Combo of targeted and immunotherapy may boost NSCLC treatment by overcoming immune resistance and enhancing anti-tumor activity

By Tarun Sai LomteReviewed by Danielle Ellis, B.Sc.Feb 15 2024

In a recent study published in Nature Medicine, researchers evaluated rational combination treatment regimens for advanced/metastatic non-small-cell lung cancer (NSCLC).

Background

Patients with advanced NSCLC initially receive therapy based on the molecular classification of the disease. Immunotherapy with anti-programmed death (ligand)-1 [anti-PD(L)-1] checkpoint inhibitors or in combination with platinum-doublet therapy is the standard of care treatment for NSCLC tumors lacking targetable molecular alterations. The tumor microenvironment (TME) and tumor-intrinsic factors influence responses to immune checkpoint blockade (ICB).

Clinical resistance to ICB is common and complex and can occur during treatment. Besides, immunosuppressive cell subsets within the TME can influence responses to ICB. Understanding the mechanisms underlying resistance and exploring effective therapies is an unmet requirement, as currently, there are no immunotherapy-based treatments for NSCLC patients who progress beyond initial ICB.

The HUDSON study is an ongoing, non-randomized, multi-center, open-label, modular, phase 2 trial testing rational combination treatments for advanced NSCLC. HUDSON investigated inhibitors of DNA damage response and repair pathways along with durvalumab (an anti-PD-L1 monoclonal antibody), given that mismatch repair deficiency is associated with benefits from immunotherapies.

The study and findings

In the present study, researchers reported clinical safety, efficacy, and translational data from four treatment modules from HUDSON in patients who received a platinum-doublet therapy and progressed on anti-PD-(L)1-based treatment. Overall, 941 patients were screened for enrolment between 2018 and 2022 and underwent molecular tumor profiling. Of these, 268 received treatment and were assigned to a biomarker-matched cohort (group A) or biomarker-non-matched cohort (B).

Treatment modules included durvalumab plus 1) ceralasertib [ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor], 2) oleclumab [anti-cluster of differentiation 73 (CD73) monoclonal antibody], 3) danvatirsen [antisense oligonucleotide targeting signal transducer and activator of transcription 3 (STAT3)], or 4) olaparib [poly-ADP ribose polymerase (PARP) inhibitor].

Seventy-nine patients received durvalumab-ceralasertib, 57 received durvalumab-oleclumab, 45 received durvalumab-danvatirsen, and 87 received durvalumab-olaparib. Within group A, patients with a mutation in the homologous recombination repair gene (HRRm) or aberrations in liver kinase B1 (LKB1) received durvalumab-olaparib. Patients showing tumors with aberrations in ataxia telangiectasia mutated (ATM) received durvalumab-ceralasertib.

Patients having tumors with high levels of CD73 received durvalumab-oleclumab. In group B, patients without prespecified biomarkers were enrolled in separate cohorts based on whether they had primary or acquired resistance to their prior anti-PD-(L)1 therapy. Patient demographics and clinical characteristics were similar across treatment modules. Efficacy was estimated to assess whether targeting resistance-associated pathways could improve outcomes.

The primary endpoint, objective response rate (ORR), was 13.9% with durvalumab-ceralasertib, while the pooled ORR across other modules was 2.6%. Further, progression-free (PFS) and overall survival (OS) were longer with durvalumab-ceralasertib than pooled estimates of other regimens.

In the ATM-altered biomarker-matched cohort, the ORR with durvalumab-ceralasertib was higher (26.1%) than ORRs in primary (13%) and acquired (6.1%) resistance biomarker-non-matched groups. Besides, PFS and OS were longer in the ATM-altered biomarker-matched cohort than biomarker-non-matched cohorts.

ORR was 4.6% with durvalumab-olaparib, 9.5% and 4.8% in HRRm and LKB1 biomarker-matched cohorts, and 0% and 4.3% in primary and acquired resistance cohorts, respectively. There were no objective responses with durvalumab-danvatirsen. A partial response was noted with durvalumab-oleclumab, suggesting CD73 inhibition was insufficient to reverse immunosuppression.

The overall incidence of treatment-emergent (TEAEs), treatment-related (TRAEs), and serious (SAEs) adverse events was similar across treatment modules. Two durvalumab-ceralasertib recipients and five in other regimens died due to a TEAE that was deemed unrelated to treatment. Additional experiments suggested that tumors with features associated with immunotherapy resistance were susceptible to durvalumab-ceralasertib.

Finally, the team performed exploratory hypothesis-generating analyses to investigate mechanisms of action with durvalumab-ceralasertib. Blood samples were collected at baseline, a week after ceralasertib treatment, and after durvalumab therapy to analyze gene expression and T cell receptor (TCR) profile dynamics.

Gene expression analysis showed dynamic, reversible changes after a week of ceralasertib and before the first durvalumab dose. Besides, changes in immunity-relevant signatures were evident. Longitudinal TCR sequencing highlighted cyclical changes such as clonality reduction after a week of ceralasertib, with a reversal to baseline following durvalumab therapy. Most patients exhibited an increase in peripheral TCR clonality after durvalumab addition.

This was followed by an increase in expanded clones. Similar changes in T cell clonality were not observed with durvalumab-danvatirsen or durvalumab-olaparib. Further, reductions in exhausted T cells and increases in interferon pathway activation were observed in the peripheral blood during the ceralasertib therapy period. In addition, the team observed enhanced expansion and maintenance of abundant clones, indicating anti-tumor response.

Conclusions

Taken together, the first report from HUDSON illustrates notable efficacy with durvalumab-ceralasertib, with substantially higher response rates and longer OS and PFS compared to other treatment regimens pooled. It had superior activity in the ATM-altered biomarker-matched cohort than in the biomarker-non-matched cohorts.

Durvalumab-ceralasertib showed a generally acceptable safety profile, with broad tolerability and a low treatment discontinuation rate due to TRAEs. These findings have promoted the initiation of a phase 3 study comparing durvalumab-ceralasertib with docetaxel. Meanwhile, HUDSON is still ongoing, accruing cohorts for additional combination regimens.