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Clinical Efficacy of HER2-targeted Monotherapy in ERBB2-mutant Non-Small-Cell Lung Cancer: A Systematic Review and
Fumihiro Kashizaki1, Ryusuke Orii1, Shohei Watanabe1
1Department of Respiratory Medicine, Yokohama Minami Kyosai Hospital, Yokohama, Japan.
Background:
ERBB2 (HER2)-mutant NSCLC, most commonly driven by exon 20 insertions, has historically shown limited benefit from early pan-ERBB inhibitors. Although multiple HER2-targeted agents have since emerged, the relationship between objective response, disease control, and durability remains incompletely defined across heterogeneous single-arm studies.
Methods:
We conducted a systematic review and single-arm meta-analysis of HER2-targeted monotherapies in advanced HER2-mutant NSCLC. Objective response rate (ORR) and disease control rate were pooled using random-effects meta-analysis of proportions with logit transformation. PFS was summarized descriptively because time-to-event outcomes were not consistently reported in a form suitable for pooling. Prespecified analyses evaluated outcomes by drug class and TKI generation, with additional analyses restricted to ERBB2 exon 20 insertion-mutant disease.
Results:
Twenty studies (n = 1489) met eligibility criteria; 7 prospective cohorts (n = 524) formed the main analysis. The pooled ORR was 0.51 (95% CI, 0.33-0.68; I2 = 89.8%). The pooled disease control rate was 0.88 (95% CI, 0.69-0.96) with limited separation across TKI generations. Median PFS ranged from approximately 5.5-11.5 months. Twelve-month overall survival estimates were similar between pyrotinib and trastuzumab deruxtecan. In exon 20-restricted analyses (n = 392), the pooled ORR was 0.52 (95% CI, 0.28-0.74).
Conclusions:
Next-generation HER2-selective TKIs achieved higher ORRs than older inhibitors, particularly in ERBB2 exon 20 insertion-mutant disease; however, differences in durability-related outcomes were less distinct in currently available later-line studies. These findings are exploratory and support prospective studies to better define durability and optimize sequencing strategies for HER2-mutant NSCLC.
Insights
Next-generation HER2-targeted therapies show improved objective response rates in HER2-mutant NSCLC, especially for exon 20 insertions. Durability differences were less clear in later-line treatments, warranting further research.
Area of Science:
- Oncology
- Medical Genetics
Background:
- Non-small cell lung cancer (NSCLC) with ERBB2 (HER2) mutations, particularly exon 20 insertions, has historically responded poorly to early pan-ERBB inhibitors.
- Despite emerging HER2-targeted agents, objective response, disease control, and treatment durability remain incompletely understood in heterogeneous single-arm studies.
Purpose of the Study:
- To systematically review and meta-analyze the efficacy of HER2-targeted monotherapies in advanced HER2-mutant NSCLC.
- To evaluate outcomes based on drug class and TKI generation, with a focus on ERBB2 exon 20 insertion-mutant disease.
Main Methods:
- Systematic review and single-arm meta-analysis of 20 studies (n=1489) involving HER2-targeted monotherapies.
- Pooled objective response rate (ORR) and disease control rate using random-effects meta-analysis.
- Descriptive summary of progression-free survival (PFS) and subgroup analyses for ERBB2 exon 20 insertion-mutant NSCLC.
Main Results:
- The pooled ORR was 0.51 (95% CI, 0.33-0.68) and the pooled disease control rate was 0.88 (95% CI, 0.69-0.96).
- Median PFS ranged from 5.5-11.5 months, with similar 12-month overall survival for pyrotinib and trastuzumab deruxtecan.
- In exon 20-restricted analyses (n=392), the pooled ORR was 0.52 (95% CI, 0.28-0.74).
Conclusions:
- Next-generation HER2-selective TKIs demonstrated higher ORRs than older inhibitors, particularly in ERBB2 exon 20 insertion-mutant NSCLC.
- Durability outcomes showed less distinct differences across TKI generations in later-line settings.
- Findings support further prospective studies to define durability and optimize treatment sequencing for HER2-mutant NSCLC.
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