Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review
<p>(<b>A</b>). Funnel plot overall survival (OS). (<b>B</b>) Funnel plot progression-free survival (PFS). (<b>C</b>) Funnel plot overall response rate (ORR).</p> "> Figure 2
<p>Study selection flow chart.</p> "> Figure 3
<p>Forrest plots of overall survival, progression-free survival, objective response rate, respectively. Overall survival (OS) and progression-free survival (PFS) were estimated using hazard ratios (HR). Objective response rate (ORR) was measured using odds ratio (OR). The bars in the figures indicate the respective confidence intervals. The sizes of the circles represent the weight of the respective study in the analysis. As demonstrated in (<b>A</b>), significant benefit was demonstrated in OS in groups receiving combination therapy in all individual studies and with a combined HR of 0.71 (95% CI 0.63–0.81). Cochran’s Q for OS was 0.31 (<span class="html-italic">p</span> = 0.96). Represented in (<b>B</b>), significant benefit was demonstrated in PFS in groups receiving combination therapy in all individual studies and with a combined HR of 0.58 (95% CI 0.52–0.64). Cochran’s Q for OS was 4.82 (<span class="html-italic">p</span> = 0.31). Similarly, in (<b>C</b>), significant benefit was demonstrated in ORR in groups receiving combination therapy in all individual studies and with a combined OR of 2.02 (95% CI 1.70–2.42).</p> "> Figure 4
<p>Relative risk (RR) of “pyrexia” adverse events; all grades. Combined RR of all studies was 1.27 (95% CI 0.59–2.73), showing no significant difference in risk of pyrexia between combination and monotherapy. Encorafenib plus binimetinib in the Dummer study had an RR of 0.65 (95% CI 0.45–0.95), revealing a significantly smaller risk of pyrexia as compare to monotherapy. Dabrafenib plus trametinib in the Robert study had an RR of 2.51 (95% CI 2.00–3.15), revealing a significantly higher risk of pyrexia in the combination group. Vemurafenib and cobimetinib compared to vemurafenib in the Ascierto study did not show and significant difference in risk of pyrexia between groups.</p> "> Figure 5
<p>Relative risk (RR) of “cough” adverse events; all grades. Combined RR for all studies was 1.24 (95% CI 0.64–2.39), showing no significant difference in risk of cough between combination and monotherapy. Dabrafenib plus trametinib in the Robert study had an RR of 2.02 (95% CI 1.38–2.97), revealing a significantly larger risk of cough as compared to vemurafenib monotherapy. Encorafenib plus binimetinib in the Dummer study and Vemurafenib plus cobimetinib in the Ascierto study did not show any significant difference in risk of cough compared to vemurafenib monotherapy.</p> "> Figure 6
<p>Relative risk (RR) of “fatigue” adverse events; all grades. Combined RR of all studies was 0.97 (95% CI 0.83–1.13), showing no significant difference in risk of fatigue between combination and monotherapy. Relative risk in individual studies also showed no significant difference in risk of fatigue between groups.</p> "> Figure 7
<p>Relative risk (RR) of “diarrhea” adverse events; all grades. Combined RR for all studies was 1.19 (95% CI 0.73–1.94), showing no significant difference in risk of diarrhea between combination and monotherapy groups. There is no significant difference in encorafenib plus binimetinib in the trial by Dummer (RR: 1.08, 95% CI 0.82–1.42) or dabrafenib plus trametinib in the trial by Robert (RR: 0.85, 95% CI 0.70–1.05) when compared to vemurafenib monotherapy. Vemurafenib plus cobimetinib in the trial by Ascierto had a relative risk of 1.84 (95% CI 1.50–2.25), showing a statistically significant high risk of diarrhea when compared to vemurafenib monotherapy.</p> "> Figure 8
<p>Relative risk (RR) of “rash” adverse events; all grades. Combined RR for all studies was 0.65 (95% CI 0.37–1.14), showing no significant difference in the risk of rash between combination therapy and monotherapy. Combination therapies of encorafenib plus binimetinib in the trial by Dummer (RR: 0.48, 95% CI 0.32–0.73) and dabrafenib plus trametinib in the trial by Robert (RR: 0.51, 95% CI 0.40–0.64) showed significantly decreased risk of rash compared to vemurafenib. Vemurafenib plus cobimetinib in the trial by (RR: 1.08, 95% CI 0.87–1.34) showed no statistical significance compared to vemurafenib.</p> ">
Abstract
:1. Introduction
2. Methods
2.1. Literature Search
2.2. Literature Selection Criteria
2.3. Data Extraction
2.4. Definition of Outcomes
2.5. Statistical Analysis
2.6. Publication Bias
3. Results
3.1. Study Selection
3.2. Survival Outcomes
3.3. Pyrexia and Other Constitutional Adverse Events
3.4. Gastrointestinal Adverse Events
3.5. Cardiac Adverse Events
3.6. Dermatology Adverse Events
4. Discussion
5. Conclusions
Supplementary Materials
Funding
Acknowledgments
Conflicts of Interest
References
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Author | Study Dates | Region | Trial Design | Treatment Regimen | OS (median mos), Combination vs. Monotherapy | PFS (median mos), Combination vs. Monotherapy | ORR, Combination vs. Monotherapy | Follow-up (median mos), Combination vs. Monotherapy |
---|---|---|---|---|---|---|---|---|
Dummer et al. 2018 [13] | December 2013–April 2015 | Worldwide (162 centers, 28 countries) | Phase III encorafenib + binimetinib (N = 192) vs. vemurafenib (N = 191) | 450 mg qd + 45 mg bid vs. 960 mg bid | 33.6 vs. 16.9 | 14.9 vs. 7.3 | 63% vs. 40% | 16.7 vs. 14.4 |
Robert et al. 2015 [12] | June 2012–October 2013 | Worldwide (193 centers) | Phase III dabrafenib + trametinib (N = 352) vs. vemurafenib (N = 352) | 150 mg bid + 2 mg qd vs. 960 mg bid | (NA), 17.2 | 11.4 vs. 7.3 | 64% vs. 51% | 11 vs. 19 |
Long et al. 2017 [11] | May 2012–November 2012 | Worldwide (113 centers, 14 countries) | Phase III dabrafenib + trametinib (N = 211) vs. dabrafenib (N = 212) | 150 mg bid + 2 mg qd vs. 150 mg bid | 25.1 vs. 18.7 | 11.0 vs. 8.8 | 68% vs. 55% | 9 (all groups) |
Ascierto et al. 2016 [9] | January 2013–January 2014 | Worldwide (135 centers, 19 countries) | Phase III vemurafenib + cobimetinib (N = 247) vs. vemurafenib (N = 248) | 960 mg bid + 60 mg qd vs. 960 mg bid | 22.3 vs. 17.4 | 12.3 vs. 7.2 | 70% vs. 50% | 14.2 (all groups) |
Flaherty et al. 2012 [10] | March 2010–July2011 | Multi-national (16 centers) | Phase I/II dabrafenib + trametinib (N = 54) vs. dabrafenib (N = 54) | 150 mg bid + 2 mg qd vs. 150 mg bid | (NA) | 9.4 vs. 5.8 | 76% vs. 54% | 14.1 (all groups) |
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Greco, A.; Safi, D.; Swami, U.; Ginader, T.; Milhem, M.; Zakharia, Y. Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review. Cancers 2019, 11, 1950. https://doi.org/10.3390/cancers11121950
Greco A, Safi D, Swami U, Ginader T, Milhem M, Zakharia Y. Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review. Cancers. 2019; 11(12):1950. https://doi.org/10.3390/cancers11121950
Chicago/Turabian StyleGreco, Austin, Danish Safi, Umang Swami, Tim Ginader, Mohammed Milhem, and Yousef Zakharia. 2019. "Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review" Cancers 11, no. 12: 1950. https://doi.org/10.3390/cancers11121950