Overcome resistance to anti-PD1(L1) immunotherapy: first lung cancer patient enrolled in the Pioneer Project’s clinical trial

Date : 20 December 2019
Category : MI Live,News,Pioneer Project

  • This randomized clinical trial is one of the pillars of the multifaceted undertaking that is The Pioneer Project, a major international research project that aims to understand, predict and overcome resistance to PD1(L1) immune checkpoint inhibitors (ICIs).
  • Coupled to an analysis of predictive biomarkers of resistance, the multicentric umbrella trial includes 4 experimental arms that each combine the anti-PDL1 durvalumab (ImfinziTM, AstraZeneca) with one of four next generation ICIs.
  • The trial’s primary endpoint is the 12-week percentage of patients that will achieve complete response, partial response or maintain a stable disease under treatment.

The Pioneer Project, a major international Hospital-University Research (RHU) project that addresses the critical challenge of resistance to PD1(L1) inhibitors, today announced that a first patient has been included in its umbrella clinical trial designed to evaluate efficacy and safety of four original ICI combinations in patients with PD1(L1) inhibitor-resistant advanced non-small-cell lung cancer.

PD1(L1) inhibitors have led to a spectacular reduction in tumour volume and a significant lengthening of life expectancy in about 20% of NSCLC patients, and yet, lung cancer remains the leading cause of cancer deaths worldwide as most patients are or become resistant to these treatments. Still largely misunderstood, these mechanisms of resistance are highly complex and vary over time and space from one patient to another and within the same patient. To embrace such complexity, The Pioneer Project has designed an unprecedented multiparametric approach that should allow to better understand, predict and obviously overcome these resistances (Figure 1).

The study first interrogates a wide panel of biomarkers[1] that are potentially linked to and could predict the response to PD1(L1)-inhibitors and other ICIs: properties of the cancer cells themselves, density, identity and degree of anti-tumour activity of immune cells in the tumour, its invasive margin and the bloodstream, and finally, identity of the microorganisms that live in the patient’s gut (microbiota) which might influence the anti-tumour immune response, as recent studies suggest.

Second, the study is not limited to examining patients for whom PD1(L1)-inhibitors have been ineffective, but instead scrutinizes advanced lung cancer patients subjected to any of the existing PD1(L1) inhibitors prior to knowing their degree of response. Both progressors and non-progressors are therefore monitored before and throughout their treatment. Such an agnostic approach is more likely to uncover unbiased predictive biomarkers.

Third, the study includes a randomized clinical trial that addresses in parallel the effectiveness of 4 combination immunotherapies with durvalumab (Imfinzi™, AstraZeneca) in early progressors (patients that progress between 6 and 18 weeks after the start of a PD1(L1)-inhibitor treatment). The 4 combinations were chosen to cover all possible tumour immune profiles: inflamed tumours (with large numbers of active immune cells within and around the tumour), immune excluded tumours (with a limited number and activity of immune cells in the tumour microenvironment) and immune deserts (absence of immune cells in and around the tumour).

Finally, the study also includes an exploratory program to uncover new pathways that might rescue immune checkpoint inhibitor resistance in pre-clinical settings.

“It is by approaching resistance to immune checkpoint inhibitors simultaneously on several fronts and with all the artillery available to us that we hope to shed light on the path to resolve this major issue. The awaited inclusion of a first patient in the clinical trial is most certainly a key milestone in the progression of our endeavour”, said Fabrice BARLESI, Coordinator of The Pioneer Project, Professor at Aix-Marseille University, Head of the multidisciplinary oncology and therapeutic innovations department at AP-HM, Coordinator of the Marseille center for early clinical assays in cancer (CLIP2) and co-founder of the French immunology cluster Marseille Immunopole. “I would like to emphasize the incredible act of altruism of our patients, especially given that only an estimated 50% of those that enter the biomarker program will benefit from the combination treatments offered in The Pioneer Project’s clinical trial. We are grateful for the commitment of our patients which today has taken us a major step ahead in the advancement of this study”.

“The Pioneer Project embodies an original approach to clinical research in immuno-oncology: it is to my knowledge the very first study that addresses resistance to immunotherapy from an agnostic perspective, searching for predictive biomarkers from the start and throughout treatment with anti-PD-1(L1) immune checkpoint inhibitors, and browses through different combination options to overcome resistance. Our expectations are obviously very high, we are aiming for life-changing solutions for our patientsreminded Solange PETERS, President-elect of the European Society for Medical Oncology (ESMO), Head of the Medical Oncology Service at the Vaud University Hospital Center in Lausanne, Switzerland, and member of The Pioneer Project’s SAB.

[1] Monville F et al. Immunogram to decipher PD1/L1 ICI resistance: a proof of concept in advanced NSCLC patients of the PIONeeR Project. SITC 2019.

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