Ovarian Cancer in the Era of Immune Checkpoint Inhibitors: State of the Art and Future Perspectives

Background: Ovarian cancer (OC) represents the eighth most common cancer and the fifth leading cause of cancer-related deaths among the female population. In an advanced setting, chemotherapy represents the first-choice treatment, despite a high recurrence rate. In the last ten years, immunotherapy based on immune checkpoint inhibitors (ICIs) has profoundly modified the therapeutic scenario of many solid tumors. We sought to summarize the main findings regarding the clinical use of ICIs in OC. Methods: We searched PubMed, Embase, and Cochrane Databases, and conference abstracts from international congresses (such as ASCO, ESMO, SGO) for clinical trials, focusing on ICIs both as monotherapy and as combinations in the advanced OC. Results: 20 studies were identified, of which 16 were phase I or II and 4 phase III trials. These trials used ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, aterolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab). There was no reported improvement in survival, and some trials were terminated early due to toxicity or lack of response. Combining ICIs with chemotherapy, anti-VEGF therapy, or PARP inhibitors improved response rates and survival in spite of a worse safety profile. Conclusions: The identification of biomarkers with a predictive role for ICIs’ efficacy is mandatory. Moreover, genomic and immune profiling of OC might lead to better treatment options and facilitate the design of tailored trials.

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Ovarian Cancer in the Era of Immune Checkpoint Inhibitors: State of the Art and Future Perspectives.

10.20944/preprints202108.0037.v1 ◽

2021 ◽

Author(s):

Brigida Anna Maiorano ◽

Mauro Francesco Pio Maiorano ◽

Domenica Lorusso ◽

Evaristo Maiello

Keyword(s):

Ovarian Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Parp Inhibitors ◽

Phase Iii ◽

High Recurrence Rate ◽

Female Population ◽

First Choice ◽

Phase Iii Trials

Background: Ovarian cancer (OC) represents the eighth most common cancer and the fifth leading cause of cancer-related deaths among the female population. In the advanced setting, chemotherapy represents the first-choice treatment, despite a high recurrence rate. In the last ten years, immunotherapy based on immune checkpoint inhibitors (ICIs) has profoundly modified the therapeutic scenario of many solid tumors. We sought to summarize the main findings regarding the clinical use of ICIs in the OC. Methods: We searched the PubMed, Embase, and Cochrane Databases, and conference abstracts from international congresses (such as ASCO, ESMO, SGO) for clinical trials, focusing on ICIs both as monotherapy and as combinations in the advanced OC. Results: 20 studies were selected, of which 16 were phase I or II and 4 phase III trials. ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, atezolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab) were employed. No significant survival improvement was achieved; conversely, early terminations due to futility or toxicity were recorded. Combinations with chemotherapy, anti-VEGF, and, overall, PARP-inhibitors seem feasible and enhance the response rate and survival, notwithstanding a worse safety profile. Conclusions: The identification of biomarkers with a predictive role for ICIs’ efficacy is mandatory. Moreover, genomic and immune profiling of the OC might lead to an improved treatments selection and design of tailored trials.

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PARP inhibitors and immunotherapy in ovarian and endometrial cancers

British Journal of Radiology ◽

10.1259/bjr.20210002 ◽

2021 ◽

pp. 20210002

Author(s):

Rowan Miller ◽

Amy Lewis ◽

Melanie E Powell

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Advanced Ovarian Cancer ◽

Parp Inhibitors ◽

Platinum Sensitive ◽

Endometrial Cancers ◽

Novel Target ◽

Defective Dna Repair

Advanced ovarian and endometrial cancers have historically been associated with poor prognosis and few treatment options, limited to single or doublet chemotherapy regimens. The introduction of novel target therapies has transformed the management of these cancers. In contrast to chemotherapy, which inhibits DNA replication and mitosis, targeted therapies target cancer signalling pathways, stroma, immune-microenvironment and vasculature in tumours tissues. The most notable advances in gynaecological cancers have come from the introduction of PARP inhibitors and immune checkpoint inhibitors for ovarian and endometrial cancer respectively. Several PARP inhibitors, which target defective DNA repair have been approved as maintenance therapy for advanced ovarian cancer in both the first line and platinum sensitive relapsed settings. Immune checkpoint inhibitors such as anti PD-1/PD-L1 antibodies have proven successful in advanced mismatch repair deficient endometrial cancers with use now being investigated beyond this population. This review will explore the biological rationale and clinical evidence behind the use of PARP inhibitors and immunotherapy in ovarian and endometrial cancers.

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Randomized phase III trial on niraparib-TSR-042 (dostarlimab) versus physician’s choice chemotherapy in recurrent ovarian, fallopian tube, or primary peritoneal cancer patients not candidate for platinum retreatment: NItCHE trial (MITO 33)

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2021-002593 ◽

2021 ◽

Vol 31 (10) ◽

pp. 1369-1373

Author(s):

Lucia Musacchio ◽

Vanda Salutari ◽

Sandro Pignata ◽

Elena Braicu ◽

David Cibula ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Recurrent Ovarian Cancer ◽

Primary Objective ◽

Phase Iii ◽

Polymerase Inhibitors

BackgroundPlatinum-resistant ovarian cancer patients have a poor prognosis and few treatment options are available. Preclinical and clinical data demonstrated that the combination of poly-ADP ribose polymerase inhibitors with immune checkpoint inhibitors could have a synergistic antitumor activity in this setting of patients.Primary ObjectiveThe primary objective is to assess the efficacy of niraparib plus dostarlimab compared with chemotherapy in recurrent ovarian cancer patients not suitable for platinum treatment.Study HypothesisThis trial will assess the hypothesis that niraparib plus dostarlimab therapy is effective to increase overall survival, progression-free survival, and time to first subsequent therapy respect to chemotherapy alone, with an acceptable toxicity profile.Trial DesignThis is a phase III, multicenter trial, where recurrent ovarian cancer patients not eligible for platinum re-treatment will be randomized 1:1 to receive niraparib plus dostarlimab vs physician’s choice chemotherapy until disease progression, intolerable toxicity, or withdrawal of patient consent. The study will be performed according to European Network for Gynaecological Oncological Trial groups (ENGOT) model B and patients will be recruited from 40 sites across MITO, CEEGOG, GINECO, HeCOG, MANGO, and NOGGO groups.Major Inclusion/Exclusion criteriaEligible patients must have recurrent epithelial ovarian cancer not eligible for platinum retreatment. Patients who received previous treatment with poly-ADP ribose polymerase inhibitors and/or immune checkpoint inhibitors will be eligible. No more than two prior lines of treatment are allowed.Primary EndpointThe primary endpoint is overall survival defined as the time from the randomization to the date of death by any cause.Sample Size427 patients will be randomized.Estimated Dates for Completing Accrual and Presenting ResultsJune 2024Trial Registration NumberNCT04679064.

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Expectations and Challenges of First-Line Maintenance Therapy for Advanced Ovarian Cancer

Medicina ◽

10.3390/medicina57050501 ◽

2021 ◽

Vol 57 (5) ◽

pp. 501

Author(s):

Tadahiro Shoji ◽

Chie Sato ◽

Hidetoshi Tomabechi ◽

Eriko Takatori ◽

Yoshitaka Kaido ◽

...

Keyword(s):

Ovarian Cancer ◽

Immune Checkpoint ◽

Clinical Studies ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Advanced Ovarian Cancer ◽

Targeted Drugs ◽

First Line ◽

Double Blind ◽

Platinum Based Chemotherapy

The incidence of ovarian cancer, which has had a poor prognosis, is increasing annually. Currently, the prognosis is expected to improve with the use of molecular-targeted drugs and immune checkpoint inhibitors as maintenance therapies after the first-line chemotherapy. The GOG218 and ICON7 studies reported the usefulness of bevacizumab and the SOLO-1 and PRIMA (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy) studies have reported the usefulness of olaparib and niraparib, respectively. The ATHENA study investigating the usefulness of rucaparib is currently ongoing. Although clinical studies of immune checkpoint inhibitors are lagging in the field of gynecology, many clinical studies using programmed death cell-1 (PD-1) and PD-1 ligand 1 (PD-L1) antibodies are currently ongoing. Some biomarkers have been identified for molecular-targeted drugs, but none have been identified for immune checkpoint inhibitors, which is a challenge that should be addressed in the future.

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Role of Immune Checkpoint Inhibitors in Cervical Cancer: From Preclinical to Clinical Data

Cancers ◽

10.3390/cancers13092089 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2089

Author(s):

Simona Duranti ◽

Antonella Pietragalla ◽

Gennaro Daniele ◽

Camilla Nero ◽

Francesca Ciccarone ◽

...

Keyword(s):

Cervical Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Hpv Infection ◽

Phase Iii ◽

Screening Programs ◽

Cervical Cancers ◽

Relapsed Disease

Human papillomavirus (HPV) infection is the recognized cause of almost all cervical cancers. Despite the reduction in incidence due to a wide use of screening programs and a specific vaccine, the prognosis of cervical cancer remains poor, especially for late-stage and relapsed disease. Considering the elevated rates of PD-L1 expression in up to 80% of cervical cancers, a strong rationale supports the use of immunotherapy to restore the immune response against tumor. The aim of this review is to analyze the possible role of immune checkpoint inhibitors in cervical cancer treatment, with a particular focus on the rationale and on the results of phase I and II clinical trials. An overview of ongoing phase III studies with possible future areas of development is also provided.

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New drug developments in metastatic gastric cancer

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284818808072 ◽

2018 ◽

Vol 11 ◽

pp. 175628481880807 ◽

Cited By ~ 6

Author(s):

Aaron C. Tan ◽

David L. Chan ◽

Wasek Faisal ◽

Nick Pavlakis

Keyword(s):

Gastric Cancer ◽

Clinical Trials ◽

Targeted Therapies ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Predictive Biomarkers ◽

Metastatic Gastric Cancer ◽

New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

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Immune-related adverse events of immune checkpoint inhibitors: a brief review

Current Oncology ◽

10.3747/co.25.4235 ◽

2018 ◽

Vol 25 (5) ◽

Cited By ~ 41

Author(s):

G. Myers

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Health Care Professionals ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Hematologic Malignancies ◽

T Cell Response ◽

Proactive Management ◽

Organ Systems

Immune checkpoint inhibitors (icis) such as inhibitors of ctla-4, PD-1, and PD-L1, given as monotherapy or combination therapy have emerged as effective treatment options for immune-sensitive solid tumours and hematologic malignancies. The benefits of icis can be offset by immune-related adverse events (iraes) that leave all organ systems vulnerable and subsequently increase the risk for morbidity and mortality.Because of fluctuating onset and prolonged duration, the toxicities associated with iraes represent a shift from the understanding of conventional anticancer toxicities. The ctla-4 and PD-1/PD-L1 inhibitors modulate T-cell response differently, resulting in distinct toxicity patterns, toxicity kinetics, and dose–toxicity relationships. Using individualized patient education, screening, and assessment for the early identification of iraes is key to proactive management and is therefore key to improving outcomes and prolonging therapy.Management of iraes is guided by appropriate grading, which sets the stage for the treatment setting (outpatient vs. inpatient), ici treatment course (delay vs. discontinuation), supportive care, corticosteroid use, organ specialist consultation, and additional immunosuppression. Health care professionals in oncology must work collaboratively with emergency and community colleagues to facilitate an understanding of iraes in an effort to optimize seamless care.

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Neoadjuvant or adjuvant immunotherapy in bladder cancer: biological opportunity or clinical utility?

Tumori Journal ◽

10.1177/03008916211061604 ◽

2021 ◽

pp. 030089162110616

Author(s):

Fausto Petrelli ◽

Gianluca Perego ◽

Ivano Vavassori ◽

Andrea Luciani

Keyword(s):

Bladder Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Urothelial Cancer ◽

Checkpoint Inhibitors ◽

Phase Iii ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Cancer Of The Bladder ◽

Muscle Invasive

In urothelial cancer of the bladder, the introduction of immunotherapy with immune checkpoint inhibitors represents progress in the management of the disease’s early and advanced stages. In particular, recent studies have implemented these drugs in the neoadjuvant and adjuvant phases to treat muscle-invasive bladder cancer. In some studies, patients received neoadjuvant immune checkpoint inhibitors alone (PURE and ABACUS) to treat muscle invasive bladder cancer, whereas other studies provided this therapy to cisplatin-ineligible patients. Furthermore, a large Phase III study (CheckMate 247) compared placebo with adjuvant nivolumab therapy in patients with high-risk urothelial cancer after neoadjuvant chemotherapy and surgery or surgery alone. Despite some uncertain niches (nonbladder, PD-L1-negative tumors, and node-negative resected cancers), certain biological opportunities (exploring new targets, evaluating in vivo pathologic response, focusing on biomarkers for response) and clinical uses (avoiding chemotherapy at all or in frail patients, attaining similar pathologic complete response rates as in cisplatin-based chemotherapy) are valid reasons for incorporating these agents into the therapeutic armamentarium of medical uro-oncologists.

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Comparative Analysis of Durable Responses on Immune Checkpoint Inhibitors Versus Other Systemic Therapies: A Pooled Analysis of Phase III Trials

JCO Precision Oncology ◽

10.1200/po.18.00114 ◽

2019 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Elvire Pons-Tostivint ◽

Aurélien Latouche ◽

Pauline Vaflard ◽

Francesco Ricci ◽

Delphine Loirat ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Phase Iii ◽

Durable Response ◽

Free Survival ◽

Drug Classes ◽

Metastatic Setting ◽

The Mean

PURPOSE Immune checkpoint inhibitors (ICIs) have been demonstrated to improve overall survival (OS) in several tumor types. Durable responses have been reported with these agents in patients with melanoma and lung cancer. We aimed to quantify the proportion of patients who experience durable responses on ICIs and to compare it with other drug classes. PATIENTS AND METHODS We retrieved published phase III randomized trials that included at least one ICI arm in the recurrent and/or metastatic setting. A durable response to treatment was defined as a progression-free survival that exceeded three times the median progression-free survival of the whole population. The proportion of patients who experienced an OS that exceeded two times the median OS of the whole patient population also was estimated. RESULTS Nineteen studies involving 11,640 patients treated in 42 treatment arms (26 ICI and 16 non-ICI arms) were included. The mean proportion of patients who experienced a durable response was 2.3 times higher in those treated with an ICI compared with those treated in the control arms (25% v 11%). Durable responses were more frequent in patients treated with anti–PD-1/PD-L1 agents than in patients treated with anti–CTLA-4 agents (28% v 18%). The mean proportion of patients who had an OS that exceeded two times the median OS was also higher in those treated with ICIs than in those treated in the control arms (30% v 23%). In multivariable analysis, the effects of treatment with anti–PD-1/PD-L1 agents and of first-line treatment were statistically associated with a higher mean proportion of durable responses. CONCLUSION Durable responses were more frequent in patients treated with ICIs, although they also occurred in patients treated with other drug classes.

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Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives

Diagnostics ◽

10.3390/diagnostics10030146 ◽

2020 ◽

Vol 10 (3) ◽

pp. 146 ◽

Cited By ~ 5

Author(s):

Fulvio Borella ◽

Eleonora Ghisoni ◽

Gaia Giannone ◽

Stefano Cosma ◽

Chiara Benedetto ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Therapeutic Approaches ◽

Medical Treatments ◽

New Therapeutic Approaches ◽

Early Phase Trials ◽

Improve Patient

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological cancers. Despite improvements in medical treatments, the prognosis for EOC remains poor, and there is an urgent need for new therapeutic strategies. Immune checkpoint inhibitors (CPIs) have dramatically improved survival of several cancers and are under evaluation in OC. Unfortunately, CPIs have shown globally unsatisfactory results. The aim of this manuscript is to critically review the results from early-phase trials with CPIs in terms of safety and activity, discuss the possible reasons for disappointing results and the new therapeutic approaches to improve patient outcomes.

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