Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody.

Abstract Background Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) are used for the treatment of various cancer types. However, immune-related adverse events (irAEs) occur in patients treated with ICIs. Several small-scale studies have reported the onset of irAEs and therapeutic effects of ICIs. Here we report a large-scale retrospective study covering a wide range of cancers. We evaluated irAEs and the therapeutic effects of ICIs and determined whether irAEs could be predicted. Methods This study included patients treated with the anti-PD-1 antibodies nivolumab or pembrolizumab at Fujita Health University Hospital between December 2015 and March 2019. We retrospectively reviewed the electronic medical records for age, cancer type, pre-treatment blood test data, presence or absence of irAE onset, type and severity of irAEs, outcome of irAE treatment, response rate, progression-free survival and overall survival. Results The subjects were 280 patients including. The overall incidence of irAEs was 41.1% (115 patients), and the incidence of severe irAEs of grade 3 and higher was 2.8% (eight patients). The most common irAEs were skin disorders, thyroid disorders and interstitial pneumonia. Patients with irAEs were significantly older than those without irAEs (69.7 versus 66.0 years, P=0.02). The objective response rate (ORR) in patients with irAEs was 30.4%, which was significantly higher than in patients without irAEs (12.7%; P<0.01). Both the median overall and progression-free survival were significantly longer in patients with irAEs. Based on the blood test data obtained before ICI therapy, hypothyroidism, thyroid-stimulating hormone levels and thyroglobulin antibody levels were associated with the onset of irAEs. In many patients with irAEs of Common Terminology Criteria for Adverse Events Grade 3 or higher, re-administration of ICIs was difficult, and their outcomes were poor. In contrast, many patients with irAEs of a lower grade were able to resume ICI therapy. Conclusion Although the onset of irAEs was difficult to predict based on pre-treatment tests. Because ICIs were more effective in improving outcomes in patients with irAEs, the continuation of ICI therapy might be beneficial with the control of symptoms after the onset of irAEs.

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Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody.

10.21203/rs.3.rs-17123/v2 ◽

2020 ◽

Author(s):

Hiroshi Matsuoka ◽

Takahiro Hayashi ◽

Karen Takigami ◽

Kazuyoshi Imaizumi ◽

Ryoichi Shiroki ◽

...

Keyword(s):

Adverse Events ◽

Test Data ◽

Blood Test ◽

Response Rate ◽

Progression Free Survival ◽

Therapeutic Effects ◽

Cancer Type ◽

Free Survival ◽

Pre Treatment ◽

Grade 3

Abstract Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) are used for the treatment of various cancer types. However, immune-related adverse events (irAEs) occur in patients treated with ICIs. Several small-scale studies have reported the onset of irAEs and therapeutic effects of ICIs. Here we report a large-scale retrospective study covering a wide range of cancers. We evaluated irAEs and the therapeutic effects of ICIs and determined whether irAEs could be predicted.Methods: This study included patients treated with the anti-PD-1 antibodies nivolumab or pembrolizumab at Fujita Health University Hospital between December 2015 and March 2019. We retrospectively reviewed the electronic medical records for age, cancer type, pre-treatment blood test data, presence or absence of irAE onset, type and severity of irAEs, outcome of irAE treatment, response rate, progression-free survival and overall survival.Results: Two hundred-eighty patients received ICIs. The overall incidence of irAEs was 41.1% (115 patients), and the incidence of severe irAEs of grade 3 and higher was 2.8% (eight patients). The most common irAEs were skin disorders, thyroid disorders and interstitial pneumonia. Patients with irAEs were significantly older than those without irAEs (69.7 versus 66.0 years, P=0.02). The objective response rate (ORR) in patients with irAEs was 30.4%, which was significantly higher than in patients without irAEs (12.7%; P<0.01). Both the median overall and progression-free survival were significantly longer in patients with irAEs. Based on the blood test data obtained before ICI therapy, hypothyroidism, thyroid-stimulating hormone levels and thyroglobulin antibody levels were associated with the onset of irAEs. In many patients with irAEs of Common Terminology Criteria for Adverse Events Grade 3 or higher, re-administration of ICIs was difficult, and their outcomes were poor. In contrast, many patients with irAEs of a lower grade were able to resume ICI therapy.Conclusion: Although the onset of irAEs was difficult to be predicted based on pre-treatment tests. It appeared that the continuation of ICI therapy, along with early detection and adequate control of irAEs, might contribute to the improved prognosis of patients.

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Toxicity and efficacy of FOLFIRI regimen and aflibercept combination in metastatic colorectal cancer: first results of a Russian multicenter retrospective study

Malignant tumours ◽

10.18027/2224-5057-0-0-0- ◽

2019 ◽

Vol 9 (2) ◽

pp. 53-63

Author(s):

M. Yu. Fedyanin ◽

L. Yu. Vladimirova ◽

V. A. Chubenko ◽

L. A. Zagorskaya ◽

A. V. Belyayeva ◽

...

Keyword(s):

Adverse Events ◽

Objective Response Rate ◽

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

Hematologic Toxicity ◽

Line Treatment ◽

Second Line ◽

Free Survival ◽

Grade 3

Purpose. To assess the incidence and severity of adverse events; to explore clinical factors associated with grade 3–4 non-hematologic toxicity; to assess the immediate efficacy and progression-free survival during treatment with the FOLFIRI regimen in combination with aflibercept in Russia.Materials and Methods. A retrospective multicenter study has been conducted with data collected from 20 clinics in 15 regions of Russia. There was no statistical hypothesis. Progression-free survival was the main efficacy criterion. The statistical analysis was performed using IBM SPPS Statistics v. 20 software.Results. FOLFIRI and Aflibercept combination was administered to 264 patients. The mean number of treatment cycles was 6 (1 to 29). The toxicity of aflibercept was addressed by dose reduction and dosing delay in 10.1 % and 11.4 % of patients, respectively, and dose reductions and dosing delays in any of FOLIFRI components were reported in 20.1 % of participants. The objective response rate was 20.3 %. The median progression-free survival in patients receiving second-line treatment was 6 months (95 % CI: 5.3–6.6 months). Seventy-two percent of patients experienced any grade of adverse events most of which were limited to grade 1–2 (62.1 %). Non-hematologic toxicity was reported in 64 % of patients (grade 3–4 in 17.9 %). Hematologic events were detected in only 17.9 % of patients. Multifactorial analysis has shown that drug therapy for concomitant diseases (OR 1.98, 95 % CI: 1.04–3.78, p = 0.037) and the number of chemotherapy lines prior to aflibercept (ОR 1.5, 95 % CI: 1.06–2.11, p = 0.02) were independent predictors of grade 3–4 non-hematologic toxicity.Conclusions. Objective response rate, progression-free survival, and frequency of toxicity-related aflibercept discontinuations in the Russian study with patients receiving aflibercept in combination with FOLFIRI regimen as a second-line treatment has shown the results that were comparable with VELOUR study. Comorbidities requiring drug treatment and the number of prior chemotherapy lines appear to be risk factors for grade 3–4 nonhematological toxicity events.

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Oral Melphalan, Prednisone and Thalidomide for Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.779.779 ◽

2005 ◽

Vol 106 (11) ◽

pp. 779-779

Author(s):

Antonio Palumbo ◽

Sara Bringhen ◽

Pellegrino Musto ◽

Tommaso Caravita ◽

Rosanna Capozzi ◽

...

Keyword(s):

Adverse Events ◽

Response Rate ◽

Progression Free Survival ◽

Hazard Ratio ◽

Newly Diagnosed ◽

Free Survival ◽

Grade 3 ◽

Lost To Follow Up ◽

To Receive

Abstract In newly diagnosed multiple myeloma (MM) patients, the combination melphalan, prednisone and thalidomide (MPT) induces a fast tumor response with a high response rate, but evidence that this translate into improved outcome is limited. This multicenter trial compared the efficacy and the toxicity of oral MPT with oral melphalan and prednisone (MP) in previously untreated patients. From January 2002 to December 2004, we randomised 255 patients, who were older than 65 years of age (median age 72). Data analysis was performed on July 2005. The MPT regimen included oral melphalan (4 mg/m2 for 7 days) and prednisone (40 mg/m2 7 days) for six four week cycles plus thalidomide (100 mg per day continuously until any sign of relapse or progressive disease) The MP regimen was as MPT without thalidomide. Patients who were not assigned to receive thalidomide were permitted to cross over to receive thalidomide after relapse or disease progression. Patients treated with MPT experienced higher response rates and a longer time to progression (primary end points) than patients who did not receive thalidomide. The overall response rate was 76% for MPT and 48% for MP alone (P<0.0001), and the near complete response rates were 28% and 7%, respectively (P<0.0001). Median progression free survival in the MPT and in the MP groups was 33 months and 14 months, respectively (hazard ratio, 0.47; P<0.001). MPT increase median progression free survival by almost 19 months. The 2-yr survival rate was 82% in MPT patients and 65% in MP patients (hazard ratio, 0.68; P=0.2). In MPT group, 33 patients did not complete the 6 courses because of progression disease (9), toxicity (16), death (2), and withdrawal of consent or lost to follow-up (6). In MP group, 32 patients did not complete the 6 courses because of progression disease (19), toxicity (3), death (3), and withdrawal of consent or lost to follow-up (7). By looking at those patients who completed the assigned 6 cycles in both arms, the 2-yr survival rate was 90% in MPT patients and 71% in MP patients, the difference was statistically significant (hazard ratio, 0.39; P<0.01). Grade 3 or 4 adverse events were reported in 49% of patients treated with MPT and in 25% of those treated with MP: they included thromboembolism (12% versus 2% of patients), infections (10% versus 1%), peripheral neuropathy (10% versus 1%), and hematologic toxicity (22% versus 25%) respectively. In the first 64 patients who received MPT, grade 3–4 adverse events were reported in 58% of patients. In the last 65 MPT patients, the incidence of grade 3–4 adverse events was 40%. By comparing the first cohort with the second one, thromboembolism dropped from 22% to 3% (P<0.01) and neurotoxicity from 13% to 8% (P=NS), respectively. The oral MPT was superior to the standard MP in patients with newly diagnosed myeloma. The adequate mangement of side effects reduced toxicity.

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Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14)

Journal of Clinical Oncology ◽

10.1200/jco.21.00443 ◽

2021 ◽

pp. JCO.21.00443

Author(s):

Nizar J. Bahlis ◽

Rachid Baz ◽

Simon J. Harrison ◽

Hang Quach ◽

Shir-Jing Ho ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Phase I ◽

Phase I Study ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Grade 3

PURPOSE Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS This phase I study ( NCT03314181 ) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

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Phase II trial of gemcitabine + cisplatin + ipilimumab in patients with metastatic urothelial cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.357 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 357-357 ◽

Cited By ~ 17

Author(s):

Matt D. Galsky ◽

Noah M. Hahn ◽

Costantine Albany ◽

Mark T. Fleming ◽

Alexander Starodub ◽

...

Keyword(s):

Adverse Events ◽

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

Immune Checkpoint Blockade ◽

Immunomodulatory Effects ◽

Free Survival ◽

Ctla4 Blockade ◽

Common Grade ◽

Grade 3

357 Background: Immune checkpoint blockade, with anti-PD-1/PD-L1 antibodies, has shown striking results in patients (pts) with mUC. While CTLA4 blockade has demonstrated pharmacodynamic effects in localized bladder cancer (Carthon, Clin Can Res, 2010), the role of CTLA4 blockade in mUC remains undefined. We hypothesized that chemotherapy may lead to immunogenic cell death, and other immunomodulatory effects, which could subsequently be exploited with the addition of ipilimumab. Methods: Pts with mUC received 2 cycles of gemcitabine + cisplatin (GC) alone followed by 4 cycles of GC + ipilimumab (GCIpi). The primary endpoint was % of patients alive at 1 year. Secondary endpoints included safety, objective response rate, and progression-free survival. Immune monitoring was performed at baseline, after GC alone, and after GCIpi. Results: 36 pts with mUC (median age 60; range: 33-80) were enrolled; KPS was 80%, 90% and 100% in 30%, 45%, and 25%; 58% had visceral metastases and 20% had liver metastases. Pts received a median of 5 cycles of GC (range: 1-6) and 3 doses of Ipi (range: 1-8). The most common grade 3-4 adverse events were neutropenia (36%), thrombocytopenia (19%), anemia (25%), hyponatremia (31%), thromboembolism (11%), and renal insufficiency (19%). The most common grade 3-4 immune-related adverse events were colitis (6%), hypophysitis (3%), hyperthyroidism (1%), and rash (1%). The objective response rate is shown in the Table. Median progression-free survival is 8 months (95% CI 6.2-9.8 months). Median follow-up is 10.4 months (range: 2.8-35.3 months). The primary endpoint analysis will be mature for the meeting. GC alone had no significant impact on circulating immune cell subsets; Ipi significantly expanded circulating CD4 and CD8 T cells. Conclusions: A phased schedule of GC plus immune checkpoint blockade was feasible in pts with mUC. Ipi induced immunomodulatory effects despite concurrent chemotherapy. Survival data are not yet mature. Ongoing analyses are exploring the impact of GC alone, and GCIpi, on antigen-specific T cell immunity and correlating such findings with “outlier” survival times. Clinical trial information: NCT01524991. [Table: see text]

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Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma

Journal of Clinical Oncology ◽

10.1200/jco.21.00675 ◽

2021 ◽

pp. JCO.21.00675

Author(s):

Adi Diab ◽

Scott S. Tykodi ◽

Gregory A. Daniels ◽

Michele Maio ◽

Brendan D. Curti ◽

...

Keyword(s):

Adverse Events ◽

Metastatic Melanoma ◽

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

First Line ◽

Free Survival ◽

Median Progression Free Survival ◽

Immune Mediated ◽

Grade 3

PURPOSE Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma. METHODS A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers. RESULTS At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was −78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response. CONCLUSION BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.

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Response and Toxicity to the Second Course of 3 Cycles of 177Lu-PSMA Therapy Every 4 Weeks in Patients with Metastatic Castration-Resistant Prostate Cancer

Cancers ◽

10.3390/cancers13102489 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2489

Author(s):

Sazan Rasul ◽

Tim Wollenweber ◽

Lucia Zisser ◽

Elisabeth Kretschmer-Chott ◽

Bernhard Grubmüller ◽

...

Keyword(s):

Response Rate ◽

Cox Regression ◽

Progression Free Survival ◽

Castration Resistant Prostate Cancer ◽

Radioligand Therapy ◽

Free Survival ◽

Castration Resistant ◽

Kaplan Meier ◽

Node Metastases ◽

Grade 3

Background: We investigated the response rate and degree of toxicity of a second course of three cycles of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) every 4 weeks in mCRPC patients. Methods: Forty-three men (71.5 ± 6.6 years, median PSA 40.8 (0.87–1358 µg/L)) were studied. The response was based on the PSA level 4 weeks after the third cycle. The laboratory parameters before and one month after the last cycle were compared. Kaplan–Meier methods were used to estimate the progression-free survival (PFS) and overall survival (OS), and the Cox regression model was performed to find predictors of survival. Results: Twenty-six patients (60.5%) exhibited a PSA reduction (median PSA declined from 40.8 to 20.2, range 0.6–1926 µg/L, p = 0.002); 18 (42%) and 8 (19%) patients showed a PSA decline of ≥50% and ≥80%, respectively. The median OS and PFS were 136 and 31 weeks, respectively. The patients with only lymph node metastases survived longer (p = 0.02), whereas the patients with bone metastases had a shorter survival (p = 0.03). In the multivariate analysis, only the levels of PSA prior to the therapy remained significant for OS (p < 0.05, hazard ratio 2.43, 95% CI 1.01–5.87). The levels of hemoglobin (11.5 ± 1.7 g/dL vs. 11 ± 1.6 g/dL, p = 0.006) and platelets (208 ± 63 g/L vs. 185 ± 63 g/L, p = 0.002) significantly decreased one month after cycle three, though only two grade 3 anemia and one grade 3 thrombocytopenia were recorded. Conclusion: A further intensive PSMA-RLT course is well tolerated in mCRPC patients and associated with promising response rates and OS.

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Gemcitabine Plus Nab-Paclitaxel as Second-Line Chemotherapy following FOLFIRINOX in Patients with Unresectable Pancreatic Cancer: A Single-Institution, Retrospective Analysis

Chemotherapy ◽

10.1159/000517244 ◽

2021 ◽

pp. 1-7

Author(s):

Kotone Hayuka ◽

Hiroyuki Okuyama ◽

Akitsu Murakami ◽

Yoshihiro Okita ◽

Takamasa Nishiuchi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Adverse Events ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Unresectable Pancreatic Cancer ◽

Line Treatment ◽

Second Line ◽

Free Survival ◽

Common Grade ◽

Grade 3

Introduction: Patients with advanced pancreatic cancer have a poor prognosis. FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GnP) have been established as first-line treatment, but they have not been confirmed as second-line treatment after FFX. The aim of this study was to evaluate the safety and efficacy of GnP as second-line therapy after FFX in patients with unresectable pancreatic cancer. Methods: Twenty-five patients with unresectable pancreatic cancer were enrolled. The patients were treated with GnP after FFX between September 2015 and September 2019. Tumor response, progression-free survival (PFS), overall survival (OS), and incidence of adverse events were evaluated. Results: The response rate, disease control rate, median PFS, and median OS were 12%, 96%, 5.3 months, and 15.6 months, respectively. The common grade 3 or 4 adverse events were neutropenia (76%) and anemia (16%). Conclusions: GnP after FOLFIRINOX is expected to be one of the second-line recommendations for patients with unresectable pancreatic cancer.

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Retrospective Review of Safety and Efficacy of Anlotinib in Advanced Osteosarcoma With Metastases After Failure of Standard Multimodal Therapy

10.21203/rs.3.rs-687587/v1 ◽

2021 ◽

Author(s):

Hanqing Li ◽

Yang Li ◽

Lei Song ◽

Qiuchi Ai ◽

shuai zhang

Keyword(s):

Adverse Events ◽

Multimodal Therapy ◽

Objective Response ◽

Progression Free Survival ◽

Complete Response ◽

Free Survival ◽

Safety And Efficacy ◽

Common Drug ◽

Grade 3 ◽

Therapeutic Doses

Abstract To study and observe the safety and efficacy of anlotinib in the treatment of advanced osteosarcoma with metastases. We retrospectively studied patients with advanced osteosarcoma and metastases who received anlotinib treatment in our hospital from June 2018 to April 2020. All patients had received standard multimodal therapies, before taking anlotinib. Therapeutic doses of anlotinib were 12 mg for adults and 10 mg for children and adolescents once a day for 2 consecutive weeks, followed by a week of withdrawal. This 3-week cycle of treatment was continued until the tumor progressed rapidly or the patients failed to tolerate the side effects. Adverse drug reactions were recorded, and therapeutic efficacy was evaluated based on progression free survival (PFS), disease control rate (DCR), overall survival (OS), and objective response rate (ORR). The median PFS was 9.81 ± 0.9 months, and the 6-month and 10-month PFS rates were 73.3% and 33.3%, respectively. The median OS was 11.43 ± 0.58 months. No patients achieved complete response. After 6 months of treatment, the DCR and ORR were 80% and 13.3%, respectively. No drug-related deaths or Grade 4 adverse events occurred in the patients. Five patients (33.3%) had Grade 3 adverse events. The most common drug-related adverse events were hand-food syndrome, fatigue, high blood pressure, anorexia, and pneumothorax. Anlotinib had a certain curative effect on patients with advanced osteosarcoma and metastases after failure of standard treatment. The adverse events were mostly tolerable or relieved after treatment.

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Biweekly Raltitrexed in Combination with Irinotecan (RIR) as Second-Line Therapy for Patients with Metastatic Colorectal Cancer: A Non-Randomized, Open-Label Phase II Trial.

10.21203/rs.3.rs-80934/v1 ◽

2020 ◽

Author(s):

Ke Cheng ◽

Yu-Wen Zhou ◽

Ye Chen ◽

Zhi-Ping Li ◽

Meng Qiu ◽

...

Keyword(s):

Adverse Events ◽

Overall Response Rate ◽

Progression Free Survival ◽

Second Line ◽

Open Label ◽

Second Line Therapy ◽

Free Survival ◽

Common Grade ◽

Open Label Phase ◽

Grade 3

Abstract Background Irinotecan-based doublet chemotherapy strategy was standard second-line backbone treatment for patients with oxaliplatin‑refractory metastatic colorectal cancer(mCRC). The aim of this study was to evaluate tolerability and efficacy of raltitrexed combined with irinotecan biweekly administered as the second-line therapy for mCRC patients.Methods The study was a single-center, non-randomized, open-label phase II trial. Patients with mCRC after failure with first-line treatment of oxaliplatin and fluoropyrimidine or its derivatives were enrolled. Irinotecan (180 mg/m2) and raltitrexed (2.5 mg/m2) were given intravenously on day 1. Cycles were repeated every 2 weeks. The primary endpoint was progression-free survival, and the secondary endpoints included overall response rate, disease control rate, overall survival and treatment related adverse events. Results Between December 2012 and October 2016, 35 patients were enrolled. 33 and 35 patients were assessed for response and safety, respectively. The overall response rate (ORR) was 8.6 %, and the disease control rate (DCR) was 71.4%. The median progression-free survival (PFS) was 4.5 months (95% CI 3.8–5.2). The median overall survival was 12.0 months (95% CI 8.5–15.5). Four patients received conversion therapy to no evidence of disease (NED), and 2 patients were still alive with beyond 24 months survival. The most common grade 3/4 hematological adverse events were leukopenia (8.6%), neutropenia (5.7%). The most common grade 3/4 nonhematological adverse events were anorexia (14.3%), vomiting (14.3%), nausea (11.4%) and fatigue (8.6%). Two patients discontinued the protocol treatment because of treatment-related gastrointestinal adverse events. No one died from treatment-related events. The incidence and severity of toxicity was irrelevant to UGT1A1 status.Conclusions The combination of irinotecan with raltitrexed is an active, convenient and acceptable toxic regimen for second-line treatment for mCRC patients, which needs further study as a chemotherapy backbone to be combined with targeted agents in mCRC.Trial registration No. ChiCTR-ONC-12002767. The study was registered with the Chinese Clinical Trial Registry at 29 Octorber 2012, http://www.chictr.org.cn/index.aspx.

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