Pharmacological Treatment of Advanced, Persistent or Metastatic Endometrial Cancer: State of the Art and Perspectives of Clinical Research for the Special Issue “Diagnosis and Management of Endometrial Cancer”

Patients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment frequently with unsatisfactory clinical outcomes. The purpose of this paper was to review the results obtained with chemotherapy, hormonal therapy, biological agents and immune checkpoint inhibitors in this clinical setting. The combination of carboplatin (CBDCA) + paclitaxel (PTX) is the standard first-line chemotherapy capable of achieving objective response rates (ORRs) of 43–62%, a median progression-free survival (PFS) of 5.3–15 months and a median overall survival (OS) of 13.2–37.0 months, respectively, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with m-TOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Disappointing ORRs have been associated with epidermal growth factor receptor (EGFR) inhibitors, HER-2 inhibitors and multi-tyrosine kinase inhibitors used as single agents, and clinical trials evaluating the addition of bevacizumab to CBDCA + PTX have reported conflicting results. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high (MSI-H)/mismatch repair (MMR)-deficient (-d) EC. In a recent study, the combination of lenvatinib + pembrolizumab produced a 24-week response rate of 38% in patients with highly pretreated EC, ranging from 64% in patients with MSI-H/MMR-d to 36% in those with microsatellite stable/MMR-proficient tumors. Four trials are currently investigating the addition of immune checkpoint inhibitors to PTX + CBDCA in primary advanced or recurrent EC, and two trials are comparing pembrolizumab + lenvatinib versus either CBDCA + PTX as a first-line treatment of advanced or recurrent EC or versus single-agent chemotherapy in advanced, recurrent or metastatic EC after one prior platinum-based chemotherapy.

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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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363 Vactosertib and durvalumab as second or later line treatment for PD-L1 positive non-small cell lung cancer: interim result

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0363 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A388-A388

Author(s):

Byoung Chul Cho ◽

Ki Hyeong Lee ◽

Ji-Youn Han ◽

Byoung Yong Shim ◽

Hye Ryun Kim ◽

...

Keyword(s):

Immune Checkpoint ◽

Objective Response Rate ◽

Immune Checkpoint Inhibitors ◽

Advanced Nsclc ◽

Response Rate ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Platinum Based Chemotherapy ◽

Number Of Patients ◽

Anti Tumor Activity

BackgroundTargeting transforming growth factor-β (TGF-β) is reported to augment the efficacy of immune checkpoint inhibitors (ICIs) through either enhanced anti-tumor immunity or the correction of tumor microenvironment (TME). Therefore, the combination of vactosertib, a highly selective TGF-β RI kinase inhibitor, and durvalumab is anticipated to improve anti-tumor activity of the ICI. A phase 1b/2a study was conducted to evaluate the combination of vactosertib and durvalumab in patients with advanced NSCLC who progressed after platinum-based chemotherapy.MethodsPatients were treated with vactosertib at a dose of 200 mg twice daily (five days on and two days off) and durvalumab at a dose of 1500 mg every four weeks. Eligible patients were ≥19 years old with good performance status (ECOG 0–1) and have no prior exposure to immune checkpoint inhibitors or other TGF- β R1 kinase inhibitors. The objectives of this analysis were to evaluate the safety, antitumor activity including objective response rate (ORR), duration of response (DOR), and time to response (TTR) as well as circulating pharmacodynamic biomarkers related to TGF-β signaling. Response was assessed per RECIST (v1.1).ResultsBy August 4 2020, twenty-six PD-L1 positive (SP263 assay) patients were analyzed. Median age was 61.5 years (range 48–83), 69.2% were male, median number of previous lines of chemotherapy was 1 (range 1–4), and all patients were PD-L1 positive (15 patients with PD-L1≥25% and 11 patients with PD-L1 1–24%). The most frequently reported treatment-related adverse events (TRAE) were itching (38.5%) and skin rash (34.6%), but no Gr≥3 itching and rash were observed. Each case of the following was reported as Grade 3 TRAEs: adrenal insufficiency, anemia, and pneumonitis; Grade 4 TRAE, CPK increase, was observed in one patient. Objective response rate was 30.8% and 40.0% in patients with PD-L1≥1% and ≥25% respectively. Circulating PAI-1 and CTGF evaluated in 15 patients decreased significantly on Cycle 1 day 5. Ongoing biomarker results will be presented.ConclusionsThe combination of vactosertib and durvalumab has demonstrated a manageable safety profile and encouraging anti-tumor activity as a potential therapeutic strategy in patients with advanced NSCLC. The efficacy outcomes of this combination in a larger number of patients with advanced NSCLC will be followed.Trial RegistrationNCT03732274Ethics ApprovalThe study was approved by Ethics Board of Severance Hospital (4-2018-0892), National Cancer Center (NCC2019-0057), St. Vincent’s Hospital (VC19MDDF0205), and Chungbuk National University Hospital (2019-08-015).

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MO153RENAL FUNCTIONS OUTCOME IN METASTATIC NON SMALL LUNG CARCINOMA PATIENTS: THE RISK OF AKI IN FIRST LINE THERAPY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab092.0031 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Francesco Trevisani ◽

Federico Di Marco ◽

Francesco Fiorio ◽

Monica Cattaneo ◽

Erika Rijavec ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Combined Therapy ◽

Overweight And Obesity ◽

Categorical Variables ◽

Rank Test ◽

First Line ◽

Metastatic Nsclc ◽

Platinum Based Chemotherapy

Abstract Background and Aims The optimal use of immune and target therapies, the optimal use of standard chemotherapy (CT) is of paramount importance, especially for patients affected by chronic kidney disease (CKD) who require dose adjustment according to the glomerular filtration rate (GFR) to avoid acute kidney injury (AKI) establishment. Immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy (CT) are options for the palliative treatment of metastatic non-small cell lung cancer (NSCLC). Recently, CT in combination with immune-checkpoint inhibitors has become the treatment of choice for this setting of patients. Therefore, it is fundamental to investigate the potential nephrotoxic effects of both treatments and their potential additive effects on renal function. Aim of our study was to compare the nephrotoxic effect of both ICIs and CT (cisplatin and carboplatin-based) in a consecutive cohort of patients affected by metastatic NSCLC. Method A consecutive cohort of 126 patients treated in first-line for NSLCL was enrolled in a single tertiary Hospital between 2018 and 2020. Inclusion criteria were: age (> 18 years old), eGFR (> 15 ml/min/1.73), histological diagnosis of metastatic NSCLC. Each patient underwent immunotherapy or CT according to clinical conditions, comorbidities and programmed death ligand 1 (PD-L1) expression status. eGFR (using CKD-EPI formula 2009) was detected at baseline and after each cycle of immunotherapy or CT (using cisplatin or carboplatin) in order to determine the correct renal status using the K-DIGO 2012 guidelines for AKI stages and CKD classes. Pts were subdivided into CKD categories G according to their eGFR values before and after the treatment. AKI onset was evaluated by rise in creatine levels according to K-DIGO criteria. Clinical stage according to cTNM (AJCC TNM system-2019) was collected at baseline before the first treatment. Comorbidities (e.g., diabetes, blood hypertension, overweight and obesity) were also included. Comparison between numerical variables was performed using linear regressions; between groups using Kruskal-Wallis rank sum test for numerical variables and Pearson’s Chi square test for categorical variables. Log rank test was used to test differences between groups in terms of AKI onset during the therapy. Results Clinical and pathological characteristics are reported in table 1. From the analysis, no significative differences were detected between Immunotherapy and CT group for age, gender, basal serum creatinine, basal eGFR, basal BMI, diagnosis of diabetes, hypertension, basal CKD G group or overall AKI onset. Treatment cycles were significantly different between the two groups (p<0.001) with a short median number of cycles for the CT group. No significative difference in terms of decay of eGFR calculated as final-basal values was detected (p=0.8). AKI onset over cycles was significantly different between the two groups (p=0.02), observing a higher risk of developing earlier AKI for CT group (cisplatin or carboplatin) (13,9%) with respect to immunotherapy (7,4%) (figure 1 and 2). Conclusion Our study highlights that both cisplatin and carboplatin-based CT displays an augmented incidence of AKI development after a lower number of therapy cycles in respect of immunotherapy. The nephrotoxic effects of combined therapy for NSLCL should be always evaluated by nephrologist during the treatment of NSLCL patients to avoid an augmented risk of AKI derived from the combination of immunotherapy and CT in first line.

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Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

Cancers ◽

10.3390/cancers13010131 ◽

2021 ◽

Vol 13 (1) ◽

pp. 131

Author(s):

Antonio Lopez-Beltran ◽

Alessia Cimadamore ◽

Ana Blanca ◽

Francesco Massari ◽

Nuno Vau ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Durable Response ◽

First Line Therapy ◽

Line Therapy

A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.

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Efficacy and toxicity of immunotherapy with immune checkpoint inhibitors in gynecologic cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18092 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18092-e18092

Author(s):

Michelle Kuznicki ◽

Amy Joehlin-Price ◽

Peter Graham Rose ◽

Haider Mahdi

Keyword(s):

Stable Disease ◽

Immune Checkpoint ◽

Clinical Benefit ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Gynecologic Cancer ◽

Objective Response ◽

Complete Response ◽

Rank Test ◽

First Line

e18092 Background: There is limited data on outcomes for gynecologic cancer patients treated with immune checkpoint inhibitors (ICI) outside the scope of clinical trials. Here we present our Institutional experience with a cohort of endometrial (EC) and ovarian cancer (OC) treated with ICI. Methods: 59 patients who received ICI were included (23 OC and 36 EC). Progression-free (PFS) and Overall survivals (OS) were determined by Kaplan-Meier (KM) curve and log rank test. Comparison of duration of response (DOR) and stable disease (DOSD) was done with unpaired t-test or one-way ANOVA. Rates of objective response (ORR) including partial response (PR) and complete response (CR), and stable disease (SD) were compared by Fischer’s exact test. Results: Median age was 66 years. 23 patients were microsatellite stable (MSS), 23 microsatellite instability high (MSI-H). Median number of prior lines was 2 (0-11). PFS and OS for EC and OC were overlapping; therefore outcomes for both were combined [(PFS 6.4m OC vs 7.3 m EC, p = 0.61), (OS 15.9 m OC vs 14.2 m EC, p = 0.78)]. Response rates consisted of 20.3% PR, 8.5% CR, 37.3% SD. Differences in responses were noted for clear cell carcinoma (CC) (33.3% PR, 11.1% CR, 33.3% SD) and MSI-H (36.4% PR, 18.2% CR, 22.7% SD) compared to MSS (11.8% PR, 0% CR, 47% SD). MSI-H had higher ORR vs. MSS (54.1% vs 11.8%, p = 0.0078). CC trended toward improved ORR vs. MSS (44.4% vs 11.8%, p = 0.14). PFS was improved for MSI-H vs. MSS (10m v 5.0m, p = 0.03). OS for CC compared to any other histology was improved (NR vs 12.8m respectively, p = 0.009). 5 recurrent MSI-H EC patients received ICI as first line monotherapy. Responses included 4 PR and 1 SD (80% ORR, 100% clinical benefit). PFS was 9.2m (3.3-13.3). 80% remained progression-free at last follow up. Overall, 38.9% experienced toxicity: hypothyroidism (15%), dermatitis (5%), pneumonitis (10%), LFT elevation (2%), amylase/lipase elevation (3%), colitis or diarrhea (5%), uveitis (2%) or nephritis (5%). 10% of patients required discontinuation of ICI secondary to toxicity. Trends for PFS and OS favored improved outcomes in patients with toxicity vs. no toxicity [(PFS 12.9m vs 5.6m, p = 0.07), (OS 22.9m vs 13.1m, p = NS)] respectively. Conclusions: In this study, immunotherapy with ICI outcomes favor MSI-H and CC compared to MSS disease. CC had promising OS compared to other histology types. ICI showed promising efficacy in MSI-H EC with 100% clinical benefit rate in chemonaive patients. First line ICI should be investigated in these patients. Positive correlation between toxicity and outcome is noted and will be further investigated.

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Association of LRP1B pathogenic genomic alterations with favorable outcomes with immune checkpoint inhibitors across multiple tumor types.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3007 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3007-3007 ◽

Cited By ~ 1

Author(s):

Landon Carter Brown ◽

Ramy Sedhom ◽

Eric B Schwartz ◽

Jason Zhu ◽

Chester Kao ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Objective Response ◽

Density Lipoprotein ◽

Primary Objective ◽

Missense Mutations ◽

Multiple Tumor ◽

Tumor Types

3007 Background: Low-density lipoprotein receptor-related protein 1b (LRP1b) is a putative tumor suppressor and one of the most frequently altered genes in cancer. Our prior single-center work suggested that LRP1B alterations may enrich for responses to immune checkpoint inhibitors (ICI) in solid tumors including prostate cancer; however, validation of these findings is needed. Methods: We conducted a multicenter, retrospective analysis of patients with LRP1B alterations (on tissue-based next-generation sequencing panels) treated with ICI at Duke, Johns Hopkins (JHU), and University of Michigan (UM). The primary objective was to assess the association between objective response rate (ORR) to ICI and pathogenic LRP1B alterations, defined as deletions or truncating alterations, when compared with LRP1B variants of undetermined significance (VUS), defined as missense mutations not predicted to be pathogenic in COSMIC. Missense changes with a COSCMIC FATHMM score of > 0.8 were categorized separately as likely pathogenic. Summary statistics, ORR, progression free survival (PFS), and overall survival (OS) were calculated. Results: 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations were treated with ICI. Median age was 61 (range 32-82). The most common tumor types by alteration (pathogenic or likely pathogenic/VUS%) were lung (33/47%), GI (17/13%), prostate (11/7%), sarcoma (2/9%), melanoma (11/0%), and others (26/24%). 93% of patients received single-agent PD-(L)1 inhibition. The ORR for patients with either pathogenic/likely pathogenic alterations, or VUS alterations was 57% and 18%, respectively. After excluding MSI-high or TMB-high ( > 10 mut/Mb) tumors, ORR was 14/25 (56%) and 6/36 (17%), respectively. Pathogenic or likely pathogenic LRP1B alterations were associated with longer PFS (HR 0.39, 95% CI 0.24-0.63) and OS (HR 0.58, 95% CI 0.36-0.95). Conclusions: This multicenter study shows impressive and durable objective response rates to ICI for patients harboring pathogenic LRP1B alterations when compared to those with LRP1B VUS, independent of TMB/MSI status. Further mechanistic insights and prospective validation studies are warranted. [Table: see text]

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Landscape of immune-checkpoint inhibitors in hepatocellular carcinoma: A systematic review with meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16632 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16632-e16632

Author(s):

Dmitrii Shek ◽

Scott A. Read ◽

Adnan Nagrial ◽

Bo Gao ◽

Golo Ahlenstiel

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Objective Response ◽

Forest Plot ◽

Second Line ◽

First Line ◽

Advanced Hcc

e16632 Background: The WHO estimates that liver cancer will cause 1 million deaths by 2030. Hepatocellular carcinoma (HCC) is a primary liver malignancy causing 4.3% of all cancer deaths in 2019 in Australia. Kinase inhibitors are standard of care (SoC) for metastatic HCC with median overall survival (mOS) of < 13 months. This meta-analysis primarily aimed to determine objective response rate (ORR) of immune-checkpoint inhibitors (ICIs) in advanced HCC. Methods: Potentially relevant clinical studies were identified through PUBMED, Scopus, ASCO and ESMO databases. Studies evaluating ICIs in patients with HCC and reporting efficacy outcomes were considered as eligible. Publication bias was assessed with Funnel plots. Data analysis was performed employing fixed and random effects model depending on study heterogeneity evaluating by I2 statistic. STATA v16 software was used for all statistical considerations. Results: 12 single arm phase II/III studies and 2 randomized clinical trials on ICIs in HCC were included into this analysis. First-line ICI: Primary forest plot established the median ORR was 26.2% (95% CI 24.7 to 27.9) in patients treated with first line ICIs monotherapy; in comparison, ORR of current SoC sorafenib is 2-3% and lenvatinib 18.8%. Moreover, nivolumab resulted in 9.8 months of OS in Child-Pugh class B (CPB) patients, previously eligible only for supportive care due to a low efficacy of sorafenib (mOS < 4.5 months). Second-line ICI: Secondary forest plot established that nivolumab at 1 mg/kg with ipilimumab 3 mg/kg Q3W resulted in mOS of 23 months with ORR of 32% in sorafenib-progressors. In comparison, current second line SoC regorafenib has mOS of 10.6 months and ORR of 17%. Conclusions: This meta-analysis suggests that ICIs may be superior (ORR) to SoC sorafenib in advanced HCC, particularly nivolumab. Secondly, nivolumab with ipilimumab were confirmed to provide higher OS in sorafenib progressors as compared to regorafenib. Of note, many of the studies included were only available in abstract form and final reporting is pending. Nevertheless, our results support higher efficacy of ICIs in HCC patients.

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Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter?

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919861905 ◽

2019 ◽

Vol 11 ◽

pp. 175883591986190 ◽

Cited By ~ 9

Author(s):

Giandomenico Roviello ◽

Silvia Paola Corona ◽

Gabriella Nesi ◽

Enrico Mini

Keyword(s):

Overall Survival ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Objective Response ◽

Progression Free Survival ◽

Pooled Analysis ◽

First Line

Background: The aim of this study was to perform a literature-based meta-analysis to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in first-line metastatic renal cell carcinoma (RCC), focusing on the predictive role of PD-L1 expression. Methods: The primary outcome was overall survival, and secondary outcomes were progression-free survival (PFS) and objective response. We planned a subgroup analysis for overall survival according to PD-L1 status. Results: Five studies were included in the analysis for a total of 4063 cases. Overall survival was greater in PD-L1 positive tumours (HR = 0.49, 95% CI: 0.36–0.67; p < 0.001). The pooled analysis of the unselected cases showed a statistically significative improvement in PFS with the use of ICIs (HR = 0.85, 95% CI: 0.72–0.99; p = 0.04) and we found a greater PFS benefit (HR = 0.65, 95% CI: 0.57–0.74; p < 0.001) in patients with PD-L1 positive tumours. Conclusions: This study supports the efficacy of ICIs and, although a significant clinical benefit has been reported in PD-L1 negative patients, a greater efficacy of ICIs was observed in PD-L1 positive patients. More prospective randomized studies are needed to clarify the role of PDL-1 status in metastatic RCC treated with ICIs.

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