Activity of PD-1 Inhibitor Combined With Anti-Angiogenic Therapy in Advanced Sarcoma: A Single-Center Retrospective Analysis

Background: Immune checkpoint inhibitors (ICIs) are employed to treat various cancers, including soft tissue sarcomas (STSs), and less than 20% of patients benefit from this treatment. Vascular endothelial growth factor (VEGF) promotes the immunosuppressive tumor microenvironment and contributes to ICI-resistant therapy. Anti-VEGF receptor tyrosine-kinase inhibitors (TKIs) combined with ICIs have shown antitumor activity in patients with alveolar soft-part sarcoma (ASPS). However, they have not been extensively studied to treat other STS subtypes, such as leiomyosarcoma (LMS), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), and angiosarcoma (AS).Methods: In this retrospective study, we collected data from 61 patients who were diagnosed with advanced STS based on imaging and histology, including LMS, DDLPS, and UPS. Among them, 41 patients were treated with ICIs combined with TKIs and 20 patients received ICI therapy. The endpoints of progression-free survival (PFS) and overall response rate (ORR) were analyzed in the two groups, and the overall response [partial response (PR), stable disease (SD), and progressive disease (PD)] of each patient was determined using RECIST 1.1 evaluation criteria.Results: In total, 61 STS patients had the following subtypes: LMS (n = 20), DDLPS (n = 17), UPS (n = 8), ASPS (n = 7), MFS (n = 7), and AS (n = 2). The median PFS (mPFS) was significantly prolonged after ICI treatment in combination with TKIs (11.74 months, 95% CI 4.41–14.00) compared to ICI treatment alone (6.81 months, 95% CI 5.43–NA) (HR 0.5464, p = 0.043). The 12-month PFS rates of patients who received ICI–TKI treatment were increased from 20.26% (95% CI 0.08–0.53) to 42.90% (95% CI 0.27–0.68). In the combination therapy group, 12 patients (30%) achieved PR, 25 patients (62.5%) achieved SD, and 3 patients (7.5%) achieved PD for 3 months or longer. In the non-TKI-combination group, 2 patients (9.5%) achieved PR, 14 patients (66.7%) achieved SD, and 5 patients (23.8%) achieved PD within 3 months. The ORRs in the two groups were 30.0% (ICI–TKI combination) and 9.5% (ICI only), respectively. A notable ORR was observed in the ICI–TKI combination group, especially for subtypes ASPS (66.7%), MFS (42.9%), and UPS (33.3%). The PD-L1 expression (n = 33) and tumor mutation burden (TMB, n = 27) were determined for each patient. However, our results showed no significant difference in PFS or response rates between the two groups.Conclusion: This study suggests that ICI–TKI treatment has antitumor activity in patients with STS, particularly the ASPS and MFS subtypes. Moreover, effective biomarkers to predict clinical outcomes are urgently needed after combination therapy in the STS subtypes.

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The Comparison of Hypomethylating Agents (HMA) Monotherapy with HMA Combined with Intensive Chemotherapy for Intermediate / High-Risk MDS or AML

Blood ◽

10.1182/blood-2019-123335 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3903-3903

Author(s):

Jiang Ji ◽

Zhao Wang ◽

Bing Han

Keyword(s):

High Risk ◽

Combination Therapy ◽

Death Rate ◽

Therapy Group ◽

Meta Analysis ◽

Combination Group ◽

Combination Therapy Group ◽

Hypomethylating Agents ◽

Monotherapy Group ◽

Significant Difference

Introduction: Hypomethylating agents (HMA) azacitidine and decitabine were the first-line therapy for intermediate/ higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients unsuitable for hematopoietic cell transplantation (HSCT). HMA combined with chemotherapy was recently used to achieve for a better outcome. However, few studies were carried out to compare the HMA monotherapy to the HMA and chemotherapy combination therapy. This meta-analysis aimed to compare the efficacy, survival benefit and safety of HMA monotherapy and combination therapy (with chemotherapy) in patients with intermediate/high-risk MDS or AML. Methods: Related articles published between January 2009 and April 2019 were selected and patients were separated as monotherapy group and combination group for meta-analysis. To further eliminate the potential influence of differences in patients' baseline characteristic between the two groups, subgroups with similar patients' baseline characteristics were selected for further analysis. Complete response (CR) rate, overall response (ORR) rate, 1-year overall survival (OS) rate, 1-month death rate and the proportion of adverse event (AE) were pooled and compared. Results: 13 RCT or cohort studies with 997 patients (790 in monotherapy group, 207 in HMA combination group) were selected for meta-analysis. For the pooled data, there was no significant difference in sex and cytogenetic risk between the 2 groups, but the age of combination therapy group was significantly younger than that of the monotherapy group (61.3±13.2 year-old vs 67.7±10.2 year-old, p=0.000). The CR and ORR rate were significantly higher in combination therapy group (53% vs 17%, p=0.000 for CR and 67% vs 44%, p=0.000 for ORR). However, the 1-year OS (56% for combination therapy vs 51% for HMA monotherapy group, p=0.282) and 1-month death rate (5% for combination therapy vs 4% for HMA monotherapy group, p=0.965) were similar between the two groups. The incidence of CTCAE grade 3-4 infection and bleeding were significantly higher (infection: 50% for combination therapy vs 25.7% for monotherapy group, p=0.003; bleeding: 27.5%% for combination therapy vs 7.8% for monotherapy group, p=0.004) in combination group. In subgroup analysis, 117 and 179 patients were included in combination group and HMA monotherapy group, respectively. There was no significant difference in age (69.5±4.6 vs 69.0±6.8 years old, p=0.451) and proportion of favorable/intermediate cytogenetic risk (62% vs 71%, p=0.114) between the two groups, but a significantly lower proportion of male was found in combination therapy group (57% vs 74%, p=0.003). Although combination group had a higher CR rate (49% vs 17%, p=0.000), it had similar ORR rate (58% vs 49%, p=0.140) to monotherapy group. Meanwhile, combination therapy came with higher 1-month death rate (12% vs 3%, p=0.008) and lower 1-year OS (54% vs 68%, p=0.013) compared with monotherapy group. Conclusions: HMA combined with chemotherapy could increase CR rate in all patients and ORR rate in younger patients, but could not improve OS. For patients with similar older age, combination therapy could result in higher 1-month death rate and less 1-year OS. Disclosures No relevant conflicts of interest to declare.

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Five-year visual outcomes after anti-VEGF therapy with or without photodynamic therapy for polypoidal choroidal vasculopathy

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2018-311963 ◽

2018 ◽

Vol 103 (5) ◽

pp. 617-622 ◽

Cited By ~ 4

Author(s):

Manabu Miyata ◽

Sotaro Ooto ◽

Kenji Yamashiro ◽

Hiroshi Tamura ◽

Masayuki Hata ◽

...

Keyword(s):

Photodynamic Therapy ◽

Combination Therapy ◽

Polypoidal Choroidal Vasculopathy ◽

Fundus Photography ◽

Combination Group ◽

Macular Atrophy ◽

Anti Vegf ◽

Significant Difference ◽

Treatment Naïve ◽

Choroidal Vasculopathy

Background/aimsTo evaluate the 5-year visual and anatomical outcomes after anti-vascular endothelial growth factor (VEGF) therapy alone or in combination with photodynamic therapy (PDT), followed by pro re nata (PRN) anti-VEGF therapy with or without PDT, for polypoidal choroidal vasculopathy (PCV).MethodsThis retrospective, observational study included 61 consecutive patients with treatment-naïve symptomatic PCV who were followed for 5 years. Twenty eyes (20 patients) initially received PDT and intravitreal injection of ranibizumab (IVR), followed by a PRN regimen of anti-VEGF therapy with or without PDT (combination group), while 41 eyes (41 patients) initially received only IVR every 3 months, followed by a PRN regimen of anti-VEGF monotherapy (IVR group). Macular atrophy including the fovea was confirmed using colour fundus photography and spectral-domain optical coherence tomography.ResultsIn both groups, the visual acuity (VA) at 1 year was better than the baseline VA, whereas the 3-year, 4-year and 5-year VA values were similar to the baseline VA. There was no significant difference in the 5-year VA, 5-year central retinal thickness and incidence of macular atrophy between the two groups (p=0.63, 0.72 and 0.06, respectively). In the combination group, the 5-year VA was correlated with the 5-year incidence of macular atrophy (p=0.02, r=0.51).ConclusionsA PRN regimen for PCV may have a limited effect for the long-term maintenance of improved VA. Macular atrophy may occur more frequently with combination therapy and is possibly associated with the 5-year VA. Thus, combination therapy should be carefully selected for patients susceptible to macular atrophy.

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Risk Versus Benefit of Combined Aspirin and Warfarin Therapy in Patients With Atrial Fibrillation

Journal of Pharmacy Practice ◽

10.1177/0897190020916638 ◽

2020 ◽

pp. 089719002091663

Author(s):

Tara A Nagaraj ◽

Melissa J. Snider ◽

Erica Davidson ◽

Raul Weiss ◽

Junan Li ◽

...

Keyword(s):

Atrial Fibrillation ◽

Combination Therapy ◽

Major Bleeding ◽

Therapy Group ◽

Stable Coronary Artery Disease ◽

Group Versus ◽

Bleeding Risk ◽

Combination Group ◽

Monotherapy Group ◽

Significant Difference

Purpose: Guidelines have differing recommendations for aspirin use in patients with an indication for anticoagulation. The purpose of this study was to evaluate the incidence of major bleeding and thromboembolic events (TEs) in patients with atrial fibrillation (AF) receiving warfarin alone (monotherapy group) versus warfarin plus aspirin (combination therapy group). Methods: This was a retrospective, cohort study including patients from a pharmacist-run anticoagulation clinic. Inclusion criteria were patients with AF receiving anticoagulation between January 2013 and January 2014 observed over 5 years. Results: One hundred forty-two patients were included in the combination group versus 89 in monotherapy group. In the combination group, 60 (42.3%) patients were on aspirin for no apparent indication, 19 (13.4%) had stable coronary artery disease and diabetes, and 26 (18.3%) had diabetes alone. Major bleeding occurred in 21 (14.9%) patients in the combination group versus 7 (7.9%) patients in the monotherapy group (odds ratio [OR] = 2.02, 95% confidence interval [CI]: 0.78-5.91; P = .17). TE occurred in 10 (7%) patients in the combination group versus 4 (4.5%) in the monotherapy group (OR = 1.61, 95% CI: 0.44-7.24; P = .57). There was no significant difference in bleeding ( P = .85) or TE ( P = .37) rates between aspirin indications in the combination group. Conclusion: Combination therapy versus monotherapy may increase bleeding risk with little benefit in decreasing AF-related stroke or cardiovascular events.

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Differential Dermatologic Adverse Events Associated With Checkpoint Inhibitor Monotherapy and Combination Therapy: A Meta-Analysis of Randomized Control Trials

Frontiers in Pharmacology ◽

10.3389/fphar.2021.640099 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yang Ge ◽

Huiyun Zhang ◽

Nathaniel Weygant ◽

Jiannan Yao

Keyword(s):

Relative Risk ◽

Combination Therapy ◽

Adverse Events ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

High Grade ◽

Treatment Regimens ◽

Increased Risk ◽

Significant Difference ◽

Dermatologic Adverse Events

Background: As immune checkpoint inhibitors (ICIs) transition to the forefront of cancer treatment, a better understanding of immune related adverse events (IRAEs) is essential to promote safe clinical practice. Dermatologic adverse events are the most common IRAEs and can lead to drug withdrawal and decreased quality of life. This meta-analysis aimed to investigate the risk of the most prevalent dermatologic adverse events (pruritus and rash) among various ICI treatment regimens.Methods: A systematic search of electronic databases was performed to identify qualified randomized controlled trials (RCTs). Data for any grade and high grade pruritus and rash were extracted for meta-analysis. Two reviewers independently assessed methodological quality. The relative risk summary and 95% confidence interval were calculated.Results: 50 RCTs involving 29941 patients were analyzed. The risk of pruritus (2.15 and 4.21 relative risk respectively) and rash (1.61 and 3.89 relative risk respectively) developing from CTLA-4 or PD-1/-L1 inhibitor were increased compared to placebo, but this effect was not dose-dependent. PD-1/-L1 plus CTLA-4 inhibitor was associated with increased risk of pruritus (1.76 and 0.98 relative risk respectively) and rash (1.72 and 1.37 relative risk respectively) compared to either monotherapy. Compared with CTLA-4 inhibitor, PD-1/-L1 inhibitor had a significantly decreased risk of pruritus and rash in both monotherapy and combination therapy (0.65 and 0.29 relative risk respectively). No significant difference was found between PD-1/-L1 inhibitor combined with chemotherapy and PD-1/-L1 monotherapy in any grade and high grade rash (0.84 and 1.43 relative risk respectively). In subgroup analyses, PD-1 inhibitor was associated with reduced risk of pruritus and rash compared to PD-L1 inhibitor.Conclusion: Our meta-analysis demonstrates a better safety profile for PD-1/-L1 inhibitor compared to CTLA-4 inhibitor in terms of pruritus and rash among both monotherapy and multiple combination therapies. PD-L1 inhibitor may contribute to an increased risk of pruritus and rash compared to PD-1 inhibitor.

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204. Clinical Outcomes with Ceftaroline Monotherapy versus Daptomycin-Ceftaroline Combination Therapy in the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.406 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S209-S210

Author(s):

Gabriela Andonie ◽

Elizabeth O Hand ◽

Kelly R Reveles ◽

Kristi A Traugott

Keyword(s):

Staphylococcus Aureus ◽

Combination Therapy ◽

Clinical Outcomes ◽

Methicillin Resistant Staphylococcus Aureus ◽

Controlled Trial ◽

Primary Source ◽

Retrospective Chart Review ◽

Combination Group ◽

Methicillin Resistant ◽

Significant Difference

Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with poor outcomes and increased mortality. Daptomycin (DAP) and ceftaroline (CPT) in combination has been explored as a potential treatment option and showed improved outcomes compared to vancomycin/standard therapy. CPT monotherapy has been evaluated as salvage therapy for MRSA bacteremia but, to our knowledge, not as a comparator to DAP-CPT combination therapy. The purpose of this study is to compare the clinical outcomes of DAP and CPT combination therapy to CPT monotherapy in the setting of MRSA bacteremia. Methods A retrospective chart review of adult patients (≥ 18 years of age) admitted to University Health from January 2017 to December 2020 with a diagnosis of MRSA bacteremia was performed. Patients received either CPT monotherapy or DAP-CPT combination therapy for a minimum of 48 hours during their course of therapy. Results Thirty-two patients met inclusion criteria and were evaluated. Primary source of infection was pulmonary in the CPT monotherapy group (n=7/24; 29.2%) and osteomyelitis in the DAP-CPT combination group (n= 4/8; 50.0%). Median duration of bacteremia was 8 days and 9 days in the CPT monotherapy and DAP-CPT combination group, respectively. Microbiological cure was achieved in 95.8% (n=23/24) of patients in the CPT monotherapy and 100% (n=8/8) of patients in the DAP-CPT combination group. Bacteremia relapse (30 day, p=0.62; 60 day, p=0.63), readmission rates (30 day, p=0.62; 60 day, p=0.63), and mortality rates (30 day, p=0.70; 90 day, p=0.85) were similar in both groups. There was no statistically significant difference in safety parameters, including incidence of acute kidney injury (p=1.00) and creatine kinase elevations (p=1.00). Bone marrow suppression after at least 72 hours of therapy, including anemia, leukopenia, and thrombocytopenia, was also not statistically significant between groups. Conclusion This study was unable to find a statistically significant difference in clinical outcomes between patients receiving CPT monotherapy or DAP-CPT combination therapy. A large prospective, randomized controlled trial to assess CPT monotherapy and DAP-CPT combination therapy for the treatment of persistent MRSA bacteremia is warranted. Disclosures All Authors: No reported disclosures

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Outcome for Advanced or Metastatic Soft Tissue Sarcoma of Nonextremities Treated with Doxorubicin-Based Chemotherapy: A Retrospective Study from a Single Cancer Institution

Sarcoma ◽

10.1155/2018/8926598 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Shoko Marshall ◽

Kenji Nakano ◽

Yoshiya Sugiura ◽

Shinichiro Taira ◽

Makiko Ono ◽

...

Keyword(s):

Prognostic Factors ◽

Retrospective Study ◽

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Combination Therapy ◽

Response Rate ◽

Overall Response ◽

Institutional Review ◽

Significant Difference ◽

Bulky Mass

Background. Doxorubicin is the key drug for treatment of advanced soft tissue sarcoma (STS). The appropriate dosage of doxorubicin, regarding monotherapy or the role of combination therapy, is unclear. Methods. We retrospectively reviewed patients with advanced or metastatic STS of nonextremities who were treated with doxorubicin-based chemotherapies in our institution. Time to treatment failure (TTF), overall survival (OS), overall response, and prognostic factors for OS were evaluated. Results. Seventy-five patients were enrolled. The median TTF was 4.7 months, and the median OS was 20.1 months. The overall response rate was 20%. Doses of doxorubicin monotherapy did not show significant difference either in TTF or in OS. There were no significant differences in OS between combination therapy and monotherapy, but the TTF with combination therapy was better than monotherapy. The overall response for combination therapy indicated a better response rate. Less number of involved organs, no bulky mass, and a normal CRP level were independent favorable prognostic factors for OS. Conclusions. Combination therapy showed better response and TTF than monotherapy but did not show better OS. Possible prognostic factors for OS were indicated. This retrospective study was approved by the institutional review board. This trial is registered with UMIN000028787.

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Response of advanced HCC to pembrolizumab and lenvatinib combination therapy despite monotherapy failure

Zeitschrift für Gastroenterologie ◽

10.1055/a-1190-5681 ◽

2020 ◽

Vol 58 (08) ◽

pp. 773-777 ◽

Cited By ~ 2

Author(s):

Nadine Schulte ◽

Moying Li ◽

Tianzuo Zhan ◽

Lena Dreikhausen ◽

Janina Sollors ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Combination Therapy ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc ◽

The World ◽

Vegf Inhibition ◽

Tki Treatment

AbstractIn recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy, and these drugs have already become essential for the treatment of various noncurable tumors. However, monotherapy in advanced hepatocellular carcinoma (aHCC) failed to show statistically significant improvement.Recently, the combination of atezolizumab and bevacizumab demonstrated efficacy of combining ICI and VEGF inhibition, further substantiating previous data on synergistic mechanisms among respective substance classes.As TKI treatment is currently standard of care for aHCC, and ICIs are approved by the FDA and available in many areas of the world, numerous patients may have been treated with monotherapy of those drugs. However, it remains unclear if failure to monotherapy has an impact on combination therapy. We therefore report a patient well responding to combination therapy despite previous failures to TKI and ICI monotherapy.

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Frameshift mutations (Fsindel) complement tumor mutation burden (TMB) in predicting survival after immune checkpoint inhibitors (ICI) in a pancancer analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2617 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2617-2617

Author(s):

Vaia Florou ◽

Wungki Park ◽

Peter Joel Hosein ◽

Breelyn A. Wilky ◽

Jonathan C. Trent ◽

...

Keyword(s):

Lung Cancer ◽

Checkpoint Inhibitors ◽

Soft Tissue Sarcomas ◽

Progression Free Survival ◽

Research Field ◽

Solid Cancer ◽

Single Nucleotide Variants ◽

Combined Model ◽

Significant Difference ◽

Active Research

2617 Background: ICI benefit certain patients (pts) with various malignancies and discovering biomarkers for response is an active research field. Recently, higher TMB (top 20% in each histology) based on nonsynonymous single nucleotide variants from MSK-IMPACT was shown to correlate with superior survival in a pancancer cohort. Fsindels may generate more immunogenic neoantigens and robust T cell infiltrates, thus predicting better responses to ICI. We previously demonstrated the clinical implication of fsindel in lung cancer pts on ICI. However, its value in other solid cancers has not been evaluated. Methods: Comprehensive genomic profiling (CGP) of the tumors was performed by FoundationOne to derive fsindel and TMB as previously described. Pts with advanced solid cancers who received ICI and had CGP available were included. We categorized pts into two groups; 0 fsindel (FS-) and more than 1 fsindel (FS+). Also, they were categorized into TMB high (top 20%) and TMB low (bottom 80%) within their own histology. Progression free survival (PFS) and overall survival (OS) were compared. Results: One hundred thirty-one pts excluding lung cancer were included. There were 11 histology groups: 14 soft tissue sarcomas, 19 GU, 23 GI, 23 skin, 10 HEENT, 10 RCC, 9 GYO, 6 pancreas, 5 mucosal melanoma, 4 breast, and 8 others. 74 pts received pembrolizumab, 25 nivolumab, 29 ipilimumab/nivolumab, and 3 atezolizumab. All pts had metastatic disease, mean age was 61 years and 55 (42%) were women. Among the 131 pts, 74 were FS- and 57 FS+. The presence of fsindel (FS+) was significantly correlated with overall response (p = 0.032) and clinical benefit rates (p = 0.025). TMB-high did not show any significant difference in PFS (p = 0.1) or OS (p = 0.28) when compared to the TMB low. However, in a combined model of TMB and fsindel, TMB high and FS+ patients had significantly better PFS compared to patients who had either TMB high or FS+ or neither (TMB low and FS-) (p = 0.021). Conclusions: Combined model of TMB high and fsindel (+) correlated with superior PFS in advanced solid cancer pts on ICI, in concordance with previous report for lung cancer. Validation in a larger cohort is underway.

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Phase I/II study to evaluate the efficacy of TAS0313, a cancer peptide vaccine, combined with pembrolizumab for locally advanced or metastatic urothelial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4522 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4522-4522

Author(s):

Ryuji Matsumoto ◽

Junji Yonese ◽

Takashi Kawahara ◽

Hideaki Miyake ◽

Nobuaki Matsubara ◽

...

Keyword(s):

Combination Therapy ◽

Phase I ◽

Urothelial Carcinoma ◽

Stable Disease ◽

Checkpoint Inhibitors ◽

Locally Advanced ◽

Peptide Vaccine ◽

Target Antigen ◽

Overall Response ◽

Platinum Based Chemotherapy

4522 Background: TAS0313 is a cancer vaccine cocktail comprising three long peptides with a total of 12 cytotoxic T lymphocyte epitope peptides. We performed a multicenter phase I/II study including patient (pts) with urothelial carcinoma (UC) treated using TAS0313 combined with pembrolizumab. Methods: The enrolled pts with a histologically or cytologically confirmed diagnosis of urothelial carcinoma had at least one of the following HLA types: HLA-A*02:01, -A*02:06, -A*02:07, -A*11:01, -A*24:02, -A*31:01, or -A*33:03. For cohort C1, eligible pts were those who received platinum-based chemotherapy and were naïve to immune checkpoint inhibitors (ICI). For cohort C2, eligible pts were those who progressed onto treatment with pembrolizumab. TAS0313 (9 mg) was subcutaneously administered on days 1, 8, and 15 of cycles 1 and 2 and day 1 of cycle 3 or later in 21-day cycles, while pembrolizumab (200 mg) was intravenously administered on day 1 of cycle 1 or later in 21-day cycles until disease progression or unacceptable toxicity occurred. Tumor response was evaluated using the RECIST v1.1 criteria. The TAS0313 target antigen-specific immunoglobulin G (IgG) was analyzed before and after treatment. The primary objective was to evaluate efficacy, while the secondary objective was to evaluate the safety and tolerability of the combination therapy. Results: As of 10th September 2020, 46 pts with a median age of 71.0 and 65.5 years, in cohort C1 (n = 36) and cohort C2 (n = 10), respectively, have been treated with the combination therapy. For cohorts C1 and C2, the median follow-up duration was 6.47 and 6.95 months, while the median treatment duration was 4.86 and 2.56 months, respectively. In cohort C1, the overall response rate and disease control rate (DCR) were 33.3% (16.7% complete response, 16.7% partial response) and 66.7% (33.3% stable disease), respectively. The median progression-free survival was 5.0 months, median overall survival (OS) was not yet reached, and 1-year OS rate was 74.3%. The best overall response in cohort C2 was stable disease in 5/10 pts, resulting in a DCR of 50.0%. Increase in IgG level was detected after treatment in both the cohorts. The most common adverse drug reactions (ADRs) of TAS0313 and/or pembrolizumab were grade 1–2 injection site reactions and pyrexia. There were no grade 3–5 ADRs with an incidence of ≥10%. Conclusions: This study confirmed the tolerability, safety, and immune response of TAS0313 combined with pembrolizumab in cohorts C1 and C2. We observed promising efficacy in pts with ICI-naïve UC in cohort C1; however, in pts with pembrolizumab-refractory UC in cohort C2, limited efficacy was seen. Therefore, a large-scale randomized study is needed to clarify the benefits of TAS0313 combined with ICI in ICI-naïve pts. Clinical trial information: 183824.

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Toxicities of single agent and combination immune checkpoint inhibitors in patients with autoimmune diseases.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14176 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14176-e14176

Author(s):

Samuel Cytryn ◽

Elizaveta Efuni ◽

Sabina Sandigursky

Keyword(s):

Overall Survival ◽

Combination Therapy ◽

Autoimmune Diseases ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Combination Group ◽

Safety And Efficacy ◽

Increased Risk

e14176 Background: Autoimmunity is associated with increased risk of malignancy. However, patients with pre-existing autoimmune diseases (AIDs) have been excluded from trials of immune checkpoint inhibitors (ICIs) known to cause immune activation and lead to immune related adverse events (irAEs). Data is limited on the safety and efficacy of these agents when used in AID patients and physicians are therefore wary to use them in this at-risk population. Methods: We conducted a single institution retrospective study to evaluate the safety and efficacy of ICI therapy in patients with pre-existing AIDs from 2011 to 2018. Primary endpoints were irAEs and AID flares. The secondary endpoint was overall survival (OS). Results: Of 84 total patients, 70 (83%) received ICI monotherapy and 14 (17%) received combination therapy. AIDs included: rheumatic 40 (48%), dermatologic 25 (30%), endocrine 16 (19%) and gastrointestinal 14 (17%) diseases of which 18 (21%) were on immune suppression. Combination therapy was associated with higher rates of severe grade 3-4 irAEs in 5/14 (36%) patients versus 8/70 (11%) with monotherapy (p = 0.022). ICIs were discontinued due to irAEs in 10/84 (12%) of all patients; 4/14 (29%) in the combination group and 6/70 (9%) in the monotherapy group (p = 0.057). While 32 patients (38%) had at least one AID flare, ICI was only permanently discontinued in 2 patients. Flare rates were higher for combination use: 8/14 (57%) compared to 23/70 (33%) for monotherapy (p = 0.086). Combination therapy was associated with higher median OS 27.8 months [95% CI 11.4-44.3] compared to monotherapy 12.3 months [95% CI 9.7-14.8] (p = 0.0007). OS had a positive correlation with flare (p = 0.007) and severe irAEs (p = 0.037). Conclusions: Our data suggest that rates of irAEs in patients with pre-existing AIDs are similar to those reported in the literature with single agent ICIs. While risk of severe irAEs and flares is increased with combination therapy, they are associated with overall survival. In our cohort, irAEs and flares were manageable and in most patients did not require permanent discontinuation for monotherapy or combination therapy suggesting that ICIs should be offered to this population, albeit with caution.

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