Sorafenib dose escalation in treatment-naïve patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study

Objective: To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma (mRCC). Patients and Methods: Intra-patient dose escalation may enhance the clinical benefit of targeted anticancer agents in metastatic disease. In this non-randomised, open-label, Phase 2b study, treatment-naïve patients with mRCC were initially treated with the standard oral sorafenib dose [400 mg twice daily (BID)]. Two dose escalations were planned, each 200 mg BID after 28 days at the prior level. Dose reductions, interruptions, or delayed escalations were used to manage adverse events (AEs). The primary endpoint was objective response rate (ORR) in the modified intent-to-treat (mITT) population, which comprised patients with ≥6 months of treatment including ≥4 months of therapy at their highest tolerated dose. Secondary endpoints included progression-free survival (PFS) and safety. Results: In all, 83 patients received sorafenib. The dose received for the longest duration was 400, 600, and 800 mg BID in 48.2%, 15.7%, and 24.1% of patients, respectively. The ORR was 44.4% [n = 8/18; 95% confidence interval (CI) 21.5–69.2] and 17.9% (n = 12/67; 95% CI 9.6–29.2) in the mITT and ITT populations, respectively. The median (95% CI) PFS was 7.4 (6.0–11.7) months (ITT). The most common AEs of any grade were hand–foot skin reaction (66.3%) and diarrhoea (63.9%). Conclusion: Sorafenib demonstrated clinical benefit in treatment-naïve patients with mRCC. However, relatively few patients could sustain doses of >400 mg BID. There was evidence that, where tolerated, escalation from the standard sorafenib dose may have enhanced clinical benefit. However, this study does not support dose escalation for most patients with treatment-naïve mRCC. Alternative protocols for sorafenib dose escalation could be explored

Biomarqueurs des immunothérapies anti-PD-1/PD-L1 : facteurs cliniques, histologiques et immunohistochimiques associés au statut PD-L1

Inhibitors of PD-1/PD-L1 have changed the treatment paradigm in oncology. However, only a minority of patients respond to these therapies and therefore there is a critical need to identify molecular predictors. PD-L1 expression, detected by immunohistochemistry is currently the most explored biomarker, but its predictive value is still unclear.We reviewed in detail the files of 309 patients who were treated with anti-PD-1/PD-L1 antibodies (pembrolizumab P, durvalumab D or atezolizumab A) at Gustave Roussy Cancer Campus between January 2014 and July 2015. Clinical, histological and immunohistochemical (IHC) features were retrospectively collected for all of them in order to identify factors affecting PD-L1 status.83 patients (26.9%) were positive for PD-L1 in IHC. PD-L1 positivity varied significantly depending on the treatment considered: P = 32.9% ; D= 30.5% et A = 11.5% (p=0.002). This suggests a relation between the companion test used for IHC and PD-L1 positivity. Multivariate analysis showed that PD-L1 expression was associated with IHC test and histological type (respectively p= 0.001 et 0.008). Atezolizumab companion test (SP142) was associated with low PD-L1 expression; while squamous cell carcinoma and urothelial carcinoma were associated with high expression. Among metastatic patients, samples from liver metastasis showed a trend for lower PD-L1 expression. There was no significant relationship with sampling method (biopsy or surgical resection), nor with sample’s age, cellularity, or sample location (primary or metastatic site).This study identified IHC and histological factors associated with PD-L1 positivity, which need to be further investigated.Les inhibiteurs de l’axe PD-1/PD-L1 marquent une révolution de la prise en charge thérapeutique en oncologie. Cependant, seule une minorité des patients répond au traitement, et des biomarqueurs prédictifs de réponse sont indispensables pour sélectionner ces patients. Le biomarqueur le plus étudié est l’expression immunohistochimique (IHC) de PD-L1, avec des résultats discordants. Les données cliniques, histologiques et IHC de 309 patients traités dans un essai anti-PD-1/PD-L1, par pembrolizumab (P), durvalumab (D) ou atezolizumab (A), entre janvier 2014 et juillet 2015 à Gustave Roussy ont été analysées de façon rétrospective à la recherche de facteurs associés au statut PD-L1. 83 patients (26,9%) étaient PD-L1 positifs, avec une différence significative en fonction de l’essai dans lequel les patients avaient été inclus : P = 32,9% ; D= 30,5% et A = 11,5% (p=0,002). En analyse multivariée, le statut PD-L1 était associé au test IHC réalisé et au type histologique (respectivement p= 0,001 et 0,008) : le test compagnon de l’atezolizumab (anticorps SP142) était associé à une moindre positivité; tandis que les histologies de type épidermoïde et carcinome urothélial étaient associées à la positivité. Parmi le sous-groupe des patients métastatiques, les prélèvements provenant de métastases hépatiques avaient tendance à être associés à une moindre positivité. L’ancienneté du prélèvement, sa cellularité, le site (primitif ou métastase) et la méthode de prélèvement (exérèse ou biopsie) n’influençaient pas le statut PD-L1. Ces résultats mettent en évidence la nécessité d’évaluer les facteurs IHC et histologiques associés au statut PD-L1, afin de prendre en compte leur impact

Is there an Exposure–Response Relationship for Nivolumab in Real-World NSCLC Patients?

Pharmacokinetic/pharmacodynamic data from real-world cohort are sparse in non small–cell lung cancer (NSCLC) patients treated with nivolumab. The aim of this prospective observational study was to explore the exposure-response relationship for effectiveness and toxicity of nivolumab in 81 outpatients with metastatic lung cancer. Nivolumab plasma trough concentrations (Cmin) were assayed at days 14, 28, and 42. Prognostic factors (including Cmin) regarding progression-free survival (PFS) and overall survival (OS) were explored using a multivariate Cox model. A Spearman’s rank test was used to investigate the relationship between Cmin and grade >2 immune-related adverse events (irAE). Mean nivolumab Cmin was 16.2 ± 6.0 µg/mL (n = 76), 25.6 ± 10.2 µg/mL (n = 64) and 33.4 ± 11.3 µg/mL (n = 53) at days 14, 28, and 42, respectively. No pharmacokinetic/pharmacodynamic (PK/PD) relationship was observed with either survival or onset of irAE. Multivariable Cox regression analysis identified Eastern Cooperative Oncology Group Performance Status (hazard ratio 1.85, 95%confidence interval 1.02–3.38, p-value = 0.043) and baseline use of corticosteroids (HR 8.08, 95%CI 1.78–36.62, p-value = 0.007) as independent risk factor for PFS and only baseline use of corticosteroids (HR 6.29, 95%CI 1.46–27.08, p-value = 0.013) for OS. No PK/PD relationship for nivolumab was observed in real-world NSCLC patients. This supports the recent use of flat dose regimens without plasma drug monitoring

Axitinib in the treatment of renal cell carcinoma: design, development, and place in therapy

Audrey Bellesoeur, Edith Carton, Jerome Alexandre, Francois Goldwasser, Olivier Huillard Department of Medical Oncology, Hopital Cochin AP-HP, Paris, France Abstract: Since 2005, the approved first-line treatment of metastatic renal cell carcinoma consists in tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptors (VEGFRs). Axitinib is an oral second-generation TKI and a potent VEGFR inhibitor with a half maximal inhibitory concentration for the VEGF family receptors 10-fold lower than other TKIs. Axitinib activity in renal cell carcinoma (RCC) patients has been studied in various settings and particularly as second-line treatment. In this setting, axitinib with clinically based dose escalation compared to sorafenib has demonstrated an improvement in progression-free survival in a randomized Phase III trial leading to US Food and Drug Administration approval. In the first-line setting, axitinib failed to demonstrate improved efficacy over sorafenib, but the field of RCC treatment is rapidly changing with novel TKIs as cabozantinib or the emergence of check point inhibitors as nivolumab and the place of axitinib in therapy is therefore challenged. In this review, we focus on axitinib pharmacological and clinical properties in RCC patients and discuss its place in the treatment of patients with RCC. Keywords: renal cell carcinoma, tyrosine kinase inhibitors, vascular endothelial growth factor, axitinib, pharmacolog

Differential Kinase Activation in Peripheral Blood Mononuclear Cells from Non-Small-Cell Lung Cancer Patients Treated with Nivolumab

In the era of precision medicine, research of biomarkers for identification of responders to nivolumab therapy is a major challenge. Peripheral blood mononuclear cells (PBMC) could be an interesting surrogate tissue for identifying pharmacodynamic biomarkers. The aim of this exploratory study was to investigate the global serine/threonine kinase (STK) activity in PBMC from non-small-cell lung cancer (NSCLC) patients using a high throughput kinomic profiling method. PamChip® microarrays were used to explore the STK kinomic profile in PBMC from 28 NSCLC patients before nivolumab initiation (D0) and on day 14 (D14) of the first administration. Two clusters of patients (A and B) were identified at D0, median overall survival (OS) tended to be longer in cluster A than in B (402 vs. 112.5 days, respectively; p = 0.15). Interestingly, the PD-L1 tumor cell score (p = 0.045), the count of CD8+ cells (p = 0.023) and the total body weight (p = 0.038) were statistically different between the clusters. On D14, clusters C and D were identified. Greater activity of most STK, especially those of the PI3K/Akt signaling pathway, was noticed among cluster C. No significant difference between C and D was observed regarding OS. Considering the small number of patients, results from this preliminary study are not conclusive. However, the 4-fold longer median OS in cluster A paves the way to further investigate, in a larger cohort of NSCLC patients, the benefit of basal STK kinomic profile in PBMC to identify responders to nivolumab therapy