Publications by authors named "Jean-Marie Michot"

98 Publications

Repurposing of anticancer drugs expands possibilities for antiviral and anti-inflammatory discovery in COVID-19.

Cancer Discov 2021 Apr 12. Epub 2021 Apr 12.

Gustave Roussy Cancer Campus

In 2020, the COVID-19 pandemic led to an unprecedented destabilization of the world's health and economic systems. The rapid spread and life-threatening consequences of COVID-19 have imposed a repurposing drug testing, by investigating drugs already used in other indications, including anti-cancer drugs. Anti-cancer drug repurposing started to contour after deciphering similarities between COVID-19 and malignancies pathogenesis, including abnormal inflammatory and immunological responses. In this review we will discuss the salient positive and negative points of repurposing the main anticancer drugs to further treat COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-21-0144DOI Listing
April 2021

Long-term impact of immunotherapy on quality of life of surviving patients: A multi-dimensional descriptive clinical study.

Eur J Cancer 2021 May 19;148:211-214. Epub 2021 Mar 19.

Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique, Le Kremlin-Bicêtre, France; INSERM, Institut National de La Santé et de La Recherche Médicale, Université Paris Saclay (COMUE), U1184, Immunologie des Maladies Virales et Auto-immunes, Le Kremlin-Bicêtre, France; Université Paris Saclay, Le Kremlin-Bicêtre, France; CEA, DSV/iMETI, IDMIT, Fontenay-aux-Roses, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.02.018DOI Listing
May 2021

Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers.

Cell Death Dis 2021 03 11;12(3):258. Epub 2021 Mar 11.

Département d'Oncologie Médicale, Gustave Roussy Cancer Campus, 94800, Villejuif, France.

The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient's plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-021-03540-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948172PMC
March 2021

Pirtobrutinib shows evidence to inaugurate a third generation of BTK inhibitors.

Lancet 2021 Mar;397(10277):855-857

Department of Hematology, Gustave Roussy, Université Paris-Saclay, Villejuif F-94500, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(21)00235-XDOI Listing
March 2021

Longitudinally Extensive Myelitis Associated With Immune Checkpoint Inhibitors.

Neurol Neuroimmunol Neuroinflamm 2021 05 26;8(3). Epub 2021 Feb 26.

From the Department of Brain and Behavioral Sciences (A.P., G.B.), University of Pavia, Italy; Regional Pharmacovigilance Center (K.B.), Department of Pharmacology, APHP; APHP (V.J., E.J.), Hôpital Saint-Antoine, Paris; CHI de Cornouaille (M.C.), Quimper; Service de Neurologie (C.C.), Hôpital Bicêtre, AP-HP, Le Kremlin-Bicetre; Hôpitaux Privés de Metz (J.P.), Metz; Gustave Roussy (P.B.), Université Paris-Saclay, Villejuif; Service de Dermatologie (N.K., B.G.), Cochin Hospital AP-HP, Paris; Centre Hospitalier Universitaire Lyon Sud (P.D.), Hospices Civils de Lyon, Pierre-Bénite; Hospices Civils de Lyon (F.D.), Hôpital Neurologique, Bron; Inserm (M.B.), CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Paris; OncoNeuroTox Group (F.B.), Hôpital Percy, Clamart; Service de Neuroradiologie (D.L.), AP-HP Pitié-Salpêtrière, Paris; Département d'Innovation Thérapeutique et d'Essais Précoces (J.-M.M.), Gustave Roussy, Villejuif; Department of Diagnostic Radiology (S.A.), Gustave Roussy, Villejuif; and Service de Neurologie 2 (D.P.), Groupe Hospitalier Pitié-Salpêtrière, APHP, Paris, France.

Objective: To define the characteristics and the outcome of myelitis associated with immune checkpoint inhibitors (ICIs).

Methods: We performed a retrospective research in the databases of the French Pharmacovigilance Agency and the OncoNeuroTox network for patients who developed myelitis following treatment with ICIs (2011-2020). A systematic review of the literature was performed to identify similar cases.

Results: We identified 7 patients who developed myelitis after treatment with ICIs (anti-PD1 [n = 6], anti-PD1 + anti-CTLA4 [n = 1]). Neurologic symptoms included paraparesis (100%), sphincter dysfunction (86%), tactile/thermic sensory disturbances (71%), and proprioceptive ataxia (43%). At the peak of symptom severity, all patients were nonambulatory. MRI typically showed longitudinally extensive lesions, with patchy contrast enhancement. CSF invariably showed inflammatory findings. Five patients (71%) had clinical and/or paraclinical evidence of concomitant cerebral, meningeal, caudal roots, and/or peripheral nerve involvement. Despite the prompt discontinuation of ICIs and administration of high-dose glucocorticoids (n = 7), most patients needed second-line immune therapies (n = 5) because of poor recovery or early relapses. At last follow-up, only 3 patients had regained an ambulatory status (43%). Literature review identified 13 previously reported cases, showing similar clinical and paraclinical features. All patients discontinued ICIs and received high-dose glucocorticoids, with the addition of other immune therapies in 8. Clinical improvement was reported for 10 patients.

Conclusion: Myelitis is a rare but severe complication of ICIs that shows limited response to glucocorticoids. Considering the poor functional outcome associated with longitudinally extensive myelitis, strong and protracted immune therapy combinations are probably needed upfront to improve patient outcome and prevent early relapses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954463PMC
May 2021

Severe anti-PD1-related meningoencephalomyelitis successfully treated with anti-integrin alpha4 therapy.

Eur J Cancer 2021 Mar 28;145:230-233. Epub 2021 Jan 28.

Department of Neurology, University Hospital Bicêtre, Le Kremlin Bicêtre, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.12.014DOI Listing
March 2021

Outcomes of Transplant-Eligible Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Salvage Chemotherapy: The Gustave Roussy Experience.

Clin Lymphoma Myeloma Leuk 2021 Apr 13;21(4):e373-e380. Epub 2020 Nov 13.

Départment d'Oncologie Médicale, Institut Gustave, Villejuif, France. Electronic address:

Introduction: After failure of frontline therapy, patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL) that does not respond to first-line salvage chemotherapy can be recommended second-line salvage chemotherapy. The available literature in this regard is weak, although many centers routinely offer this type of second-line salvage chemotherapy to their patients.

Patients And Methods: This retrospective study included transplant-eligible patients with RR-DLBCL treated at Gustave Roussy between January 2008 and April 2020. Eligible patients were those who received second-line salvage chemotherapy using R-DHAP or R-ICE in patients who experienced an insufficient partial response, stable disease, or progressive disease in response to first-line salvage chemoimmunotherapy using an alternative regimen.

Results: Forty-six RR-DLBCL patients received second-line salvage regimen, which yielded an objective response rate of 33%, median progression-free survival of 2.1 months, and overall survival of 11.4 months. Twelve patients proceeded to autologous stem-cell transplantation (ASCT), of whom 70% remained alive 1 year after ASCT. To explore the impact of transplantation, a multivariate analysis (excluding response to the first-line salvage regimen because this covariate was totally embedded within the transplantation covariate), ASCT was associated with progression-free survival (hazard ratio = 0.16; 95% confidence interval, 0.06-0.42) and overall survival (hazard ratio = 0.27; 95% confidence interval, 0.08-0.88).

Conclusion: Second-line salvage chemotherapy with R-DHAP or R-ICE followed by ASCT leads to a favorable outcome in almost one third of patients with RR-DLBCL and offers a median overall survival of approximately 1 year. These data support the administration of second-line salvage chemotherapy followed by ASCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.11.008DOI Listing
April 2021

Belantamab Mafotodin-Induced Epithelial Keratopathy Masquerading Myopic Surgery.

Ophthalmology 2020 12;127(12):1626

Department of Ophthalmology, Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, Paris-Saclay University, French Reference Center for FAP (NNERF), French reference network for rare ophthalmologic diseases (OPHTARA), Le Kremlin-Bicêtre, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ophtha.2020.07.047DOI Listing
December 2020

How to manage patients with corticosteroids in oncology in the era of immunotherapy?

Eur J Cancer 2020 12 16;141:239-251. Epub 2020 Nov 16.

Early Drug Development Department, Gustave Roussy, Villejuif, France. Electronic address:

Corticosteroids are among the most prescribed drugs in oncology. The indications range from cancer-related indications for refractory symptoms, anti-cancer effects mainly in hematology, supportive measures for cancer-specific treatments and more recently immune-related adverse events induced by modern immunotherapies. In oncological emergencies, corticosteroids are common first-line treatments because of their rapid effect and wide variety of actions. In the last 5 years, with the advance of immune checkpoint inhibitors, corticosteroids are becoming routinely used to manage immune-related adverse effects. Preclinical studies suggested that corticosteroid-induced immunosuppression might dampen the activity of immunotherapies. Prospective clinical studies show that corticosteroid use is a prognostic marker for the cancer outcome in metastatic setting but does not significantly alter the patient's response to immunotherapies per se. Here, we review the state of the art on corticosteroid use in oncology, with a focus on the drugs' potential impact on immunotherapy activity. The comprehensive pharmacological characteristics of corticosteroid drugs, clinical indications, modality of administration and associated precautions for use are discussed in this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.09.032DOI Listing
December 2020

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.

JHEP Rep 2020 Dec 11;2(6):100170. Epub 2020 Aug 11.

AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, INSERM Unit 1193, Univ Paris-Sud, Université Paris-Saclay, FHU Hépatinov, Villejuif, F-94800, France.

Immune checkpoint inhibitors (ICIs) improve clinical outcomes in patients suffering from different types of cancer. Liver toxicity is one of the immune-related adverse events associated with immunotherapy; although not common, its management is challenging as it is extremely heterogeneous in terms of presentation and severity. Differences in the development and evolution of ICI-related toxicity in healthy or cirrhotic livers have not yet been elucidated. Assessing causality is key to diagnosing ICI-induced liver toxicity; liver biopsies can assist not only in the differential diagnosis but also in assessing the severity of histological liver damage. The current classification of severity overestimates the grade of liver injury and needs to be revised to reflect the views of hepatologists. Spontaneous improvements in ICI-related liver toxicity have been reported, so corticosteroid therapy should probably be individualised not systematic. The reintroduction of ICIs in a patient with previous immune-mediated hepatitis may be possible, but the risk/benefit ratio should be considered, as the risk factors for hepatitis recurrence are currently unclear. The management of these patients, requiring a balance between efficacy, toxicity and specific treatments, necessitates multidisciplinary collaboration. The incidence of immune-related liver toxicity will continue to rise based on the increasing use of ICIs for most cancers, mandating improved understanding and management of this complication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhepr.2020.100170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648167PMC
December 2020

Infectious complications in patients treated with immune checkpoint inhibitors.

Eur J Cancer 2020 12 30;141:137-142. Epub 2020 Oct 30.

Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique, Le Kremlin-Bicêtre, France; INSERM, U1184, Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin-Bicêtre, France; Université Paris Sud, UMR 1184, Le Kremlin-Bicêtre, France; CEA, DSV/iMETI, IDMIT, Fontenay-aux-Roses, France. Electronic address:

Objective: Immune checkpoint inhibitor (ICI) antibodies constitute a new generation of cancer treatments, associated with immune-related adverse events (irAEs). A previous retrospective study of patients with metastatic melanoma (treated mostly with anti-CTLA4 antibodies) reported a serious infection rate of 7.3%. The main risk factors were corticoids and infliximab use. We sought to describe infections and risk factors among patients receiving anti-PD-1/PD-L1 ICIs.

Patients And Methods: We reviewed 200 medical records sampled randomly from a French prospective registry, which collates patients treated with anti-PD-1/PD-L1 ICIs. We recorded demographic data, the occurrence of irAEs, immunosuppressant use, and the outcome.

Results: Thirty-six patients (18%) experienced an infection by a median (interquartile range) of 47 (19.2-132) days after initiation of the ICI. Twenty-one patients (58.3%) had a lung infection, seven (19.4%) had a skin infection, seven (19.4%) had a urinary tract infection, and all of them received antibiotics. The infection was generally mild, and the patients were treated as outpatient. There were no infection-related deaths and no opportunistic infection. Sixty percent of the patients were being treated for metastatic melanoma and 35.5% for non-small cell lung cancer, and 106 irAEs (mostly grade II) were reported. Forty-seven patients received steroids for cancer symptoms or irAEs, and five received immunosuppressants during the immunotherapy. We did not observe any association between corticosteroid or immunosuppressant use and the occurrence of an infection.

Conclusion: The infection rate in patients treated with an anti-PD-1/PD-L1 ICI was 18%, without any severe or opportunistic infection. The occurrence of an infection was not associated with corticosteroid or immunosuppressant use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.09.025DOI Listing
December 2020

Can Next-Generation PI3K Inhibitors Unlock the Full Potential of the Class in Patients With B-Cell Lymphoma?

Clin Lymphoma Myeloma Leuk 2021 Jan 18;21(1):8-20.e3. Epub 2020 Sep 18.

Institut de Cancérologie Gustave Roussy, Villejuif, France. Electronic address:

Although outcomes after first-line therapy for patients with indolent or aggressive non-Hodgkin lymphoma (NHL) are continually improving, relapse is still common. Current treatment options for patients with relapsed or refractory disease have limited efficacy, and various targeted therapies are under investigation to help improve outcomes in this patient population. The phosphatidylinositol 3-kinase (PI3K) pathway was identified as being involved in hematologic malignancies, leading to significant research for potential therapeutic agents. This has led to 3 PI3K inhibitors (idelalisib, copanlisib, and duvelisib) being approved for the treatment of patients with relapsed or refractory follicular lymphoma who have received at least 2 prior systemic therapies, with reported response rates of 40% to 59%. With potential class-specific and PI3K isoform-related toxicities that may limit clinical utility, the safety of the approved PI3K inhibitors has been carefully evaluated to weigh the risk/benefit ratio of therapy. Currently, there are no approved PI3K inhibitors for patients with aggressive NHL. A number of newer PI3K inhibitors are in clinical development for the treatment of relapsed or refractory NHL, aiming to improve treatment benefit for patients. We discuss a number of attributes that are important to increase the therapeutic potential of newer PI3K inhibitors. More promising results may come from combination trials with these newer PI3K inhibitors, developed to limit toxicities (including long-term adverse events), and other antitumor agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.08.022DOI Listing
January 2021

New insights on IgA vasculitis with underlying solid tumor: a nationwide French study of 30 patients.

Clin Rheumatol 2021 May 24;40(5):1933-1940. Epub 2020 Oct 24.

Department of Internal Medicine and Clinical Immunology, CHRU Tours, Tours, France.

Objective: IgA vasculitis (IgAV) frequently occurs during or after a mucosal infection; it also rarely occurs in patients with cancer. We hypothesized that cancer could impact the baseline characteristics and/or outcome of vasculitis. We aimed to describe the presentation of IgAV in patients with cancer (IgAV ca+) compared to patients without cancer.

Methods: We conducted a nationwide retrospective study of adult patients in France who presented with both IgAV and cancer. Baseline characteristics were described and compared with those of the 260 patients included in a nationwide French IgAV study.

Results: Thirty patients were included. The mean age was 69 ± 12 years; 80% were men. Compared to patients without underlying cancer, IgAV ca+ patients were older (69 ± 12 vs. 50 ± 18 years; p < 0.0001) and they presented more frequently with necrotic purpura (53 vs. 26%; p < 0.002) and intra-alveolar hemorrhage (10 vs. 0.5%; p < 0.0001). IgAV ca+ patients frequently had elevated serum IgA levels (79 vs. 53%; p < 0.034); most (n = 22, 73%) had adenocarcinoma or urothelial carcinoma involving the large intestines (n = 6), bladder (n = 5), and lung (n = 5). Most IgAV ca+ patients had progressive cancer (n = 21); a minority had metastatic disease (n = 2) at IgAV diagnosis. After a median follow-up of 3 months, 8 deaths were observed but none was related to IgAV.

Conclusion: Compared to their noncancer counterpart, patients with IgAV related to cancer were older and more frequently presented with necrotizing purpura, intra-alveolar hemorrhage, and elevated serum IgA levels. Adult patients with IgAV and these latter characteristics should be carefully screened for cancer. Key Points • Clinical and biological characteristics of patients presenting with IgAV are distinct depending on the underlying cause of vasculitis related to cancer. • Patients with IgAV related to cancer are older, and compared to their counterparts without IgAV, they present more frequently with necrotic purpura, alveolar hemorrhage, and elevated serum IgA levels. • All adult patients with IgAV should be screened for cancer, and there should be a focus on elderly male patients presenting with necrotic purpura and/or alveolar hemorrhage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10067-020-05455-zDOI Listing
May 2021

Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients.

J Immunother Cancer 2020 10;8(2)

Department of Medicine, Centre Léon Bérard, Lyon, France.

Background: This phase Ib study evaluated the safety, clinical activity, pharmacokinetics, and pharmacodynamics (PD) of emactuzumab (anti-colony stimulating factor 1 receptor monoclonal antibody (mAb)) in combination with selicrelumab (agonistic cluster of differentiation 40 mAb) in patients with advanced solid tumors.

Methods: Both emactuzumab and selicrelumab were administered intravenously every 3 weeks and doses were concomitantly escalated (emactuzumab: 500 to 1000 mg flat; selicrelumab: 2 to 16 mg flat). Dose escalation was conducted using the product of independent beta probabilities dose-escalation design. PD analyzes were performed on peripheral blood samples and tumor/skin biopsies at baseline and on treatment. Clinical activity was evaluated using investigator-based and Response Evaluation Criteria In Solid Tumors V.1.1-based tumor assessments.

Results: Three dose-limiting toxicities (all infusion-related reactions (IRRs)) were observed at 8, 12 and 16 mg of selicrelumab together with 1000 mg of emactuzumab. The maximum tolerated dose was not reached at the predefined top doses of emactuzumab (1000 mg) and selicrelumab (16 mg). The most common adverse events were IRRs (75.7%), fatigue (54.1%), facial edema (37.8%), and increase in aspartate aminotransferase and creatinine phosphokinase (35.1% both). PD analyzes demonstrated an increase of Ki67-activated CD8 T cells accompanied by a decrease of B cells and the reduction of CD14 CD16 monocytes in peripheral blood. The best objective clinical response was stable disease in 40.5% of patients.

Conclusion: Emactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses.

Trialregistration Number: NCT02760797.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590375PMC
October 2020

Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit.

Ann Intensive Care 2020 Oct 16;10(1):143. Epub 2020 Oct 16.

Service de Réanimation Médicale, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France.

Background: Immune checkpoint inhibitors have reshaped the standard of care in oncology. However, they have been associated with potentially life-threatening immune-related adverse events. With the growing indications of immune checkpoint inhibitors and their position as a pillar of cancer treatment, intensive care physicians will be increasingly confronted with their side effects. The outcome of patients with severe immune-related adverse events in the intensive care unit remains unknown. This retrospective multicentric study aims to describe the characteristics of patients admitted to the intensive care units of 4 academic hospitals in Paris area while receiving immune checkpoint inhibitor treatment between January 2013 and October 2019.

Results: Over the study period, 112 cancer patients who received immune checkpoint inhibitors were admitted to the intensive care unit within 60 days after the last dose. ICU admission was related to immune-related adverse events (n = 29, 26%), other intercurrent events (n = 39, 35%), or complications related to tumor progression (n = 44, 39%). Immune-related adverse events were pneumonitis (n = 8), colitis (n = 4), myocarditis (n = 3), metabolic disorders related to diabetes (n = 3), hypophysitis (n = 2), nephritis (n = 2), meningitis or encephalitis (n = 2), hepatitis (n = 2), anaphylaxis (n = 2) and pericarditis (n = 1). Primary tumors were mostly melanomas (n = 14, 48%), non-small-cell lung cancers (n = 7, 24%), and urothelial carcinomas (n = 5, 17%). Diagnosis of melanoma and a neutrophil/lymphocyte ratio < 10 were associated with immune-related diagnosis versus other reasons for ICU admission. During their ICU stay, immune-related adverse events patients needed vasopressors (n = 7), mechanical ventilation (n = 6), and extra-corporeal membrane oxygenation (n = 2). One-year survival was significantly higher for patients admitted for irAE compared to patients admitted for other reasons (p = 0.004).

Conclusions: Admission to the intensive care unit related to immune-related adverse event was associated with better outcome in cancer patients treated with immune checkpoint inhibitors. Our results support the admission for an intensive care unit trial for patients with suspected immune-related adverse events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13613-020-00761-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567777PMC
October 2020

Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study.

Lancet Haematol 2020 Sep 3;7(9):e649-e659. Epub 2020 Aug 3.

Institut Gustave Roussy, Villejuif, France.

Background: Avadomide (CC-122) is a novel oral cereblon-modulating agent with promising activity in non-Hodgkin lymphoma. We aimed to examine the safety and preliminary activity of avadomide plus obinutuzumab in patients with relapsed or refractory non-Hodgkin lymphoma.

Methods: CC-122-NHL-001 was a phase 1b dose escalation and expansion study at eight sites in France, Italy, and the Netherlands. Eligible patients (aged ≥18 years) had histologically confirmed CD20-positive relapsed or refractory non-Hodgkin lymphoma, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received previous treatment. In the dose expansion phase, only patients with previously treated relapsed or refractory follicular lymphoma (grade 1, 2, or 3a) were included. Avadomide was administered in escalating doses and two formulations: active pharmaceutical ingredient in capsule in 1·0 mg, 2·0 mg, 3·0 mg, and 4·0 mg doses and as formulated capsules in 3·0 mg and 4·0 mg doses orally once daily on days 1-5 followed by 2 days off (5-7-day schedule) every week of each 28-day cycle. Obinutuzumab 1000 mg was administered intravenously on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2-8. Primary objectives were to determine the safety and tolerability, the non-tolerated dose, maximum tolerated dose, and recommended phase 2 dose (RP2D). All patients who received treatment were included in the safety analyses. Efficacy-evaluable patients completed at least one cycle of treatment and had baseline and at least one post-baseline assessment. The study is registered with ClinicalTrials.gov, NCT02417285 and EudraCT 2014-003333-26, and is ongoing.

Findings: Between June 24, 2015, and Dec 5, 2018, 73 patients were enrolled and treated; 19 had diffuse large B-cell lymphoma, 53 follicular lymphoma, and one marginal zone lymphoma. Median follow-up was 253 days (IQR 127-448). The median number of previous anticancer regimens was three (IQR 2-4). The maximum tolerated dose and non-tolerated dose were not reached in the dose escalation phase. On the basis of safety and pharmacokinetic-pharmacodynamic data, the avadomide RP2D was established as 3·0 mg as formulated capsules on a 5-7-day schedule in combination with 1000 mg of obinutuzumab. Patients enrolled in the expansion cohort received the established RP2D of avadomide. Across all doses, three patients had dose-limiting toxicities; one patient treated at the RP2D had dose-limiting toxicity (grade 3 sepsis). The most common adverse events of grade 3 and above were neutropenia (41 [56%] of 73) and thrombocytopenia (17 [23%] of 73). 34 (47%) patients had serious adverse events, which were considered to be avadomide-related in 23 (32%) of 73 patients and obinutuzumab-related in 20 (27%) of 73 patients. Two treatment-related deaths occurred, one owing to tumour flare and one from acute myeloid leukaemia after study discontinuation.

Interpretation: Avadomide plus obinutuzumab has a manageable toxicity, being a tolerable treatment option for most patients. Although the prespecified threshold for activity was not met in the trial, we believe that the preliminary antitumour activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated relapsed or refractory non-Hodgkin lymphoma warrants further investigation as a chemotherapy-free option in this setting.

Funding: Celgene Corporation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(20)30208-8DOI Listing
September 2020

Patterns of progression in patients treated for immuno-oncology antibodies combination.

Cancer Immunol Immunother 2021 Jan 22;70(1):221-232. Epub 2020 Jul 22.

Drug Development Department (DITEP), Gustave Roussy, Université Paris-Saclay, Villejuif, 94805, France.

Background: New patterns of progression under immune-oncology (IO) antibodies (mAb) have been described such as pseudoprogression. Except for melanoma, variations between studies reveal difficulties to establish their prevalence.

Methods: This retrospective study enrolled patients participating in IO phase I trials at Gustave Roussy cancer center for solid tumors excluding melanoma. Radiological assessment according to iRECIST was correlated with prospectively registered patient characteristics and outcomes. Pseudoprogression (PsPD) was defined as RECIST-defined progression followed by stabilization or decrease at the next imaging, and dissociated response (DisR) as concomitant decrease in some tumor lesions and increase in others at a same timepoint.

Results: Among 360 patients included, 74% received IO mAb combination: 45% with another IO mAb, 20% with targeted therapy and 10% with radiotherapy. The overall response rate was 19.7%. PsPD were observed in 10 (2.8%) patients and DisR in 12 (3.3%) patients. Atypical responses (AR), including PsPD and DisR, were not associated with any patient's baseline characteristics. Compare with typical responder patients, patients experiencing AR presented a shorter iPFS (HR 0.34; p < 0.001) and OS (HR 0.27; p = 0.026). Among the 203 patients who progressed in 12 weeks, 80 (39.4%) patients were treated beyond progression. PD was confirmed in 80% of cases, while 10% of patients presented a response.

Conclusion: Pseudoprogression and dissociated response are uncommon patterns of progression. Their prevalence should be balanced with the rate of real progressing patients treated beyond progression. Prognosis or on-treatment biomarkers are needed to identify early patients who will benefit from immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-020-02647-zDOI Listing
January 2021

KEYNOTE-013 4-year follow-up of pembrolizumab in classical Hodgkin lymphoma after brentuximab vedotin failure.

Blood Adv 2020 06;4(12):2617-2622

University of Miami Sylvester Comprehensive Cancer Center, Miami, FL.

The KEYNOTE-013 study was conducted to evaluate pembrolizumab monotherapy in hematologic malignancies; classical Hodgkin lymphoma (cHL) was an independent expansion cohort. We present long-term results based on >4 years of median follow-up for the cHL cohort. The trial enrolled cHL patients who experienced relapse after, were ineligible for, or declined autologous stem cell transplantation and experienced progression with or did not respond to brentuximab vedotin. Patients received IV pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points were safety and complete response (CR) rate by central review. Enrolled patients (N = 31) had received a median of 5 therapies (range, 2 to 15). After a median follow-up of 52.8 months (range, 7.0 to 57.6 months), CR rate was 19%, and median duration of response (DOR) was not reached; 24-month and 36-month DOR rates were both 50% by the Kaplan-Meier method. Median overall survival was not reached; 36-month overall survival was 81%. Six patients (19%) experienced grade 3 treatment-related adverse events (AEs); there were no grade 4 or 5 treatment-related AEs. With long-term follow-up among a heavily pretreated cohort, pembrolizumab had a favorable safety profile; some patients maintained long-term response with pembrolizumab years after end of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01953692.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019001367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322954PMC
June 2020

Letter responds to the comment in 'immune thrombocytopenia of haematological immune-related adverse events in cancer immunotherapy: Most and mighty'.

Eur J Cancer 2020 07 26;134:60-61. Epub 2020 May 26.

Hôpitaux de Paris, Hôpital Bicêtre, Médecine Interne et Immunologie Clinique, F-94275, Le Kremlin-Bicêtre, France; INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, F-94276, Le Kremlin-Bicêtre, France; Université Paris Sud, UMR 1184, F-94276, Le Kremlin-Bicêtre, France; CEA, DSV/iMETI, IDMIT, F-92265, Fontenay-aux-Roses, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.03.012DOI Listing
July 2020

Repeated courses of low-dose 2 × 2 Gy radiation therapy in patients with indolent B-cell non-Hodgkin lymphomas.

Cancer Med 2020 06 6;9(11):3725-3732. Epub 2020 Apr 6.

Department of Radiation Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Purpose: In patients with indolent B-cell non-Hodgkin's lymphoma (B-NHL), one course of low-dose radiotherapy (LD-RT) 2 × 2 Gy is emerging as new option of therapy in palliative setting. Efficacy of LD-RT when repeated remains to be determinate. This study aims to assess the efficacy of repeated LD-RT given in patients with indolent B-NHL.

Materials And Methods: All consecutive adult patients who received two or more courses of LD-RT 2 × 2 Gy for indolent B-NHL at Gustave Roussy institution, during the period 1990-2015 were retrospectively investigated.

Results: Thirty-three patients received two or more courses of LD-RT for indolent B-NHL during the study period. The median age was 57 (range 37-80) years, histological types were distributed among follicular lymphoma (n = 24 pts; 73%), marginal-zone lymphoma (n = 6 pts; 18%), and primary cutaneous follicle center lymphoma (n = 3 pts; 9%). The median number of low-dose radiation therapy courses given per patients was 2 (range 2-6). The overall response rates following the first and the second course of LD-RT were 96% and 88%, respectively (P = .31). The 1- and 2-years local control rates following the first courses of LD-RT were 94% (CI 95: 86-100) and 94% (CI 95: 86-98); and were 91% (CI 95: 82-100) and 88% (CI 95: 77-100) following the second course of LD-RT (P = .39).

Conclusion: The repeated courses of LD-RT offered similar efficacy compare with the first course in patients with indolent B-NHL. LD-RT repeated is a simple, easy to give, and non-toxic asset that could be investigated as treatment option in patients with indolent B-NHL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.2796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286454PMC
June 2020

Haemophagocytic lymphohistiocytosis associated with immune checkpoint inhibitors: a descriptive case study and literature review.

Br J Haematol 2020 06 3;189(5):985-992. Epub 2020 Apr 3.

Service de Médecine Interne et d'Immunologie Clinique, AP-HP Université Paris-Saclay, Hôpital Bicêtre, Villejuif, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16630DOI Listing
June 2020

The 2016-2019 ImmunoTOX assessment board report of collaborative management of immune-related adverse events, an observational clinical study.

Eur J Cancer 2020 05 12;130:39-50. Epub 2020 Mar 12.

Gustave Roussy, Université Paris-Saclay, Département des Innovations Thérapeutiques et Essais Précoces, Villejuif, France.

Purpose: We investigated the activities of an ImmunoTOX board, an academic, multidisciplinary group of oncologists and organ specialists that adopts a real-life, case-by-case approach in the management of patients with immune-related adverse events (irAEs).

Experimental Design: The ImmunoTOX assessment board was set up in 2016 at Gustave Roussy in France. It meets every 2 weeks to discuss the case-by-case management of patients presenting with irAEs. Here, we describe the ImmunoTOX board's activities between 2016 and 2019.

Results: Over study period, 398 requests (concerning 356 patients) were submitted to the ImmunoTOX board. Most of the requests concerned the putative causal link between immunotherapy and the irAE (n = 148, 37%), followed by possible retreatment after temporary withdrawal because of an adverse event (n = 109, 27%), the clinical management of complex situations (n = 100, 25%) and the initiation of immunotherapy in patients with pre-existing comorbidities (n = 41, 10%). The ImmunoTOX board discerned 273 irAEs. The five organ systems most frequently involved by irAEs were lung (n = 58, 21%), gastrointestinal tract (n = 36, 13%), liver or biliary tract (n = 33, 12%), musculoskeletal system (n = 27, 10%), and nervous system (n = 23, 8%). The time to occurrence was shorter for severe irAEs (grade III and VI) than for mild irAEs (grades I and II), with medians of 47 and 91 days, respectively (p = 0.0216).

Conclusion: The main medical needs in the management of irAEs involved the lung organ. Severe irAEs were expected to occur earlier than mild irAEs. This real-life study can help to better estimate medical needs and therefore help to assess the management of irAEs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.02.010DOI Listing
May 2020

Burkitt and Burkitt-Like Lymphomas: a Systematic Review.

Curr Oncol Rep 2020 03 6;22(4):33. Epub 2020 Mar 6.

Département d'Hématologie, Institut de Cancérologie Gustave Roussy, 114 Rue Edouard Vaillant, 94810, Villejuif, France.

Purpose Of Review: Burkitt's lymphoma and its leukemic form (Burkitt cell acute lymphoblastic leukemia) are a highly aggressive disease. We review the classification, clinical presentation, histology, cytogenetics, and the treatment of the disease.

Recent Findings: Burkitt's lymphoma might be associated with tumor lysis syndrome which is a potentially fatal complication that occurs spontaneously or upon initiation of chemotherapy. Major improvements were made in the treatment of pediatric and adults population using short-course dose-intensive chemotherapy regimens, usually 1 week after a prephase induction. Addition of Rituximab to chemotherapy has become a standard of care. Relapsed/refractory disease has a very poor prognosis and the benefit from autologous/allogeneic hematopoietic stem cell transplant remains uncertain. Rituximab-based short-course dose-intensive chemotherapy is the standard of care of Burkitt's lymphoma even in the immunodeficiency-related form.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11912-020-0898-8DOI Listing
March 2020

Impact of aging on immune-related adverse events generated by anti-programmed death (ligand)PD-(L)1 therapies.

Eur J Cancer 2020 04 3;129:71-79. Epub 2020 Mar 3.

Gustave Roussy, Université Paris-Saclay, Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Villejuif, France; INSERM U1015, Gustave Roussy, Villejuif, France.

Background: Aging is an important risk factor for cancers and is associated with poor prognosis. Weakness of the immune system, also called immunosenescence may occur with older age. The impact of aging on efficacy and safety of immune checkpoint blockers, such as anti-programmed death (ligand) PD-(L)1, remains undetermined. This study aims to evaluate the incidence of immune-related adverse events (irAEs) in patients aged 70 years or older than their younger counterparts.

Methods: Patients with advanced solid tumors treated at Gustave Roussy with an anti-PD-(L)1 monotherapy between June 2014 and October 2017 were prospectively included within the dedicated irAEs pharmacovigilance registry REISAMIC (Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie). The incidence of irAEs of grade ≥II was compared between patients aged ≥70 (old patients, OP) versus patients aged < 70 years (young patients, YP) using a chi-squared test. Survivals were estimated using the Kaplan-Meier method.

Results: Among the 603 patients treated by anti-PD(L)1, 191 were ≥70 y.o (OP) and 424 < 70 y.o (YP). The median (range) age of OP and YP were respectively 77 (70-93) and 59 years old (17-69). A total of 165 irAEs occurred in these patients (103 grade II and 58 grade III-IV). The overall incidence of grade ≥II irAEs was higher in OP than in YP (33% versus 25%, p = 0.03). In addition, OP were more prone of having multiples irAEs compared with YP (p = 0.037). Skin toxicities were more frequent in OP than in YP (p = 0.007) but endocrine toxicities were less frequent in OP than in YP (p = 0.044). This higher level of irAEs seems to be responsible for a higher rate of treatment discontinuation in OP (p = 0.2). There was no statistical difference in median time to toxicity, exposure to steroids or survival between the two groups.

Conclusion: Although anti-PD-(L)1 immunotherapies remain an acceptable treatment option for older patients, prescribers should be aware that irAEs are more frequent in the elderly. Further translational studies are warranted to better understand the relationship between aging and irAEs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.01.013DOI Listing
April 2020

A LYSA Phase Ib Study of Tazemetostat (EPZ-6438) plus R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) with Poor Prognosis Features.

Clin Cancer Res 2020 07 2;26(13):3145-3153. Epub 2020 Mar 2.

Department of Hematology, Gustave Roussy, Université Paris-Saclay, INSERM U1170, Villejuif, France.

Purpose: The histone-methyl transferase EZH2, catalytic subunit of the PRC2 complex involved in transcriptional regulation, is mutated in approximately 25% of germinal center B-cell lymphomas. Aberrant proliferative dependency on EZH2 activity can be targeted by the orally available EZH2 inhibitor tazemetostat (EPZ-6438). We report the results of the phase Ib tazemetostat plus R-CHOP combination (NCT02889523), in patients 60 to 80 years of age with newly diagnosed diffuse large B-cell lymphoma.

Patients And Methods: The primary objective of this dose-escalation study was to evaluate the safety of the combination and to determine the recommended phase II dose (RP2D) of tazemetostat.

Results: A total of 17 patients were enrolled. During C1 and C2, two dose-limiting toxicities were observed: one grade 3 constipation at 400 mg and one grade 5 pulmonary infection at 800 mg. Grade 3 or more toxicities observed in more than 10% of the patients were constipation (24%), nausea (12%), and hypokalemia (12%). Grade 3 to 4 hematologic adverse events were recorded in 8 patients (47%): neutropenia (47%), leukopenia (29%), anemia (18%), and thrombocytopenia (12%). The tazemetostat RP2D was 800 mg. No organ-oriented toxicity increased with tazemetostat dosage escalation (severity and incidence). At 800 mg, AUC and C of tazemetostat were similar compared with the single-agent study (E7438-G000-101).

Conclusions: The RP2D of tazemetostat combined with R-CHOP is 800 mg twice a day. The association presents safety and PK comparable with R-CHOP alone. Preliminary efficacy data are encouraging and further investigations in phase II trial are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-3741DOI Listing
July 2020

Evidence of pseudoprogression in patients treated with PD1/PDL1 antibodies across tumor types.

Cancer Med 2020 04 19;9(8):2643-2652. Epub 2020 Feb 19.

Drug Development Department (DITEP), Gustave Roussy, Saclay University of Paris, Villejuif, France.

Background: PD(L)1 antibodies (anti-PD(L)-1) have been a major breakthrough in several types of cancer. Novel patterns of response and progression have been described with anti-PD(L)-1. We aimed at characterizing pseudoprogression (PSPD) among patients with various solid tumor types treated by anti-PD(L)-1.

Methods: All consecutive patients (pts) enrolled in phase 1 trials with advanced solid tumors and lymphomas treated in phase I clinical trials evaluating monotherapy by anti-PD(L)-1 at Gustave Roussy were analyzed. We aimed to assess prevalence and outcome of PSPD across tumor types. We also intended to describe potential clinical and pathological factors associated with PSPD.

Results: A total of 169 patients treated with anti-PD(L)-1 were included in the study. Most frequent tumor types included melanoma (n = 57) and non-small cell lung cancer (n = 19). At first tumor evaluation 77 patients (46%) presented with immune unconfirmed progressive disease. Six patients (8%) experienced PSPD: 2 patients with partial response; 4 patients with stable disease. Increase in target lesions in the first CT-scan was more frequently associated to PSPD (67% vs 33%; P = .04). Patients with a PSPD had a superior survival when compared to patients progressing (median OS: 10.7 months vs 8.7 months; P = .07).

Conclusions: A small subset of PSPD patients may experience response after an initial progression. Assessment of the current strategy for immune-related response evaluations may require further attention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.2797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163099PMC
April 2020

Composite and sequential lymphoma between classical Hodgkin lymphoma and primary mediastinal lymphoma/diffuse large B-cell lymphoma, a clinico-pathological series of 25 cases.

Br J Haematol 2020 04 6;189(2):244-256. Epub 2020 Feb 6.

Department of Haematology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite cedex, France.

Composite and sequential lymphomas involving both classical Hodgkin lymphoma (CHL) and primary mediastinal B-cell lymphoma (PMBCL) are rare phenomena. Beyond the relevant biological interest raised by these cases, treatments and outcome data are poorly covered in the recent literature. This retrospective analysis describes the pathological and clinical characteristics of 10 composite and 15 sequential cases included after a central pathological review. At diagnosis, 70% of the composite lymphomas presented a disseminated and extranodal disease. Among the 15 sequential lymphomas, 12 were CHL at first occurrence and three were PMBCL. Based on their clinical evolution, these sequential lymphomas could be divided into early (i.e., diagnosis of second lymphoma within a year) and late [(i.e., a second lymphoma occurrence occurring after a long period of complete remission]). All composite cases were alive in complete remission after a median follow-up of 34 months. If the early sequential lymphoma presented a particularly poor outcome with a median overall survival shorter than one year, the late cases were efficiently salvaged. Further molecular studies are needed to describe the underlying biology of these rare diseases, possibly representing the extreme of tumour cell plasticity found in grey-zone lymphoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16331DOI Listing
April 2020

High-dose cyclophosphamide for hard-to-treat patients with relapsed or refractory B-cell non-Hodgkin's lymphoma, a phase II result.

Eur J Haematol 2020 Apr 28;104(4):281-290. Epub 2020 Jan 28.

Département des Innovations Thérapeutiques et Essais Précoces, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Background: High-dose cyclophosphamide to treat solid refractory tumors demonstrated meaningful activity, while data to treat lymphoma remain scarce. This study aims to assess high-dose cyclophosphamide to treat relapsed or refractory lymphoma.

Methods: A phase II study included adult patients with relapsed or refractory B-cell non-Hodgkin's lymphoma, previously treated by ≥2 prior lines with no other available option of therapy. High-dose cyclophosphamide was given intravenously 3 g/m over two consecutive days and repeated once at 28 days in responding patients. Rituximab 375 mg/m intravenously was added in patients not refractory to anti-CD20 antibody.

Results: Forty-two patients with median age 65 [56-70] years were included. Patients had previously received a median of four lines of therapies. Tumor types were diffuse large B-cell lymphoma (n = 26; 62%), indolent B-cell non-Hodgkin lymphoma (n = 10; 24%), or mantle lymphoma (n = 6; 14%). Hematologic and non-hematologic grade 3-5 toxicities occurred in 42 (100%) and 18 (43%) of patients, respectively. The overall response rate was 45%.

Conclusion: One to two cycles of high-dose cyclophosphamide in hard-to-treat patients with relapsed or refractory B-cell non-Hodgkin lymphoma demonstrated a favorable safety and efficacy profile. This regimen could serve as a bridge to modern cellular therapy with CAR-T cell.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13369DOI Listing
April 2020

Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study.

J Immunother Cancer 2019 12 3;7(1):337. Epub 2019 Dec 3.

Hospices Civils de Lyon, French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, SynatAc Team, Institut NeuroMyoGène. INSERM U1217/CNRS UMR 5310, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.

Background: Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy.

Methods: We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively.

Findings: Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45-88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1-2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1.

Interpretation: Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40425-019-0821-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892018PMC
December 2019

Phase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and Solid Tumors.

Clin Cancer Res 2019 12 30;25(24):7331-7339. Epub 2019 Aug 30.

Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom.

Purpose: Enhancer of zeste homolog 2 (EZH2) activity is dysregulated in many cancers.

Patients And Methods: This phase I study determined the safety, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977). Doses of GSK2816126 ranged from 50 to 3,000 mg twice weekly, and GSK2816126 was given 3-weeks-on/1-week-off in 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen.

Results: Forty-one patients (21 solid tumors, 20 lymphoma) received treatment. All patients experienced ≥1 adverse event (AE). Fatigue [22 of 41 (53.7%)] and nausea [20 of 41 (48.8%)] were the most common toxicity. Twelve (32%) patients experienced a serious AE. Dose-limiting elevated liver transaminases occurred in 2 of 7 patients receiving 3,000 mg of GSK2816126; 2,400 mg was therefore established as the MTD. Following intravenous administration of 50 to 3,000 mg twice weekly, plasma GSK2816126 levels decreased biexponentially, with a mean terminal elimination half-life of approximately 27 hours. GSK2816126 exposure (maximum observed plasma concentration and area under the plasma-time curve) increased in a dose-proportional manner. No change from baseline in H3K27me3 was seen in peripheral blood mononuclear cells. Fourteen of 41 (34%) patients had radiological best response of stable disease, 1 patient with lymphoma achieved a partial response, 21 of 41 (51%) patients had progressive disease, and 5 patients were unevaluable for antitumor response.

Conclusions: The MTD of GSK2816126 was established at 2,400 mg, but the dosing method and relatively short half-life limited effective exposure, and modest anticancer activity was observed at tolerable doses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-4121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377921PMC
December 2019