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

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

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

Clinical and kinomic analysis identifies peripheral blood mononuclear cells as a potential pharmacodynamic biomarker in metastatic renal cell carcinoma patients treated with sunitinib

International audienceBackground: Sunitinib is a protein tyrosine kinase (PTK) inhibitor that has immune-modulating properties. In this context, peripheral blood mononuclear cells (PBMC), mainly constituted by lymphocytes, could be a perfect surrogate tissue for identifying and assaying pharmacodynamic biomarkers of sunitinib. In this study, we investigated the changes in lymphocytes count as pharmacodynamic biomarker in metastatic renal cell carcinoma (mRCC) patients under sunitinib therapy. Thereafter, we studied the ex vivo effect of sunitinib and SU12262 (active metabolite) on PBMC from naïve mRCC patients using a high throughput kinomic profiling method. Methods: The prognostic value of total lymphocytes count between Day 0 and Day 21 (expressed as a ratio D21/D0) was retrospectively investigated in 88 mRCC patients under sunitinib therapy. PTK PamChip ® microarrays were used to explore prospectively the ex vivo effect of sunitinib and SU12662 on PTK activity in PBMC from 21 naïve mRCC patients. Results: In this retrospective study, D21/D0 lymphocytes ratio (Hazard Ratio, 1.83; CI95%, 1.24-2.71; p=0.0023) was independently associated with PFS. Interestingly, kinomic analysis showed that D21/D0 lymphocytes ratio and Heng prognostic model was statistically associated with the ex vivo sunitinib and SU12662 effect in PBMC. Conclusion: The present study highlights that D21/D0 total lymphocytes ratio could be a promising pharmacodynamic biomarker in mRCC patients treated with sunitinib. Additionally, it paves the way to investigate the kinomic profile in PBMC as a prognostic factor in a larger cohort of mRCC patients under sunitinib therapy

Oral Etoposide and Trastuzumab Use for HER2-Positive Metastatic Breast Cancer: A Retrospective Study from the Institut Curie Hospitals

International audienceBackground: The TOP2A and ERBB2 genes are co-amplified in about 40% of HER2 positive (HER2+) breast cancers. Oral etoposide (VP16), an inhibitor of topoisomerase-II (encoded by TOP2A), has demonstrated clinical activity in metastatic breast cancer (MBC). The benefit of oral VP16 combined with trastuzumab (VP16-T) in HER2+ MBC has not yet been evaluated.Methods: Patients treated at the Institut Curie Hospitals with VP16-T for HER2+ MBC were retrieved by an in silico search. Progression-free survival (PFS), overall survival (OS), response rate, prolonged PFS (defined as at least 6 months), clinical benefit, and toxicity were assessed. The co-amplification of ERBB2 and TOP2A was assessed by shallow whole genome sequencing on tumor tissue whenever available.Results: Forty-three patients received VP16-T after a median number of six prior treatment lines for HER2+ MBC. Median PFS and OS were 2.9 months (95% CI [2.4–4.7]) and 11.3 months (95% CI [8.3–25.0]), respectively. Three patients had a complete response, while 12/40 (30%) experienced clinical benefit. Only three patients stopped treatment for toxicity. Seven (35%) patients displayed a TOP2A/ERBB2 co-amplification. No statistically significant correlation was found between outcome and TOP2A/ERBB2 co-amplification.Conclusion: Our analysis suggests a favorable efficacy and toxicity profile for VP16-T in patients with heavily pretreated HER2+ MBC

COVID-19 in breast cancer patients: a cohort at the Institut Curie hospitals in the Paris area

BACKGROUND: Cancer patients have been reported to be at higher risk of COVID-19 complications and deaths. We report the characteristics and outcome of patients diagnosed with COVID-19 during breast cancer treatment at Institut Curie hospitals (ICH, Paris area, France). METHODS: An IRB-approved prospective registry was set up at ICH on March 13, 2020, for all breast cancer patients with COVID-19 symptoms or radiologic signs. Registered data included patient history, tumor characteristics and treatments, COVID-19 symptoms, radiological features, and outcome. Data extraction was done on April 25, 2020. COVID-19 patients were defined as those with either a positive RNA test or typical, newly appeared lung CT scan abnormalities. RESULTS: Among 15,600 patients actively treated for early or metastatic breast cancer during the last 4 months at ICH, 76 patients with suspected COVID-19 infection were included in the registry and followed. Fifty-nine of these patients were diagnosed with COVID-19 based on viral RNA testing (N = 41) or typical radiologic signs: 37/59 (63%) COVID-19 patients were treated for metastatic breast cancer, and 13/59 (22%) of them were taking corticosteroids daily. Common clinical features mostly consisted of fever and/or cough, while ground-glass opacities were the most common radiologic sign at diagnosis. We found no association between prior radiation therapy fields or extent of radiation therapy sequelae and extent of COVID-19 lung lesions. Twenty-eight of these 59 patients (47%) were hospitalized, and 6 (10%) were transferred to an intensive care unit. At the time of analysis, 45/59 (76%) patients were recovering or had been cured, 10/59 (17%) were still followed, and 4/59 (7%) had died from COVID-19. All 4 patients who died had significant non-cancer comorbidities. In univariate analysis, hypertension and age (> 70) were the two factors associated with a higher risk of intensive care unit admission and/or death. CONCLUSIONS: This prospective registry analysis suggests that the COVID-19 mortality rate in breast cancer patients depends more on comorbidities than prior radiation therapy or current anti-cancer treatment. Special attention must be paid to comorbidities when estimating the risk of severe COVID-19 in breast cancer patients