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Gene expression profiles predict response to atezolizumab + platinum-etoposide in eSCLC

Presented by
Dr Martina Lorenzi, University of Padova, Italy
ESMO 2022
A prospective translational study presented at the European Society of Medical Oncology (ESMO) 2022 Congress, held in Paris, France 9-13 September, identified a differential expression of genes encoded for costimulatory molecules and cytokines between patients with extensive small-cell lung cancer (eSCLC) who responded with longer progression-free survivals (PFSs) to the new first-line standard of care platinum-etoposide plus atezolizumab (PEA) and those who had shorter PFSs [1]. Medicom talked to first author Dr Martina Lorenzi (University of Padova, Italy) to discuss the study design, results, and implications of the results.

A single-centre prospective translational study evaluated the predictive value of circulating and tissue biomarkers, including gene expression profiles, in patients with eSCLS who received the novel first-line standard of care PEA. At ESMO, Dr Lorenzi presented preliminary results of the association between gene expression profiles of tumour samples and outcome. The analysis included 20 patients with eSCLC who were treated with PEA and 770 immune/cancer-related genes were assessed.

Responders (63%) and patients with a longer progression-free survival (PFS) displayed a differential expression of genes encoded for costimulatory molecules and cytokines compared to non-responders and patients with a shorter PFS. An upregulation of cell proliferation genes (P=0.037) and downregulation of the Notch signalling pathway (P=0.06) was reported in responders. Also, a lower cytotoxic T-cells/tumour-infiltrating lymphocytes (TILs) signature scores ratio (ssr) was related to a shorter PFS (P=0.006) and overall survival (P=0.052) in the study population. In contrast, low macrophages/TILs ssr (P=0.04), high T-cells/TILs ssr (P=0.02), and mast cells/TILs (P=0.003), were linked to improved outcomes.

Medicom was able to ask Dr Lorenzi some questions to place these results in context.
Medicom: Generally, what are the unmet needs in eSCLC pts?

‘’We need to start with the fact that eSCLC is an aggressive disease with a dismal prognosis. The standard of care for first-line therapy in the last 40 years has been platinum-based chemotherapy. Although patients with eSCLC initially respond well to chemotherapy, they typically progress within 1 year; this disease is still associated with very poor outcomes, with a median overall survival (OS) of about 10 months.

Addition of immunotherapy to standard platinum-based chemotherapy became the new standard of care due to improving outcomes demonstrated in several RCTs. However, longer benefit appears evident for a selected group of patients, despite that no predictive markers have been identified so far to select patients who are more likely to benefit from immunotherapy. Identifying biomarkers will help address this unmet medical need. For example, there is still a lack of evidence regarding the addition of consolidation thoracic radiotherapy after response to first line chemo-immunotherapy combination treatment. As second line treatment, immunotherapy does not demonstrate a clinically significant improvement of outcomes compared with chemotherapy and the prognosis of these patients is poor.”
Medicom: How does the addition of PD-L1 inhibitors to front-line chemotherapy impact eSCLC outcomes?

“Several studies consistently established the superiority of adding immunotherapy to standard chemotherapy in eSCLC, although the clinical benefit remains limited to a few months. For example. the phase III IMpower133 trial evaluated atezolizumab plus carbo-etoposide for 4 cycles followed by atezolizumab maintenance compared to chemotherapy. This study established a new standard of care showing that the combination significantly prolongs OS (median OS 12.3 vs. 10.3 months; HR 0.76; 95% CI 0.60 - 0.95; P=0.0154). The CASPIAN study demonstrated the same magnitude of benefit with durvalumab plus standard platinum-based chemotherapy as IMpower133 trial with a median OS of 13 months with the combination therapy compared with 10.3 in the standard of care arm (HR 0.73). Of note, the KEYNOTE 604 trial with the anti-PD1 agent pembrolizumab met the primary PFS endpoint, but not the co-primary OS endpoint; so, it was not approved.

Two other important trials, CAPSTONE-1 with anti PD-L1 adebrelimab in the Chinese population and ASTRUM 005 with anti-PD1 serplulimab in which there was a 30% of Caucasian patients, consistently confirmed the superiority of chemo-immuno-oncology agent combination strategies. Collectively these data are very convincing.”
Medicom: Specific to your study presented at ESMO, how is the gene expression profile affected by adding atezolizumab to frontline platinum-etoposide?

“Our study is a single-centre prospective translational study on eSCLC patients receiving first-line platinum etoposide plus atezolizumab, investigating the predictive value of circulating and tissue biomarkers. At ESMO, we reported preliminary data of gene expression profile on tumour tissue samples collected at baseline, in a training set of patients. We investigated the gene signatures before treatment start in order to identify upfront predictive signature score.”
Medicom: What are the implications of your study; why is understanding the gene expression profile important to understand?

“We identified predictive and prognostic immune signatures in eSCLC receiving chemo-immunotherapy through GEP analysis; in particular we found that a higher ratio between cytotoxic T cell and tumour-infiltrating lymphocytes (TILs) signature scores as well as high ratio between T-cells and TILs signature scores, were associated with longer OS, PFS and time to treatment failure, suggesting a positive role of T cells in patient response and outcome. On the other hand, macrophages seem to have a negative role in patient prognosis, as a higher ratio between macrophages and TILs signature scores was associated with a worse outcome.

Understanding the biology and tumour microenvironment of this disease is basis to develop new treatments or new targets to modulate; moreover, predictive biomarkers may help to select patients for intensify treatment strategies.”
Medicom: Is this a step towards the use of other immune-modulating options for the future?

“Of course. Establishing, for instance, that there is a differential expression of genes encoded for costimulatory molecules and cytokines or chemokines between responders and non-responders and in patients with longer compared to shorter survival is hypothesis generating and could encourage drugs research on these pathways. For example, we found that the CXCL13-mRNA, encoding a chemokine which plays a critical role in lymphocyte infiltration, is overexpressed in patients with longer OS, so maybe targeting this pathway could enhance immune response and outcomes? Obviously further investigations are needed.

We are performing additional analyses on tissue with multiplex immunofluorescence staining in order to investigate the tumour microenvironment and on plasma collected at different timepoints in order to study dynamic biomarkers. In plasma we are investigating cell-free DNA using Next-Generation Sequencing, microRNA profiling, and Telomerase Reverse Transcriptase- TERT- mRNA levels.”
Medicom: Are there resistance mechanisms observed and can understanding gene expression dynamics help patient selection?

“We identified that macrophages seem to have a negative role, as a higher ratio between macrophages and TILs signature scores is associated with a worse outcome. In the second part of the project, not presented at ESMO, we studied immune microenvironment on tumour tissue and confirmed this data, so we selected patients who are less likely to benefit from chemo-immunotherapy treatment compare to others.“
Medicom: Do you have any final words?

“I would like to thank the patients and families who participated, as well as acknowledge my mentor and PI of the study Dr Giulia Pasello, and Prof. Antonio Rosato and Dr Anna Tosi for their role in generating these new results.”

  1. Lorenzi M, et al. Gene expression profile (GEP) of extensive small-cell lung cancer (eSCLC) patients (pts) receiving first-line platinum-etoposide plus atezolizumab (PEA). Poster Session 07, 19P, European Society of Medical Oncology Congress 2022, Paris, 09-13 September.

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