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A phase II study of sitravatinib combined with tislelizumab plus docetaxel for acquired resistance to PD-(L)1 in patients with advanced/metastatic non-small cell lung cancer

ABSTRACT: In this phase Ⅱ study, 13 patients with stage III/Ⅳ immune checkpoint inhibitors (ICIs) - acquired resistant non-small cell lung cancer (NSCLC) were treated with tislelizumab, sitravatinib, and docetaxel. The primary endpoint is a 6-month progression-free survival (PFS) rate. Although the target enrollment was not reached, the 6-month PFS rate among the enrolled patients was 58.9% (95% CI 0.234 - 0.825), with a median PFS of 7.589 months (95% CI 1.873 - 14.423) and a median OS of 17.150 months (95% CI 1.873 - not reached). The ORR was 58.3% (7 of 12 patients, 1 not evaluable), and the DCR was 100% (12 of 12 patients). Following treatment with sitravatinib, T-cell diversity (+0.435, p = 0.5) and the PSI of CD4⁺ T cells tend to increase (+21.948, p = 0.8438), whereas the PSI of CD8+ T cells declines (-174.16, p = 0.0938). High CD4⁺ T cells ΔPSI (>40) was associated with a strong trend of longer PFS (14.400 vs 7.6 months, p = 0.0499). In conclusion, sitravatinib combination therapy demonstrated promising clinical benefit and manageable safety in NSCLC patients with acquired resistance to ICIs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309446 | GEO | 2025/12/17

REPOSITORIES: GEO

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Project description:Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients. Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination. Design: Open label non-randomized phase I/II clinical trial Setting: Prospective therapeutic clinical trial conducted in 4 centers Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients Intrevention: HCQ twice daily, dabrafenib 150 mg twice daily and trametinib 2 mg daily (D+T) Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH, 52% were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of HCQ at either 400 (n=3) or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41% (95% CI = ), median PFS was 11.9 months (95% CI = ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network.

Project description:Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However, evidence illustrates that targeting FAK is most effective in combination therapy rather than in monotherapy. Here, we demonstrated that the FAK inhibitor, IN10018, and pegylated liposome doxorubicin (PLD) exerted effective antitumor activity preclinically and clinically (clinical trial ID: CTR20200913). The clinical study is a phase Ib trial which includes dose confirmation and expansion sections. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. As of the data cutoff date (30 November 2022), a total of 61 platinum-resistant ovarian cancer (PROC) patients were enrolled and no IN10018-related grade 4 or 5 adverse effects (AEs) were reported. The ORR was 46.3% (95% confidence interval (CI): 32.6%, 60.4%) and the DCR was 83.3% (95% CI: 70.7%, 92.1%). The median PFS was 7.26 months (95% CI: 5.16 - 8.02 months), and the median duration of response (DoR) was 6.93 months (95% CI: 4.17 - 9.13 months). The primary and secondary endpoints were met. The median OS was not reached, and still maturing. Notably, the regimen exhibited response latency and long-lasting effects in the clinical trial, outcomes frequently observed in immunotherapy. Our preclinical study revealed that the 2-drug combination can maximize the immunogenic cell death (ICD) of cancer cells, boosting the maturation of dendritic cells (DCs) and stimulating CD8 T cells to strengthen the antitumor effects. At present, immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of immunogenic niche. Our work confirmed that IN10018 in combination with PLD can prime the tumor microenvironment, supplementing it with sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. Correspondingly, animal studies validated that the antitumor effects of ICB can be significantly enhanced by this doublet regimen. The preclinical results warrant further clinical exploration for the triplet regimen with IN10018, PLD, and ICB.

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A phase II study of sitravatinib combined with tislelizumab plus docetaxel for acquired resistance to PD-(L)1 in patients with advanced/metastatic non-small cell lung cancer

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