A phase II umbrella HUDSON study has demonstrated an efficacy signal with durvalumab plus ceralasertib in patients with advanced/metastatic non-small cell lung cancer (NSCLC) following prior failure to anti-PD1/PD-L1 immunotherapy and platinum-doublet therapy. The regimen showed particular efficacy in patients with ATM alterations and in biomarker-nonmatched primary and acquired resistance cohorts across various subgroups recalcitrant to immune checkpoint blockade.
The first report from HUDSON demonstrates a notable efficacy signal with durvalumab plus ceralasertib, with substantially higher response and disease control rates and substantially longer progression-free survival (PFS) and overall survival (OS) than with the other regimens, pooled according to Dr. John V. Heymach of the Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center in Houston, TX, US, and colleagues who published the findings on 13 February 2024 in the Nature Medicine.
For patients without targetable molecular alterations, standard-of-care treatment comprises immunotherapy with an anti-PD1/PD-L1 checkpoint inhibitor alone or with platinum-doublet therapy. Currently, there are few options offering clinical benefit for patients following failure to the standard-of-care treatment. Understanding mechanisms of resistance, which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumour microenvironment, development of effective therapies to overcome them, remains an unmet need.
The ongoing, open-label, multicentre, non-randomised, modular, phase II umbrella HUDSON study was designed to build a comprehensive understanding of key features in patients and their tumours associated with disease progression and to differentiate tumour characteristics and treatment activity in primary and acquired resistance phenotypes. Rational combination therapies were selected for investigation in HUDSON based on targeting proposed mechanisms of immunosuppression with the aim of reinvigorating immune-mediated antitumour activity. Treatments received in these modules were durvalumab plus ceralasertib (ATR kinase inhibitor), olaparib (PARP inhibitor), danvatirsen (STAT3-targeting antisense oligonucleotide) or oleclumab (anti-CD73 monoclonal antibody).
Patients underwent tumour molecular profiling at screening and were assigned to either a biomarker-matched cohort treated with durvalumab plus ceralasertib in patients with ATM altered tumours, durvalumab plus olaparib in homologous recombination repair altered, STK11/LKB1 altered, durvalumab plus oleclumab in high CD73 expression, or a biomarker-nonmatched group. Patients in the latter group were further stratified into primary or acquired resistance cohorts. Multi-omic longitudinal peripheral biomarker profiling was used for hypothesis-generating exploratory analyses of possible underlying mechanisms of action driving treatment outcomes.
A total of 268 patients received treatment. Greatest clinical benefit was observed with durvalumab plus ceralasertib; objective response rate which was a primary outcome was 13.9% versus 2.6% with other regimens, pooled. In terms of secondary outcomes, median PFS was 5.8 (80% confidence interval [CI] 4.6–7.4) versus 2.7 (CI 1.8–2.8) months, and median OS was 17.4 (CI 14.1–20.3) versus 9.4 (CI 7.5–10.6) months.
Benefit with durvalumab plus ceralasertib was consistent across known immunotherapy-refractory subgroups. In patients with ATM altered tumours hypothesised to harbour vulnerability to ATR inhibition, objective response rate was 26.1%, median PFS 8.4 months and median OS 22.8 months. Durvalumab–ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumour immunity.
The authors commented that with its innovative, modular study design incorporating patient cohorts with specific biomarkers as well as biomarker-nonmatched cohorts with primary or acquired resistance, coupled with comprehensive characterisation of key gene alterations via biological analysis of tumour material, HUDSON has enabled evaluation of multiple rational combinations and investigation of specific biomarkers associated with resistance.
Median PFS and OS with durvalumab plus ceralasertib of 5.8 and 17.4 months are notable in the context of reports from prospective clinical trials in previously treated NSCLC of docetaxel as second- or third-line treatment following platinum-based chemotherapy and immunotherapy (median PFS and OS of 4.0 and 10.5 months in the CONTACT-01 study; median OS of 8.3 months with docetaxel or pemetrexed in the ATALANTE-1 study; median PFS and OS of 4.5 and 11.3 months in primarily non-squamous NSCLC in the CodeBreaK 200 study) or following platinum-based chemotherapy (median PFS and OS ranges of 2.8–4.2 and 8.1–9.9 months), in which findings were better than or similar to the data for the other HUDSON regimens, pooled.
Findings from the HUDSON study have resulted in initiation of the phase III LATIFY study, which compares durvalumab plus ceralasertib versus docetaxel for the treatment of patients with NSCLC whose disease progressed during or following prior anti-PD1/PD-L1 therapy and platinum-based chemotherapy. Additionally, HUDSON is ongoing, with continued accrual to biomarker-matched and biomarker-nonmatched cohorts receiving durvalumab plus ceralasertib or ceralasertib monotherapy and to cohorts investigating additional treatment combinations of durvalumab plus trastuzumab deruxtecan or cediranib.
The study was funded by AstraZeneca.
Reference
Besse B, Pons-Tostivint E, Park K, et al. Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial. Nature Medicine; Published online 13 February 2024. DOI: https://doi.org/10.1038/s41591-024-02808-y