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. 2021 Aug 19:11:731210.
doi: 10.3389/fonc.2021.731210. eCollection 2021.

Efficacy and Safety of Anti-HER2 Agents in Combination With Chemotherapy for Metastatic HER2-Positive Breast Cancer Patient: A Network Meta-Analysis

Xiaohui Zhang  1 , Junsheng Leng  2 , Yidong Zhou  1 , Feng Mao  1 , Yan Lin  1 , Songjie Shen  1 , Qiang Sun  1
Affiliations

Efficacy and Safety of Anti-HER2 Agents in Combination With Chemotherapy for Metastatic HER2-Positive Breast Cancer Patient: A Network Meta-Analysis

Xiaohui Zhang et al. Front Oncol. .

Abstract

Background: The presence of anti-HER2 agents, such as trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1), significantly improved the prognosis of metastatic HER2-positive (HER2+) breast cancers (BC). However, drug resistance and disease progression are still common. In order to further improve the treatment efficacy, new clinical trials about anti-HER2 agents in combination with chemotherapy are growing rapidly. We conducted the network meta-analysis to synthesize evidences of clinical trials to identify the best therapy for metastatic HER2+ BC.

Methods: A systematic search of randomized controlled trials regarding anti-HER2 agents in combination with chemotherapy for advanced or metastatic breast cancers up to May 2020 was conducted in Embase, PubMed, and the Cochrane Library. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR), and safety. Bayesian network meta-analysis was conducted to synthesize the results and rank the therapies.

Results: Twenty-six studies, including 16 studies for first-line treatments and 10 studies for second- or later-line treatments were included in the network meta-analysis. For first-line studies, the THP (taxanes + trastuzumab + pertuzumab) regimen exhibited the highest probability to be the optimal treatment in all efficacy outcomes and moderate safety. For second- or later-line studies, the T-DM1 and XHTuC (capecitabine + trastuzumab + tucatinib) regimens ranked top two in all efficacy outcomes according to the surface under the cumulative ranking (SUCRA) results. T-DM1 ranked first in PFS and OS whereas XHTuC ranked first in ORR. The safety outcomes of T-DM1 and XHTuC were acceptable.

Conclusions: THP was still the optimal first-line treatment for metastatic HER2+ BC. T-DM1 and XHTuC were recommended for second-line treatments.

Systematic review registration: INPLASY.com, identifier (INPLASY202090086).

Keywords: anti-HER2 agents; efficacy; metastatic HER2-positive breast cancer; network meta-analysis; safety.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
PRISMA flow diagram.
Figure 2
Figure 2
(A) Network plot of PFS in first-line studies. (B) Forest plot of PFS in first-line studies. Notes: The size of the blue node is proportional to the total number of participants assigned to each intervention. The width of the line is proportional to the number of trials comparing each pair of treatment. The thickness of the edge for connecting nodes means the amount of data. TH, Taxanes + Trastuzumab; VH, Trastuzumab + Vinorelbine; TXH, Capecitabine + Taxanes + Trastuzumab; TCbH, Carboplatin + Taxanes + Trastuzumab; TdmP, Pertuzumab + trastuzumab emtansine; TEveH, Everolimus + Taxanes + Trastuzumab; T-DM1, trastuzumab emtansine; H, Trastuzumab; TL, Lapatinib + Taxanes; TBevH, Bevacizumab + Taxanes + Trastuzumab; T, Taxanes; TAH, NPLD + Taxanes + Trastuzumab; THP, Pertuzumab + Taxanes + Trastuzumab; TN, Neratinib + Taxanes.
Figure 3
Figure 3
(A) Ranking histogram for PFS in first-line studies. (B) Result of SUCRA for PFS in first-line studies.
Figure 4
Figure 4
(A) Network plot of PFS in second- or other-line studies. (B) Forest plot of PFS in second- or other-line studies Notes: The size of blue node is proportional to the total number of participants assigned to each intervention. The width of the line is proportional to the number of trials comparing each pair of treatment. The thickness of the edge for connecting nodes means the amount of data. XH, Capecitabine + Trastuzumab; XHTuc, Capecitabine + Trastuzumab + Tucatinib; N, Neratinib; TPC, Physician’s choice; T-DM1, trastuzumab emtansine; X, Capecitabine; XL, Capecitabine + Lapatinib; XHP, Capecitabine + Pertuzumab + Trastuzumab.
Figure 5
Figure 5
(A) Ranking histogram for PFS in second- or other-line studies. (B) Result of SUCRA for PFS in second- or other-line studies.
Figure 6
Figure 6
(A) Network plot of OS in first-line studies. (B) Forest plot of OS in first-line studies. Notes: The size of the blue node is proportional to the total number of participants assigned to each intervention. The width of the line is proportional to the number of trials comparing each pair of treatment. The thickness of the edge for connecting nodes means the amount of data. TH, Taxanes + Trastuzumab; VH, Trastuzumab + Vinorelbine; TCbH, Carboplatin + Taxanes + Trastuzumab; TdmP, Pertuzumab + trastuzumab emtansine; TEveH, Everolimus + Taxanes + Trastuzumab; T-DM1, trastuzumab emtansine; H-T, Sequential Trastuzumab → Docetaxel; TL, Lapatinib + Taxanes; TBevH, Bevacizumab + Taxanes + Trastuzumab; T, Taxanes; TAH, NPLD + Taxanes + Trastuzumab; THP, Pertuzumab + Taxanes + Trastuzumab; TN, Neratinib + Taxanes.
Figure 7
Figure 7
(A) Ranking histogram for OS in first-line studies. (B) Result of SUCRA for OS in first-line studies.
Figure 8
Figure 8
(A) Network plot of OS in second- or other-line studies. (B) Forest plot of OS in second or other line studies. Notes: The size of the blue node is proportional to the total number of participants assigned to each intervention. The width of the line is proportional to the number of trials comparing each pair of treatment. The thickness of the edge for connecting nodes means the amount of data. XH, Capecitabine + Trastuzumab; XHP, Capecitabine + Pertuzumab + Trastuzumab; XHTuc, Capecitabine + Trastuzumab + Tucatinib; N, Neratinib; TPC, Physician’s choice; T_DM1, trastuzumab emtansine; X, Capecitabine; XL, Capecitabine + Lapatinib.
Figure 9
Figure 9
(A) Ranking histogram for OS in second- or other-line studies. (B) Result of SUCRA for OS in second- or other-line studies.
Figure 10
Figure 10
(A) Network plot of ORR in first-line studies. (B) Forest plot of ORR in first-line studies. Notes: The size of the blue node is proportional to the total number of participants assigned to each intervention. The width of the line is proportional to the number of trials comparing each pair of treatment. The thickness of the edge for connecting nodes means the amount of data. TH, Taxanes + Trastuzumab; TXH, Capecitabine + Taxanes + Trastuzumab; TCbH, Carboplatin + Taxanes + Trastuzumab; TEveH, Everolimus + Taxanes + Trastuzumab; T-DM1, trastuzumab emtansine; H-T, Sequential Trastuzumab → Docetaxel; TL, Lapatinib + Taxanes; TBevH, Bevacizumab + Taxanes + Trastuzumab; T, Taxanes, TAH, NPLD + Taxanes + Trastuzumab; THP, Pertuzumab + Taxanes + Trastuzumab; TN, Neratinib + Taxanes; VH, Trastuzumab + Vinorelbine; TdmP, Pertuzumab + trastuzumab emtansine.
Figure 11
Figure 11
(A) Ranking histogram for ORR in first-line studies. (B) Result of SUCRA for ORR in first-line studies.
Figure 12
Figure 12
(A) Network plot of ORR in second- or other -line studies. (B) Forest plot of ORR in second- or other-line studies. Notes: The size of the blue node is proportional to the total number of participants assigned to each intervention. The width of the line is proportional to the number of trials comparing each pair of treatment. The thickness of the edge for connecting nodes means the amount of data. XH, Capecitabine + Trastuzumab; XHP, Capecitabine + Pertuzumab + Trastuzumab; XHTuc, Capecitabine + Trastuzumab + Tucatinib; N, Neratinib; LTop, Lapatinib + topotecan; TPC, Physician’s choice; T-DM1, trastuzumab emtansine; VL, Lapatinib + Vinorelbine; XL, Capecitabine + Lapatinib; X, Capecitabine.
Figure 13
Figure 13
(A) Ranking histogram for ORR in second- or other-line studies. (B) Result of SUCRA for ORR in second- or other-line studies.
Figure 14
Figure 14
Result of SUCRA for (A) leucopenia, (B) neutropenia, (C) febrile neutropenia, and (D) cardiac adverse events. Notes: The larger the SUCRA, the lower the probability of adverse events. H-T, Sequential Trastuzumab → Docetaxel; T, Taxanes; TAH, NPLD + Taxanes + Trastuzumab; TBevH: Bevacizumab + Taxanes + Trastuzumab; TCbH, Carboplatin + Taxanes + Trastuzumab; T-DM1, trastuzumab emtansine; TdmP, Pertuzumab + trastuzumab emtansine; TEveH, Everolimus + Taxanes + Trastuzumab; TH, Taxanes + Trastuzumab; THP, Pertuzumab + Taxanes + Trastuzumab; TL, Lapatinib + Taxanes; TN, Neratinib + Taxanes; TXH, Capecitabine + Taxanes + Trastuzumab; VH, Trastuzumab + Vinorelbine.
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