Loading ...

Two phase 3 trials offer potential first-line alternatives to platinum-based chemotherapy for patients with advanced non-small cell lung cancer (NSCLC), with each targeting a distinct population and each evaluating a frontline strategy that avoids conventional platinum chemotherapy.

In the multinational WU-KONG28 trial, the oral epidermal growth factor receptor (EGFR) TKI sunvozertinib significantly prolonged progression-free survival and nearly doubled response rates compared with platinum doublet chemotherapy in patients with EGFR exon 20 insertion mutations. In the OptiTROP-Lung05 trial, adding the TROP2-directed antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) to pembrolizumab reduced the risk for disease progression or death by 65% compared with pembrolizumab alone in patients with PD-L1-positive tumors lacking targetable driver mutations. However, overall survival data were immature in both studies.

The trials were presented at the American Society of Clinical Oncology (ASCO) 2026. The WU-KONG28 trial was also published online on May 29 in The New England Journal of Medicine, and the OptiTROP-Lung05 trial was published simultaneously in The Lancet.

During the presentation, John V. Heymach, MD, PhD, chair of the Department of the Thoracic-Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, and senior author of WU-KONG28, said the findings support sunvozertinib as a first-line treatment “with the advantage of a single oral agent administration.”

Caicun Zhou, MD, PhD, Department of Oncology, Shanghai East Hospital, Tongji University, Shanghai, China, and senior author of OptiTROP-Lung05, said that sac-TMT plus pembrolizumab may expand first-line treatment options for patients with PD-L1-positive advanced NSCLC.

Inside WU-KONG28

For patients with EGFR exon 20 insertion-positive NSCLC, first-line treatment has generally relied on platinum-based chemotherapy, with amivantamab plus chemotherapy recently emerging as an evidence-based option. Mobocertinib, the only other TKI to reach a first-line phase 3 trial in this population, was withdrawn from the market after failing to show superiority over chemotherapy.

EGFR exon 20 insertions, which account for about 4%-12% of EGFR-mutant NSCLC, have resisted conventional EGFR TKIs because the mutations create a rigid, narrow drug-binding pocket. Sunvozertinib was designed with a flexible structure that allows it to fit the narrowed binding pocket, achieving up to roughly 10-fold selectivity for exon 20 insertion mutants over wild-type EGFR.

Sunvozertinib already holds accelerated FDA approval for previously treated EGFR exon 20 insertion-positive NSCLC. To evaluate the TKI in the first-line, Heymach and colleagues randomly assigned 324 treatment-naive patients across 15 countries to receive sunvozertinib 300 mg once daily or carboplatin-pemetrexed for up to six cycles followed by pemetrexed maintenance. Patients in the chemotherapy arm could cross over to receive sunvozertinib after disease progression was confirmed.

Median progression-free survival was about 3 months longer in the sunvozertinib arm — 10.3 months vs 7.5 months with chemotherapy (hazard ratio [HR], 0.65; P < .001). The confirmed objective response rate was 58.9% vs 31.1%, and the median duration of response was 11.2 vs 7.1 months.

Despite nearly 90% of chemotherapy-arm patients crossing over to sunvozertinib at progression, second progression-free survival still favored the sunvozertinib arm at 21.7 vs 15.5 months. Overall survival was immature, at 38.9% maturity, confounded by the high crossover rate.

Grade 3 or higher adverse events occurred in 75.5% of patients receiving sunvozertinib vs 56.7% with chemotherapy. The grade 3 or higher adverse events in the sunvozertinib arm were driven largely by asymptomatic creatine kinase elevations (20.9%), which Heymach characterized as laboratory abnormalities rather than clinically meaningful toxicity.

Treatment-related discontinuation was lower with sunvozertinib than chemotherapy (7.4% vs 11.3%), and no treatment-related deaths occurred in the sunvozertinib arm.

Inside OptiTROP-Lung05

Patients with PD-L1-positive NSCLC who lack targetable driver mutations may have a new option to pair with pembrolizumab rather than platinum-based chemotherapy: sac-TMT, a TROP2-directed ADC.

Sac-TMT enters a field where other TROP2-directed ADCs, including datopotamab deruxtecan and sacituzumab govitecan, have shown mixed results in NSCLC. Sac-TMT differs from these agents through its bifunctional linker and membrane-permeable payload, which enable a bystander effect that can kill adjacent tumor cells that may not express TROP2.

The phase 3 OptiTROP-Lung05 open-label trial, conducted at 68 hospitals in China, randomly assigned 413 patients with PD-L1 tumor proportion score (TPS) ≥ 1% to receive sac-TMT 4 mg/kg every 2 weeks plus pembrolizumab 400 mg every 6 weeks, or pembrolizumab alone. All patients had locally advanced or metastatic NSCLC without EGFR or ALK alterations.

At a median follow-up of 10.5 months, median PFS was not reached in the sac-TMT arm vs 5.7 months with pembrolizumab alone (HR, 0.35; P < .0001). Twelve-month PFS rates were 62% vs 29%, and the objective response rate was 70% vs 42%.

Zhou noted that the PFS benefit held across PD-L1 subgroups (TPS, 1%-49%: HR, 0.28; TPS ≥ 50%: HR, 0.47) and in both squamous (HR, 0.44) and nonsquamous (HR, 0.28) histologies.

Zhou said overall survival data were not mature but showed a clear favorable trend toward the combination at 12 months (80% vs 69%; HR, 0.55).

Grade 3 or higher adverse events were more frequent with sac-TMT plus pembrolizumab (55% vs 31%), which Zhou said were mainly driven by the hematologic toxicity of sac-TMT — neutropenia (17%), anemia (9%), and stomatitis (5%).

Alopecia occurred in 66% of combination-treated patients, and ocular surface toxicities, including dry eye and conjunctivitis, were reported in 14%, all grade 1 or 2. The most frequently reported adverse events of special interest were pneumonitis (13% vs 7%), hypothyroidism (13% vs 11%), and hyperthyroidism (7% vs 5%). Treatment-related adverse events leading to death were reported in one patient in the sac-TMT group and three in the control group.

Successes and Caveats

The discussant for WU-KONG28, Daniel Shao-Weng Tan, MBBS, PhD, National Cancer Centre Singapore, said sunvozertinib “now joins amivantamab chemo as an evidence-based frontline option.”

Key differentiators between sunvozertinib monotherapy and the amivantamab-chemotherapy combination, he said, “will likely be the toxicity profiles, route of administration, CNS [central nervous system] activity, and patient and physician preference.”

Tan noted that brain metastases were present at baseline in only 12% of WU-KONG28 patients, but the trial’s ability to assess sunvozertinib’s intracranial activity was limited.

The discussant for OptiTROP-Lung05, Natalie Vokes, MD, of MD Anderson Cancer Center, Houston, called the results potentially “practice-changing” but said “we do need to have global validation.”

Vokes addressed the comparator question: The strong HR in the PD-L1 low subgroup “probably comes from the underperformance here of the pembrolizumab control arm,” she said, but the PD-L1 high subgroup, where “pembrolizumab alone is a reasonable control arm,” also showed significant benefit.

She also raised quality-of-life concerns about adding an ADC to immunotherapy, noting that about 20% of patients do well on immunotherapy alone, and sac-TMT adds alopecia, stomatitis, and cytopenias.

Furthermore, Vokes noted that dose modification and interruption data for sac-TMT were not presented, which she said would be “important to address to better understand the drug exposure.”

WU-KONG28 was funded by Dizal Pharmaceutical. Heymach reported having consulting or advisory relationships with AstraZeneca, Bristol Myers Squibb, Janssen, and others and holding patents related to treatment of EGFR exon 20 mutations. OptiTROP-Lung05 was funded by Sichuan Kelun-Biotech Biopharmaceutical. Zhou reported receiving honoraria from MSD, Lilly, Sanofi, and others. Tan reported having institutional consulting or advisory relationships with AstraZeneca, Roche, Pfizer, and others. Vokes reported having consulting or advisory relationships with AstraZeneca, Lilly, Pfizer, and others and receiving research funding from Bristol Myers Squibb, Sanofi, and others.