The overall response rate to afatinib is
The 13% overall response rate to afatinib is comparable to a 19% response rate reported by Peters et al.  in a separate retrospective series investigating the use of afatinib in more heavily pretreated patients with HER2-mutant lung adenocarcinomas. Our 13% response rate is also comparable to an earlier phase II trial that yielded a 12% response rate using dacomitinib, a selective and irreversible pan-HER inhibitor, in stage IIIB/IV patients with HER2-mutant lung adenocarcinomas . Overall, the activity of afatinib seen in this study confirms the earlier reports of activity in small case series; De Greve et al.  reported PR in all of three patients on afatinib, and Mazières et al. , ] reported PR in one of three patients. While the common YVMA mutation was found in two of three responders to afatinib in our study, it was also found in two of seven patients with PD (Table 2). These findings emphasise the need for better understanding of the underlying biology of the various HER2 mutation subtypes and potential differences in their response to HER2-targeted therapies. One patient treated with afatinib was found to have an SNP in HER2, which resulted in the substitution of valine for isoleucine at SynaptoRedTM C2 655 (Ile655Val) of the HER2 protein. The role of Ile655Val in driving oncogenesis has been explored in prior studies in patients with breast cancer with conflicting results, and this SNP has not been well characterised in HER2-mutant lung adenocarcinomas . While RECIST data were unavailable for this patient, the patient experienced clinical benefit while on treatment with afatinib for 4 months. Thus, larger clinical series of this variant are needed to help draw conclusions regarding its predicted response to afatinib and other HER2-targeted agents. The identification of this SNP further underscores the molecular heterogeneity of HER2 alterations in lung adenocarcinomas. While the median duration of treatment on afatinib for all patients was 3 months, the range varied from 1 month to ongoing treatment at 30 months (YVMA mutation). Five patients (19%; 5/27) remained on treatment for more than 6 months, including a patient with an YVMA mutation who experienced PR. This demonstrates that afatinib has the potential for durable disease control in a subset of patients with HER2-mutant lung adenocarcinomas. Median OS of all patients treated with afatinib in our study was 23 months, which was comparable to prior studies that examined survival of advanced stage (stages IIIB-stage IV) HER2-mutant lung adenocarcinomas , , . There are several limitations to this study due to its retrospective nature, including reporting bias, a lack of central molecular assessment and variable imaging intervals. Nevertheless, as our study was conducted in a heavily pretreated patient population with higher likelihood for development of drug resistance, it is unlikely to overestimate the efficacy of afatinib. Moreover, our study was conducted outside of a clinical trial, which broadens its applicability and generalisability to patients worldwide who have either a poor performance status or a lack of access to therapies on clinical trial. The use of afatinib in HER2-mutant lung adenocarcinomas currently is being studied in two separate prospective phase II clinical trials: the ETOP-NICHE trial (NCT02369484) in Europe and the NCI-MATCH trial (NCT02465060) in the US. Interim results from the ETOP-NICHE trial were reported at the 2017 ASCO Annual Meeting and did not demonstrate the expected ability of afatinib to control disease, and the final results of the study are still yet to be reported . These upcoming results may help to confirm our findings of afatinib use outside of a clinical trial in a real-world setting. Other HER2-targeted agents are being explored in patients with HER2-mutant lung adenocarcinomas. Single-agent neratinib recently demonstrated only a 4% overall response rate for HER2-mutant lung adenocarcinomas in a phase II basket trial, and the combination of neratinib with trastuzumab is being explored in a cohort expansion of the trial (NCT01953926) . Neratinib is also being tested in combination with temsirolimus, and the preliminary results from a phase II trial testing this combination in HER2-mutant lung adenocarcinomas reported a response rate of 19% (eight of 43 patients) (NCT NCT01827267) . In addition, the early results from a phase II study examining the effects of poziotinib, a novel irreversible pan-HER inhibitor, reported a PR in eight of 11 (73%) patients with lung adenocarcinomas harbouring EGFR exon 20 insertions (NCT03066206) . In a recent study published by Oh et al., poziotinib was found to induce PR in two patients and SD in three of six total treated patients . Owing to these promising results, poziotinib is currently being tested in patients with lung adenocarcinomas harbouring HER2 exon 20 mutations (NCT03318939). Similarly, pyrotinib, another irreversible pan-HER inhibitor, is also being investigated in a phase I trial cohort expansion for HER2-mutant lung adenocarcinomas (NCT02500199). Recently, a phase II trial using ado-trastuzumab emtansine (T-DM1) in patients with HER2-mutant lung adenocarcinomas reported an overall response rate of 44%, and this has been incorporated as a treatment recommendation for HER2-mutant lung adenocarcinomas by the 2018 National Comprehensive Cancer Network Clinical Practice Guidelines . A further expansion study of T-DM1 in both HER2-amplified and HER2-mutant solid tumours is ongoing (NCT02675829).