Abstract
Objective
To compare the efficacy and safety of sacituzumab tirumotecan (sac-TMT) with docetaxel in patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after previous treatment failure with EGFR-tyrosine kinase inhibitors and platinum based chemotherapy.
Design
Multicentre, open label, randomised controlled trial.
Setting
48 centres in China, 1 September 2023 to 31 December 2024.
Participants
137 adults (aged 18-75 years) with EGFR-mutated advanced or metastatic NSCLC after previous treatment failure with EGFR-tyrosine kinase inhibitors and platinum based chemotherapy.
Intervention
Patients were randomly assigned (2:1) to receive sac-TMT (5 mg/kg) on days 1 and 15 of each four week cycle, or docetaxel (75 mg/m2) on day 1 of each three week cycle. Patients in the docetaxel group were permitted to crossover to sac-TMT treatment on disease progression.
Main outcome measures
The primary endpoint was objective response rate as assessed by a blinded independent review committee (BIRC). The secondary endpoints included objective response rate assessed by the investigator; disease control rate, progression-free survival, time to response, and duration of response assessed by BIRC and the investigator; overall survival; and safety.
Results
137 patients were randomised to receive sac-TMT (n=91) or docetaxel (n=46). Median follow-up was 12.2 months at the data cut-off for efficacy (31 December 2024). BIRC assessed objective response rate was significantly higher in the sac-TMT group (45% (41/91)) v docetaxel (16% (7/45)), with a difference of 29% (95% confidence interval (CI) 15% to 43%; one sided P<0.001). Median progression-free survival was longer with sac-TMT than with docetaxel assessed by BIRC (6.9 v 2.8 months; hazard ratio 0.30, 95% CI 0.20 to 0.46; one sided P<0.001) and the investigator (7.9 v 2.8 months; hazard ratio 0.23, 0.15 to 0.36; one sided P<0.001). The 12 month overall survival rate was 73% with sac-TMT and 54% with docetaxel (hazard ratio 0.49, 0.27 to 0.88; one sided P=0.007). After adjustment for crossover using the rank-preserving structural failure time model, sac-TMT also showed improved overall survival (hazard ratio 0.36, 0.20 to 0.66). Grade ≥3 treatment related adverse events were less frequent with sac-TMT than with docetaxel (56% v 72%), with no new safety signals identified.
Conclusions
Sac-TMT showed statistically significant and clinically meaningful improvements in objective response rate, progression-free survival, and overall survival compared with docetaxel, with a manageable safety profile in patients with EGFR-mutated locally advanced or metastatic NSCLC.
Trial registration
ClinicalTrials.gov NCT05631262.
Introduction
Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, accounting for about 85% of all patients.1 Epidermal growth factor receptor (EGFR) mutations are present in 10-15% of patients with NSCLC in non-Asian populations and 50% in Asian populations.2 EGFR tyrosine kinase inhibitors are the standard first line treatment for advanced EGFR-mutated NSCLC,3 but resistance inevitably develops.4 When resistance occurs and no additional targetable mutations are identified, platinum based chemotherapy is typically used since no novel targeted drugs or combination regimens have been approved.3 For those whose disease progresses despite both treatments, the latest guidelines recommend single agent chemotherapy, with docetaxel the most widely used agent. However, the efficacy of docetaxel in this patient population remains suboptimal, and concerns about its toxicities persist.5 6 7 These factors underscore an important unmet clinical need for more effective treatment options.
Trophoblast cell surface antigen 2 is a transmembrane glycoprotein that plays an important role in cellular processes such as adhesion and proliferation in cancers.8 In EGFR-mutated NSCLC, expression of trophoblast cell surface antigen 2 is notably high and may be associated with resistance to EGFR tyrosine kinase inhibitors.9 Two trophoblast cell surface antigen 2 directed antibody-drug conjugates, sacituzumab govitecan and datopotamab deruxtecan, have both shown promising clinical activity in advanced NSCLC in phase 1 and phase 2 trials.10 11 However, randomised phase 3 trials of sacituzumab govitecan and datopotamab deruxtecan in biomarker unselected patients with previously treated, advanced NSCLC (regardless of actionable genomic alterations) did not reach statistical significance for overall survival improvement.12 13 To date, the US Food and Drug Administration has not approved any trophoblast cell surface antigen 2 directed antibody-drug conjugate for NSCLC.
Sacituzumab tirumotecan (sac-TMT, also known as MK-2870/SKB264) is a novel antibody-drug conjugate targeting trophoblast cell surface antigen 2, designed using a proprietary Kthiol (pyrimidine-thiol) linker to conjugate the topoisomerase I inhibitor KL610023, with an average drug to antibody ratio of 7.4.14 Sac-TMT specifically recognises trophoblast cell surface antigen 2 on the tumour cell surface.14 Once internalised by the tumour cell, the payload (cytotoxic component of antibody-drug conjugate) is released intracellularly, inducing DNA damage and leading to cell cycle arrest and apoptosis. The membrane permeability of the payload KL610023 also promotes cytotoxic bystander activity.14 This antibody-drug conjugate has shown promising clinical efficacy and safety across several malignancies expressing trophoblast cell surface antigen 2, such as metastatic triple negative breast cancer and gastro-oesophageal adenocarcinoma.15 16 17 In NSCLC, mechanistic exploration in a recent study has shown that the presence of EGFR mutations substantially increases the internalisation and lysosomal uptake of sac-TMT.18 Notably, EGFR-mutated NSCLC cell lines resistant to tyrosine kinase inhibitors showed an even higher uptake rate of sac-TMT than cells naive to tyrosine kinase inhibitors.18 The phase 1 and 2 single arm clinical trials also showed that sac-TMT monotherapy provided clinically meaningful benefit for patients with EGFR-mutated NSCLC that was refractory to treatment with tyrosine kinase inhibitors.18 It is imperative that higher level evidence from randomised controlled trials be obtained in this molecularly targeted population. Given these encouraging findings, the OptiTROP-Lung03 trial (NCT05631262) was designed in two parts: the first comprised an exploratory study of sac-TMT in multiple NSCLC cohorts and one nasopharyngeal cancer cohort,18 19 and the second comprised a randomised trial to compare sac-TMT with docetaxel for EGFR-mutated locally advanced or metastatic NSCLC with disease progression after previous treatment with EGFR-tyrosine kinase inhibitors and platinum based chemotherapy. This paper reports findings from the randomised controlled trial.
Methods
Trial design and participants
Part II of the OptiTROP-Lung03 trial is a phase 2, open label, randomised controlled trial conducted across 48 centres in China. Eligible patients were randomly assigned to receive sac-TMT monotherapy or docetaxel in a 2:1 ratio, with the allocation allowing more patients access to sac-TMT, given its promising antitumour activity data reported in previous studies.18 20
Eligible patients were aged 18 to 75 years and had histologically or cytologically confirmed non-squamous NSCLC. Patients had either locally advanced (stage IIIB or IIIC) or metastatic (stage IV) disease that was deemed unsuitable for radical surgery or definitive radiotherapy. All patients had sensitising EGFR mutations and disease progression after treatment with EGFR-tyrosine kinase inhibitors and platinum based chemotherapy (in sequential order or in combination) for advanced or metastatic NSCLC. Patients who had previously received antiangiogenic therapy or immunotherapy, or both, were eligible if those treatments were administered in combination with EGFR-tyrosine kinase inhibitors or chemotherapy. Disease progression during treatment with EGFR-tyrosine kinase inhibitors was defined as progression after treatment with first or second generation EGFR-tyrosine kinase inhibitors in patients who tested negative for the EGFR p.Thr790Met (T790M) resistance mutation, or after receiving a third generation EGFR-tyrosine kinase inhibitor as first or second line treatment. Exclusion criteria included untreated brain metastases (patients with stable, treated metastases were eligible), active interstitial lung disease, or a history of pneumonitis requiring intravenous glucocorticoids. Full eligibility criteria are provided in the protocol (see supplementary appendix). All patients provided written informed consent before enrolment.
Randomisation and masking
An independent statistician generated the 2:1 randomisation schedule using SAS software (version 9.4). A stratified block design was applied, with stratification by brain metastases (yes or no). The study implemented a centralised interactive response technology system that assigned treatments according to randomisation schedule after confirming patient eligibility. This system enabled competitive enrolment across all participating centres. The treatment assignment was not masked to investigators and participants, but the central evaluation by a blinded independent review committee (BIRC) was conducted in a masked manner. The study team did not perform or have access to efficacy analysis or summary during the trial.
Interventions
Sac-TMT was administered intravenously at 5 mg/kg on days 1 and 15 of each four week cycle. The first four infusions of sac-TMT for each participant were administered over 90 (±15) minutes, and no less than 75 minutes. Docetaxel was administered intravenously at a dose of 75 mg/m2 every three weeks, on day 1 of each cycle. The protocol details the drugs used before sac-TMT and docetaxel (see supplementary appendix). Patients in the docetaxel group with BIRC confirmed progressive disease were permitted to crossover to sac-TMT treatment. The study treatment was continued until there was no further clinical benefit, intolerable toxicity occurred, the patient requested discontinuation of study treatment, or other discontinuation criteria specified in the protocol were met, whichever occurred first.
Assessments and endpoints
Tumour assessments were conducted according to the RECIST (response evaluation criteria in solid tumours) version 1.1, with evaluations performed every six weeks during the first 48 weeks after randomisation and every 12 weeks thereafter. The primary endpoint was BIRC assessed objective response rate, defined as the proportion of patients with a confirmed complete response or partial response as the best overall response. The secondary endpoints included investigator assessed objective response rate; BIRC and investigator assessed disease control rate (proportion of patients with complete response, partial response, or stable disease as best overall response), progression-free survival (time from start of randomisation to progressive disease or death, whichever occurred first), time to response (time from start of randomisation to first documentation of objective response), and duration of response (time from date of first documented complete response or partial response to progressive disease or death due to any cause, whichever occurred first); overall survival (time from start of randomisation to death due to any cause); safety; and the correlation between expression levels of tumour cell membrane trophoblast cell surface antigen 2 and antitumour activity. Progression-free survival and overall survival were assessed in the intention-to-treat population, defined as all patients randomly allocated to treatment. Responses were assessed in the full analysis set, which included the intention-to-treat population with measurable disease at baseline. Safety was assessed in the safety analysis set, which included all patients who received at least one dose of the assigned study treatment. Trophoblast cell surface antigen 2 expression was assessed by immunohistochemistry (monoclonal antibody: EPR20043), performed by MEDx Translational Medicine.
Statistical analysis
The data cut-off date for the primary analysis of objective response rate (ie, when all patients had the opportunity to be followed for at least three post-baseline tumour assessments) was 6 June 2024. The prespecified interim analysis of overall survival was conducted alongside the final progression-free survival analysis, with a data cut-off date of 31 December 2024. With a planned enrolment of about 126 patients, the trial had at least 85% power to detect a 25% difference (docetaxel 10%; sac-TMT 35%) in objective response rate at a one sided α of 0.025. The overall type I error rate was strictly controlled at a one sided α of 0.025 by a fixed sequence, closed testing procedure (in the order of BIRC assessed objective response rate, investigator assessed objective response rate, BIRC assessed progression-free survival, investigator assessed progression-free survival, and overall survival), as detailed in the supplementary appendix. The prespecified interim analysis of overall survival (with an information fraction of at least 60% and maturity of about 34%) was conducted alongside the final progression-free survival analysis, with a one sided α of 0.0123 determined by an α spending function (Hwang-Shih-DeCani with gamma of −1).
The primary endpoint of objective response rate was summarised with exact two sided confidence intervals (CIs) estimated using the Clopper-Pearson method. Treatment groups were compared using the Cochran-Mantel-Haenszel test, stratified by the presence of brain metastases. Duration of response, progression-free survival, and overall survival were summarised and presented graphically using the Kaplan-Meier method, with median event times and two sided 95% CIs estimated using the Brookmeyer and Crowley method. Treatment differences in progression-free survival and overall survival were assessed using a stratified log-rank test. Hazard ratios and associated 95% CIs were estimated using a stratified Cox proportional hazards model with Efron’s method for tie handling. The same stratification factor used for randomisation was applied to all stratified statistical analyses. To adjust for the crossover effect on overall survival, we performed two supplementary analyses including the rank-preserving structural failure time model and a censoring approach. The key assumption of the model is common treatment effect, implying that the treatment effect for a patient remains constant regardless of when the patient initiates the study drug. Further details are provided in the statistical analysis plan in the supplementary appendix. All statistical analyses were conducted using SAS software (version 9.4).
Patient and public involvement
As patient and public involvement was not a routine practice in the areas where this trial was conducted, no patients were involved in the design or implementation of this trial. Nor did patients participate in the subsequent data analysis, interpretation, or writing of the manuscript. All patients were, however, aware of the trial objectives and protocols during recruitment.
Results
Patients
Between 1 September 2023 and 30 January 2024, a total of 197 patients were screened for eligibility, of whom 137 were enrolled and randomly assigned in a 2:1 ratio to receive sac-TMT (91 patients) or docetaxel (46 patients) (fig 1). The baseline characteristics of the patients, except for EGFR mutation type, were well balanced between the two groups (table 1). The median age of the study population was 56 years, 44% (60/137) were men, 98% had stage IV disease (134/137), and 20% had brain metastases (28/137). Overall, 37% of the patients (51/137) had received more than two previous systemic treatment lines. Most patients (93%, 128/137) had previously received a third generation EGFR-tyrosine kinase inhibitor, with 58% receiving it as first line treatment (80/137). Additionally, 68% of patients had received antiangiogenic therapy (93/137) and 15% had received immunotherapy (21/137).
Fig 1.
Trial profile. *Four patients had radiology detected disease progression verified by blinded independent review committee (BIRC). sac-TMT=sacituzumab tirumotecan
Table 1.
Baseline personal and clinical characteristics of intention-to-treat population with EGFR-mutated non-small cell lung cancer, according to treatment. Values are numbers (percentages) unless stated otherwise
| Characteristics | Sac-TMT (n=91) | Docetaxel (n=46) | Total (n=137) |
|---|---|---|---|
| Median (range) age (years) | 57 (37-75) | 55 (34-74) | 56 (34-75) |
| Age ≥65 years | 19 (21) | 8 (17) | 27 (20) |
| Men | 38 (42) | 22 (48) | 60 (44) |
| Histological type, adenocarcinoma | 91 (100) | 46 (100) | 137 (100) |
| Clinical stage: | |||
| IIIb | 2 (2) | 1 (2) | 3 (2) |
| IV | 89 (98) | 45 (98) | 134 (98) |
| ECOG performance status 1 | 76 (84) | 37 (80) | 113 (82) |
| Brain metastases | 18 (20) | 10 (22) | 28 (20) |
| Liver metastases | 18 (20) | 7 (15) | 25 (18) |
| EGFR mutation type: | |||
| Exon 19 deletion | 43 (47) | 32 (70) | 75 (55) |
| L858R mutation | 48 (53) | 14 (30) | 62 (45) |
| T790M mutation status: | |||
| Positive | 19 (21) | 10 (22) | 29 (21) |
| Negative | 32 (35) | 13 (28) | 45 (33) |
| Unknown | 40 (44) | 23 (50) | 63 (46) |
| Previous lines of systemic therapy: | |||
| 1* | 9 (10) | 5 (11) | 14 (10) |
| 2 | 52 (57) | 20 (43) | 72 (53) |
| >2 | 30 (33) | 21 (46) | 51 (37) |
| Previous EGFR-TKI treatment: | 91 (100) | 46 (100) | 137 (100) |
| Previous third generation EGFR-TKI treatment | 84 (92) | 44 (96) | 128 (93) |
| Third generation EGFR-TKI in first line treatment | 54 (59) | 26 (57) | 80 (58) |
| Third generation EGFR-TKI in second line treatment | 30 (33) | 18 (39) | 48 (35) |
| No previous third generation EGFR-TKI | 7 (8) | 2 (4) | 9 (7) |
| Previous antiangiogenic therapy | 60 (66) | 33 (72) | 93 (68) |
| Previous immunotherapy | 15 (16) | 6 (13) | 21 (15) |
Patients had previously progressed after first line treatment with combination regimen of EGFR-TKI and platinum based chemotherapy.
ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth factor receptor; sac-TMT=sacituzumab tirumotecan; TKI=tyrosine kinase inhibitor.
At the data cut-off (31 December 2024), 25% of patients (23/91) in the sac-TMT group and 4% (2/46) in the docetaxel group remained on the assigned treatment. The main reason for treatment discontinuation was disease progression (76% with sac-TMT (52/68) and 91% with docetaxel (40/44)) (fig 1). Among the 44 patients who had discontinued docetaxel, 36% (16/44) crossed over to receive sac-TMT.
Efficacy
At the data cut-off (31 December 2024), median follow-up was 12.2 months (range 9.5-15.6). The BIRC assessed objective response rate was 45% (41/91; 95% CI 35% to 56%) in the sac-TMT group and 16% (7/45; 95% CI 7% to 30%) in the docetaxel group, with a difference of 29% (95% CI 15% to 43%; one sided P<0.001) (table 2, fig 2, fig 3). The investigator assessed objective response rate was similar, with a difference of 25% (95% CI 13% to 38%; one sided P<0.001) (see supplementary table S1, fig S1A, and fig S1B).
Table 2.
Blinded independent review committee assessed efficacy endpoints in patients with EGFR-mutated non-small cell lung cancer, according to treatment. Values are numbers (percentages) unless stated otherwise
| Efficacy endpoints | Sac-TMT (n=91) | Docetaxel (n=45) |
|---|---|---|
| Tumour response: | ||
| Partial response | 41 (45) | 7 (16) |
| Stable disease | 34 (37) | 20 (44) |
| Progressive disease | 11 (12) | 17 (38) |
| Not evaluable | 5 (5) | 1 (2) |
| Objective response rate: | ||
| No (%, 95% CI) | 41 (45, 35 to 56) | 7 (16, 7 to 30) |
| Difference (% (95% CI)) | 29 (15 to 43) | — |
| P value (one sided) | <0.001 | — |
| Disease control rate: | ||
| No (%, 95% CI) | 75 (82, 73 to 90) | 27 (60, 44 to 74) |
| Difference (% (95% CI)) | 22 (6 to 39) | — |
Data cut-off date for efficacy analysis was 31 December 2024. Responses were assessed according to RECIST version 1.1 by blinded independent review committee. Members of the committee were unaware of treatment group assignments. All responses were confirmed by blinded independent review committee.
CI=confidence interval; RECIST=response evaluation criteria in solid tumour; sac-TMT=sacituzumab tirumotecan.
Fig 2.
Waterfall plots showing antitumour activity assessed by blinded independent review committee in patients with EGFR-mutated non-small cell lung cancer. EGFR=epidermal growth factor receptor; sac-TMT=sacituzumab tirumotecan
Fig 3.
Time to response and duration of response in patients with EGFR-mutated non-small cell lung cancer according to treatment. PR=partial response; sac-TMT=sacituzumab tirumotecan
BIRC assessed median progression-free survival was 6.9 months (95% CI 5.4 to 8.2) in the sac-TMT group compared with 2.8 months (1.6 to 4.1) in the docetaxel group. The sac-TMT group showed a significant 70% reduction in risk of disease progression or death (hazard ratio 0.30, 95% CI 0.20 to 0.46; one sided P<0.001) (fig 4A). Similarly, investigator assessed median progression-free survival was longer in the sac-TMT group (7.9 months, 95% CI 6.2 to 9.5) compared with 2.8 months (1.5 to 3.8) in the docetaxel group, corresponding to a 77% reduction in the risk of disease progression or death (hazard ratio 0.23, 95% CI 0.15 to 0.36; one sided P<0.001) (fig 4B).
Fig 4.
Kaplan-Meier curves for progression-free survival and overall survival in patients with EGFR-mutated non-small cell lung cancer receiving sac-TMT or docetaxel. (Panel A) Progression-free survival assessed by blinded independent review committee; (panel B) progression-free survival assessed by investigator; (panel C) overall survival; and (panel D) overall survival using RPSFT model to adjust for crossover effects. BIRC=blinded independent review committee; CI=confidence interval; EGFR=epidermal growth factor receptor; NE=not evaluable; NR=not reached; RPSFT=rank-preserving structural failure time; sac-TMT=sacituzumab tirumotecan
At the data cut-off (31 December 2024) for the prespecified interim analysis of overall survival, with 46 events (about 34% maturity), neither group reached the median overall survival (fig 4C). The sac-TMT group showed a 51% reduction in risk of death (hazard ratio 0.49, 0.27 to 0.88; one sided P=0.007), which was well below the predefined boundary for significance (one sided α of 0.0123). The 12 month overall survival rate was 73% (95% CI 62% to 81%) in the sac-TMT group and 54% (39% to 67%) in the docetaxel group. Notably, the supplementary survival analysis adjusted using the rank-preserving structural failure time model to account for crossover showed that sac-TMT reduced the risk of death by 64% (adjusted median overall survival not reached versus 9.3 months; hazard ratio 0.36, 95% CI 0.20 to 0.66) (fig 4D). The 12 month overall survival rate adjusted by the rank-preserving structural failure time model was 73% (95% CI 62% to 81%) in the sac-TMT group and 43% (26% to 60%) in the docetaxel group. In a supplementary analysis adjusted by censoring at crossover, sac-TMT led to a 67% reduction in risk of death compared with docetaxel (median overall survival not reached versus 9.2 months; hazard ratio 0.33, 95% CI 0.18 to 0.62) (see supplementary fig S2).
The BIRC assessed disease control rate was 82% (75/91; 95% CI 73% to 90%) in the sac-TMT group and 60% (27/45; 44% to 74%) in the docetaxel group. Figure 2 shows the best change from baseline in target lesion size, evaluated by BIRC for the sac-TMT group, with a median reduction of 38.5% (fig 2, top panel), compared with 14.8% in the docetaxel group (fig 2, bottom panel). The median time to response based on BIRC assessment was 1.5 months in both treatment groups. The BIRC assessed duration of response was 7.0 months in the sac-TMT group and 5.1 months in the docetaxel group (hazard ratio 0.40, 95% CI 0.16 to 1.00) (fig 3). Investigator assessed disease control rate, time to response, and duration of response were similar to BIRC assessments (see supplementary table S1 and fig S1C).
Subgroup analyses of objective response rate and progression-free survival, assessed by both BIRC (see supplementary fig S3A and fig S3B) and investigator (see supplementary fig S4A and fig S4B), showed that sac-TMT provided benefit over docetaxel across all subgroups.
In the sac-TMT group, 54 patients received subsequent anticancer treatments after disease progression, with most (83% (45/54)) undergoing targeted treatments, and a substantial proportion received chemotherapy (35% (19/54)) or immunotherapy (17% (9/54)). Among the 44 patients who had discontinued docetaxel, 52% (23/44) subsequently received other anticancer treatments. These 23 patients all received targeted therapy, with some also receiving chemotherapy (nine patients), immunotherapy (five patients), or radiotherapy (one patient).
Safety
All 137 patients received at least one dose of study treatment and were included in the safety analysis set. At the data cut-off for the primary analysis (6 June 2024), the median duration of drug treatment was 5.0 months (range 0.5-9.2) in the sac-TMT group and 2.8 months (0.7-6.1) in the docetaxel group. Most patients in both the sac-TMT group (98% (89/91)) and the docetaxel group (98% (45/46)) experienced treatment related adverse events (table 3). Among these, grade ≥3 treatment related adverse events occurred in 51 out of 91 patients (56%) in the sac-TMT group and 33 out of 46 patients (72%) in the docetaxel group. The most common grade ≥3 treatment related adverse events were decreased neutrophil count (43% with sac-TMT (39/91) v 59% with docetaxel (27/46)), decreased white blood cell count (25% (23/91) v 52% (24/46)), and stomatitis (16% (15/91) v 2% (1/46)) (table 3). No cases of febrile neutropenia were observed in the sac-TMT group, compared with 20% in the docetaxel group. Treatment related serious adverse events occurred in 15 out of 91 patients (16%) in the sac-TMT group and 19 out of 46 patients (41%) in the docetaxel group. The most common treatment related serious adverse events were decreased neutrophil count (7% (6/91) v 22% (10/46)), decreased white blood cell count (2% (2/91) v 20% (9/46)), and febrile neutropenia (0% (0/91) v 13% (6/46)).
Table 3.
Treatment related adverse events in safety analysis set of patients with EGFR-mutated non-small cell lung cancer, according to treatment. Values are numbers (percentages)
| Adverse events | Sac-TMT (n=91) | Docetaxel (n=46) | |||
|---|---|---|---|---|---|
| Any grade | Grade ≥3 | Any grade | Grade ≥3 | ||
| Any adverse events | 89 (98) | 51 (56) | 45 (98) | 33 (72) | |
| Serious adverse events | 15 (16) | 19 (41) | |||
| Outcome of adverse events: | |||||
| Dose reduction | 29 (32) | 20 (43) | |||
| Dose interruption | 32 (35) | 13 (28) | |||
| Treatment discontinuation | 0 | 1 (2) | |||
| Death | 0 | 0 | |||
| Preferred term*: | |||||
| Anaemia | 70 (77) | 11 (12) | 31 (67) | 2 (4) | |
| Decreased white blood cell count | 62 (68) | 23 (25) | 29 (63) | 24 (52) | |
| Decreased neutrophil count | 60 (66) | 39 (43) | 27 (59) | 27 (59) | |
| Stomatitis | 56 (62) | 15 (16) | 3 (7) | 1 (2) | |
| Alopecia | 43 (47) | 0 | 23 (50) | 0 | |
| Decreased platelet count | 32 (35) | 5 (5) | 9 (20) | 0 | |
| Asthenia | 24 (26) | 0 | 14 (30) | 2 (4) | |
| Decreased weight | 19 (21) | 1 (1) | 1 (2) | 0 | |
| Nausea | 17 (19) | 0 | 13 (28) | 0 | |
| Decreased lymphocyte count | 17 (19) | 6 (7) | 10 (22) | 4 (9) | |
| Hypoalbuminaemia | 13 (14) | 0 | 10 (22) | 0 | |
| Febrile neutropenia | 0 | 0 | 9 (20) | 9 (20) | |
| Decreased appetite | 18 (20) | 1 (1) | 4 (9) | 0 | |
| Hypertriglyceridaemia | 12 (13) | 1 (1) | 5 (11) | 0 | |
| Oedema peripheral | 1 (1) | 0 | 6 (13) | 1 (2) | |
| Cough | 9 (10) | 1 (1) | 3 (7) | 0 | |
| Diarrhoea | 2 (2) | 0 | 4 (9) | 1 (2) | |
| Hypokalaemia | 8 (9) | 3 (3) | 0 | 0 | |
| Hypocalcaemia | 7 (8) | 1 (1) | 2 (4) | 0 | |
| Pneumonia | 1 (1) | 1 (1) | 3 (7) | 2 (4) | |
| Nervous system disorder | 0 | 0 | 1 (2) | 1 (2) | |
| Hypertension | 2 (2) | 1 (1) | 0 | 0 | |
Data cut-off for safety analysis was 6 June 2024. The safety analysis set included all patients who received at least one dose of study drug, with at least one post-treatment safety assessment. Shown are adverse events that were considered by the investigator to be related to study treatments. Patients may have had multiple adverse events of different grades, which were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.
Adverse events with ≥20% incidence in either group and any other adverse events of grade ≥3.
Supplementary table S2 shows adverse events of special interest with sac-TMT. The most common was stomatitis (64% (58/91)), which is a preferred term comprising stomatitis (62% (56/91)), oral ulcer (2% (2/91)), and aphthous ulcer (0% (0/91)), with 19% of grade 1 severity (17/91), 29% of grade 2 (26/91), and 16% of grade 3 (15/91). These patients with stomatitis were managed with symptomatic treatment and dose modification of sac-TMT (see protocol in the supplementary appendix for details of management strategies and dose modification criteria). Specifically, 11 patients (12% (11/91)) required dose interruption and 13 patients (14% (13/91)) underwent dose reductions, with none of the patients discontinuing sac-TMT due to stomatitis. Ocular surface toxicity was rare (2%; one patient with blurred vision and one with ophthalmodynia, both grade 1), as was pneumonitis (1%; one patient with grade 2 pneumonitis). No cases of interstitial lung disease were observed. No infusion related reactions or hypersensitivity reactions occurred.
Biomarker analyses
Tumour tissue samples were obtained for patients at or after diagnosis of locally advanced or metastatic disease. Both archived tumour samples obtained within three years before the first dose of study treatment and newly collected samples were acceptable. Of the 110 patients with known expression levels for tumour cell membrane trophoblast cell surface antigen 2, 58% (64/110) showed high expression (defined as an immunohistochemistry H-score >200), 26% (29/110) showed medium expression (H-score 100 to ≤200), and 15% (17/110) showed low expression (H-score ≤100). Expression of trophoblast cell surface antigen 2 was medium to high in 85% of patients and did not show an obvious association with either treatment response or progression-free survival. Among patients with low or medium trophoblast cell surface antigen 2 expression, sac-TMT showed a higher BIRC assessed objective response rate than docetaxel (37% (11/30) v 13% (2/15)), with a notable difference in median progression-free survival (6.1 v 2.8 months; hazard ratio 0.34, 0.17 to 0.70) (see supplementary table S3 and fig S5A). Similarly, in the high expression group, sac-TMT showed better efficacy compared with docetaxel in both response rate (57% (26/46) v 22% (4/18)) and progression-free survival (8.1 v 4.3 months; hazard ratio 0.43, 0.23 to 0.82) (see supplementary fig S5B).
Discussion
This randomised controlled trial showed benefit of a trophoblast cell surface antigen 2 directed antibody-drug conjugate in patients with EGFR-mutated, locally advanced or metastatic NSCLC after previous treatment failure with EGFR-tyrosine kinase inhibitors and platinum based chemotherapy. The study met its primary endpoint, as sac-TMT showed a statistically significant higher BIRC assessed objective response rate of 45% compared with 16% for docetaxel, with a difference of 29% (95% CI 15% to 43%). Moreover, sac-TMT showed statistically significant and clinically meaningful improvements in progression-free survival and overall survival. The risk of disease progression or death was statistically significantly reduced with sac-TMT treatment, showing a 70% reduction for BIRC assessments and 77% for investigator assessments. Sac-TMT also reduced the risk of death by 51% compared with docetaxel, achieving a one year overall survival rate of 73%. As 36% (16/44) of patients in the docetaxel group crossed over to receive sac-TMT, we performed two supplementary analyses for overall survival to adjust for crossover. These analyses highlighted even greater survival benefits with sac-TMT. The overall survival analysis adjusted using the rank-preserving structural failure time model revealed that sac-TMT reduced the risk of death by 64% compared with docetaxel. Taken together, these findings suggest that sac-TMT is a promising treatment option combining meaningful clinical efficacy with a manageable safety profile for patients with pre-treated, EGFR-mutated, locally advanced or metastatic NSCLC.
Comparison with other studies
The patients in this study, with disease progression after EGFR-tyrosine kinase inhibitors and platinum based chemotherapy, represent a challenging population for treatment. In the first line setting, EGFR-tyrosine kinase inhibitors have shown efficacy, particularly with osimertinib.21 22 However, resistance inevitably develops, leading to disease recurrence and limited survival benefits, with median progression-free survival of about 5.5 to 7.2 months despite recent innovative efforts in clinical trials such as the ORIENT-31 and AK112-301 studies.23 24 25 Options for patients with treatment failure after both EGFR-tyrosine kinase inhibitors and platinum based chemotherapy become increasingly restricted. The most commonly used subsequent treatment, docetaxel, has shown limited efficacy in this patient population, with a median progression-free survival of about three months, accompanied by a substantial burden of toxicity.5 6 7 Recent studies investigating HER3-antibody-drug conjugates have provided potential alternatives, with patritumab deruxtecan demonstrating an objective response rate of 29.8%, a median progression-free survival of 5.5 months, and a median overall survival of 11.9 months in EGFR-mutated NSCLC.26 Despite these promising developments, an urgent need remains to explore and develop novel therapeutic agents to further improve outcomes for this challenging patient population.
Recently, trophoblast cell surface antigen 2 has emerged as a promising target for antibody-drug conjugate with high therapeutic potential for NSCLC. Previous studies have investigated other trophoblast cell surface antigen 2 directed antibody-drug conjugates in patients with NSCLC. The large phase 3 EVOKE-01 trial, which evaluated the trophoblast cell surface antigen 2 directed antibody-drug conjugate sacituzumab govitecan in NSCLC, reported an objective response rate of 14% and a progression-free survival of 4.1 months, with no statistically significant difference compared with docetaxel. The EVOKE-01 trial population was heterogeneous, with a low proportion of patients with actionable genomic alterations that were potentially responsive to the corresponding targeted therapies, and a substantial proportion of patients with squamous cell carcinoma.12 Although a numerical improvement in overall survival was observed in the subgroup with actionable genomic alterations, this exploratory analysis was not supported by prespecified statistical hypothesis testing.12 In the large phase 3 TROPION-Lung01 trial, another trophoblast cell surface antigen 2 directed antibody-drug conjugate, datopotamab deruxtecan, showed an objective response rate of 26%, with a median progression-free survival of 4.4 months and an overall survival of 12.9 months, with no statistically significant difference in overall survival compared with docetaxel.13 However, patients with actionable genomic alterations, including those with EGFR mutations, showed better efficacy, with an objective response rate of 38%.27 Further analysis pooling patients with EGFR mutations from both the TROPION-Lung01 and TROPION-Lung05 studies showed an even higher objective response rate, of 42.7%, and a median progression-free survival of 5.8 months; however, this pooled analysis lacked a comparison with standard of care.28 These findings suggest that trophoblast cell surface antigen 2 directed antibody-drug conjugates may be used in EGFR-mutated NSCLC to achieve optimal benefit.
Unlike the TROPION-Lung01 and EVOKE-01 studies, which evaluated trophoblast cell surface antigen 2 directed antibody-drug conjugates in NSCLC populations with or without actionable genomic alterations,12 13 the current trial specifically focused on patients with NSCLC and sensitising EGFR mutation with disease progression after EGFR-tyrosine kinase inhibitors and platinum chemotherapy. This targeted approach was guided by evidence suggesting enhanced therapeutic potential in this molecularly defined subgroup. Mechanistic studies showed that cells with EGFR mutations, particularly those with acquired resistance to tyrosine kinase inhibitors, exhibit increased trophoblast cell surface antigen 2 mediated internalisation of sac-TMT compared with EGFR wild type models.18 Clinically, previous data from phase 1 and 2 trials have revealed particularly robust activity in EGFR-mutated NSCLC.18 Furthermore, emerging biological evidence links trophoblast cell surface antigen 2 overexpression to EGFR-tyrosine kinase inhibitor resistance through activation of parallel survival pathways.9 The patient population in the current, OptiTROP-Lung03, trial aligns with current clinical practice, including the frequent use of third generation EGFR-tyrosine kinase inhibitors (93%) and antiangiogenic therapies (68%). In patients previously treated with antiangiogenic therapy, a BIRC assessed objective response rate of 31.7% was achieved for sac-TMT. This study only allowed one line of previous chemotherapy, and a proportion of patients underwent treatment with a third generation EGFR-tyrosine kinase inhibitor after previous treatment with a first or second generation EGFR-tyrosine kinase inhibitors. For the subgroup with more than two previous treatment lines, a high objective response rate of 40% was obtained with sac-TMT. An objective response rate of 40% was also obtained in patients in the sac-TMT group who had previous immunotherapy. In this context, the study highlights the substantial improvements in objective response rate, progression-free survival, and overall survival with sac-TMT compared with standard of care in this heavily pre-treated patient population. These improvements in efficacy were also observed across other clinically relevant subgroups, including patients with brain metastases, a population with particularly limited treatment options and unfavourable prognosis. Furthermore, previous randomised trials targeting trophoblast cell surface antigen 2 lacked prespecified statistical hypothesis testing for overall survival in previously treated EGFR-mutated NSCLC. The current randomised controlled trial showed statistically significant overall survival benefits for a trophoblast cell surface antigen 2 directed antibody-drug conjugate in patients with EGFR-mutated NSCLC.
The most frequently observed adverse events related to sac-TMT were haematological toxicities, which are commonly attributed to the payload of trophoblast cell surface antigen 2 directed antibody-drug conjugates. These treatment related adverse events of any grade with sac-TMT were generally comparable to those observed with docetaxel, whereas the incidences of grade ≥3 decreased white blood cell count and decreased neutrophil count were lower. Notably, febrile neutropenia was not observed in the sac-TMT group, in contrast with 20% in the docetaxel group. Although grade ≥3 anaemia was more common in the sac-TMT group, it did not lead to treatment discontinuation and was manageable with supportive care or dose modifications. As an on-target toxicity, stomatitis is also observed at a relatively high frequency with trophoblast cell surface antigen 2 directed antibody-drug conjugates such as datopotamab deruxtecan.11 For optimal management, we recommend a graded approach according to the severity of stomatitis, as detailed in the protocol (see supplementary appendix). All patients with stomatitis were adequately managed, without leading to treatment discontinuation. Ocular surface and pulmonary toxicities are also commonly associated with trophoblast cell surface antigen 2 directed antibody-drug conjugates.11 13 29 In our study, sac-TMT was associated with a low incidence of ocular surface toxicity (2%: one patient with blurred vision and one patient with ophthalmodynia) and one case of pneumonitis; none of these cases reached grade 3 severity. Interstitial lung disease was not observed in the sac-TMT group. Overall, the safety profile of sac-TMT in this study was generally manageable, with no new safety signals observed.
Limitations of this study
Although the modest sample size was appropriate for this phase 2 trial, the enrolled patients were all Chinese, which may limit the generalisability of the findings. This trial used the surrogate endpoint of objective response rate as the primary endpoint. The substantial treatment effect on objective response rate could be indicative of survival benefits. Although this study was not adequately powered for overall survival, the key secondary endpoints, including progression-free survival and overall survival, both showed statistically significant improvements through hierarchical fixed sequence testing. To further validate the findings, several phase 3 randomised controlled trials are ongoing. The phase 3 OptiTROP-Lung04 trial in China (NCT05870319), which enrolled 376 patients with EGFR-mutated NSCLC and failure of previous EGFR-tyrosine kinase inhibitor treatment, has already met its primary endpoint of progression-free survival.30 Two ongoing global phase 3 randomised trials in patients with previously treated EGFR-mutated NSCLC (NCT06074588 and NCT06305754) both adopted overall survival and progression-free survival as co-primary endpoints. Although the current study showed improved survival outcomes with sac-TMT, quality of life was not included through questionnaires such as EORTC Quality of Life Questionnaire-Core 30 and EORTC QLQ-Lung Cancer 13. Based on reported adverse events, we observed that decreased appetite and weight were more common in the sac-TMT group. These adverse events were generally of low grade and did not require specific interventions, and thus might not have an important effect on daily life. The quality of life of patients receiving sac-TMT will be considered in the aforementioned ongoing phase 3 trials.
Conclusions
This multicentre, randomised controlled trial found statistically significant improvements in objective response rate, progression-free survival, and overall survival with sac-TMT compared with docetaxel in patients with EGFR-mutated locally advanced or metastatic NSCLC, with a manageable safety profile. This study provides evidence supporting sac-TMT as an effective treatment for these patients with disease progression after treatment with EGFR-tyrosine kinase inhibitors and platinum based chemotherapy. Based on the promising results of the current, OptiTROP-Lung03, trial, the China National Medical Products Administration has recently approved the use of sac-TMT, establishing it as the first trophoblast cell surface antigen 2 directed antibody-drug conjugate approved for the treatment of lung cancer in the world.
What is already known on this topic
Latest guidelines recommend single agent chemotherapy in patients with non-small cell lung cancer (NSCLC) after previous treatment failure with EGFR-tyrosine kinase inhibitors and platinum based chemotherapy, with docetaxel the most widely used agent
Previous trophoblast cell surface antigen 2 directed antibody-drug conjugates have been investigated in NSCLC with or without actionable genomic alterations but have not shown survival benefits
What this study adds
The novel trophoblast cell surface antigen 2 directed antibody-drug conjugate sacituzumab tirumotecan (sac-TMT) showed higher response rates, longer progression-free survival, and improved overall survival with manageable toxicity for patients with pre-treated advanced EGFR-mutated NSCLC compared with docetaxel
These findings for sac-TMT may redefine treatment standards for this population
Acknowledgments
We thank the patients who volunteered to participate in the OptiTROP-Lung03 study and their families for their valuable contribution and commitment, and the dedicated clinical trial investigators and team members for participating in the OptiTROP-Lung03 study.
Web extra.
Extra material supplied by authors
Supplementary information: Clinical study protocol
Supplementary information: Statistical analysis plan
Supplementary information: Supplementary methods
Supplementary information: Code for statistical analyses
Contributors: WF, XL, QW, and XM contributed equally to this article and are joint first authors. WF, JG, and LZ are joint corresponding authors. LZ, WF, YD, JY, XJ, and JG conceived and designed the study. LZ, WF, XL, QW, XM, WZheng, LS, WY, WZhuang, YF, MZ, YL, ZZ, XS, and RY contributed to the enrolment and treatment of patients. LZ, WF, XL, QW, XM, WZheng, LS, WY, WZhuang, YF, MZ, YL, ZZ, XS, and RY collected and assembled the data. LZ, WF, XL, QW, XM, XJ, JG, YD, and JY analysed and interpreted the data. All authors contributed to the writing and revision of the manuscript and approved the final draft. LZ is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding: This study was funded by Sichuan Kelun-Biotech Biopharmaceutical and partly supported by the National Natural Science Foundation of China (grants 82241232 and 82272789 awarded to LZ, grants 82173101 and 82373262 awarded to WF) and Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0519700 awarded to LZ). This trial was designed by the authors in collaboration with Sichuan Kelun-Biotech Biopharmaceutical. The authors and Sichuan Kelun-Biotech Biopharmaceutical were involved in data collection, analysis, and interpretation and guaranteed the accuracy and completeness of the data, the writing of the paper, and the decision to submit the manuscript for publication. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from Sichuan Kelun-Biotech Biopharmaceutical, and partial support from the National Natural Science Foundation of China and Noncommunicable Chronic Diseases-National Science and Technology Major Project for the submitted work; JY, YD, XJ, and JG are employed by Sichuan Kelun-Biotech Biopharmaceutical YD, XJ, and JG hold company stock; no other relationships or activities that could appear to have influenced the submitted work.
Transparency: The lead author (LZ) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Dissemination to participants and related patient and public communities: The findings of this study will be disseminated to participants, patient communities, and the general public through a press release. The press release will be distributed through our institutional website, official WeChat and LinkedIn accounts, and PR Newswire to ensure wide reaching visibility.
Provenance and peer review: Not commissioned; externally peer reviewed.
Ethics statements
Ethical approval
This study was conducted in accordance with the principles of the Declaration of Helsinki, good clinical practice guidelines, and applicable laws and regulations. The study protocol was reviewed and approved by the ethics committee of Sun Yat-sen University Cancer Centre on 14 October 2022 (A2022-175-01) and at each participating centre before initiation.
Data availability statement
The code used to analyse the data in the paper can be found in the supplementary files. The data underlying the findings in this paper are openly and publicly available and can be found at https://data.mendeley.com/datasets/hts8z9mx4w/1. If you encounter problems accessing the data, please contact the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary information: Clinical study protocol
Supplementary information: Statistical analysis plan
Supplementary information: Supplementary methods
Supplementary information: Code for statistical analyses
Data Availability Statement
The code used to analyse the data in the paper can be found in the supplementary files. The data underlying the findings in this paper are openly and publicly available and can be found at https://data.mendeley.com/datasets/hts8z9mx4w/1. If you encounter problems accessing the data, please contact the corresponding author.