Sacituzumab tirumotecan, a novel TROP2 antibody-drug conjugate, was found to significantly improve both progression-free and overall survival compared with platinum-based chemotherapy in patients with EGFR-mutated non–small cell lung cancer (NSCLC) who had experienced disease progression following EGFR tyrosine kinase inhibitor therapy. Data presented during the European Society for Medical Oncology (ESMO) Congress 2025 and simultaneously published in TheNew England Journal of Medicine position sacituzumab tirumotecan as a potential new standard of care for this challenging patient population.^1,2

According to presenting author Li Zhang, MD, of Sun Yat-sen University Cancer Center, Guangzhou, China, the randomized, multicenter, phase III OptiTROP-Lung04 study demonstrated a highly statistically significant and clinically meaningful improvement across key efficacy endpoints. The median progression-free survival with sacituzumab tirumotecan was 8.3 months compared with 4.3 months with chemotherapy, and the median overall survival with sacituzumab tirumotecan was not yet reached vs 17.4 months with chemotherapy. The safety profile was manageable, with no unexpected signals and notably no reported cases of interstitial lung disease or pneumonitis.

Sacituzumab tirumotecan is positioned as a promising treatment option and a potential new standard of care for this population [EGFR tyrosine kinase inhibitor–resistant NSCLC].

— LI ZHANG, MD

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As Dr. Zhang explained, third-generation EGFR tyrosine kinase inhibitors represent the standard first-line therapy for patients with EGFR-mutated NSCLC, but the inevitable development of resistance limits subsequent treatment options. In this context, he noted that platinum-based doublet chemotherapy has been the standard of care but offers only modest efficacy, with reported progression-free survival typically ranging from 4.3 to 4.8 months.

While recent therapeutic advancements have explored various multiagent regimens, said Dr. Zhang, not one has consistently achieved statistically significant overall survival benefits. The transmembrane glycoprotein TROP2 is highly expressed in EGFR-mutated NSCLC, particularly in cases with acquired EGFR tyrosine kinase inhibitor resistance. Preclinical studies have shown that EGFR mutations enhance sacituzumab tirumotecan internalization and uptake, with tyrosine kinase inhibitor–resistant cells exhibiting even higher uptake than tyrosine kinase inhibitor–naive cells, providing rationale for its investigation.

Study Methods

Eligible patients had advanced nonsquamous EGFR-mutated NSCLC, good performance status (defined as Eastern Cooperative Oncology Group [ECOG] performance status score 0–1), and had experienced disease progression after third-generation (or first- or second-generation with negative T790M status) EGFR tyrosine kinase inhibitor therapy.

Patients were stratified by prior EGFR tyrosine kinase inhibitor therapy and the presence of brain metastases. They were then randomized 1:1 to receive either sacituzumab tirumotecan monotherapy (5 mg/kg intravenously every 2 weeks) or platinum-based chemotherapy (pemetrexed 500 mg/m² plus carboplatin [AUC 5] or cisplatin 75 mg/m² every 3 weeks for four cycles, followed by pemetrexed maintenance). Treatment in both arms continued until disease progression or unacceptable toxicity.

The primary endpoint was progression-free survival assessed by blinded independent review committee, with overall survival as a key secondary endpoint tested hierarchically. Other secondary endpoints included investigator-assessed progression-free survival, objective response rate, disease control rate, duration of response, and safety.

A total of 376 patients (median age = 59.5 years; male: 39.6%; 79.3% with an ECOG performance status score of 1; 94.7% with prior third-generation EGFR tyrosine kinase inhibitor therapy) were randomized, with 188 in each arm. At the data cutoff of July 6, 2025, and a median follow-up of 18.9 months, 21.3% of the sacituzumab tirumotecan arm vs 1.6% of the chemotherapy arm remained on treatment.

Significant Improvements Across Key Efficacy Endpoints

As Dr. Zhang reported, sacituzumab tirumotecan demonstrated highly statistically significant and clinically meaningful improvements across all key efficacy endpoints.

Progression-free survival: Assessed by blinded independent review committee, the median progression-free survival was 8.3 months with sacituzumab tirumotecan vs 4.3 months with chemotherapy (hazard ratio [HR] = 0.49; P < .0001). The 1-year progression-free survival rate was 32% with sacituzumab tirumotecan vs 7.9% with chemotherapy. Investigator-assessed progression-free survival showed a similar benefit for sacituzumab tirumotecan, with a median of 9.4 vs 4.8 months, respectively (HR = 0.51; P < .0001).

Overall survival: At interim analysis, the median overall survival was not reached in the sacituzumab tirumotecan arm compared with 17.4 months in the chemotherapy arm (HR = 0.60; P = .001). This indicates a 40% reduced risk of death with sacituzumab tirumotecan. The 18-month overall survival rate was 65% with sacituzumab tirumotecan vs 48% with chemotherapy.

Objective response rate: The blinded independent review committee–assessed objective response rate was 60% with sacituzumab tirumotecan vs 43% with chemotherapy, representing a 17% absolute difference.

Duration of response: The median duration of response was 8.3 months with sacituzumab tirumotecan vs 4.2 months with chemotherapy.

According to Dr. Zhang, the progression-free survival and overall survival benefits of sacituzumab tirumotecan were consistently observed across all predefined subgroups. Regarding subsequent anticancer treatment, 72% of the sacituzumab tirumotecan arm and 85% of the chemotherapy arm received subsequent therapy.

“Importantly, when censoring patients at the date of initiation of subsequent antibody-drug conjugate treatment in the control arm, sacituzumab tirumotecan still significantly improved overall survival (HR = 0.56), demonstrating the robustness of the overall survival benefit,” commented Dr. Zhang.

The safety profile of sacituzumab tirumotecan was manageable, said Dr. Zhang, with the median duration of treatment being longer for sacituzumab tirumotecan (9.6 months) than for chemotherapy (4.9 months).

The incidence of any-grade treatment-related adverse events seemed to be similar between the arms, with 49.5% of patients treated with sacituzumab tirumotecan and 52.2% of those who received chemotherapy experiencing grade 3 or higher treatment-related adverse events. Serious treatment-related adverse events were reported less frequently with sacituzumab tirumotecan (7.4% vs 17.0%). No treatment-related adverse events led to treatment discontinuation or death in the sacituzumab tirumotecan arm. The most common treatment-related adverse events in both arms were hematologic toxicities.

Sacituzumab tirumotecan was found to be associated with higher incidences of stomatitis (64%) and ocular surface toxicity (9.6%), but these were mostly grade 1 or 2 and manageable. Of note, no cases of interstitial lung disease or pneumonitis were reported in either arm.

“Sacituzumab tirumotecan is the first TROP2 antibody-drug conjugate to significantly improve progression-free survival and overall survival over platinum-based chemotherapy, with manageable safety in EGFR tyrosine kinase inhibitor–resistant NSCLC,” Dr. Zhang concluded. “Sacituzumab tirumotecan is positioned as a promising treatment option and a potential new standard of care for this population.”

Further global phase III studies of sacituzumab tirumotecan alone and in combination with the third-generation EGFR tyrosine kinase inhibitor osimertinib are ongoing.

DISCLOSURE: Dr. Zhang reported financial interests with Akesobio, Sichuan Biokin Pharmaceutical, China Shiyao Pharma, Jiangsu Hengrui, Kelun Pharmaceutical, Novartis, Pierre-Fabre, Pfizer, Qilu Pharmaceutical, AstraZeneca, and Roche.

REFERENCES

1. Zhang L, Fang W, Wu L, et al: Sacituzumab tirumotecan vs platinum-based chemotherapy in EGFR-mutated non-small cell lung cancer following progression on EGFR-TKIs: Results from the randomized, multi-center phase 3 OptiTROP-Lung04 study. ESMO Congress 2025. Abstract LBA5. Presented October 19, 2025.

2. Fang W, Wu L, Meng X, et al: Sacituzumab tirumotecan in EGFR-TKI-resistant, EGFR-mutated advanced NSCLC. N Engl J Med. October 19, 2025 (early release online).

EXPERT POINT OF VIEW

Invited discussant Antonio Passaro, MD, PhD, from the Division of Thoracic Oncology at the European Institute of Oncology in Milan, Italy, discussed the OptiTROP-Lung04 study, highlighting its strong data as potentially “breaking the glass ceiling of EGFR tyrosine kinase inhibitors.”

Dr. Passaro acknowledged the challenge of resistance that occurs in nearly all patients with EGFR-mutated non–small cell lung cancer (NSCLC) after tyrosine kinase inhibitor therapy. He emphasized that while biomarker-driven strategies exist, their application is limited by tissue biopsy constraints and the observation that most disease progressions occur in the absence of clear actionable alterations. He underscored the scientific rationale for targeting TROP2 in EGFR-mutated NSCLC, noting its high and homogeneous expression that persists and is amplified after tyrosine kinase inhibitor resistance, as well as evidence of a positive feedback loop whereby TROP2 inhibition can further increase its expression.

Antonio Passaro, MD, PhD

Dr. Passaro praised the “clearly positive” results of OptiTROP-Lung04, which showed a significant improvement in progression-free survival (hazard ratio [HR] = 0.49) and an overall response rate of 60%. In addition, he highlighted the overall survival benefit—despite the median not yet being reached in the investigational arm—as a high point for an antibody-drug conjugate.

However, Dr. Passaro also stressed the need for better understanding and management of brain metastases, a common site of disease progression in EGFR-mutated NSCLC, affecting around 67% of patients in natural history. Although sacituzumab tirumotecan showed brain activity (HR 0.73), he suggested the trial design might have underestimated this. He advocated for future trials to routinely include patients with untreated brain metastases, differentiating between the blood-brain barrier and blood-tumor barrier, to improve understanding of new drugs’ efficacy in this area.

Regarding safety, Dr. Passaro found the overall safety analysis “very interesting and reassuring,” particularly given the longer exposure time (sacituzumab tirumotecan vs chemotherapy: 9.6 vs 4.9 months) and very low discontinuation rates. However, he emphasized that “mucositis from antibody-drug conjugates is not mucositis from chemotherapy,” stressing the need for improved understanding, close monitoring, and prophylactic measures.

Dr. Passaro concluded that sacituzumab tirumotecan is poised to be considered a new standard of care in this field because of its strong and consistent data, as well as its favorable safety profile. However, he raised a crucial point regarding its development trajectory: “With this level of evidence in the context of a Chinese trial, is a confirmation within a global study truly required for U.S. Food and Drug Administration [FDA] and/or European Medicines Agency [EMA] approval?”

DISCLOSURE: Dr. Passaro reported financial relationships with ArriVent BioPharma, AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Janssen, Johnson & Johnson, Gilead, GSK, Merck Sharp and Dohme, Novartis, Pfizer, Roche/Genentech, Mundipharma, Summit Therapeutics, Amgen, Cullinan Therapeutics (formerly Cullinan Oncology), Merck Serono, Mirati Therapeutics, RMC, Taiho Oncology, AiCME, ecancer, Medscape, Takeda, PeerVoice, PeerView, OncLive, and touchONCOLOGY.