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

Cancers ◽

10.3390/cancers13174438 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4438

Author(s):

Brigida Anna Maiorano ◽

Mauro Francesco Pio Maiorano ◽

Domenica Lorusso ◽

Evaristo Maiello

Keyword(s):

Ovarian Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Parp Inhibitors ◽

Phase Iii ◽

High Recurrence Rate ◽

Female Population ◽

First Choice

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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Comparative analysis of durable responders on immune checkpoint inhibitors (ICI) versus other systemic therapies: A meta-analysis of phase III trials.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.3070 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 3070-3070 ◽

Cited By ~ 1

Author(s):

Elvire Pons-Tostivint ◽

Aurélien Latouche ◽

Pauline Vaflard ◽

Francesco Ricci ◽

Delphine Loirat ◽

...

Keyword(s):

Comparative Analysis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Phase Iii ◽

Phase Iii Trials ◽

Systemic Therapies

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Erratum to “Critical reappraisal of phase III trials with immune checkpoint inhibitors in non-proportional hazards settings” [Eur J Cancer 136 (September 2020) 159−168]

European Journal of Cancer ◽

10.1016/j.ejca.2020.10.003 ◽

2021 ◽

Vol 142 ◽

pp. 152-153

Author(s):

Eduardo Castañón ◽

Alvaro Sanchez-Arraez ◽

Felipe Alvarez-Manceñido ◽

Paula Jimenez-Fonseca ◽

Alberto Carmona-Bayonas

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Proportional Hazards ◽

Checkpoint Inhibitors ◽

Phase Iii ◽

Phase Iii Trials

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Approaches to High-Risk Resected Stage II and III Melanoma

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_239283 ◽

2019 ◽

pp. e207-e211 ◽

Cited By ~ 2

Author(s):

Melinda Yushak ◽

Janice Mehnert ◽

Jason Luke ◽

Andrew Poklepovic

Keyword(s):

High Risk ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Stage Ii ◽

Phase Iii ◽

Adjuvant Setting ◽

Number Of Patients ◽

Phase Iii Trials ◽

Resected Stage

Over the last decade, several therapies, including both targeted and immune checkpoint inhibitors, have dramatically changed the treatment landscape for patients with metastatic melanoma. These same therapies are now being used in the adjuvant setting with the hope of delaying or preventing the development of metastatic disease. Although phase III trials have shown a clear benefit for patients with resected bulky nodal disease, treatment decisions for patients with earlier-stage (high-risk stage II and stage IIIA) melanoma in the adjuvant setting are less straightforward given the small number of patients studied so far. Among patients with stage IIIB and worse disease, both targeted and immune checkpoint inhibitors have shown benefit in recurrence-free survival. Although a head-to-head comparison has not been completed, patient and tumor characteristics can guide the optimal treatment of an individual.

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Critical reappraisal of phase III trials with immune checkpoint inhibitors in non-proportional hazards settings

European Journal of Cancer ◽

10.1016/j.ejca.2020.06.003 ◽

2020 ◽

Vol 136 ◽

pp. 159-168 ◽

Cited By ~ 2

Author(s):

Eduardo Castañon ◽

Alvaro Sanchez-Arraez ◽

Felipe Alvarez-Manceñido ◽

Paula Jimenez-Fonseca ◽

Alberto Carmona-Bayonas

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Proportional Hazards ◽

Checkpoint Inhibitors ◽

Phase Iii ◽

Phase Iii Trials

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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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The importance of evaluating long term responder fraction using complementary statistical approaches in immune checkpoint inhibitors phase III trials: An in-silico study using keynote 045 study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16512 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16512-e16512

Author(s):

Fanny Mathevet ◽

Damien Pouessel ◽

Jean-Yves Dauxois ◽

Nadine Houede ◽

Christine Chevreau ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cox Model ◽

Phase Iii ◽

Kaplan Meier ◽

Phase Iii Trials ◽

Statistical Approaches ◽

Term Benefit

e16512 Background: Immune-checkpoint-inhibitors (ICI) provide durable antitumor activity even for recurrent and/or metastatic disease. As illustrated in the Keynote-045 study (pembrolizumab (pembro.) in second line metastatic urothelial carcinoma; Fradet, 2019), improvement in long-term responder fraction does not always translate into progression-free survival (PFS) improvement. Despite a long-term benefit improvement (2 years PFS: 12.4% vs 3%), there was no significant difference in PFS (HR 0.98; 95% CI, 0.81-1.19; p=0.42). Benefits in terms of OS were not deemed sufficient by the French health authorities in charge of health technology assessment and reimbursement of medicinal products to consider that pembro. brought a significant improvement upon existing drugs in urothelial carcinoma. Thus, although recommended by scientific societies, this treatment has only been available in France since January 2020. The main objective is to illustrate the importance of using complementary statistical approaches when evaluating ICI phase III trials. Methods: PFS curves of the Keynote-045 study available in publications (Bellmunt, 2017; Fradet, 2019) were digitized to reconstruct pseudo individual patient data as per established methods. Survival rates were estimated using Kaplan-Meier method and comparison between groups were performed using Cox model. Flexible parametric survival models with cure (FPCM) were then used to estimate the treatment benefit in terms of long-term responder fraction and evaluate the treatment effect on PFS in the non–long-term responder population. Results: In both first and updated data, there were no significant between-group difference in the duration of PFS in the total population (2017: HR=0.95, 95%CI 0.79–1.15; 2019: HR=0.93, 95%CI 0.77–1.11). Using FPCM, we demonstrated that the long-term responder fraction (LRF) was higher with pembro. compared to chemotherapy (2017: Pembro 14.0% 95%CI 10.2-18.3; Chemo.: 7.7% 95%CI 4.9-11.2; 2019: Pembro 11.0% 95%CI 7.8-14.9; Chemo.: 4.6% 95%CI 2.7-7.3). Differences in LRF were estimated to 6.3% (95%CI 1.5–11.13) and 6.4% (95%CI 2.4-10.4]) in the first and updated analysis, respectively. In the non–long-term responder population, ICI was first associated with a higher risk of progression or death and then a lower risk. Conclusions: While ICIs show a substantial shift towards long-term benefit in terms of PFS, greater emphasis should be placed on rigorously evaluating this quantity instead of only reporting Kaplan-Meier estimation or comparing PFS curves using classical Cox model. Despite the long-term responder fraction improvement was constant between analysis, relative variations in LRFs were observed. This suggests that the follow-up of this study was not long enough to properly characterize long term responders.

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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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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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