Clinical efficacy and safety of proton beam or photon radiation in combination with immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma.

e16113 Background: Management of advanced hepatocellular carcinoma (HCC) remains a challenge. IMbrave150, a pivotal trial reported impressive overall survival benefit using combination strategy of atezolizumab and bevacizumab compared to sorafenib. We wonder the efficacy and safety when combining radiotherapy with immune checkpoint inhibitors (ICIs), which radiation might provide better local treatment and possible trigger abscopal effect. The aim of this study is retrospectively reporting the real-world efficacy and tolerability of proton beam or photon radiation plus ICIs in patients with advance stage HCC. Methods: We retrospectively reviewed all BCLC stage C HCC patients who have received combination therapy with ICIs plus proton or photon therapy with well documented basic characteristics and prompt treatment efficacy evaluation between 1st of January 2016 to 31st of October 2019 at a single medical center in Taiwan. 20 patients had ICIs plus proton and 32 patients had ICIs plus photon were included for analysis. Overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier estimator. Results: Baseline characteristics were generally similar between ICIs plus proton or ICIs plus photon, while most patients in proton group did not receive prior systemic treatment and had less local therapies prior ICIs combine with radiotherapy. Median follow-up time was 10.7 months. The median Progression free survival (PFS) was not reached in ICIs plus proton group and 3.6 months (95% CI 2.7-4.6) in ICIs plus photon group (P = 0.007). The median OS was not reach in ICIs plus proton group and 12.1months (95% CI 6.4-17.7) in ICIs plus photon group (P = 0.007). Comparing ICIs plus proton group versus photon group, objective tumor response is 50% versus 9%, disease control rate is 80% versus 47% in each group. During follow-up, 7 patients (35%) in proton group achieved complete remission (CR). There was difference in radiation filed, 19 patients (95%) in proton group and 15 patients (47%) in photon group targeted on liver tumors, and more patient received > 50Gy treatment dose in proton group compared to photon group (90% versus 20%). Proton group has lower failure rate in both inner- or out-field compared to photon group. Grade 1 to grade 2 skin-dermatological and gastrointestinal toxicity remained the most frequent reported adverse events in both groups. There are only one therapy related grade 3 dermatitis in ICIs plus proton group and one grade 3 hepatitis, one grade 5 pneumonitis in ICIs plus photon group. Conclusions: This study reported real-world efficacy and safety of ICIs in combination with proton or photon therapy. Most adverse events were manageable. The combination of ICIs and proton therapy has impressive CR rate and OS benefit. Further prospective randomized trial is warranted for confirm our finding.

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Treatment of Angiosarcoma with Pazopanib and Paclitaxel: Results of the EVA (Evaluation of Votrient® in Angiosarcoma) Phase II Trial of the German Interdisciplinary Sarcoma Group (GISG-06)

Cancers ◽

10.3390/cancers13061223 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1223

Author(s):

Daniel Pink ◽

Dimosthenis Andreou ◽

Sebastian Bauer ◽

Thomas Brodowicz ◽

Bernd Kasper ◽

...

Keyword(s):

Immune Checkpoint Inhibitors ◽

Median Overall Survival ◽

Phase Ii Trial ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Free Survival ◽

Safety And Efficacy ◽

Future Studies ◽

Entire Cohort

We aimed to evaluate the efficacy and toxicity of paclitaxel combined with pazopanib in advanced angiosarcoma (AS). The primary end point was progression-free survival (PFS) rate at six months (PFSR6). Planned accrual was 44 patients in order to detect a PFSR6 of >55%, with an interim futility analysis of the first 14 patients. The study did not meet its predetermined interim target of 6/14 patients progression-free at 6 months. At the time of this finding, 26 patients had been enrolled between July 2014 and April 2016, resulting in an overrunning of 12 patients. After a median follow-up of 9.5 (IQR 7.7–15.4) months, PFSR6 amounted to 46%. Two patients had a complete and seven patients a partial response. Patients with superficial AS had a significantly higher PFSR6 (61% vs. 13%, p = 0.0247) and PFS (11.3 vs. 2.7 months, p < 0.0001) compared to patients with visceral AS. The median overall survival in the entire cohort was 21.6 months. A total of 10 drug-related serious adverse effects were reported in 5 patients, including a fatal hepatic failure. Although our study did not meet its primary endpoint, the median PFS of 11.6 months in patients with superficial AS appears to be promising. Taking recent reports into consideration, future studies should evaluate the safety and efficacy of VEGFR and immune checkpoint inhibitors with or without paclitaxel in a randomized, multiarm setting.

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Development of thrombocytopenia is associated with improved survival in patients treated with immunotherapy

Future Science OA ◽

10.2144/fsoa-2020-0021 ◽

2020 ◽

Vol 6 (7) ◽

pp. FSO581

Author(s):

Hussein A Assi ◽

Adam S Asch ◽

Michael Machiorlatti ◽

Sara K Vesely ◽

Sami Ibrahimi

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Platelet Count ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Free Survival ◽

Immune Mediated ◽

Follow Up Studies

Background: Immune-related adverse events are associated with efficacy of immune checkpoint inhibitors (ICIs). We hypothesize that immune-mediated thrombocytopenia could be a biomarker for response to ICIs. Materials & methods: This retrospective study included 215 patients with metastatic malignancies treated with ICIs. Patients were stratified by nadir platelet count. Outcomes of interest were progression-free survival and overall survival. Results: On multivariate analysis, grade 1 thrombocytopenia was positively associated with overall survival compared with patients who did not develop thrombocytopenia (hazard ratio [HR]= 0.28 [95% CI: 0.13–0.60]; p = 0.001), while grade 2–4 thrombocytopenia was not (HR= 0.36 [95% CI: 0.13–1.04]; p = 0.060). There was no association between degree of thrombocytopenia and progression-free survival. Conclusion: Follow-up studies are warranted to substantiate the predictive significance of thrombocytopenia in patients receiving ICIs.

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Efficacy and Safety of TACE Combined With Sorafenib Plus Immune Checkpoint Inhibitors for the Treatment of Intermediate and Advanced TACE-Refractory Hepatocellular Carcinoma: A Retrospective Study

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.609322 ◽

2021 ◽

Vol 7 ◽

Author(s):

Liyun Zheng ◽

Shiji Fang ◽

Fazong Wu ◽

Weiqian Chen ◽

Minjiang Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cox Regression ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Efficacy And Safety ◽

Free Survival ◽

Factors Affecting ◽

Pugh Class

Purpose: The study aims to retrospectively investigate the efficacy and safety of sorafenib combined with transarterial chemoembolization (TACE) (TACE+Sor) vs. TACE combined with sorafenib plus immune checkpoint inhibitors (TACE+Sor+ICIs) in treating intermediate and advanced TACE-refractory hepatocellular carcinoma (HCC).Materials and Methods: This study was approved by the ethics committee of Lisui Hospital, Zhejiang University, China. From January 2016 to June 2020, 51 eligible patients with intermediate or advanced TACE-refractory HCC received TACE+Sor (n = 29) or TACE+Sor+ICIs (n = 22). The differences in tumor response, adverse events (AEs), progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Factors affecting PFS and OS were determined by Cox regression.Results: The disease control rate was higher in the TACE+Sor+ICIs group than in the TACE+Sor group (81.82 vs. 55.17%, P = 0.046). Compared with the TACE+Sor group, PFS and OS were prolonged in the TACE+Sor+ICIs group (median PFS: 16.26 vs. 7.30 months, P < 0.001; median OS: 23.3 vs. 13.8 months, P = 0.012). Multivariate analysis showed that BCLC stage, alpha-fetoprotein and treatment were independent factors of PFS; BCLC, Child-Pugh class, ablation after disease progression and treatment were independent predictive factors of OS. Four patients in the TACE+Sor+ICIs group and three patients in the TACE+Sor group suffered from dose reduction or interruption (18.18 vs. 10.34%, P = 0.421). The incidence of ICI-related AEs in the TACE+Sor+ICIs group was well-controlled.Conclusion: The therapeutic schedule of TACE+Sor+ICIs demonstrated efficacy and safety in intermediate and advanced TACE-refractory HCC.

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Efficacy, safety and prognostic factors in patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil plus bevacizumab in a real-world setting

10.21203/rs.3.rs-1251622/v1 ◽

2022 ◽

Author(s):

Nieves Martínez-Lago ◽

Teresa Calleja Chucla ◽

Beatriz Alonso de Castro ◽

Rafael Varela Ponte ◽

Cristina Reboredo Rendo ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Real World ◽

Progression Free Survival ◽

Efficacy And Safety ◽

Free Survival ◽

Common Grade ◽

Third Line ◽

Grade 3

Abstract We evaluated the efficacy and safety of trifluridine/tipiracil (TAS-102) plus bevacizumab in treating refractory metastatic colorectal cancer (mCRC) in a retrospective, observational study. Patients refractory or intolerant to standard therapies received TAS-102 (30–35 mg/m2 twice daily on days 1–5 and days 8–12 every 28 days) plus bevacizumab 5 mg/kg on days 1 and 15. Clinical and pathological characteristics, overall response rate (ORR) and disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) data were collected and analysed. Thirty-five patients were treated from July 2019 to October 2021 (median age 64 years). The majority of patients (68.6%) were receiving TAS-102 plus bevacizumab as third-line treatment. Patients received a median of 4 (range 2–15) cycles of treatment. Among 31 patients evaluable for response (88.6%), ORR and DCR were 3.2% and 51.6%, respectively. After a median 11.6 months’ follow-up, median PFS was 4.3 (95% confidence interval [CI] 3.4–5.1) months and median OS was 9.3 (95% CI 6.6–12.1) months. The most common grade 3–4 toxicities were neutropenia, asthenia and nausea/vomiting, and there were no treatment-related deaths. This real-world study confirms the efficacy and safety of TAS-102 plus bevacizumab in patients with refractory mCRC.

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A phase 2 study of s-1 plus leucovorin in patients with untreated advanced cholangiocarcinoma (CCA).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.467 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 467-467

Author(s):

Suebpong Tanasanvimon ◽

Teerapat Ungtrakul ◽

Nattaya Poovorawan ◽

Napa Parinyanitikul ◽

Chanida Vinayanuwattikun ◽

...

Keyword(s):

Progression Free Survival ◽

Phase 2 ◽

Efficacy And Safety ◽

Free Survival ◽

Primary Endpoints ◽

Phase 2 Study ◽

Common Grade ◽

Secondary Endpoints ◽

Grade 3

467 Background: Patients with CCA usually present with advanced disease leading to the grave prognosis. Currently, cisplatin and gemcitabine is the standard treatment in advanced CCA. However, the CCA treatment outcomes are still poor and the options of treatment are quite limited. This study aimed to explore the efficacy and safety of S-1 plus leucovorin in patients with untreated advanced CCA. Methods: This single-arm two-center phase 2 study evaluated the efficacy and safety of S-1 40, 50 and 60 mg according to body surface area and leucovorin 15 mg , both given orally twice daily for one week, repeated every two weeks. Treatment was continued until complete 12 cycles, disease progression or unacceptable toxicity. The primary endpoints were overall response rate (ORR) and disease control rate (DCR) per RECIST version 1.1. The secondary endpoints were progression free survival (PFS), overall survival (OS) and toxicity. Results: Of total 32 patients and a median follow up time of 9.5 months, the ORR was 25% (95%CI 9.1-40.9) and the DCR was 62.5% (95% CI 44.8-80.2). In 25 response evaluable patients, the ORR was 32% (95% CI 12.4-51.7). The PFS was 8.0 (95%CI 5.59-10.4) months. The OS was 11.0 (95%CI 9.47-12.53). The most common grade 3 or 4 toxicities were anemia, mucositis and diarrhea. There was one patient discontinuing treatment due to treatment related toxicity. Conclusions: S-1 plus leucovorin was active and tolerable in patients with advanced CCA. Clinical trial information: TCTR20160313001.

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The anti–PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600–mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-i.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9531 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9531-9531 ◽

Cited By ~ 18

Author(s):

Georgina V. Long ◽

Celeste Lebbe ◽

Victoria Atkinson ◽

Mario Mandalà ◽

Paul D. Nathan ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Objective Response ◽

Safety Data ◽

Stage Iv ◽

Progression Free Survival ◽

Antigen Expression ◽

Synergistic Activity ◽

Efficacy And Safety ◽

Grade 3

9531 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with BRAF V600–mutant advanced melanoma; however, many pts progress and new treatment (tx) strategies are needed. BRAF inhibition increases T-cell infiltration, melanoma antigen expression, and PD-1/PD-L1 expression, which may lead to synergistic activity with anti–PD-1 therapy. Methods: COMBI-i is investigating first-line S 400 mg Q4W + D 150 mg BID + T 2 mg QD in pts with unresectable or metastatic BRAF V600–mutant melanoma (NCT02967692). Here we report pooled efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort). Response was assessed per RECIST v1.1. Results: 36 pts were enrolled (part 1: n = 9; part 2: n = 27); 18 (50%) had stage IV M1c and 15 (42%) had elevated LDH levels. At the data cutoff (median follow-up, 15.2 mo), tx was ongoing in 17 pts (47%). The confirmed objective response rate (ORR) by investigator assessment was 75% (n = 27), with 33% complete responses (CRs; n = 12). Medians for duration of response (DOR; 7/27 pts with events), progression-free survival (PFS; 13/36 pts with events), and overall survival (OS; 7/36 pts with events) were not reached. 12-mo DOR rate was 71.4% (95% CI, 49%-85%). 12-mo PFS and OS rates were 65.3% (95% CI, 47%-79%) and 85.9% (95% CI, 69%-94%), respectively. In pts with high baseline LDH: ORR was 67%, with 3 CRs (20%), median PFS was 10.7 mo (events in 10/15 pts [67%]), and median OS was not reached, with events in 6/15 pts (40%). All pts had ≥ 1 AE; 27 (75%) had grade ≥ 3 AEs. 6 pts (17%) had AEs leading to discontinuation of all 3 study drugs. Any-grade AEs in ≥ 40% of pts included pyrexia, chills, fatigue, cough, and arthralgia. Grade ≥ 3 AEs in > 3 pts were neutropenia, pyrexia, and increased lipase. One pt died of cardiac arrest that was not considered related to study tx. Conclusions: S+D+T showed promising and durable ORR (75%) with CR in 33% of pts. With > 15 mo of follow-up, median PFS was not reached. The safety profile was manageable reflecting individual toxicities of D, T, and S. The global, placebo-controlled, randomized phase 3 (part 3) of COMBI-i is ongoing. Clinical trial information: NCT02967692.

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The anti–PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600–mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-I.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.57 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 57-57 ◽

Cited By ~ 3

Author(s):

Georgina V. Long ◽

Celeste Lebbe ◽

Victoria Atkinson ◽

Mario Mandalà ◽

Paul D. Nathan ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Objective Response ◽

Safety Data ◽

Stage Iv ◽

Progression Free Survival ◽

Antigen Expression ◽

Synergistic Activity ◽

Efficacy And Safety ◽

Grade 3

57 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with BRAF V600–mutant advanced melanoma; however, many pts progress and new treatment (tx) strategies are needed. BRAF inhibition increases T-cell infiltration, melanoma antigen expression, and PD-1/PD-L1 expression, which may lead to synergistic activity with anti–PD-1 therapy. Methods: COMBI-i is investigating first-line S 400 mg Q4W + D 150 mg BID + T 2 mg QD in pts with unresectable or metastatic BRAF V600–mutant melanoma (NCT02967692). Here we report pooled efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort). Response was assessed per RECIST v1.1. Results: 36 pts were enrolled (part 1: n = 9; part 2: n = 27); 18 (50%) had stage IV M1c and 15 (42%) had elevated LDH levels. At the data cutoff (median follow-up, 15.2 mo), tx was ongoing in 17 pts (47%). The confirmed objective response rate (ORR) by investigator assessment was 75% (n = 27), with 33% complete responses (CRs; n = 12). Medians for duration of response (DOR; 7/27 pts with events), progression-free survival (PFS; 13/36 pts with events), and overall survival (OS; 7/36 pts with events) were not reached. 12-mo DOR rate was 71.4% (95% CI, 49%-85%). 12-mo PFS and OS rates were 65.3% (95% CI, 47%-79%) and 85.9% (95% CI, 69%-94%), respectively. In pts with high baseline LDH: ORR was 67%, with 3 CRs (20%), median PFS was 10.7 mo (events in 10/15 pts [67%]), and median OS was not reached, with events in 6/15 pts (40%). All pts had ≥ 1 AE; 27 (75%) had grade ≥ 3 AEs. 6 pts (17%) had AEs leading to discontinuation of all 3 study drugs. Any-grade AEs in ≥ 40% of pts included pyrexia, chills, fatigue, cough, and arthralgia. Grade ≥ 3 AEs in > 3 pts were neutropenia, pyrexia, and increased lipase. One pt died of cardiac arrest that was not considered related to study tx. Conclusions: S+D+T showed promising and durable ORR (75%) with CR in 33% of pts. With > 15 mo of follow-up, median PFS was not reached. The safety profile was manageable reflecting individual toxicities of D, T, and S. The global, placebo-controlled, randomized phase 3 (part 3) of COMBI-i is ongoing. Clinical trial information: NCT02967692.

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CMET-01. IMMUNE CHECKPOINT INHIBITORS FOR NON-SMALL CELL LUNG CANCER WITH BRAIN METASTASIS: THE ROLE OF GAMMA KNIFE RADIOSURGERY

Neuro-Oncology ◽

10.1093/neuonc/noz175.202 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi51-vi51

Author(s):

Min Ho Lee ◽

Kyung-Rae Cho ◽

Jung-Il Lee

Keyword(s):

Lung Cancer ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Gamma Knife Radiosurgery ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

Free Survival ◽

Group A

Abstract PURPOSE Immune checkpoint inhibitors (ICIs) are approved for the treatment of non-small cell lung cancer (NSCLC), but the safety and efficacy of the combined treatment with ICIs and gamma knife radiosurgery (GKS) remain undefined. METHODS We retrospectively reviewed the medical records of patients with brain metastases from NSCLC who were treated with ICIs between January 2015 and December 2017 at our institute. Of the 134 patients identified, 77 who were assessable for brain responses were categorized into three groups based on the medication administered and GKS: Group A, ICI alone; Group B, ICI with concurrent GKS within 14 days; and Group C, ICI with non-concurrent GKS. RESULTS The median follow-up duration after the diagnosis of brain metastases was 19.1 (range, 1–68.7) months. At the last follow-up, 48 patients (62.3%) died. The overall survival was shorter in Group A than in Groups B and C (P=0.001). There were no statistically significant differences in the intracranial disease progression-free survival (P=0.514), local progression-free survival (P=0.358), and complication rates among the three groups. Twelve patients presented with leptomeningeal seeding (LMS) during follow-up. There was a significant difference in the LMS-free duration from the time of administering ICIs (P=0.011) and the diagnosis of metastasis (P< 0.001). CONCLUSION GKS in combination with ICI showed no favorable overall survival outcome in the treatment of brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, compared with ICI alone, GKS with ICI may be associated with a reduced incidence of LMS.

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Immune checkpoint inhibitors in patients with pre-existing psoriasis: safety and efficacy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003066 ◽

2021 ◽

Vol 9 (10) ◽

pp. e003066

Author(s):

Briana Rose Halle ◽

Allison Betof Warner ◽

Farzana Y Zaman ◽

Andrew Haydon ◽

Prachi Bhave ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Topical Therapy ◽

Progression Free Survival ◽

Disease Exacerbation ◽

Prior Therapy ◽

Immune Mediated ◽

Grade 3

BackgroundImmune checkpoint inhibitors (ICIs) are approved to treat multiple cancers. Retrospective analyses demonstrate acceptable safety of ICIs in most patients with autoimmune disease, although disease exacerbation may occur. Psoriasis vulgaris is a common, immune-mediated disease, and outcomes of ICI treatment in patients with psoriasis are not well described. Thus we sought to define the safety profile and effectiveness of ICIs in patients with pre-existing psoriasis.MethodsIn this retrospective cohort study, patients from eight academic centers with pre-existing psoriasis who received ICI treatment for cancer were evaluated. Main safety outcomes were psoriasis exacerbation and immune-related adverse events (irAEs). We also assessed progression-free survival (PFS) and overall survival.ResultsOf 76 patients studied (50 (66%) male; median age 67 years; 62 (82%) with melanoma, 5 (7%) with lung cancer, 2 (3%) with head and neck cancer, and 7 (9%) with other cancers; median follow-up 25.1 months (range=0.2–99 months)), 51 (67%) received anti-PD-1 antibodies, 8 (11%) anti-CTLA-4, and 17 (22%) combination of anti-PD-1/CTLA-4. All patients had pre-existing psoriasis, most frequently plaque psoriasis (46 patients (61%)) and 15 (20%) with psoriatic arthritis. Forty-one patients (54%) had received any prior therapy for psoriasis although only two (3%) were on systemic immunosuppression at ICI initiation. With ICI treatment, 43 patients (57%) experienced a psoriasis flare of cutaneous and/or extracutaneous disease after a median of 44 days of receiving ICI. Of those who experienced a flare, 23 patients (53%) were managed with topical therapy only; 16 (21%) needed systemic therapy. Only five patients (7%) required immunotherapy discontinuation for psoriasis flare. Forty-five patients (59%) experienced other irAEs, 17 (22%) of which were grade 3/4. PFS with landmark analysis was significantly longer in patients with a psoriasis flare versus those without (39 vs 8.7 months, p=0.049).ConclusionsIn this multicenter study, ICI therapy was associated with frequent psoriasis exacerbation, although flares were manageable with standard psoriasis treatments and few required ICI discontinuation. Patients who experienced disease exacerbation performed at least as well as those who did not. Thus, pre-existing psoriasis should not prevent patients from receiving ICIs for treatment of malignancy.

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