A B7H3-targeting antibody-drug conjugate in advanced solid tumors: a phase 1/1b trial

Abstract

Antibody-drug conjugates (ADCs) have emerged as a transformative modality in the treatment of solid tumors. YL201, a novel B7H3-targeting ADC, leverages a tumor microenvironment activable linker-payload platform, coupled with a novel topoisomerase 1 inhibitor via a protease-cleavable linker. Here we report the findings from a large-scale, global, multicenter, phase 1 trial evaluating the safety, pharmacokinetics and preliminary efficacy of YL201 in patients with advanced solid tumors refractory to standard therapies. The trial included a dose-escalation part (phase 1) and a dose-expansion part (phase 1b). A total of 312 patients were enrolled across multiple tumor types, including extensive-stage small cell lung cancer (ES-SCLC), nasopharyngeal carcinoma (NPC), non-small cell lung cancer, esophageal squamous cell carcinoma and other solid tumors. The maximum tolerated dose was determined to be 2.8 mg kg^-1, and the recommended expansion dose was selected as 2.0 mg kg^-1 and 2.4 mg kg^-1 every 3 weeks. The most common grade 3 or higher treatment-related adverse events included neutropenia (31.7%), leukopenia (29.5%) and anemia (25.0%). Only 4 cases of interstitial lung disease (1.3%) and 1 case of infusion reactions (0.3%) were observed. Encouraging anti-tumor activity was observed, particularly in patients with ES-SCLC (objective response rate (ORR), 63.9%), NPC (ORR, 48.6%), lung adenocarcinoma (ORR, 28.6%) and lymphoepithelioma-like carcinoma (ORR, 54.2%). No significant correlation between B7H3 membrane expression and the ORR was found. YL201 demonstrated an acceptable safety profile and a promising efficacy in heavily pretreated patients with advanced solid tumors, particularly in those with ES-SCLC, NPC or lymphoepithelioma-like carcinoma. Phase 3 clinical trials for patients with SCLC and NPC have already been initiated. ClinicalTrials.gov identifiers: NCT05434234 and NCT06057922 .

Fig. 1. Study flowchart and patient disposition.

Q3W, 1 dose every 3 weeks per cycle.

Fig. 2. Waterfall plot of tumor response from baseline and swimming plot.

a,c,e,g, The waterfall plot depicts the best objective responses concerning the tumor size in all patients (a), ES-SCLC (c), NPC (e) and LELC (g). b,d,f,h, Swimmer plots depict responses to treatment and the duration of treatment in all patients (b), ES-SCLC (d), NPC (f) and LELC (h).

Fig. 3. Expression of B7-H3 in different tumor types and the relationship between B7-H3 expression and response.

a, Expression of B7H3 in different tumor types. b–f, The relationship between B7-H3 expression and response in all patients (b), ES-SCLC (c), NPC (d), ESCC (e) and LELC (f). The median, quartile, and maximum and minimum values are shown. Comparisons were performed using Kruskal–Wallis one-way ANOVA tests. NE, not evaluated; cBOR, confirmed best overall response. Source data

Extended Data Fig. 1. Overview of the dose-escalation and dose-expansion studies.

DLT, dose-limiting toxicity; ESCC, esophageal squamous cell carcinoma; ES-SCLC, extensive-stage small cell lung cancer; NPC, nasopharyngeal carcinoma; NSCLC, non-small cell lung cancer; Q3W, once every 3 weeks.

Extended Data Fig. 2. Waterfall plot of tumor response from baseline and swimmers plot in lung adenocarcinoma, lung squamous cell carcinoma, esophageal squamous cell carcinoma, and other tumor patients.

The waterfall plot depicts the best objective responses concerning the tumor size in lung adenocarcinoma (a), lung squamous cell carcinoma (c), ESCC(e) and other tumors (g). Corresponding swimmer plots depict the treatment duration and response patterns for lung adenocarcinoma (b), lung squamous cell carcinoma (d), ESCC (f), and other tumors (h). BOR, the best of response; PR, partial response; SD, stable disease; PD, progressive disease. ESCC, esophageal squamous cell carcinoma.

Extended Data Fig. 3. Waterfall plot of best response of intracranial target lesions in patients with evaluable brain metastases at baseline.

ES-SCLC, extensive-stage small cell lung cancer; NSCLC, non-small cell lung cancer; adeno, adenocarcinoma; ESCC, esophageal squamous cell carcinoma.

Extended Data Fig. 4. Typical radiographic images of patients who achieved partial responses.

(a) A 51-year-old small cell lung cancer patient achieved partial responses after two and four cycles of YL201 treatment (red arrow showing target lesion in the lymph node metastasis). (b) A 49-year-old nasopharyngeal carcinoma patient achieved partial responses after two and four cycles treatment (red arrow showing target lesion in the liver metastasis). (c) A 62-year-old lung lymphoepithelioma-like carcinoma patient achieved partial responses after four and six cycles treatment (red arrow showing target lesion in the lung).

Extended Data Fig. 5. Single dose concentration-time plot concentration over time at different dosage regimens.

Single dose concentration-time plot concentration different dosage regimens of YL201-ADC, YL201-TAB and YL0010014 in the first cycle in the dose-escalation phase. Data are represented as mean and the standard deviation. ADC, antibody-drug conjugate; TAB, total antibody.

Extended Data Fig. 6. The correlation analysis of tumor B7-H3 Expression and objective response across different tumor types.

According to the cutoff of the H-score of 100, the patients were divided into two groups: low expression of B7H3 and high expression of B7H3, and the difference of objective response rate between two groups in ES-SCLC (a), NPC (b), ESCC (c), ESCC (d), and NSCLC adenocarcinoma (e) was compared. Statistical significance was determined using Chi-squared test. ES-SCLC, extensive-stage small cell lung cancer; NPC, nasopharyngeal carcinoma; NSCLC, non-small cell lung cancer; LELC, lymphoepithelioma-like carcinoma; ESCC, esophageal squamous cell carcinoma; NE, not evaluated; PD, progressive disease; SD, stable disease; PR, partial response. Source data

Extended Data Fig. 7. Scatter plot of pre-treatment soluble B7-H3 concentration by objective responses across different tumor types.

Concentration of soluble B7-H3 in different tumor types (a). The relationship between the soluble B7-H3 concentration and the response in all patients (b), ES-SCLC (c), NPC (d), ESCC (e), lung adenocarcinoma (f), lung squamous cell carcinoma (g) and LELC (h). The median, quartile, maximum and minimum values are shown. Comparisons were performed using Kruskal-Wallis one-way ANOVA tests followed by Dunn’s correction for multiple comparisons. ES-SCLC, extensive-stage small cell lung cancer; NPC, nasopharyngeal carcinoma; NSCLC, non-small cell lung cancer; lung lymphoepithelioma-like carcinoma. sB7H3, soluble B7-H3; ES-SCLC, extensive-stage small cell lung cancer; ESCC, esophageal squamous cell carcinoma; ade, adenocarcinoma; squ-NSCLC, lung squamous cell carcinoma; LELC, lymphoepithelioma-like carcinoma. Source data