With zongertinib (Hernexeos) and sevabertinib (Hyrnuo) now both approved for frontline use in HER2-mutant non–small cell lung cancer (NSCLC), the debate among specialists has shifted from whether to start a targeted therapy up front to how mutation subtype and central nervous system (CNS) involvement should steer the choice among agents.
“You always have to weigh the adverse effect data because with any TKI, you expect your patients to be [receiving it] for longer than shorter periods of time...and the brain is an area where we like to have protection,” Edward S. Kim, MD, MBA, of City of Hope in Duarte, California, said during a recent OncLive® Scientific Interchange and Workshop.
Faculty worked through 2 evolving patient cases to test how mutation subtype and brain metastasis status should guide sequencing among TKIs, antibody-drug conjugates (ADCs), and chemotherapy-based regimens.
Broad next-generation sequencing (NGS) is standard at diagnosis, but workflows vary: most institutions reflex tissue-based NGS, while HER2 immunohistochemistry is typically ordered later, on archival tissue, once fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) is being considered. A case presented at the workshop—a 69-year-old, never-smoking man with a HER2 exon 20 insertion mutation and small, asymptomatic brain metastases—prompted unanimous agreement about the use of frontline zongertinib. The panelists were less confident when the mutation fell outside the kinase domain.
“The data for TKIs are much stronger with the kinase domain mutation. In the frontline setting, I still might elect to use TKIs, but I would be a bit more worried and careful,” said Misako Nagasaka, MD, PhD, of the University of California (UC) Irvine. Julia Rotow, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, was blunter about the alternative, noting that T-DXd’s activity in patients with non-TKD mutations remains thin.
In the phase 1 Beamion LUNG-1 trial (NCT04886804), treatment-naive patients treated with zongertinib achieved a 76% objective response rate (ORR; 95% CI, 65%-84%) and an 11% complete response rate; the median progression-free survival (PFS) was 14.4 months (95% CI, 11.1-not evaluable [NE]), with a median duration of response (DOR) of 15.2 months (95% CI, 9.8-NE).1
Updated data for sevabertinib in the treatment-naive cohort of patients from the phase 1/2 SOHO-01 trial (NCT05099172; n = 73) showed a 75% ORR (95% CI, 64%-85%), with 73% of responders achieving a DOR of at least 6 months, and 38% of responders having a DOR lasting at least 12 months.2 The faculty largely favored zongertinib based on the collective data.
“Zongertinib has a superiority to establish it as a standard of care for the time being, and we wait for the next generations [of TKIs],” said Solange Peters, MD, PhD, of Lausanne University Hospital in Switzerland, citing more mature CNS data and better patient adherence.
Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute, said that current data support starting select patients on a TKI. “It’s good enough to start a patient with a small asymptomatic brain metastases with zongertinib, with serial follow-up. If they have a lesion that’s not responding, that’s the time to call a radiation oncologist.”
In a second case, a 64-year-old woman with a HER2 exon 20 insertion mutation had progressed 12 months after receiving carboplatin plus pemetrexed and pembrolizumab (Keytruda), developing a new asymptomatic brain lesion. The faculty reached a strong consensus favoring zongertinib in the second-line setting, with most also recommending a radiation oncology consult.
In the phase 2 DESTINY-Lung05 trial (NCT05246514), T-DXd produced a 46.7% (95% CI, 28.3%-65.7%) confirmed ORR (cORR) and a median PFS of 8.0 months (95% CI, 5.8-15.3) in patients with baseline CNS metastases (n = 30), vs a 64.3% (95% CI, 48.0%-78.4%) cORR and a median PFS of 13.0 months (95% CI, 7.2-NE) in those without (n = 42), underscoring the reduced but still meaningful CNS activity seen with T-DXd.3
“There are decent data [showing] T-DXd [being associated with] a higher ILD risk for patients who had baseline pulmonary symptoms,” said Deborah B. Doroshow, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York, noting that she favors radiosurgery plus continued TKI therapy in that scenario.
Jonathan W. Riess, MD, MS, of UC Davis Comprehensive Cancer Center in Sacramento, California, agreed, noting that liver function tests remain his institution’s main monitoring focus with zongertinib use.
The faculty noted that they were encouraged by early data with trastuzumab rezetecan (SHR-A1811), an investigational ADC using a more potent topoisomerase-1 payload than other ADCs. This agent generated a high ORR with a numerically lower ILD rate vs T-DXd in the phase 1/2 HORIZON-Lung trial (NCT04818333).4
Still, the panelists explained that resistance mechanisms across TKI and ADC use remain poorly defined, and sequencing 2 ADCs with the same payload was viewed as ineffective.
Peters said the field still lacks dedicated trials establishing CNS efficacy in patients with asymptomatic brain metastases, emphasizing, “we need...dedicated 1-arm trials showing brain efficacy in patients with asymptomatic brain metastases for all of these compounds, including ADCs.”
Amy L. Cummings, MD, PhD, of UCLA in Los Angeles, California, named the most consequential gap directly, stating that the HER2-positive NSCLC field still needs effective neoadjuvant therapy.
Rotow said that the next phase of development should mirror the EGFR-directed therapy paradigm, adding that “there’s space for that development...to optimize the ongoing suppression of the HER2-mutant clone for these patients.”
