Therapies for patients with previously treated lung cancer

The need for second-line therapies for patients with small cell lung cancer and non–small cell lung cancer (NSCLC) that are effective, safe, and well tolerated is driving research that targets different mutations of the disease. Two therapies recently received accelerated approval from the US Food and Drug Administration (FDA): tarlatamab, a bispecific T-cell engager immunotherapy that concomitantly targets delta-like ligand 3 (DLL3) and CD3 on cells, and zongertinib, an oral, irreversible, HER2-selective tyrosine kinase inhibitor.

In May, the FDA granted accelerated approval of tarlatamab-dlle for the treatment of extensive-stage small cell lung cancer in patients who were previously treated with platinum-based chemotherapy.¹ Approval was based on the phase 2 DeLLphi-301 trial, which showed a 40% objective response rate with a median duration of response of 9.7 months in this setting.²

Based on this information, investigators conducted a multinational, phase 3, open-label trial (DeLLphi-304) to assess the efficacy and safety of tarlatamab compared to chemotherapy as a second-line treatment in this setting. Of the 509 patients in the study, 254 were randomized to tarlatamab, and 255 patients were randomized to chemotherapy (topotecan, lurbinectedin, or amrubicin).³ All patients had disease progression during or after at least one line of platinum-containing therapy with or without a programmed death ligand 1 or programmed death 1 inhibitor. The main endpoint was overall survival.

The study confirmed the superiority of tarlatamab over chemotherapy in overall survival. Patients treated with tarlatamab had significantly longer overall survival (13.6 months) than those treated with chemotherapy (8.3 months). The difference represents a 40% reduction in death (hazard ratio, 0.60; 95% CI, 0.47–0.77; p < .001).

At 12 months, progression-free survival (PFS) improved by 20% in patients treated with tarlatamab versus 4% in patients treated with chemotherapy. Patients treated with tarlatamab had meaningful symptom relief in comparison with patients treated with chemotherapy, such as improvement in cough (16% vs. 9%). Patients treated with tarlatamab also had a lower rate of grade 3 or higher adverse events than patients treated with chemotherapy (54% vs. 80%) and a lower incidence of adverse events leading to discontinuation of treatment (5% vs. 12%). The most common adverse events with tarlatamab were cytokine release syndrome, dysgeusia, and pyrexia.

The study authors, led by Giannis Mountzios, MD, a thoracic oncologist and director of the 4th Oncology Department and Clinical Trials Unit at the Henry Dunant Hospital Center in Athens, Greece, called the study “a landmark trial that represents an important advance in the treatment of patients with small cell lung cancer” and said that the results “support the use of tarlatamab for small cell lung cancer that has progressed during or after initial platinum-based chemotherapy.”³

Fatemeh Ardeshir-Larijani, MD, MSc, a thoracic oncologist and assistant professor in the Discovery and Developmental Therapeutics Research Program at the Winship Cancer Institute of Emory University in Atlanta, Georgia, says that the results “establish tarlatamab as a preferred second-line therapy in extensive stage small cell lung cancer.”

She underscores that “post-infusion monitoring is recommended due to the risk of cytokine release syndrome” and says that the study indicates that a safe strategy to do this involves outpatient monitoring instead of inpatient monitoring.

On August 8, zongertinib—an oral, irreversible, HER2-selective tyrosine kinase inhibitor—received accelerated approval from the FDA for adults with HER2-mutant unresectable or metastatic nonsquamous NSCLC after prior systemic therapy.⁴

Approval was based on the results of the first-in-human, open-label, dose-escalation and dose-expansion phase 1a/b trial (Beamion LUNG-1) assessing the efficacy of zongertinib in patients with HER2-altered advanced or metastatic solid cancers (the phase 1a dose-escalation phase) and in patients with HER2-mutant advanced or metastatic NSCLC (the phase 1b dose-expansion phase). Results of the phase 1a dose escalation of the trial previously were reported and showed a low incidence of grade 3 or higher toxic effects in patients treated with zongertinib.⁵

The primary analysis of the trial—the phase 1b dose-expansion part of the study—was first presented at the American Association for Cancer Research annual meeting in 2025 and published in The New England Journal of Medicine.⁶

The study evaluated the safety and efficacy of 120 mg of zongertinib once daily in three cohorts. Cohort 1 included patients with nonsquamous NSCLC with a mutation in the tyrosine kinase domain (TKD) (n = 75) treated with a 120-mg dose of zongertinib. Cohort 3 included patients with non-TKD mutations (n = 20), and cohort 5 included patients with a TKD mutation who received prior HER2-directed antibody–drug conjugate therapy (n = 31). The primary endpoint was an objective response assessed by blinded independent central review (cohorts 1 and 5) or by investigator review (cohort 3), with duration of response and PFS as secondary endpoints.

A confirmed objective response occurred in 71% of the patients in cohort 1 (95% CI, 60–80), in 48% in cohort 5 (95% CI, 32–65), and in 30% in cohort 3 (95% CI, 15–52).

Although zongertinib showed some clinical activity in patients with non-TKD mutations (cohort 3), with an overall response rate of 30%, investigators led by John V. Heymach, MD, PhD, chair of thoracic/head and neck medical oncology at the MD Anderson Cancer Center in Houston, Texas, called this an exploratory cohort that requires further research because of the high heterogeneity of the mutations.

The study also found no major safety concerns, with the most common adverse events including diarrhea in 55.3% of patients overall (1.5% of these cases were grade 3 or higher), rash in 26.5% of patients overall, and elevated aspartate aminotransferase/alanine aminotransferase levels in 22.7% of patients overall (up to 9.1% of these cases were grade 3 or higher).

“This is a novel therapy for TKI [tyrosine kinase inhibitor] oral therapy with better efficacy and tolerability in HER2-mutant NSCLC,” says Dr Ardeshir-Larijani, adding that the most common side effect was gastrointestinal and was well controlled.