Risk of scleroderma according to the type of immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Among them, ICIs-induced systemic sclerosis (SSc) is poorly known. METHODS: To better characterize this irAE, our comprehensive approach combined the description of ICIs-induced scleroderma cases, the systematic review of the literature and the analysis of VigiBase, the WHO pharmacovigilance database. RESULTS: We identified two cases with underlying limited cutaneous SSc who presented a dramatic increase in the skin thickening following pembrolizumab, associated with scleroderma renal crisis in one case. In the literature, four cases of scleroderma and four cases of morphea have been reported with pembrolizumab or nivolumab. None following ipilimumab, atezolizumab or durvalumab were retrieved. Skin changes appeared or worsened more quickly with pembrolizumab than nivolumab, and had different patterns between both drugs. Patients with generalized skin changes required high-dose prednisone to improve skin thickening. Among the 2527 scleroderma cases identified in VigiBase, 35 were associated with ICIs. Nivolumab and pembrolizumab showed a disproportionality in scleroderma reporting. No disproportionality was found for ipilimumab, atezolizumab or durvalumab. CONCLUSION: The risk of scleroderma or fibrosis extension in SSc patients should be considered when initiating anti-PD-1 agents. It suggests the role of PD-1/PD-L1 interaction in the pathophysiology of SSc.

[Antibody-drug conjugates in oncology. Recent success of an ancient concept]. / Les immuno-conjugués en oncologie - Les raisons du succès récent d'une approche ancienne.

An Antibody-Drug Conjugate (armed antibody) is a vectorized chemotherapy that results from the grafting of a cytotoxic agent on a monoclonal antibody thanks to a judiciously designed spacer arm. ADCs have made considerable progress in 10 years. In 2009, only gemtuzumab ozogamicin (Mylotarg®) was used clinically. In 2019, 4 other ADCs have been approved and more than 80 others are in active clinical trials. The first part of this review will focus on Food and Drug Administration-approved Antibody-Drug Conjugates, their limitations as well as their associated toxicity and resistance mechanisms.

TITLE: Les immuno-conjugués en oncologie - Les raisons du succès récent d'une approche ancienne. ABSTRACT: Un anticorps armé (antibody-drug conjugate en anglais) est une chimiothérapie vectorisée qui résulte du greffage d'un agent cytotoxique sur un anticorps monoclonal par l'intermédiaire d'un bras espaceur judicieusement construit. Les anticorps armés ont fait des progrès considérables en 10 ans. En 2009, seul le gemtuzumab ozogamicine (Mylotarg®) était utilisé en clinique. En 2019, 4 autres ADC ont été approuvés par la Food and drug administration et plus de 80 autres sont en études cliniques actives. La première partie de cette revue sera focalisée sur les anticorps armés approuvés, leurs limitations, ainsi que leur toxicité et mécanismes de résistances associés.

[Antibody-drug conjugates in oncology. New strategies in development]. / Les immunoconjugués en oncologie - Les nouvelles stratégies en développement.

An Antibody-Drug Conjugate (armed antibody) is a vectorized chemotherapy that results from the grafting of a cytotoxic agent on a monoclonal antibody via a judiciously designed spacer arm. ADCs have made considerable progress in 10 years. In 2009, only gemtuzumab ozogamicin (Mylotarg®) was used clinically. In 2019, 4 other ADCs have been approved and more than 80 others are in active clinical trials. The second part of this review will focus on new emerging strategies to address ADCs drawbacks and attempt to broaden their therapeutic window. Finally, combinations with conventional chemotherapy or checkpoint inhibitors will be discussed, in the pursuit to make Antibody-Drug Conjugates the embodiment of Paul Ehrlich's dream of the magic bullet.

TITLE: Les immunoconjugués en oncologie - Les nouvelles stratégies en développement. ABSTRACT: Un anticorps armé (ADC, antibody-drug conjugate en anglais) est une chimiothérapie vectorisée qui résulte du greffage d'un agent cytotoxique sur un anticorps monoclonal par l'intermédiaire d'un bras espaceur judicieusement construit. Les anticorps armés ont fait des progrès considérables en 10 ans. En 2009, seul le gemtuzumab ozogamicine (Mylotarg®) était utilisé en clinique. En 2019, 4 autres ADC ont été approuvés par la Food and Drug Administration et plus de 80 autres sont en études cliniques actives. La seconde partie de cette revue sera focalisée sur les nouvelles stratégies émergentes pour faire face aux limitations des ADC actuels et pour tenter d'élargir leur fenêtre thérapeutique. Enfin, les combinaisons avec la chimiothérapie classique ou les inhibiteurs de points de contrôles seront discutées, pour tenter de faire des anticorps armés la magic bullet dont rêvait Paul Ehrlich.

Combination Immune Checkpoint Blockade Strategies to Maximize Immune Response in Gynecological Cancers.

PURPOSE OF REVIEW: Immune checkpoint blockade targeting PD-1 and PD-L1 improves immune recognition of tumor cells but had only modest success in gynecological cancers as monotherapy. Growing focus has been placed on combination immunotherapy strategies to overcome this resistance, and this review serves to discuss some of the most promising studies in gynecological cancers. RECENT FINDINGS: PD-1- and PD-L1-targeting antibodies are being combined with many novel agents including anti-CTLA-4 antibodies, PARP inhibitors, targeted agents, and traditional chemotherapy in promising studies with the hopes of increasing the immune response and overcoming resistance by targeting other pathways. Novel immune techniques including vaccines and adoptive cell therapies are also being implemented in gynecological cancers. Immune checkpoint combinations and novel immunotherapy strategies have demonstrated potential to overcome resistance to PD-1/PD-L1 blockade in gynecological cancers. Identification of biomarkers of response and resistance is a priority to tailor specific combination therapies to the appropriate patients.

Current landscape of immunotherapy for the treatment of metastatic non-small-cell lung cancer.

For patients with advanced non-small-cell lung cancer (nsclc) lacking a targetable molecular driver, the mainstay of treatment has been cytotoxic chemotherapy. The survival benefit of chemotherapy in this setting is modest and comes with the potential for significant toxicity. The introduction of immunotherapeutic agents targeting the programmed cell death 1 protein (PD-1) and the programmed cell death ligand 1 (PD-L1) has drastically changed the treatment paradigms for these patients. Three agents-atezolizumab, nivolumab, and pembrolizumab-have been shown to be superior to chemotherapy in the second-line setting. For patients with tumours strongly expressing PD-L1, pembrolizumab has been associated with improved outcomes in the first-line setting. Demonstration of the significant benefits of immunotherapy in nsclc has focused attention on new questions. Combination checkpoint regimens, with acceptable toxicity and potentially enhanced efficacy, have been developed, as have combinations of immunotherapy with chemotherapy. In this review, we focus on the published trials that have changed the treatment landscape in advanced nsclc and on the ongoing clinical trials that offer hope to further improve outcomes for patients with advanced nsclc.

Association of Immunotherapy With Durable Survival as Defined by Value Frameworks for Cancer Care.

IMPORTANCE: Modern immuno-oncology agents have generated great excitement because of their potential to provide durable survival for some patients. However, there is concern regarding the cost of cancer care, and multiple frameworks have been developed to assess value. The American Society of Clinical Oncology (ASCO) framework awards bonus points if substantial durable survival is demonstrated. OBJECTIVE: To assess whether modern immuno-oncology agents reach defined efficacy thresholds in value frameworks. DESIGN, SETTING, AND PARTICIPANTS: In this analysis, all US Food and Drug Administration (FDA) approvals for immuno-oncology agents between March 2011 and August 2017 were reviewed. Data required for the ASCO framework were collected, specifically improvement in proportion of patients alive with the test regimen and survival rate with standard treatment. MAIN OUTCOMES AND MEASURES: Awarding of bonus points for durable survival based on the ASCO criteria. RESULTS: Twenty-three metastatic indications for 6 immuno-oncology agents (ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab) were approved by the FDA from March 2011 to August 2017. Ten (43%) of the approvals were based on survival end points, while 13 (57%) were based on response rates. Only 3 drug indications fulfilled the threshold defined for the survival rate of patients receiving standard care (minimum 20%). Nine indications achieved the required level of improvement in proportion to patients alive in the test regimen compared with the standard (above 50%). There was overlap between these 2 criteria for 3 drug indications, allowing them to gain the durable survival bonus points awarded by the ASCO framework. CONCLUSIONS AND RELEVANCE: Durable survival and response rates of modern immuno-oncology agents are rarely recognized as significant by current oncology value frameworks. This may be due to insufficient demonstration of efficacy of such agents or inappropriately calibrated value frameworks.

Precision Medicine in Metastatic Colorectal Cancer: Relevant Carcinogenic Pathways and Targets-PART 1: Biologic Therapies Targeting the Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor.

The survival of patients with metastatic colorectal cancer has improved dramatically in recent years, with overall survival exceeding 3 years in large randomized clinical trials. There are now several treatment options for patients with metastatic colorectal cancer. In addition to chemotherapy backbones utilizing fluoropyrimidine, oxaliplatin, and irinotecan combinations, biologic agents that target specific oncogenic pathways have contributed to the improved survival observed in this patient population. This class of medications includes epidermal growth factor receptor (EGFR)-targeted drugs (cetuximab and panitumumab) and vascular endothelial growth factor (VEGF)-targeted therapies (bevacizumab, ramucirumab, ziv-aflibercept, and regorafenib). Bevacizumab remains the only VEGF-targeted agent approved by the US Food and Drug Administration in the first-line metastatic setting. EGFR-directed treatment should be restricted to patients with extended RAS and BRAF wild-type tumors. Tumor sidedness may be a more powerful prognostic and predictive biomarker than tumor mutational profile. Patients with left-sided primary tumors derive greater benefit from EGFR-targeted therapies whereas patients with right-sided primary tumors benefit more from bevacizumab. Herein we review drugs that target the EGFR and VEGF pathways, focusing on patient selection, drug toxicities, and how to choose agents for first-line therapy.

Precision Medicine in Metastatic Colorectal Cancer: Relevant Carcinogenic Pathways and Targets-PART 2: Approaches Beyond First-Line Therapy, and Novel Biologic Agents Under Investigation.

A frequent quandary for oncologists is the selection of chemotherapy and biologic therapy for patients with metastatic colorectal cancer in second-line and higher treatment settings. While not approved by the US Food and Drug Administration (FDA) in the first-line setting, the vascular endothelial growth factor (VEGF)-targeting agents ziv-aflibercept and ramucirumab are appropriate treatment options in the second-line setting, as is continuation of first-line bevacizumab. Tumor RAS mutational status is helpful to determine which patients may benefit from epidermal growth factor receptor (EGFR)-directed therapies, and other novel biomarkers (BRAF, HER2, and mismatch repair deficiency) allow us to select patients who may benefit from biologic therapies that are FDA-approved for other malignancies. Maintenance therapy for patients with stable disease following first-line therapy is a unique clinical situation that warrants special attention. Immunotherapy has thus far been ineffective for patients with mismatch repair-proficient tumors, but novel combination strategies are being studied to break through this treatment barrier. Finally, several new biologic therapies with novel targets are under development and will likely contribute to the growing arsenal of treatment options for patients with metastatic colorectal cancer.