, 2025. doi:10.1016/j.esmoop.2025.105807
3. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90. doi:10.1016/j.annonc.2023.10.117
4. Lisberg A, Ahn M-J, Kitazono S, et al. Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously treated advanced/metastatic non-small cell lung cancer (a/m NSCLC) with actionable genomic alterations (AGA): results from TROPION-Lung05. J Clin Oncol. 2024;42(suppl 16):8593. doi:10.1200/JCO.2024.42.16_suppl.8593
5. Le X, Passaro A, Laskin J, et al. 15P Intracranial (IC) efficacy of ivonescimab (ivo) plus chemotherapy (chemo) in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutated non-small cell lung cancer (NSCLC) in the HARMONi study. ESMO Open. 2026;11(suppl 3):106322. doi:10.1016/j.esmoop.2026.106322