Introduction
Standard treatment for non-small-cell lung cancer (NSCLC) without targetable molecular alterations is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, durable benefit isn't guaranteed for all patients, and resistance to immune checkpoint blockade is common. Mechanisms of resistance include defects in DNA damage response and repair pathways, STK11/LKB1 alterations, antigen-presentation pathway changes, and immunosuppressive tumor microenvironment (TME) components. The phase 2 HUDSON study aimed to address this unmet need by evaluating rational combination regimens for advanced NSCLC that had progressed after anti-PD-(L)1 immunotherapy and platinum-doublet therapy. The study chose combinations targeting proposed mechanisms of immunosuppression to reinvigorate immune-mediated antitumor activity. Mismatch repair deficiency is linked to better immunotherapy response, hence the trial included DDR pathway inhibitors (PARP and ATR inhibitors) combined with durvalumab. The study also explored targeting STAT3 signaling (to reverse immunosuppression) and CD73 (to increase CD8+ effector cell activity).
Literature Review
The introduction extensively reviews the current standard of care for NSCLC, the prevalence of resistance to immune checkpoint inhibitors (ICB), and the known mechanisms of this resistance. It cites numerous studies highlighting the roles of genomic features (STK11/LKB1, KEAP1 mutations, alterations in antigen presentation), and immunosuppressive components of the TME (MDSCs, Treg cells). The rationale for the choice of combination therapies in the HUDSON trial is clearly explained based on pre-clinical data and known associations between specific genetic alterations and drug sensitivity (e.g., ATR inhibition in ATM-altered tumors, PARP inhibition in tumors with DDR defects).
Methodology
The HUDSON study (NCT03334617) is an open-label, multicenter, non-randomized, modular phase 2 umbrella trial. 941 patients were screened, with 268 receiving treatment across four modules. Patients were assigned to biomarker-matched (Group A) or biomarker-nonmatched (Group B) cohorts based on tumor molecular profiling (NGS and IHC). Group A cohorts received durvalumab plus olaparib (HRR or STK11/LKB1 alterations), ceralasertib (ATM alterations), or oleclumab (high CD73 expression). Group B patients (primary or acquired resistance to prior ICB) received durvalumab with one of the three combination partners. The primary endpoint was ORR (RECIST v1.1). Secondary endpoints included disease control rate, PFS, OS, safety, and tolerability. Exploratory analyses included multi-omic longitudinal peripheral biomarker profiling (gene expression and TCR sequencing) to investigate mechanisms of action. Tumor molecular profiling was conducted using FoundationOne CDx NGS and IHC assays. Bulk RNA sequencing and NanoString gene expression analysis were done on pre- and post-treatment blood samples. TCR sequencing assessed longitudinal changes in the T cell repertoire. Statistical analyses included Kaplan-Meier estimation for PFS and OS and appropriate tests for biomarker analyses.
Key Findings
The durvalumab-ceralasertib combination demonstrated superior efficacy compared to the other durvalumab-based combinations. The ORR was significantly higher (13.9% vs 2.6%), with longer median PFS (5.8 months vs 2.7 months) and OS (17.4 months vs 9.4 months). This benefit was consistent across various subgroups known to be associated with poor response to immunotherapy (primary resistance, PD-L1-negative tumors, squamous histology). The durvalumab-ceralasertib combination showed particularly strong activity in patients with ATM alterations (ORR 26.1%, longer PFS and OS). In contrast, the other combinations (durvalumab-olaparib, durvalumab-danvatirsen, durvalumab-oleclumab) showed limited activity. The safety profile of durvalumab-ceralasertib was acceptable, with similar or lower rates of grade 3+ TEAEs compared to the other combinations despite longer treatment duration. Exploratory biomarker analyses revealed that ceralasertib induced systemic immunomodulation, potentially enhancing durvalumab's effects by reducing exhausted T cells and increasing interferon pathway activation. This was observed through changes in gene expression signatures and T cell receptor clonality. These changes were not observed in patients receiving other combinations.
Discussion
The HUDSON study's findings highlight the potential of durvalumab-ceralasertib as a valuable treatment option for patients with advanced NSCLC who have progressed after prior ICB and platinum-based chemotherapy. The superior efficacy observed in this study, particularly in patients with ATM alterations, warrants further investigation. The broad activity seen across multiple ICB-refractory subgroups, including those with primary resistance and PD-L1 negative tumors, suggests a potential synergistic interaction between durvalumab and ceralasertib. The mechanistic studies reveal that ceralasertib may act by inducing systemic immunomodulation, thereby priming the immune system for a stronger anti-tumor response when combined with durvalumab. This is a significant observation and could inform the development of future therapeutic strategies targeting ICB resistance. While the study was limited by its non-randomized design and some variations in patient characteristics across the cohorts, the overall findings strongly support the further evaluation of this combination therapy in larger, randomized trials.
Conclusion
The HUDSON study demonstrates significant efficacy of the durvalumab-ceralasertib combination in advanced NSCLC patients who failed prior ICB and platinum-based chemotherapy, especially in those with ATM alterations. The observed immunomodulatory effects of ceralasertib provide insights into potential mechanisms of action. This warrants further investigation in larger, controlled trials, such as the ongoing phase 3 LAT-IFY study. Future research could explore the role of other biomarkers (like RBM10) and additional combination therapies within this challenging patient population.
Limitations
The HUDSON study's open-label, non-randomized design limits the strength of comparisons between treatment arms. The study did not include a durvalumab monotherapy arm, precluding direct assessment of the added benefit of each combination partner. Variations in patient demographics and baseline characteristics across cohorts could confound comparisons. The limited follow-up for some patients receiving durvalumab-ceralasertib might also affect the interpretation of some results. Finally, the use of different NGS and IHC assays for biomarker selection highlights the need for standardized biomarker testing in future studies.
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