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Anita Sultan, Sriman Swarup, Somedeb Ball, Miguel Quirch, Meily Arevalo, Yin M. Myat, Ye Aung, Myo H. Zaw and Kyaw Z. Thein

Background: CDK4 and CDK6 are cyclin-dependent kinases that control transition between G1 and S phases of the cell cycle, hence controlling cell cycle progression by reversible combination with cyclin D1. In cancer cell, CDK4/6 activity is overexpressed, which can lead to amplification or overexpression of the genes encoding for CDK 4/6 or the cyclin D. Additionally, loss of endogenous INK4 inhibitors can also lead to over activity of CDK4 and CDK6. We undertook a meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities associated with CDK 4/6 inhibitors. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018. In our analysis, we incorporated RCTs that mention GI toxicities and elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) as adverse effects. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: A total of 4,557 patients with advanced breast cancer from 7 phase III and 1 phase II RCTs were eligible. The study arms used were palbociclib/ribociclib/abemaciclib or placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agents. The RR of all-grade side effects were as follows: diarrhea, 1.691 (95% CI: 1.220–2.345; P=.002); nausea, 1.632 (95% CI: 1.447–1.840; P<.001); vomiting, 1.684 (95% CI: 1.256–2.259, P=.001); stomatitis, 2.160 (95% CI: 1.332–3.503; P=.002); elevated AST, 1.832 (95% CI: 1.312–2.558; P<.001); and elevated ALT, 2.150 (95% CI: 1.649–2.803; P<.001). The RR of high-grade side effects were as follows: diarrhea, 2.592 (95% CI: 0.853–7.877; P=.093); nausea, 1.326 (95% CI: 0.589–2.988; P=.496); vomiting, 1.089 (95% CI: 0.479–2.476; P=.839); stomatitis, 2.097 (95% CI: 0.502–0.753; P=.310); elevated AST, 2.274 (95% CI: 1.173–4.410; P=.015); and elevated ALT, 3.988 (95% CI: 2.387–6.663; P<.001). Conclusions: Our study demonstrated that the risk of developing all grade GI toxicities and all grades of hepatic side effects including grade 3 and 4, was high in CDK 4/6 inhibitors group, compared to control arm, and prompt intervention with good supportive care is required.

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Sriman Swarup, Anita Sultan, Nusrat Jahan, Upama Sharma, Nimesh Adhikari, Yin M. Myat, Ye Aung, Myo H. Zaw and Kyaw Z. Thein

Background: VEGFR, KIT, RET, and MET pathways are implicated in several solid tumors. Cabozantinib is an oral inhibitor of these kinase pathways, and hence has found its use in treatment of multiple malignancies. However, it has several side effects that can limit tolerance amongst patients. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of health-related quality of life (HRQOL) events in patients with advanced solid tumors treated with cabozantinib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 30, 2018. Phase 3 trials that mention HRQOL events like pain, arthralgia, fatigue, and reduced appetite 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: 4 phase 3 RCTs with a total of 2,703 patients with medullary thyroid cancer, prostate cancer, renal cell carcinoma, and hepatocellular carcinoma were eligible. Studies comparing cabozantinib (C) vs everolimus, C vs placebo, C vs prednisone were included in the analysis. The relative risks of all-grade side effects were as follows: fatigue, 1.378 (95% CI: 1.236–1.536; P<.0001); asthenia, 1.704 (95% CI: 1.190–2.441; P=.004); reduced appetite, 2.088 (95% CI: 1.471–2.964; P<.0001); back pain, 1.047 (95% CI: 0.871–1.259; P=.626); pain in limbs, 1.444 (95% CI: 1.128–1.847; P=.004); arthralgia, 0.982 (95% CI: 0.707–1.363; P=.912). The RR of high-grade side effects were as follows: fatigue, 1.937 (95% CI: 1.483–2.528; P<.0001); asthenia, 2.211 (95% CI: 1.536–3.184; P<.0001); reduced appetite, 4.329 (95% CI: 2.372–7.900; P<.0001); back pain, 1.227 (95% CI: 0.738–2.040; P=.431); pain in limbs, 2.933 (95% CI: 1.127–7.635; P=.028); arthralgia, 0.820 (95% CI: 0.394–1.709; P=.597). Conclusion: Our meta-analysis showed that cabozantinib contributed to significant toxicity of all grades of fatigue, asthenia, pain in limbs, and reduced appetite. Identifying and addressing these toxicities will be important in improving quality of life for these patients.

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Apostolia M. Tsimberidou, Alexandra M. Adamopoulos, Yang Ye, Sarina Piha-Paul, Filip Janku, Siqing Fu, David Hong, Gerald S. Falchook, Aung Naing, Jennifer Wheler, Adoneca Fortier, Razelle Kurzrock and Kenneth R. Hess

Bendamustine, a cytotoxic alkylating agent, has shown promising results in solid tumors. An investigator-initiated phase I clinical trial of the anti-vascular endothelial growth factor agent bevacizumab and bendamustine was conducted in patients with advanced cancer, because the 2 drugs have different mechanisms of antitumor activity and nonoverlapping toxicity. Patients were treated with escalating doses of intravenous bendamustine (70, 80, 90, and 100 mg/m2; days 1 and 2) and intravenous bevacizumab (10 mg/kg; days 1 and 15). A conventional “3 + 3” study design was used. Forty-two patients were treated: 23 women and 19 men. The median age was 60 years. Patients had received a median of 4 prior therapies (range, 1-10). The most common cancer types were colorectal (n=9), head and neck (n= 8), non-small cell lung (n=6), and breast (n=5). Overall, 117 cycles were administered (median per patient, 2; range, 1-8). No dose-limiting toxicities were noted during the escalation phase. Therefore, the highest dose (level 4) of bendamustine (100 mg/m2) was used in the expansion phase. The most common toxicities were fatigue (n=22), nausea (n=14), anorexia (n=9), and thrombocytopenia (n=7). Of 38 patients who were evaluable for response, 23 (61%) had stable disease, including 2 (5.2%) who had stable disease for 6 months or more (1 with adenoid cystic carcinoma and 1 with non-small cell lung cancer). This regimen of bendamustine (100 mg/m2) and bevacizumab (10 mg/kg) was well tolerated and yielded disease stabilization in selected heavily pretreated patients with advanced cancer.

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Anita Sultan, Sriman Swarup, Francis Mogollon-Duffo, Ye Aung, Yin M. Myat, Myo H. Zaw, Rachana Yendala, Nicholas D’Cunha and Kyaw Z. Thein

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.