Pyrotinib for HER2-positive metastatic breast cancer: a systematic review and meta-analysis
Original Article

Pyrotinib for HER2-positive metastatic breast cancer: a systematic review and meta-analysis

Wenyu Hu1, Jixin Yang1, Ze Zhang2, Dongdong Xu1, Nanlin Li1

1Surgery of Thyroid Breast Vascular Surgery, Xijing Hospital, Air Force Military Medical University, Xi’an, China; 2Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

Contributions: (I) Conception and design: W Hu, N Li; (II) Administrative support: N Li; (III) Provision of study materials or patients: W Hu, N Li; (IV) Collection and assembly of data: W Hu, J Yang; (V) Data analysis and interpretation: W Hu, J Yang, Z Zhang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Nanlin Li. Surgery of Thyroid Breast Vascular Surgery, Xijing Hospital, Air Force Military Medical University, Xi’an 710032, Shaanxi, China. Email: linanlingo@163.com.

Background: Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer patients continue to progress despite multiple anti-HER2-targeted treatments. A number of studies have found that Pyrotinib, a small-molecule pan-ErbB receptor tyrosine kinase inhibitor (TKI), is effective in treating patients with HER2-positive metastatic breast cancer. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of Pyrotinib in the treatment of HER2-positive metastatic breast cancer.

Methods: PubMed, Embase, Web of Science, and Cochrane Library databases were searched until February 2022. Research on HER2-positive metastatic breast cancer being treated with Pyrotinib in any line of therapy was included, both prospective and retrospective. Statistical pooling and meta-analysis of data from the included studies were performed to explore the efficacy and safety of Pyrotinib in HER2-positive metastatic breast cancer.

Results: In this meta-analysis, 23 studies were included. The overall objective response rate was 0.49 (95% CI: 0.40, 0.58) for Pyrotinib in HER2-positive metastatic breast cancer and 0.52 (95% CI: 0.32, 0.71) in those with brain metastases. The objective response rate of Pyrotinib was superior to that of other second-line therapeutics in comparison (RR =1.38, 95% CI: 1.25, 1.52), but was relatively inferior to trastuzumab emtansine (T-DM1) (RR =0.82, 95% CI: 0.36, 1.85). The combined median progression-free survivals (PFSs) for Pyrotinib in metastatic breast cancer and those with brain metastases were 8.2 (95% CI: 6.8, 9.5) months and 8.9 (95% CI: 6.2, 11.7) months, respectively. The most common adverse reaction was diarrhea with an all-grade incidence of 0.84 (95% CI: 0.74, 0.92), followed by nausea and vomiting of 0.52 (95% CI: 0.36, 0.68).

Conclusions: In any line of treatment for HER2-positive metastatic breast cancer, the Pyrotinib-containing regimens demonstrated considerable tumor response, disease control, and survival with manageable adverse effects.

Keywords: Pyrotinib; metastatic breast cancer; HER2-positive

Submitted Jul 09, 2022. Accepted for publication Dec 23, 2022. Published online Feb 21, 2023.

doi: 10.21037/tcr-22-1746

Introduction

According to the World Health Organization’s (WHO) 2020 Global Cancer Statistics Report, there are approximately 2.3 million newly diagnosed breast cancer patients worldwide, accounting for 11.7% of the overall new cancer cases, which has surpassed lung cancer as the most frequent malignant tumor (1). Breast cancer has become an increasingly severe disease burden that threatens women’s health (2). Approximately 15% to 20% of breast cancers are overexpressed with human epidermal growth factor receptor 2 (HER2), which are more biologically aggressive, less responsive to chemotherapy, and have higher rates of recurrence and metastasis (3). Researchers have produced several medications that specifically target HER2, with a combination of trastuzumab and pertuzumab being widely utilized in clinical practice as first-line therapy, significantly improving the prognosis of patients with HER2-positive breast cancer. Nevertheless, patients will inevitably develop resistance to anti-HER2-targeting agents and relapse. As a result, the continual examination of relevant resistance mechanisms and the development of novel anti-HER2-targeted medications are crucial.

Pyrotinib, an irreversible tyrosine kinase inhibitor (TKI) that is independently developed in China, can inhibit the HER1, HER2, and HER4 families. The efficacy and tolerability of Pyrotinib have been demonstrated in clinical trials in comparison to lapatinib, an approved reversible HER2 TKI (4,5). Additionally, Pyrotinib administered with brain irradiation exhibited a superior therapeutic impact on brain metastases in patients with metastatic breast cancer (6). Since its listing in 2018 in China, Pyrotinib has been broadly applied in clinical practice as a recommended second-line treatment for metastatic breast cancer in developing nations lacking access to innovative antibody-drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) and different trials have been conducted to prove its efficacy and safety. Therefore, to determine the efficacy and safety of Pyrotinib in treating patients with HER2-positive metastatic breast cancer, we performed this systematic review and meta-analysis. We present the following article in accordance with the MOOSE checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-1746/rc).

Methods

Search strategy

This meta-analysis research protocol was submitted and registered on the INPLASY platform, registration number: INPLASY202230076. When writing this systematic review and meta-analysis, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. PubMed, Embase, Web of Science, and the Cochrane Library were searched with “Pyrotinib” as the major search phrases. The retrieval date is up to February 2022. Table S1 illustrates the detailed search strategy for the literature.

Criteria for study selection

Literature was assessed for inclusion and exclusion criteria by two separately. The inclusion criteria were: (I) patients with HER2-positive metastatic breast cancer; (II) previously treated with Pyrotinib in any line of therapy; (III) prospective or retrospective clinical trials, and (IV) single- or dual-arm studies. The exclusion criteria were: (I) review, letter comments or case reports; (II) in vitro experiments, animal studies; (III) other irrelevant research; (IV) clinical trials in the neoadjuvant phase; (V) ongoing clinical trials; (VI) duplicate publications in different journals.

Data extraction and quality assessment

Data were collected independently by two data extractors. The extracted basic information included author, year, study type, sample size, median age, treatment regimen, treatment line, doses of Pyrotinib, etc. The primary outcome endpoints extracted were overall objective response rate (ORR), progression-free survival (PFS) and safety data. Secondary endpoint data were the ORR rate in patients previously treatmed with lapatinib or trastuzumab/T-DM1 and those with brain metastases.

The literature included in the analysis was assessed with appropriate methods and tools: the Cochrane collaboration’s tool for assessing the risk of bias was used to evaluate randomized controlled trials (RCTs), the Newcastle-Ottawa Scale (NOS) was used to assess cohort studies and case-control studies, and the MINORS tool was used to evaluate single-arm studies, the Agency for Healthcare Research and Quality (AHRQ) was used to assess real-world studies.

Statistical analysis

R software (version 4.0.3) was used for performing this meta-analysis. The means of single-group descriptive statistics were combined and proportionate meta-analyses were performed to evaluate weighted pooled incidence rates dependent on the amount of diagnostically assessable patients. For dichotomous variables, with reference to the magnitude of heterogeneity, a fixed-effect model or a random-effects model was chosen to combine the effect sizes. The I2 statistic refers to the proportion of observed between-study variation (observed due to true heterogeneity rather than chance). The I2 statistic was calculated to assess study heterogeneity (7), I2 values of 25%, 50% and 75% were categorized as low, medium and high heterogeneity, respectively (8). Random-effects models were used to estimate heterogeneous effect sizes for each trial if P=0.10 or I2>50%; otherwise, a fixed-effects model was employed. Relative risks (RR) or odds ratios (OR) were used as pooled statistics to explain the statistical outcomes of several studies of dichotomous variables. The rate distribution must follow as nearly as feasible to the normal distribution due to the single-group rate data. In the case that the initial rate did not correspond to the normal distribution, the rate would need to be altered to conform to or approximate the normal distribution to increase the reliability of the combined results. The method of pooling was determined by the rate distribution. Pooled hazard ratios (HR) were calculated to compare PFS with Pyrotinib versus lapatinib, funnel plots and Egger’s test were then used to examine the results for publication bias. The major results were evaluated through sensitivity analysis, and heterogeneity was identified through subgroup analysis.

Results

Figure 1 demonstrates the flow chart for this study. By reviewing the titles and abstracts of 449 articles, 226 duplicates and 161 irrelevant articles were eliminated from the electronic database search result. Among the remaining publications, articles of interest were further reviewed, with twelve duplicate reports and twenty-seven ineligible articles excluded. A total of 23 studies were included, including three randomized controlled trials (RCT) (4,5,9), six prospective trials (10-15), eight retrospective trials (16-23), and six real-world studies (6,24-28). The baseline characteristics of the studies included are summarized in Table 1. The methodological quality of the included studies was evaluated, and the results are presented in Table S2.

Figure 1 The flow chart of literature screening.

Table 1

The baseline of the included studies

Study/year Study design Sample, size (n) Median age (years) Treatment Treatment line Pyrotinib dose (mg) No. of BM ORR PFS
Overall BM Overall BM
Li et al. 2021 (6) Real world 218 51 [34–75] Pyrotinib/+H/X/N/nab-p 1–3 line 400, 320, 240 53 96 23 9.3 (8.6–10.0) 7.0 (6.1–7.8)
Sun et al. 2021 (24) Real world 65 50 [31–75] Pyrotinib/+X/N/T ≥2 line 400, 320 NR 47 8 NR NR
Anwar et al. 2021 (25) Real world 168 50 [28–73] Pyrotinib +H/X/T All line 400, 320 39 68 NR 8.0 (7.3–10.5) 8.7 (6.4–11.9)
Li et al. 2019 (10) Prospective 28 48 [24–59] Pyrotinib +X 1-2 line 160, 240, 320, 400 NR 22 NR 22.1 (9.0–26.2) NR
Li et al. 2021 (16) Retrospective 97 53 [26–74] Pyrotinib +N 400, 320 23 33 NR 7.8 (4.7–10.8) 6.3 (3.4–9.2)
Ma et al. 2017 (11) Prospective 36 47 [29–67] Pyrotinib 1-2 line 80, 160, 240, 320, 400, 480 NR 18 NR 8.9 (5.8–10.0) NR
Zhang et al. 2021 (12) Prospective 141 52 [29–78] Pyrotinib +H/X/T NR 400, 320 21 27 7 12.0 (8.1–17.8) 18.4 (5.5–18.8)
Ouyang et al. 2021 (26) Real world 94 49 [28–71] Pyrotinib 1-3 line NR NR 38 NR NR NR
Lin et al. 2020 (17) Retrospective 113 53 [24–84] Pyrotinib/+H/X/N/T All line 400, 320, 240, 160 31 31 NR 6.3 (5.5–7.1) 6.7 (4.7–8.7)
Song et al. 2020 (18) Retrospective 72 55 [32–79] Pyrotinib +H/X/N/T/ET All line NR 15 19 NR 7.6 (5.5–9.7) 6.0 (2.2–9.8)
Yang et al. 2022 (19) Retrospective 31 56 [31–69] Pyrotinib +H/X/N/T ≥2 line 400 NR 8 NR 4.5 (3.1–5.9) 5.2
Hua et al. 2020 (20) Retrospective 66 NR Pyrotinib ≥2 line NR NR 11 NR 6.4 (3.6–9.2) NR
Yan et al. 2020 (21) Retrospective 52 NR Pyrotinib +X NR 400 NR 41 41 NR NR
Hao et al. 2021 (27) Real world 254 50 Pyrotinib/+X/N/T All line NR NR 89 NR 11 NR
Luo et al. 2021 (13) Prospective 113 NR NR 1-3 line NR NR 75 NR 14.1 15.2
Yan et al. 2021 (14) Prospective 23 NR Pyrotinib + dalpiciclib 1 line 400 NR 15 NR NR NR
Yan et al. 2021 (15) Prospective 78 NR Pyrotinib +X NR 400 78 NR 52 NR 12.1 (9.0–14.7)
Yang et al. 2021 (22) Retrospective 68 44 [33–55] Pyrotinib +X/N/T/Others ≥2 line 320 NR 41 NR 9.0 NR
96 Pyrotinib +X/N/T/Others 33 NR 6.2 NR
Xie et al. 2021 (23) Retrospective 92 52 [26–74] Pyrotinib +N NR 320, 400 NR NR NR 8.3 NR
132 Lapatinib +X NR NR 5.0 NR
Li et al. 2021 (28) Real world 55 47 [27–73] Pyrotinib/+X/N/T/others ≥2 line 400 NR 9 NR 6.0 (4.7–7.3) NR
50 T-DM1 10 NR 4.2 (3.6–4.8) NR
Ma et al. 2019 (4) RCT 65 48 [25–70] Pyrotinib +X 1–3 line 400 NR 51 NR 18.1 (13.9–NR) NR
63 Lapatinib +X 36 NR 7.0 (5.6–9.8) NR
Xu et al. 2021 (5) RCT 134 50 [42–55] Pyrotinib +X 1–3 line 400 NR 90 NR 12.5 (9.7–NR) NR
132 Lapatinib +X 68 NR 6.8 (5.4–8.1) NR
Jiang et al. 2019 (9) RCT 185 NR Pyrotinib +X NR 400 NR 127 NR 11.1 (9.7–16.5) 6.9 (5.4-NR)
94 Placebo +X 15 NR 4.1 (2.8–4.1) 4.2

ORR, objective response rate; PFS, progression-free survival; RCT, randomized controlled trial; BM, brain metastases; H, Trastuzumab; X, capecitabine; N, Vinorelbine; T, Taxane; nab-p, nab-paclitaxel; ET, endocrine therapy; NR, not report.

The ORR of Pyrotinib in HER2-positive metastatic breast cancer

A total of 1,997 patients from twenty-one individual groups were included in the meta-analysis of ORR, with an overall ORR rate of 0.49 (95% CI: 0.40, 0.58), and the corresponding funnel plot of Egger’s test reveals publication bias (Egger’s test: t=0.42, P value =0.6757) (Figure 2A,2B, Figure S1). The result of the sensitivity analyses is shown in Figure S2. The overall ORR rate was 0.33 (95% CI: 0.24, 0.43) in patients previously treated with lapatinib, and 0.52 (95% CI: 0.32, 0.71) in brain metastatic patients (Figure 2C,2D). In ORR, Pyrotinib was superior to selected second-line drugs (RR =1.38, 95% CI: 1.25, 1.52) and lapatinib (RR =1.40, 95% CI: 1.21, 1.61), with significant statistical differences, but relatively inferior to T-DM1 (RR =0.82, 95% CI: 0.36, 1.85) (Figure 2E). Pyrotinib remained efficacious in patients pretreated with trastuzumab/T-DM1, with a relatively lower ORR rate than patients who had not previously received trastuzumab (RR =0.70, 95% CI: 0.61, 0.81); The ORR rate was lower in patients who had previously received lapatinib when compared with those who had not previously received lapatinib (RR =0.71, 95% CI: 0.54, 0.93) (Figure 2F).

Figure 2 The objective response rate of Pyrotinib in HER2 positive metastatic breast cancer. (A) Single-arm studies, (B) Funnel plot, studies including patients: (C) had previously treated lapatinib, (D) with brain metastases, (E) receiving Pyrotinib vs. other second-line regimens (F) had vs. had not received lapatinib treatment.

The survival outcome

Patients receiving Pyrotinib had a significantly longer PFS than those receiving lapatinib (HR =0.45, 95% CI: 0.37, 0.55) (Figure 3).

Figure 3 Progression-free survival of Pyrotinib vs. lapatinib in HER2 positive metastatic breast cancer.

The safety analysis

Table 2 contains information on adverse reactions. The most common adverse reaction of any grade was diarrhea, with an incidence of 0.84 (95% CI: 0.74, 0.92), followed by nausea and vomiting 0.52 (95% CI: 0.36, 0.68), neutropenia 0.35 (95% CI: 0.23, 0.48), leukopenia 0.34 (95% CI: 0.23, 0.47), and palmoplantar erythema (PPE) 0.31 (95% CI: 0.16, 0.48). The most common adverse reaction of grade 3 or greater was diarrhea, with an incidence of 0.18 (95% CI: 0.15, 0.22), followed by PPE 0.07 (95% CI: 0.03, 0.11), neutropenia 0.05 (95% CI: 0.04, 0.07), and leukopenia 0.04 (95% CI: 0.02, 0.06).

Table 2

The incidence of adverse reactions

Adverse reactions Study/n No. of people ≥ Grade 3 I2 P Study/n No. of people All grade I2 P
Diarrhea 18 1,841 0.18 (95% CI: 0.15, 0.22) 75 <0.01 13 1,026 0.84 (95% CI: 0.74, 0.92) 93 <0.01
PPE 14 1,561 0.07 (95% CI: 0.03, 0.11) 87 <0.01 12 995 0.31 (95% CI: 0.16, 0.48) 97 <0.01
Neutropenia 12 1,099 0.05 (95% CI: 0.04, 0.07) 21 0.24 11 702 0.35 (95% CI: 0.23, 0.48) 89 <0.01
Leukopenia 11 1,160 0.04 (95% CI: 0.02, 0.06) 70 <0.01 9 702 0.34 (95% CI: 0.23, 0.47) 90 <0.01
Thrombocytopenia 9 873 0.00 (95% CI: 0.00, 0.01) 46 0.06 6 415 0.09 (95% CI: 0.05, 0.15) 60 0.03
thrombocytopenia 10 1,040 0.01 (95% CI: 0.00, 0.02) 62 <0.01 8 620 0.25 (95% CI: 0.15, 0.37) 89 <0.01
Aminotransferase increased 10 1,004 0.02 (95% CI: 0.01, 0.03) 44 0.07 8 584 0.25 (95% CI: 0.14, 0.37) 90 <0.01
Blood bilirubin increased 8 842 0.01 (95% CI: 0.00, 0.02) 62 0.01 6 481 0.27 (95% CI: 0.17, 0.39) 86 <0.01
Rash 9 1,020 0.00 (95% CI: 0.00, 0.01) 41 0.09 8 697 0.11 (95% CI: 0.05, 0.21) 84 <0.01
Nausea and vomiting 12 1,195 0.03 (95% CI: 0.01, 0.05) 73 <0.01 11 888 0.52 (95% CI: 0.36, 0.68) 96 <0.01
Fatigue 8 745 0.00 (95% CI: 0.00, 0.01) 27 0.22 5 287 0.14 (95% CI: 0.02, 0.33) 92 <0.01
Dizziness 5 636 0.00 (95% CI: 0.00, 0.01) 73 0.01 5 426 0.05 (95% CI: 0.02, 0.10) 71 <0.01
Oral mucositis 7 1,017 0.01 (95% CI: 0.00, 0.02) 56 0.04 5 428 0.11 (95% CI: 0.04, 0.19) 84 <0.01
Blood creatinine increased 3 226 0.00 (95% CI: 0.00, 0.00) 0 1.00 4 264 0.16 (95% CI: 0.05, 0.32) 91 <0.01
Decreased appetite 5 558 0.01 (95% CI: 0.00, 0.03) 53 0.08 6 596 0.17 (95% CI: 0.07, 0.30) 93 <0.01

PPE, palmar-plantar erythrodysesthesia.

Discussion

In recent years, ADCs such as T-DXd have made breakthroughs in the second-line treatment of breast cancer (29). However, since ADCs are currently unavailable in developing countries, Pyrotinib remains an inexpensive, safe, and effective therapeutic option. The efficacy and safety of Pyrotinib had been further established through persistent verification in clinical practice. Our study discovered an overall ORR rate of 0.49 (95% CI: 0.40, 0.58) for Pyrotinib in patients with HER2-positive metastatic breast cancer and 0.52 (95% CI: 0.32, 0.71) in those with brain metastases, indicating that Pyrotinib as a small-molecule HER-targeted drug has considerable efficacy in the second-line treatment of metastatic breast cancer and a definite effect on patients with brain metastases. One of the biggest challenges in treating breast cancer is its tendency to metastasize to other parts of the body, and after lung cancer, breast cancer is the second most common source of brain metastases (30). The most common site of metastasis in patients with HER2-positive breast cancer was found to be the brain (31). In studies that have demonstrated improved efficacy in patients with brain metastases, the majority include whole-brain radiotherapy (when multiple brain metastases are present) or local radiotherapy [stereotactic radiosurgery (SRS) when one or two brain metastases are present] in their treatment regimens to disrupt the blood-brain barrier, allowing Pyrotinib to reach the brain metastases. These treatments provide favorable clinical practice evidence for radiation therapy for brain metastases from breast cancer (32). After transtuzumab/T-DM1 or lapatinib therapy, it continues to work effectively, implying that Pyrotinib has the potential to reverse HER2 resistance. The latest basic experiments demonstrate that Pyrotinib combined with a novel CDK4/6 inhibitor SHR6390 can synergistically inhibit CDK4/6 and HER2 signaling pathways (33); a followed phase II research is underway to examine the efficacy of Pyrotinib in conjunction with the CDK4/6 inhibitor SHR6390 in patients with advanced HER2+/ER+ breast cancer who had previously received trastuzumab (34).

Due to the favorable anticancer activity and tolerability of Pyrotinib in combination with capecitabine in patients with recurrent or metastatic breast cancer that is positive for HER2, further trials of Pyrotinib in the neoadjuvant phase are also underway and have generated early findings. Xuhong et al. initially investigated the efficacy and safety of Pyrotinib in combination with epirubicin and cyclophosphamide, followed by docetaxel and trastuzumab in neoadjuvant treatment of stage I–III HER2-positive breast cancer, the pathological complete response rate in 19 patients was 73.7% (95% CI: 48.8–90.9) (35). The recently reported Panphila trial using TCbH combined with Pyrotinib (taxane + platinum + trastuzumab + Pyrotinib) neoadjuvant therapy achieved a pCR rate of 55.1% in 69 patients (36). Additionally, an ongoing neoadjuvant clinical trial compares the efficacy of Pyrotinib and pertuzumab when combined with trastuzumab plus nab-paclitaxel in the treatment of early or locally advanced HER2-positive breast cancer (37); another ongoing phase II trial is exploring the efficacy of Pyrotinib combined with neoadjuvant chemotherapy in patients with HR+/HER2-, HER4 overexpressing breast cancer (38). We are optimistic about Pyrotinib’s efficacy in the neoadjuvant treatment of HER2-positive breast cancer.

This meta-analysis has some limitations. Firstly, some analyses revealed significant heterogeneity. The possible explanations include discrepancies in study design, treatment line, disease assessment, and participant counts. Secondly, since individual patient data were not available, factual subgroup analyses were not performed (e.g., Estrogen receptor status, number of metastases, treatment lines, medication regimen, etc.). Thirdly, a subset of the survival data was extracted from the survival curves, which would culminate in error creation. Finally, since the majority of the studies were individual clinical trials, the evidence quality was weaker than meta-analyses of RCTs included.

Conclusions

The Pyrotinib-containing regimens exhibited satisfactory tumor response, disease control, and survival with tolerable adverse effects in patients with HER2-positive metastatic breast cancer receiving any line of therapy.

Acknowledgments

We would like to thank Professor Anhui Wang from the Military Preventive Medicine Teaching and Research Section of the Air Force Military Medical University, for his inspection and suggestions on the statistical aspects of this study are very significant to us.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the MOOSE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-1746/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-1746/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Hu W, Yang J, Zhang Z, Xu D, Li N. Pyrotinib for HER2-positive metastatic breast cancer: a systematic review and meta-analysis. Transl Cancer Res 2023;12(2):247-256. doi: 10.21037/tcr-22-1746

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