Background
HER2-mutated non-small cell lung cancer (NSCLC) can only obtain limited clinical benefit from targeted therapies such as pan-HER tyrosine kinase inhibitors (TKIs) or TKIs targeting EGFR/HER1 or HER2 [
1‐
3]. Although ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan-nxki (T-DXd) are recommended as treatment options for advanced
HER2-mutant NSCLC patients by the National Comprehensive Cancer Network (NCCN) guidelines based on ORRs of 44% (
N = 18) and 72.7% (
N = 11), respectively in advanced
HER2-mutant lung adenocarcinomas, these two drugs have not been approved yet for treating this subset of patients [
4,
5]. Chemotherapy remains the current standard-of-care for
HER2-mutated NSCLC; however, it typically yields an ORR of 10–43.5% (1st-line, 43.5%; 2nd-line, 10%) and a PFS of 4.3-6 months (1st-line, 6 months; 2nd-line, 4.3 months) [
6,
7]. Therefore, there exists an unmet need for effective HER2-targeting therapies to improve patients’ outcomes. Multiple NSCLC trials are ongoing to evaluate other novel TKIs, including tarloxotinib (NCT03805841), TAK-788 (NCT02716116), and poziotinib (NCT03318939; NCT04044170) [
8].
Pyrotinib is an oral, irreversible pan-HER TKI, which has been adopted as the combination partner of capecitabine for treating advanced
HER2- positive breast cancer in China [
9]. In patient-derived lung cancer xenograft mouse models harboring
HER2 exon 20 insertions, pyrotinib demonstrated stronger antitumor activities than T-DM1 or afatinib [
10]. In a phase II study (
N = 60) conducted by Zhou C et al., chemotherapy-treated NSCLC patients with
HER2 mutations within exon 20 and 19 achieved an ORR of 30% upon pyrotinib, with mPFS of 6.9 months and median overall survival (mOS) of 14.4 months [
11]. Evidence regarding efficacy and safety of pyrotinib remains to be confirmed in larger sample sizes, particularly in patients with
HER2 mutations outside of exon 20. Moreover, the underlying mechanism of resistance to pyrotinib and its efficacy in patients who had brain metastases and prior exposure to anti-HER2 therapy has not been well elucidated.
The aim of this study was to evaluate the efficacy and safety of pyrotinib in advanced NSCLC patients harboring HER2 mutations. The impact of different HER2 mutation types on sensitivity to pyrotinib, the association between baseline characteristics and response, and the potential of utilizing mutational profile information derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored.
Discussion
HER2 mutations are rarely observed in NSCLC. There exists little evidence regarding effective treatment of NSCLC patients with HER2 mutations, especially those with non-exon 20 mutations. Herein, we reported the effect of pyrotinib in 78 advanced lung adenocarcinoma patients harboring different types of HER2 mutations. In the total population, pyrotinib produced 6-month PFS rate of 49.5%, mPFS of 5.6 months, mOS of 10.5 months, and ORR of 19.2%. In line with previous studies, the most common TRAE was diarrhea, and grade 3 diarrhea occurred in 16.7% of the patients. Among patients with HER2 mutations in different exons, patients harboring non-exon 20 aberrations achieved comparable ORR than those with exon 20 mutations. Patients who had brain metastases and prior exposure to anti-HER therapy could benefit from pyrotinib. Moreover, loss of HER2 mutations, appearance of HER2 amplification, and aberrations in EGFR, MET, KRAS, and BRAF were detected upon disease progression, suggesting their potential roles in the resistance to pyrotinib.
Chemotherapy, the current standard treatment for advanced NSCLC patients with
HER2 mutations, typically elicits an ORR of 10% and an mPFS of 4.3 months in a second-line setting (6). TKIs targeting HER2 or pan-HER have been investigated for treating
HER2-mutated lung cancer patients. However, afatinib, neratinib, and dacomitinib only elicited ORR of 7.7%, 3.8%, and 12% [
1‐
3]. The ORRs upon T-DM1 and T-DXd treatment could reach up to 44% (8/18) and 72.7% (8/11), respectively [
4,
5]. The mPFS of T-DM1-treated NSCLC patients as previously reported was 5.0 months, which was similar to that observed in the present study (5.0 vs. 5.6 months). Most recently, the results of the phase II study DESTINY-Lung trial were released in which T-DXd showed an ORR of 55% (50/91) and mPFS of 8.2 months in patients with previously treated NSCLC with
HER2 mutation [
17]. Albeit encouraging anti-tumor activity, grade 4 and 5 TRAEs occurred upon T-DXd, whereas in our study, no grade 4 or 5 TRAEs were observed, suggesting that pyrotinib is safer than T-DXd [
5,
17]. Poziotinib, another promising anti-HER2 TKI, has exhibited an ORR of 42% in
HER2-mutated NSCLC patients (
N = 12), causing grade 3 or 4 AEs in 66.7% of the patients [
18].
Treatment of
HER2-mutated NSCLC with pyrotinib has been previously reported. In phase II trials conducted by Wang Y et al. and Zhou C et al., treatment with pyrotinib was associated with ORRs of 53.3% and 30%, and mPFSs of 6.4 months and 6.9 months in cohorts of 15 and 60
HER-mutated advanced NSCLC patients [
10,
11]. Both studies reported better efficacy than our observations (ORR, 19.2%; PFS, 5.6 months). This could have been explained by the fact that our study enrolled patients with a PS score of 2 (7/78, 9%) whereas Zhou C’s study only included patients with a PS score of 0–1. A higher percentage of patients in our cohort had brain metastases at baseline (25.6% vs. 20%) and more patients received pyrotinib in the third line or higher (51.3% vs. 41.6%) than in their study. In addition, patients who had prior exposure to HER2-targeted drugs were also included in our study. Of note, the duration of response in the present study was 9.9 months, which was longer than 6.9 months documented in Zhou C’s study.
The sensitivities to anti-HER2 TKIs in patients bearing different
HER2 mutations were also distinct. In patients with
HER2-mutated NSCLC, the major
HER2 mutation type was exon 20 insertions, occurring in 1.5% of NSCLC and accounting for 90% of all NSCLC with
HER2 mutations [
19‐
22]. Previous studies have been mainly focusing on these insertions. Two prospective studies investigating pyrotinib employed the ADx HER2 Mutation Detection Kit for
HER2 genotyping, which only allows for detection of exon 20 and 19 mutations [
10,
11]. In our study, we utilized NGS to detect
HER2 mutations, which was capable of identifying mutations outside of exons 20 and 19. Indeed, patients carrying mutations outside of exon 20 were also able to benefit from pyrotinib. A numerically higher ORR was observed among patients carrying non-exon 20 mutations, especially those carrying exon 19 mutations. These observations were consistent with previous findings that
HER2 exon 20 insertions are less sensitive to currently available TKIs than mutations in other exons, potentially due to the structural difference of mutant in this exon from in others [
19].
HER2 exon 20 insertions primarily affected two structural regions: the αC- helix, comprising residues 770–774, and the loop region at residues 775–783 [
20,
21,
23]. Structure-based comparison of behaviors between these variant types needs to be further studied.
Patients with
HER2 exon 20 mutation Y772_A775dup, the most common
HER2 mutation in NSCLC, failed to respond to afatinib and dacomitinib as reported [
1,
24,
25]. Surprisingly, pyrotinib produced an ORR and a DCR of 23.8% and 78.6%, respectively, in 42 patients harboring Y772_A775dup in our study [
24,
25]. Consistent with the results of Zhou C’s study, although none of the 11 patients carrying G776delinsVC achieved PR in our study, the DCR of this subset reached 63.6%, which was similar to that of the other mutation types [
11]. Clinical efficacy regarding anti-HER2 TKIs has been poorly investigated in patients with
HER2 TMD mutations [
26,
27]. In our study, three patients harbored
HER2 TMD, including two with V659E and one with I655V. The PFS and OS of the patients with V659E was 2.9–5.6 months and 5.3–5.6 months, respectively. The other patient bearing I655V, however, experienced PD three weeks after initiation of pyrotinib. Collectively, our results revealed variable efficacy of pyrotinib in NSCLC patients with different
HER2 mutations and warrant further validation in larger randomized clinical trials.
Another point to be noted was the monitoring of acquired resistance to pyrotinib by using blood sample profiling, highlighting the importance of liquid biopsy in this setting. In this study, we also explored potential resistance mechanisms underlying disease progression upon pyrotinib.
HER2 CNA was identified from two patients upon PD, consistent with a previous report that
HER2 CNA conferred resistance to anti-HER2 TKIs in
HER2-mutated NSCLC patients [
28]. Of note,
EGFR CNA was also detected from these two patients upon PD, indicating the concurrent
HER2 CNA and
EGFR CNA may engender resistance to pyrotinib. In another four PD patients,
HER2 mutation, which existed at baseline, was not detected from the blood sample at PD, rending it rational to speculate that the loss of
HER2 mutations may engender resistance to pyrotinib as well. In addition,
MET CNA,
KRAS (p.G12D),
BRAF CNA, and
EGFR (p.E330K) were also detected from patients at PD.
MET CNA has been reported to be associated with resistance to anti-HER2 TKIs in
EGFR-mutant NSCLC,
HER2-amplified breast cancer, and
HER2-mutated NSCLC [
28‐
30]. Based on these results, we propose that strategies combining pyrotinib and EGFR TKI or other TKIs targeting the above alternations might be a potential treatment option to vanquish resistance or potentiate the antitumor activities in treating this subset of patients.
Indeed, Rolfo C et al. summarized a series of novel agents that has potential against
HER2-mutated NSCLC [
8]. Interestingly, the combinational treatment of a pan-HER inhibitor (neratinib) and T-DM1 or T-DXd induced a superior activity compared with T-DM1 alone [
31]. Similarly, preclinical studies revealed that the novel pan-HER TKI poziotinib could up-regulate HER2 cell-surface expression and increase the activity of T-DM1 in tumors with
HER2-mutation [
32]. In addition, Bob T. Li et al. reported that the combination of T-DM1 and irreversible pan-HER inhibitors (neratinib or afatinib) could enhance the duration of the responses in HER2-altered lung cancers [
31]. Pyrotinib is an irreversible pan-HER inhibitor, also presenting promising activity in
HER2-mutated NSCLC as observed in our study. Part of data of this trial (ChiCTR1800020262) was published recently which has shown the efficacy of pyrotinib in NSCLC patients with
HER2 amplification (6-month PFS rate: 51.9%, ORR: 22.2%, mPFS: 6.3 months, mOS: 12.5 months) [
33]. Therefore, a combination of T-DM1/T-DXd and pyrotinib may become a potentially effective therapy for these
HER2-altered patients. These results indicate that combining T-DM1/T-DXd and anti-HER2 TKI might be a potential treatment option to increase antitumor activity or conquer resistance to targeted therapies. The above proposals are a ray of hope shining the future of patients with
HER2 alternations.
Despite being the largest prospective study investigating pyrotinib effects in NSCLC, our study is still limited by the small sample size due to the low prevalence of HER2 mutations in NSCLC. Second, comparison with chemotherapy or other targeted therapies was not feasible due to a lack of control arm. The findings of the current study should be examined in larger randomized clinical trials.
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