The unmet needs of the non-small cell lung cancer (NSCLC) population after EGFR TKI resistance created the usual anticipation at last month's World Conference on Lung Cancer. Although multiple drugs presented highly promising clinical data, by the end of the conference no therapy had emerged that could achieve dual benefits in both progression free survival (PFS) and the more stringent overall survival (OS) compared to standard chemotherapy [1].
Yet, within a month, a new turning point arrived.
On October 11, China-based Kelun-Biotech's TROP2 antibody-drug conjugate (ADC) drug sacituzumab tirumotecan secured a third indication approval — monotherapy for EGFR-mutated non squamous NSCLC patients who progressed after EGFR TKI treatment — becoming the world's first TROP2 ADC to cover second-line and above lung cancer treatment, providing a new treatment option beyond chemotherapy for the EGFR TKI-resistant population.
The approval was based in the Phase III OptiTROP Lung04 study, which met the primary endpoint of significantly prolonged PFS. More importantly, the drug also achieved significant benefit in the OS metric. This breakthrough not only represents a major advancement for Chinese innovative drugs in the lung cancer field, but also serves as another powerful testament to the transition of the country's pharmaceutical industry from follower to leader.

Advancing from the Back to the Second Line
The journey of sacituzumab tirumotecan in lung cancer began with its outstanding performance in third-line treatment. Key Phase II study (OptiTROP Lung03) results showed that, compared to single-agent chemotherapy, the drug could extend PFS by four months and increase objective response rate (ORR) by nearly three times in third-line EGFR-mutated NSCLC patients [2]. It is worth mentioning that compared to the docetaxel arm, the sacituzumab tirumotecan group showed statistically significant improvement in OS (median OS not reached in both), with a 19% increase in 12-month OS rate and a 51% reduction in risk of death. With these results, sacituzumab tirumotecan received approval from the China's National Medical Products Administration (NMPA) in March this year for third-line treatment of EGFR-mutated NSCLC, becoming the world's first TROP2 ADC approved in the lung cancer space and taking a step towards revolutionising the field.
With this second-line indication approval, sacituzumab tirumotecan has once again achieved a global first milestone. The supporting Phase III OptiTROP Lung04 study showed that the monotherapy achieved statistically significant and clinically meaningful improvements in both key efficacy endpoints of PFS and OS compared to current standard chemotherapy. This positive result makes Kelun's ADC the first to achieve dual benefits in PFS and OS for second-line EGFR-mutated NSCLC.
Prior to this, many drugs had attempted breakthroughs in Phase III studies. PD-1 /L1monoclonal antibodies (mAbs) were the earliest explorers, including pembrolizumab [3], nivolumab [4], atezolizumab [5,6] and sintilimab [7] with disclosed Phase III results, but none achieved dual benefits in PFS and OS.
Even among ADC drugs focusing on the same indication, datopotamab deruxtecan, which also targets TROP2, is still awaiting final validation from Phase III studies, while HER3-targeting patritumab deruxtecan had its marketing application withdrawn after failing to achieve statistical significance in OS. Latecomer sacituzumab tirumotecan was the first to break the deadlock and achieve impressive PFS and OS data.
Although ivonescimab, sintilimab and amivantamab have been approved in China for second-line treatment of EGFR-mutated NSCLC, they mostly show only PFS improvement [8,9] with unclear OS benefits. Additionally, they mostly adopt combination regimens, while sacituzumab tirumotecan demonstrates significant efficacy as monotherapy.

Expanding the Disease Landscape
The rapid advancement in lung cancer treatments has not only solidified the position of sacituzumab tirumotecan as the world's first TROP2 ADC game changer in the field, but also clarified the direction for subsequent development pathways. With the gradual release of its best-in-class (BIC) potential, Kelun's product is pointing to a broader disease landscape.
Sacituzumab tirumotecan's clinical studies cover highly prevalent or refractory cancers such as breast cancer, lung cancer, gastric cancer, endometrial cancer, cervical cancer, ovarian cancer and urothelial carcinoma. This is driven not only by high TROP2 target expression in various epithelial-derived tumours, but also represents Kelun's effort to maximise value based on the therapeutic potential of sacituzumab tirumotecan.
From an indications perspective, sacituzumab tirumotecan is leading the charge against the two most clinically urgent cancers — lung cancer and breast cancer — establishing quite a comprehensive clinical development pathway.
Analysis of its lung cancer indications reveals a clear clinical development strategy for this drug — diverse coverage from later-line to front-line, from monotherapy to combination therapy.
The successive breakthroughs in second- and third-line NSCLC indications have opened an opportunity for sacituzumab tirumotecan to further explore the lung cancer field. As for the more critical first-line setting, the ADC is leveraging even greater possibilities.
Currently, Kelun has initiated multiple Phase III trials of sacituzumab tirumotecan combined with different drugs for first-line treatment of various types of NSCLC, including combination with immuno-oncology (IO) in the form of sacituzumab tirumotecan + pembrolizumab for PD-L1-positive (TPS ≥1%) NSCLC in the OptiTROP Lung05 study, and for PD-L1-negative (TPS <1%) NSCLC in the OptiTROP Lung06 study.
Previous data has suggested the synergistic effect of sacituzumab tirumotecan combined with IO — the Phase II OptiTROP Lung01 study indicated [10] that sacituzumab tirumotecan (5 mg/kg Q2W) combined with the PD-L1 mAb tagitanlimab for first-line NSCLC treatment achieved an ORR as high as 77.6%, with good efficacy across different PD-L1 expression levels and patient subtypes.
Beyond the popular ADC+IO strategy, sacituzumab tirumotecan is also being explored in different combination approaches. Its pairing with osimertinib to advance first-line treatment for EGFR-mutated NSCLC might prove combination with targeted small molecules to be a powerful alternative. This Phase III study boldly includes a head-to-head comparison with osimertinib, showing how this Chinese innovative drug is entering the global arena to challeng mainstream therapies.

Global Journey Gains Momentum
International competition has become a key issue that Chinese innovative drugs must face directly. Sacituzumab tirumotecan gained the favour of international giant MSD several years ago.
In May 2022, MSD obtained exclusive rights to the drug outside Greater China. After the transaction, MSD fully explored the candidate's application potential, advancing 14 global multi-centre Phase III studies, signalling the ADC had become a clinical development priority for the Big Pharma company. As data emerge in the coming years, sacituzumab tirumotecan will advance towards becoming the next blockbuster oncology drug.
The strategy for sacituzumab tirumotecan's global competition becomes evident from MSD's plans for lung cancer.
First, disrupting the global EGFR mutation-resistance treatment following the development logic already validated by sacituzumab tirumotecan in China.
Second, using early clinical data to identify the population that can benefit most, such as PD-L1-high expression (TPS ≥50%) NSCLC patients, to expand global influence;
Third, exploring the boundaries of treatment by delving into different stages of disease to elevate lung cancer treatment standards.
Currently, the ADC+IO paradigm is reshaping the oncology treatment landscape, which is also seen by MSD as an opportunity for differentiation. Previously, sacituzumab tirumotecan displayed its monotherapy strength to disrupt later-line lung cancer treatment.
Now MSD is building on this success and expanding its combination strategy to earlier treatment scenarios such as adjuvant and neoadjuvant treatments, such as the TroFuse 019 study of sacituzumab tirumotecan + pembrolizumab as adjuvant treatment for NSCLC patients who did not achieve pathological complete response after surgery. If this combination can be the first to demonstrate clinical benefits, it is expected to revolutionise the standard treatment model for NSCLC adjuvant therapy and take a major step towards covering the entire lung cancer treatment cycle.
From breaking through in later-lines to advancing in first-line and exploring adjuvant pathways, this journey reveals Kelun's ambition to conquer the global lung cancer field. This global approach will also be replicated in other disease areas, the current breakthroughs marking only the beginning.

Conclusion
As more Chinese innovative drugs directly compete with global pharmaceutical companies in main battlefields such as lung cancer and breast cancer, Chinese developers will increasingly become a key force in reshaping the global anti-tumour drug landscape, completing their transformation from followers to leaders, the trajectory of Kelun's sacituzumab tirumotecan serving as an important witness to this transition.