Outcome comparison of pyrotinib with current standard of care in the second/third line setting in advanced non-small cell lung cancer patients with HER2 mutation.

To the Editor: In recent years, impressive outcomes have been achieved in patients harboring human epidermal growth factor receptor 2 (HER2) mutations, which accounts for 1% to 4% of cases in non-small cell lung cancer (NSCLC).[1] Previously, we observed that pyrotinib showed potent efficacy in HER2 exon 20 YVMA insertion NSCLC patient-derived organoids and patient-derived xenograft models,[2] and confirmed its efficacy in a phase II clinical trial with an objective response rate (ORR) of 30.0% and a median progression-free survival (PFS) of 6.9 months in the later-line setting,[3] suggesting the potential of pyrotinib to serve as a novel standard of care (SoC) in the later-line setting. Currently, single agent chemotherapy or immune checkpoint inhibitors (ICIs) are the SoC for the later-line treatment of advanced NSCLC, and recent studies have found that the combination of chemo-immunotherapy treatment shows superior efficacy.[4] To compare the efficacy of pyrotinib with current SoC in the second- or third-line settings, we retrospectively collected data of 182 patients from Tongji University School of Medicine Cancer Institute and reported the outcomes here. Patients who were confirmed to have HER2 mutations at Tongji University School of Medicine Cancer Institute from January 2014 to August 2020 were reviewed. The main inclusion criteria were as follows: (1) histologically or cytologically confirmed stage IV NSCLC, (2) complete medical records, (3) disease progression after using first-line chemotherapy with or without bevacizumab, and (4) pyrotinib as a second- or third-line treatment, chemotherapy as a second-line treatment, or ICIs with or without chemotherapy as a second- or third-line treatment. Clinicopathological characteristics were extracted, including age, sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), smoking history, histological types, metastatic sites, treatment lines, therapeutic regimens, and date of death or last follow-up. The treatment strategy was decided by both the patient and the doctor with full informed consent. This study was approved by the Ethics Committee of Shanghai Pulmonary Hospital (No. K16–223-1). All procedures performed in this study were in accordance with the Declaration of Helsinki (as revised in 2013). Written informed consent forms were obtained from all individual participants. HER2 mutations were detected by the amplification refractory mutation system method as described in our previous publications.[2,3] The categorical variables were compared using the chi-squared test or Fisher's exact test when needed. PFS and overall survival (OS) were estimated by the Kaplan-Meier method, and compared by the log-rank test. Cox proportional hazard models were performed for univariate and multivariable survival analyses. Parameters with P value <0.10 in the univariate analysis were included in the multivariate model. P values were two-sided, and the significance level was set as P < 0.05. All statistical analyses were performed using SPSS statistical software (version 22.0; IBM Corporation, Armonk, NY, USA). Plots were generated by GraphPad Prism (version 7; GraphPad Software Inc., San Diego, CA, USA) and R software (version 4.0.2, https://www.r-project.org). In total, we identified 182 patients with HER2 mutations. Among them, 70 patients who met the inclusion criteria were included in the present study. The workflow of this research is shown in Supplementary Figure 1, https://links.lww.com/CM9/B291. A total of 34, 27, and 9 patients received pyrotinib, chemotherapy alone, and ICI-based immunotherapy, respectively. Chemotherapy and ICI-based immunotherapy were defined as SoC. As a result, patients were dichotomized into pyrotinib and SoC groups. The baseline characteristics are presented in Supplementary Table 1, https://links.lww.com/CM9/B291, and there were no significant differences in the demographic and clinical characteristics between the two groups. The best response to pyrotinib or the SoC is demonstrated in Supplementary Figure 2A, https://links.lww.com/CM9/B291 and Supplementary Table 2, https://links.lww.com/CM9/B291. Patients treated with pyrotinib had a significantly higher ORR (35.3% [12/34] vs. 8.3% [3/36], P = 0.006) and disease control rate (85.3% [29/34] vs. 52.8% [19/36], P = 0.003) than those treated with SoC. The best changes in tumor size from baseline are presented in Supplementary Figure 2B, https://links.lww.com/CM9/B291. The median follow-up time was 15.9 months. Patients treated with pyrotinib showed significantly longer PFS (median, 7.0 vs. 3.6 months, P = 0.036 [Supplementary Figure 2C, https://links.lww.com/CM9/B291]; hazard ratio (HR) = 0.558, 95% confidence interval (CI): 0.320–0.972, P = 0.039) and numerically longer OS (median 26.9 vs. 14.3 months, P = 0.064 [Supplementary Figure 2D, https://links.lww.com/CM9/B291]; HR = 0.512, 95% CI: 0.249–1.052, P = 0.069) than patients treated with SoC. For patients who received ICI-based treatment (n = 9), the ORR was 22.2%, the median PFS was 4.5 months, and the median OS was not reached. In subgroup analysis, pyrotinib showed a superior PFS in male, but not OS [Supplementary Figures 3A and 3B, https://links.lww.com/CM9/B291]. The univariate and multivariable Cox regression analyses are presented in Supplementary Tables 3, https://links.lww.com/CM9/B291 and 4, https://links.lww.com/CM9/B291, respectively. In the univariate analysis, patients with ECOG PS 0–1 and those treated with pyrotinib had significant benefits in regard to PFS, and the significance remained in the multivariable analysis. The simultaneous use of ICIs and targeted therapy might result in a higher rate of immune-related adverse events (AEs). We further evaluated the feasibility of sequential therapy with ICIs and pyrotinib. Among the 70 patients, 14 received pyrotinib and ICI-based therapy (sequential treatment with pyrotinib and ICIs, whichever came first). Individual treatment duration, the best response to pyrotinib and ICIs, HER2 mutation variants, and programmed death-ligand 1 status are presented in Supplementary Figure 2E, https://links.lww.com/CM9/B291. Among the five patients who received ICIs first followed by pyrotinib, the best response to pyrotinib was zero partial response (PR), four stable disease (SD), zero progressive disease, and one patient who discontinued treatment due to grade 3 diarrhea, vomiting, and abnormal hepatic function. Among the nine patients who were treated with pyrotinib first followed by ICIs, five PR and four SD with pyrotinib were observed without grade 3 or higher AEs during follow-up. HER2 mutation has distinct features from HER2 protein overexpression or amplification and is associated with poor prognosis in patients with advanced NSCLC. The targeted drugs, such as lapatinib, neratinib, trastuzumab, and pertuzumab, which are approved for HER2-overexpression or HER2-amplified breast or gastric cancer have poor efficacy in NSCLC. Meanwhile, the pan-ErbB receptor tyrosine kinase inhibitors afatinib and dacomitinib also show very limited efficacy in NSCLC. As the most frequent mutation variants, exon 20 insertions account for 90% of all HER2 mutations. In vitro models revealed that the insertions in HER2 restricted the size of the drug-binding pocket, thus limiting the binding of large, rigid inhibitors.[5] Therefore, an alternative strategy is urgently needed. Fortunately, there are some inspiring results from several agents. Ado-trastuzumab emtansine was confirmed to be associated with an ORR of 44% and a median PFS of 5 months in the later-line setting.[6] Similarly, DS-8201a achieved an ORR of 55%, a median PFS of 8.2 months, and a median OS of 17.8 months in 91 patients harboring HER2 mutations.[7] In our previous phase II study, pyrotinib as a second- or later-line treatment showed an ORR of 30.0%, with a median PFS and OS of 6.9 and 14.4 months, respectively.[3] In addition, poziotinib and mobocertinib also showed promising results in their phase II trials.[8] Nevertheless, all the studies were single-arm clinical designs and lacked comparison with SoC. In the current study, we firstly compared the efficacy of pyrotinib with SoC, and found that pyrotinib was significantly associated with an improved ORR, prolonged PFS, and numerically prolonged OS. The efficacy was in line with the results from prospective clinical trials, suggesting a preferred recommendation of pyrotinib compared with SoC in this setting. Since the simultaneous or sequential use of ICIs and osimertinib has resulted in significantly increased grade 3/4 side effects, we also assessed the efficacy and side effects of the sequential use of ICIs and pyrotinib. The result was consistent with the findings of the sequential use of ICIs and osimertinib and suggested that pyrotinib should precede the use of ICIs. Several limitations must be acknowledged for this study. First, this study is retrospective in nature and includes patients from a single center. Second, a relatively small number of patients, especially only five patients who received the sequential use of ICIs and pyrotinib, were enrolled in the final analysis. Third, antibody-drug conjugates such as T-DM1 and DS-8201a are unavailable in China, thus the findings of this study cannot be generalized to the global population. In conclusion, pyrotinib showed superior ORR, PFS, and OS compared with SoC as a second- or third-line treatment in patients with HER2-mutant advanced NSCLC. Further phase III randomized trial is ongoing to validate the findings of this study. Funding This work was supported by grants from the National Natural Science Foundation of China (Nos. 81972167, 82172869 and 82002419), Shanghai Shenkang Hospital Development Center (No. SHDC12019133), Clinical Research Foundation of Shanghai Pulmonary Hospital (No. FKLY20008) and Shanghai Innovative Collaboration Project (No. 2020CXJQ02). Conflicts of interest None.