Abstract P5-14-10: Relative risk of grade 3 and higher hematological toxicities with trastuzumab emtansine: A systematic review and meta-analysis of published phase 3 randomized controlled trials

e13037 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) such as palbociclib, abemaciclib, and ribociclib have changed the landscape of management of estrogen receptor-positive and HER2-negative breast cancer in recent years. We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of hepatic dysfunction associated with the use of CDK4/6i. Methods: We conducted a systematic search using PRISMA guidelines in PubMed, EMBASE, American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer Symposium meeting abstracts from inception through Jan 30, 2021. Phase 3 RCTs using CDK4/6i in the intervention arm and reporting the number of events for elevation of liver enzymes were included in the analysis. The Cochran-Mantel-Haenszel method and random effects model were used to calculate the pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested by Cochran’s Q test and I2 value. Results: Nine phase 3 RCTs — MONALEESA-2, MONALEESA-3, MONALEESA-7, MONARCH 2, MONARCH 3, MONARCH plus, monarchE, PALOMA-2, and PALOMA-3 — randomizing 5,809 patients in the CDK4/6i arms and 4,638 patients in the control arms were included in the analysis. The CDK4/6i arms used CDK4/6i such as palbociclib, abemaciclib, or ribociclib in combination with one of the standard-of-care endocrine therapies such as letrozole, anastrozole, tamoxifen, or fulvestrant. The control arms received placebo along with respective endocrine therapies. The incidence of any grade alanine aminotransferase (ALT) elevation was 13.1% in the CDK4/6i arm and 5.4% in the control arm, pooled RR: 2.18, 95% CI: 1.74-2.72, P < 0.00001, I2 = 45%. The incidence of any grade aspartate aminotransferase (AST) elevation was 12.5% in the CDK4/6i arm and 5.3% in the control arm, pooled RR: 2.00, 95% CI: 1.57-2.54, P < 0.00001, I2 = 57%. The incidence of grade 3/4 ALT elevation was 4.1% in the CDK4/6i arm and 0.8% in the control arm, pooled RR: 4.43, 95% CI: 3.08-6.37, P < 0.00001, I2 = 0%. The incidence of grade 3/4 AST elevation was 2.9% in the CDK4/6i arm and 0.9% in the control arm, pooled RR: 2.70, 95% CI: 1.75-4.19, P < 0.00001, I2 = 29%. No fatal case of hepatotoxicity has been reported. Conclusions: Cyclin-dependent kinase 4/6 inhibitors are associated with significant risk of any grade and grade 3/4 hepatic enzymes elevation. Regular monitoring of liver function is a key to early detection and initiation of appropriate management.

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Relative risk of pneumonitis or interstitial lung disease (ILD) associated with the use of cyclin-dependent kinase inhibitors (CDK4/6i): A systematic review and meta-analysis of phase 3 randomized controlled trials.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1072 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1072-1072

Author(s):

Nusrat Jahan ◽

Sariya Wongsaengsak ◽

Shabnam Rehman ◽

Myrian Vinan-Vega ◽

Lukman Aderoju Tijani ◽

...

Keyword(s):

Systematic Review ◽

Relative Risk ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Controlled Trials ◽

Cyclin Dependent Kinase ◽

Phase 3 ◽

Randomized Controlled

1072 Background: All three currently approved cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) such as palbociclib, abemaciclib, and ribociclib are reported to cause significant pulmonary toxicities including fatal pneumonitis or interstitial lung disease (ILD). We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of pneumonitis or ILD associated with CDK4/6i. Methods: We conducted a systematic search using PRISMA guidelines in PubMed, EMBASE, American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meeting abstracts from inception through Jan 30, 2021. Phase 3 RCTs using CDK4/6i in the intervention arm and reporting the number of events for pneumonitis or ILD were included in the analysis. The Cochran-Mantel-Haenszel method and random effects model were used to calculate the pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested by Cochran’s Q test and I2 value. Results: Five phase 3 RCTs — MONALEESA-3, MONALEESA-7, MONARCH plus, monarchE, and PALLAS — reported the number of events for any grade pneumonitis or ILD and were included in the final analysis. A total of 13,191 patients — 6,758 in the CDK4/6i arm and 6,433 in the control arm — were analyzed. Following regimens were used in CDK4/6i arms — MONALEESA-3: ribociclib + fulvestrant; MONALEESA-7: ribociclib + tamoxifen or a non-steroidal aromatase inhibitor + goserelin; MONARCH plus: in cohort A, abemaciclib + anastrozole or letrozole, and in cohort B, abemaciclib + fulvestrant; MonarchE: abemaciclib + standard-of-care adjuvant endocrine therapy (ET); PALLAS: Palbociclib + ET. In the control arms, all studies used placebo and respective endocrine therapies. Any grade pneumonitis or ILD was reported in 1.64% of patients in the CDK4/6i arm versus 0.68% of patients in the control arm. The pooled RR of any grade pneumonitis or ILD was 2.26, 95% CI: 1.60-3.19, P < 0.00001, I2 = 0%. Grade 3/4 pneumonitis or ILD was reported in 0.28% of patients in the CDK4/6i arm and 0.06% of patients in the control arm with pooled RR of 2.35, 95% CI: 0.37-15.08, P = 0.37, I2 = 34%. One grade 5 pneumonitis was reported in the monarchE. Conclusions: Cyclin-dependent kinase 4/6 inhibitors are associated with increased risk of any grade pneumonitis or ILD. Early detection and prompt initiation of appropriate interventions are vital to reduce the morbidity and mortality associated with CDK4/6i induced pneumonitis or ILD.

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Abstract P5-14-15: Risk of peripheral neuropathy with trastuzumab emtansine: A systematic review and meta-analysis of published phase 3 randomized controlled trials

10.1158/1538-7445.sabcs19-p5-14-15 ◽

2020 ◽

Author(s):

Nusrat Jahan ◽

Fred Hardwicke

Keyword(s):

Systematic Review ◽

Peripheral Neuropathy ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Controlled Trials ◽

Trastuzumab Emtansine ◽

Phase 3 ◽

Randomized Controlled

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Bendamustine Is Not Associated With An Increase In Infections – Systematic Review and Meta-Analysis Of Randomized Controlled Trials

Blood ◽

10.1182/blood.v122.21.5125.5125 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5125-5125 ◽

Cited By ~ 1

Author(s):

Anat Gafter-Gvili ◽

Ronit Gurion ◽

Pia Raanani ◽

Ofer Shpilberg ◽

Liat Vidal

Keyword(s):

Systematic Review ◽

Randomized Controlled Trials ◽

Alkylating Agent ◽

Meta Analysis ◽

Alkylating Agents ◽

Cochrane Library ◽

Controlled Trials ◽

Randomized Controlled ◽

Solid Malignancies ◽

Grade 3

Abstract Background Bendamustine is a chemotherapeutic drug with structural similarities to both alkylating agents (nitrogen mustard derivative) and purine analogues (benzimidazole ring). Theoretically, due to its nucleoside-like properties it might be associated with more infections. Data in the literature is lacking regarding the infection-related adverse events of bendamustine-containing regimens. Thus, we aimed to assess this risk. Methods Systematic review and meta-analysis of all randomized controlled trials comparing bendamustine containing regimens (alone or combined with other chemotherapeutic agents and/or rituximab) to any other regimens. Trials evaluating bendamustine for any indication (hematological as well as solid malignancies) were included. A comprehensive search of The Cochrane Library, MEDLINE, conference proceedings and references was conducted until July 2013. Two reviewers appraised the quality of trials and extracted data. Outcomes assessed were: any infections, grade 3-4 infections, fatal infections, grade 3-4 neutropenia and grade 3-4 lymphopenia. For dichotomous data, relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. We used fixed effect model to pool data, unless there was significant heterogeneity, in which case we used the random effects model. Results Ten trials conducted between the years 1998 and 2013 and randomizing 2360 patients were included. We included 4 trials of patients with non-Hodgkin lymphoma (Rummel 2013, Rummel 2010, Herold 2006 and the Bright study 2013), 3 trials of CLL (Knauf 2009, Niederle 2013, LeBlond 2013), 1 trial of patients with multiple myeloma (Ponish 2006) and 2 trials of breast carcinoma patients. The bendamustine arm included: bendamustine alone (2 trials), bendamustine-rituximab (BR) (4 trials), bendamustine, vincristine, prednisone (BOP) (1 trial), bendamustine, MTX. 5FU (BMF) (2 trials) and bendamustine, prednisone (BP) (1 trial). The comparator arms in 8 of the trials included other alkylating agents: chlorambucil, R -CHOP, cyclophosphamide, MTX, 5-FU (CMF) and melphalan-prednisone (MP) – each regimen used in 2 trials and COP used in 1 trial. In 2 trials the comparator arm included fludarabine based regimens (alone or with rituximab). There was no statistically significant effect for bendamustine on the rate of any type of infection (RR 1.06 [95% CI 0.83, 1.34], 6 trials, figure). This analysis included only trials of hematological malignancies. There was no increase in the rate of grade 3-4 infections (RR 1.45 [95% CI 0.86, 2.45], 7 trials) or fatal infection (RR 0.69 [95% CI 0.30, 1.58], 3 trials). Data were too scarce to analyze by specific types of infections separately. There was no increase in the rate of grade 3-4 neutropenia in the bendamustine arm (RR 0.9 [95% CI 0.58, 1.42], 6 trials). This was true both when the comparator was alkylating agent containing regimens (RR 0.87 [95% CI 0.52, 1.48], 4 trials) or fludarabine containing regimens (RR 1.02 [95% CI 0.54, 1.91], 2 trials). There was a significant increase in grade 3-4 lymphopenia in the bendamustine arm compared to alkylating agent containing regimens (RR 1.95[95% CI 1.54, 2.47). Conclusions Our systematic review demonstrates no effect of bendamustine on the rate of infections when compared to either alkylating agents or fludarabine, in hematological as well as in solid malignancies, despite an increase in lymphopenia. Thus, bendamustine remains a safe therapeutic option. The main drawback of this meta-analysis is the heterogeneity between malignancies and treatments. Disclosures: No relevant conflicts of interest to declare.

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Mindfulness training for smoking cessation: A meta-analysis of randomized-controlled trials

Journal of Health Psychology ◽

10.1177/1359105316637667 ◽

2016 ◽

Vol 22 (14) ◽

pp. 1841-1850 ◽

Cited By ~ 36

Author(s):

Maria Theodora Oikonomou ◽

Marios Arvanitis ◽

Robert L Sokolove

Keyword(s):

Systematic Review ◽

Smoking Cessation ◽

Relative Risk ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Mindfulness Training ◽

Controlled Trials ◽

Percent Confidence Interval ◽

Review Of The Literature ◽

Randomized Controlled

Recent studies have shown that mindfulness training has a promising potential for smoking treatment. In order to examine the efficacy of mindfulness training in smoking cessation, we performed a systematic review of the literature and meta-analysis of randomized controlled trials. Four randomized controlled trials with 474 patients were included in our analysis. The results showed that 25.2 percent of participants remained abstinent for more than 4 months in the mindfulness group compared to 13.6 percent of those who received usual care therapy (relative risk, 1.88; 95 percent confidence interval, 1.04–3.40). Our results suggest that mindfulness training may have an important role to play in efforts to lower cigarette smoking rates.

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EPR19-74: Risk of Cabozantinib-Associated Gastrointestinal and Hepatic Toxicities in Patients With Metastatic Solid Tumors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2018.7155 ◽

2019 ◽

Vol 17 (3.5) ◽

pp. EPR19-74

Author(s):

Anita Sultan ◽

Sriman Swarup ◽

Francis Mogollon-Duffo ◽

Ye Aung ◽

Yin M. Myat ◽

...

Keyword(s):

Systematic Review ◽

Side Effects ◽

Randomized Controlled Trials ◽

Solid Tumors ◽

Meta Analysis ◽

Controlled Trials ◽

Growth Factor Signaling ◽

High Grade ◽

Phase 3 ◽

Randomized Controlled

Background: Cabozantinib is an oral inhibitor of multiple tyrosine kinases and is used in treatment of multiple solid tumors, targeting several pathways such as vascular endothelial growth factor signaling pathway and proto-oncogenes MET, KIT, RET. These pathways are implicated in several tumor development and progression. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities among patients with metastatic solid tumors treated with cabozantinib. Methods: MEDLINE, EMBASE databases, and meeting abstracts from inception to September 2018 were queried. Phase 3 RCTs that mention GI and elevation of liver enzymes as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: We included 4 phase 3 RCTs with a total of 2,703 patients with various solid tumors. The study arm used cabozantinib while the control arm utilized everolimus or placebo or prednisone. The relative risks of all-grade side effects were as follows: diarrhea, 2.495 (95% CI: 2.149–2.897, P<.0001); nausea, 1.849 (95% CI: 1.649–2.072; P<.0001); vomiting, 2.335 (95% CI: 1.724–3.163; P<.0001); stomatitis, 4.541 (95% CI: 0.908–22.696; P=.065); dysgeusia, 4.428 (95% CI: 2.67–7.343; P<.0001); elevated AST, 2.002 (95% CI: 1.331–3.011; P=.001); and elevated ALT, 1.988 (95% CI: 0.936–4.222; P=.074). The RR of high-grade side effects were as follows: diarrhea, 5.913 (95% CI: 3.655–9.566; P<.0001); nausea, 3.098 (95% CI: 1.266–7.581; P=.013); vomiting, 1.298 (95% CI: 0.395–4.265; P=.668); stomatitis, 3.837 (95% CI: 0.749–19.665; P=.107); dysgeusia, 1.522 (95% CI: 0.159–14.574; P=.716); elevated AST, 1.733 (95% CI: 1.101–2.728; P=.018); and elevated ALT, 2.489 (95% CI: 1.164–5.326; P=.019). Conclusion: The risk of developing all grades of diarrhea, nausea, elevated AST, and any-grade vomiting, dysgeusia as well as high-grade elevated ALT, was high in cabozantinib group. Timely recognition and providing good supportive care will enhance patients’ quality of life.

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Treatment of Advanced Gastro-Entero-Pancreatic Neuro-Endocrine Tumors: A Systematic Review and Network Meta-Analysis of Phase III Randomized Controlled Trials

Cancers ◽

10.3390/cancers13020358 ◽

2021 ◽

Vol 13 (2) ◽

pp. 358

Author(s):

Claudio Ricci ◽

Giuseppe Lamberti ◽

Carlo Ingaldi ◽

Cristina Mosconi ◽

Nico Pagano ◽

...

Keyword(s):

Systematic Review ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Progression Free Survival ◽

Phase Iii ◽

Neuroendocrine Neoplasms ◽

Controlled Trials ◽

Endocrine Tumors ◽

Randomized Controlled ◽

Grade 3

Several new therapies have been approved to treat advanced gastro-entero-pancreatic neuroendocrine neoplasms (GEP–NENs) in the last twenty years. In this systematic review and meta-analysis, we searched MEDLINE, ISI Web of Science, and Scopus phase III randomized controlled trials (RCTs) comparing two or more therapies for unresectable GEP–NENs. Network metanalysis was used to overcome the multiarm problem. For each arm, we described the surface under the cumulative ranking (SUCRA) curves. The primary endpoints were progression-free survival and grade 3–4 of toxicity. We included nine studies involving a total of 2362 patients and 5 intervention arms: SSA alone, two IFN-α plus SSA, two Everolimus alone, one Everolimus plus SSA, one Sunitinib alone, one 177Lu-Dotatate plus SSA, and one Bevacizumab plus SSA. 177Lu-Dotatate plus SSA had the highest probability (99.6%) of being associated with the longest PFS. This approach was followed by Sunitinib use (64.5%), IFN-α plus SSA one (53.0%), SSA alone (46.6%), Bevacizumab plus SSA one (45.0%), and Everolimus ± SSA one (33.6%). The placebo administration had the lowest probability of being associated with the longest PFS (7.6%). Placebo or Bevacizumab use had the highest probability of being the safest (73.7% and 76.7%), followed by SSA alone (65.0%), IFN-α plus SSA (52.4%), 177Lu-Dotatate plus SSA (49.4%), and Sunitinib alone (28.8%). The Everolimus-based approach had the lowest probability of being the safest (3.9%). The best approaches were SSA alone or combined with 177Lu-Dotatate.

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Obinutuzumab-Related Adverse Events: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2019-128677 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5259-5259

Author(s):

Irina Amitai ◽

Anat Gafter-Gvili ◽

Pia Raanani ◽

Ronit Gurion

Keyword(s):

Systematic Review ◽

Adverse Events ◽

Randomized Controlled Trials ◽

Lymphoproliferative Disorder ◽

Meta Analysis ◽

Lymphoproliferative Disorders ◽

Controlled Trials ◽

Toxicity Profile ◽

Randomized Controlled ◽

Grade 3

Background: Rituximab, the first FDA-approved anti-CD20 monoclonal antibody has dramatically improved outcomes for patients with CD20 positive lymphoproliferative disorders for 2 decades. Obinutuzumab was developed to potentiate activity and overcome resistance to rituximab. Clinical data suggest obinutuzumab is superior to rituximab in specific lymphoproliferative disorder, at the potential cost of increased toxicity, especially infections. In order to better define the toxicity profile of obinutuzumab as opposed to rituximab, we conducted a systematic review and meta‐analysis of all randomized controlled trials comparing obinutuzumab with rituximab, either alone or combined with chemotherapy for any CD20 positive lymphoproliferative disorder, in order to assess safety. Methods: A comprehensive search was conducted until June 2019. Two reviewers appraised the quality of trials and extracted data. The Primary outcome was grade 3 to 4 infections; secondary outcomes included any adverse events, serious adverse events, and other grade 3 to 4 hematologic toxicity. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled. A fixed‐effect model was used to pool data unless there was significant heterogeneity, in which case a random‐effects model was used. Results: Our search yielded 4 randomized controlled trials conducted between the years 2009 and 2014, including 3429 patients. Median age of patients in the trials was 58 to 62 years. The trials included patients with follicular lymphoma (FL) (2 trials), chronic lymphocytic leukemia, (1 trial), and diffuse large B cell lymphoma (1 trial). All trials compared between obinutuzumab and rituximab therapy: in 3 trials the antibody was combined with chemotherapy and in 1 trial it was given alone. In 2 trials, which included FL patients, the antibody was given also as maintenance therapy for up to 2 years. There was a statistically marginally increased rate of grade 3-4 infections (RR 1.17 [95% CI, 1.0‐1.36]) and febrile neutropenia (RR 1.23 [95% CI, 1.0‐1.5]) and a statistically significant increased rate of grade 3-4 adverse events (RR 1.15 [95% CI, 1.09‐1.2]) in the obinutuzumab arm vs rituximab. Also, the obinutuzumab arm showed increased risk of grade 3-4 thrombocytopenia (RR 2.8 [95% CI, 1.92‐4.06]), infusion related reactions (RR 2.8 [95% CI, 2.16‐3.64]) and cardiac events (RR 1.65 [95% CI, 1.11‐2.46]). There was no significant difference in grade 3-4 anemia and neutropenia rates, nor in the mortality rate at 36 months (RR 0.93 [95% CI, 0.78‐1.11]). Conclusions: Our systematic review and meta-analysis demonstrates that obinutuzumab has a more severe toxicity profile as compared to rituximab. As better clinical outcomes were reported with obinutuzumab in several CD20 positive lymphoproliferative disorders, but with more toxicity, clinicians are faced with a challenge upon deciding which therapy to choose for their patients. Disclosures Gurion: Roche: Consultancy.

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Incidence of palmar-plantar erythrodysesthesia and hypothyroidism in patients with metastatic cancer treated with cabozantinib: A systematic review and meta-analysis of randomized controlled trials.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.31_suppl.204 ◽

2017 ◽

Vol 35 (31_suppl) ◽

pp. 204-204

Author(s):

Kyaw Zin Thein ◽

Myo Zaw ◽

Myat M. Han ◽

Jirapat Teerakanok ◽

Catherine Jones ◽

...

Keyword(s):

Systematic Review ◽

Randomized Controlled Trials ◽

Tyrosine Kinases ◽

Metastatic Cancer ◽

Meta Analysis ◽

Control Group ◽

Controlled Trials ◽

High Grade ◽

Phase 3 ◽

Randomized Controlled

204 Background: Cabozantinib is an oral inhibitor of multiple tyrosine kinases, including VEGFR, KIT, RET and MET, and is proven to be beneficial in different types of tumors. Nevertheless, there are noteworthy safety concerns. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of palmar-plantar erythrodysesthesia (PPE) and hypothyroidism among patients with metastatic cancer treated with cabozantinib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through January 31, 2017. The randomized controlled phase 3 trials that mention PPE and hypothyroidism as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Random effects model was applied. Results: Three phase 3 RCTs with a total of 1999 patients were eligible for analysis. Studies compared cabozantinib (C) vs everolimus, C vs placebo, C vs prednisone, were included in the analysis. All grade-PPE incidence was 499 (36.6%) in cabozantinib arm vs 26 (3.36%) in control arm with a RR of 13.998 (95% CI: 5.409 – 36.224, P < 0.0001). The absolute RD was 0.374 (95% CI: 0.258 – 0.489, P < 0.0001). High-grade PPE was reported in 93 (7.58%) in cabozantinib group vs 3 (0.39%) in control group with a RR of 12.486 (95% CI: 4.529 – 34.426, P < 0.0001). The RD was 0.080 (95% CI: 0.045 – 0.115, P < 0.0001). The overall incidence of hypothyroidism was noted in 292 (23.82%) in cabozantinib arm vs 24 (3.1%) in control arm. The pooled RR of hypothyroidism was 15.825 (95% CI: 1.229 – 203.820, P = 0.034) and RD was 0.237 (95% CI: 0.113 – 0.361, P < 0.0001). Conclusions: Our meta-analysis demonstrated that cabozantinib contributed to significant toxicity of all-grade and high-grade PPE as well as hypothyroidism. Identifying these toxicities may aide physicians in providing good supportive care and patients’ quality of life.

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