A PD-1/PD-L1 Proximity Assay as a Theranostic Marker for PD-1 Blockade in Patients with Metastatic Melanoma.

PURPOSE: Less than 50% of patients with melanoma respond to anti-programmed cell death protein 1 (anti-PD-1), and this treatment can induce severe toxicity. Predictive markers are thus needed to improve the benefit/risk ratio of immune checkpoint inhibitors (ICI). Baseline tumor parameters such as programmed death ligand 1 (PD-L1) expression, CD8+ T-cell infiltration, mutational burden, and various transcriptomic signatures are associated with response to ICI, but their predictive values are not sufficient. Interaction between PD-1 and its main ligand, PD-L1, appears as a valuable target of anti-PD-1 therapy. Thus, instead of looking at PD-L1 expression only, we evaluated the predictive value of the proximity between PD-1 and its neighboring PD-L1 molecules in terms of response to anti-PD-1 therapy. EXPERIMENTAL DESIGN: PD-1/PD-L1 proximity was assessed by proximity ligation assay (PLA) on 137 samples from two cohorts (exploratory n = 66 and validation n = 71) of samples from patients with melanoma treated with anti-PD-1±anti-CTLA-4. Additional predictive biomarkers, such as PD-L1 expression (MELscore), CD8+ cells density, and NanoString RNA signature, were also evaluated. RESULTS: A PD-1/PD-L1 PLA model was developed to predict tumor response in an exploratory cohort and further evaluated in an independent validation cohort. This score showed higher predictive ability (AUC = 0.85 and 0.79 in the two cohorts, respectively) for PD-1/PD-L1 PLA as compared with other parameters (AUC = 0.71-0.77). Progression-free and overall survival were significantly longer in patients with high PLA values (P = 0.00019 and P < 0.0001, respectively). CONCLUSIONS: The proximity between PD-1 and PD-L1, easily assessed by this PLA on one formalin-fixed paraffin-embedded section, appears as a new biomarker of anti-PD-1 efficacy.

[Treatment of melanoma with immune checkpoints inhibitors]. / Traitement du mélanome par les inhibiteurs du contrôle immunitaire.

Treatment of melanoma with immune checkpoints inhibitors .Immunotherapy with checkpoints inhibitors stimulates the anti-tumor response. It has dramatically changed the prognosis of advanced melanoma and other cancers. Anti-PD1, alone or in combination with anti-CTLA4, has demonstrated significantly better response and overall survival rates than chemotherapy. The immuno-mediated toxicity is more frequent and more serious with the combination of anti-PD1 and anti-CTLA4, which also appears as the most effective treatment for metastatic melanoma. Adjuvant anti-PD1 therapy is also effective in preventing recurrence in patients with resected stage III or IV melanoma. Studies are underway to evaluate this treatment in a neo-adjuvant situation and in localized melanomas with high risk of recurrence (stage II) with promising results.

Traitement du mélanome par les inhibiteurs du contrôle immunitaire .L'immunothérapie, en inhibant les points de contrôle (« checkpoints ¼) immunitaire, stimule la réponse antitumorale. Elle a considérablement modifié la prise en charge du mélanome et d'autres cancers. Les anticorps monoclonaux anti-PD-1, seuls ou en association aux anti-CTLA4, ont permis d'obtenir des taux de réponse et de survie globale largement supérieurs à la chimiothérapie. La toxicité, immunomédiée, est plus fréquente et plus grave avec l'association anti-PD-1 et anti-CTLA4, qui semble aussi être le traitement le plus efficace actuellement dans le mélanome métastatique. L'immunothérapie adjuvante par anti-PD-1 a également démontré son efficacité en prévention d'une récidive dans les mélanomes de stade III ou IV opérés. Des études sont en cours pour évaluer ce traitement en situation néo-adjuvante et dans les mélanomes localisés à haut risque de récidive (stades II) avec des résultats prometteurs.

Clinical impact of COVID-19 on patients with cancer treated with immune checkpoint inhibition.

BACKGROUND: Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer. METHODS: We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality. FINDINGS: Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off. INTERPRETATION: COVID-19-related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.

[Immune checkpoint inhibitors for treatment of advanced stage melanoma]. / Immunothérapie dans le traitement du mélanome au stade avancé.

Immune checkpoint inhibitors for treatment of advanced stage melanoma. Immunotherapy, which stimulates the anti-tumor immune response, has significantly modified the prognosis of advanced stage melanoma. Anti-CTLA4 monoclonal antibody, ipilimumab, showed a benefit on survival compared to chemotherapy in 2011. Anti-PD1, nivolumab and pembrolizumab subsequently showed superior clinical benefit including overall survival and tolerance over anti-CTLA4. Currently, the combination of ipilimumab and nivolumab appears as the most effective immunotherapy but the toxicity of this regimen is a limitation. Anti-PD1 antibodies have also been evaluated in the adjuvant setting for patients with stage III or IV resected melanoma where they have shown a significant benefit in term of relapse-free-survival. Studies are underway to evaluate these drugs in stage II resected melanoma and in neo-adjuvant setting with promising results.

Immunothérapie dans le traitement du mélanome au stade avancé. L'immunothérapie, consistant à stimuler la réponse immunitaire antitumorale, a considérablement modifié la prise en charge du mélanome au stade avancé. En 2011, l'ipilimumab, un anticorps monoclonal anti-CTLA-4, a été le premier à montrer un bénéfice en survie par rapport à la chimiothérapie. Le nivolumab et le pembrolizumab sont des anticorps anti-PD-1 qui ont été développés par la suite. Ils ont montré leur supériorité en termes de taux de réponse et de survie globale et une meilleure tolérance par rapport à l'anti-CTLA-4. Actuellement, l'association ipilimumab-nivolumab semble être l'immunothérapie la plus efficace, mais au prix d'une toxicité importante. Les anti-PD1 ont également démontré un bénéfice en situation adjuvante chez des patients opérés d'un mélanome à haut risque de récidive (stades III et IV). Des études sont en cours pour évaluer ces traitements dans les stades II opérés et en situation néo-adjuvante, avec des résultats prometteurs.

Transient pituitary ACTH-dependent Cushing syndrome caused by an immune checkpoint inhibitor combination.

Immune checkpoint inhibitors have improved survival in numerous advanced malignancies, but are associated with a number of immune-related adverse events, including endocrinopathies. Endogenous Cushing's syndrome (CS) is a rare disorder resulting from exposure to high levels of circulating cortisol. CS can be caused either by adrenal cortex tumors or hyperplasia or by pituitary or extra-pituitary tumors over-secreting ACTH (known as ACTH-dependent CS). We report the first case of transient ACTH-dependent CS, which appeared after combined ipilimumab and nivolumab therapy. Our patient presented typical clinical features of CS after three infusions of combined therapy, high serum and daily urinary free cortisol, and high serum ACTH levels. Pituitary MRI showed an enlargement of the pituitary gland suggesting ACTH secretion of pituitary origin, which was confirmed by inferior petrosal sinus sampling. The pituitary findings were preceded by thyroiditis. The evolution was characterized by spontaneous CS regression and subsequent appearance of severe corticotroph deficiency consistent with destructive hypophysitis. Immunotherapy is a novel cause of CS.