HER2 mutations in our cohort included point mutations, in-frame insertions, which counted the most, and gene amplification seen in one patient with squamous cell lung cancer. Mutation in squamous cell lung cancer is rather rare, and HER2 mutation was not publicly reported before. Among HER2 exon 20 insertions, there were A775_G776insYVMA, G776delinsVC, V777_G778insGSP and so on, with the most common type being YVMA, in accordance with previous findings. We also paid attention to the co-mutations of HER2, for patients harboring exon 20 insertions, TP53 was the most common co-mutation. However, limited by various NGS platforms from different gene companies, we could not summarize the relevance between mutation abundance and clinical characteristics of those patients.
Consistent with former studies, HER2 mutated patients in our cohort were mainly females, never or light smokers, poorly or moderately differentiated adenocarcinoma. They were younger, with more than three quarters aged less than 65 years old.
In terms of treatment outcome, only first and second lines of treatment were analyzed. In the first line settings, our data showed that HER2 targeted therapy had inferior outcome than standard of care chemotherapy. This was in contrary with previous studies. One study including 24 HER2 exon 20 insertion lung cancer patients revealed that the overall survival of targeted therapy was longer than non-targeted agents, with 2.1 years and 1.4 years, respectively. Another article involved 38 cases of HER2 mutated patients, the PFS of HER2-TKIs was 2.2 months, with 5.2 months in first line treatment and 1.8 months in latter lines. And the overall median PFS of chemotherapy was 4.3 months, with pemetrexed plus platinum or bevacizumab possessing the longest of 6.2 months. The PFS of first line HER2-TKIs in our study was longer than previously reported, and chemotherapy was longer as well. Maybe this was because a majority of patients used pemetrexed plus platinum as their chemotherapy regimen.
In subtype analysis, the conclusion remained. Within YVMA subtype, afatinib was inferior than chemotherapy. This finding was again in contrary with some of the previous studies. One article argued that the time to treatment failure(TTF) was 9.6 months in YVMA subtype, much longer than the 2.9 months of all patients. Another study compared the different responses to first-line chemotherapy, finding that YVMA had a PSF of 0.9 month shorter than the overall. Our result indicated that for YVMA patients, chemotherapy would be a better choice in first line treatment. Since patients with YVMA in our cohort had been exposed to both treatment, our result might represent a more direct conclusion. In subtypes other than YVMA, there was no significant difference seen between chemotherapy and HER2-TKIs.
The HER2-TKIs used as first or second lines in our patient cohort were mainly afatinib. This is partly because of the availability of legal drugs in China. Orally taken HER2-TKIs such as poziotinib, dacotinib and pyrotinib were rarely used. So was trastuzumab and T-DM1which were used as intravenous agents in health care centers. But that does not mean that these drugs were invalid for HER2 mutated lung cancer patients. For HER2 amplification positive lung cancer patients, adding trastuzumab to chemotherapy seemed not to bring more clinical benefit to them. However, it was reported that trastuzumab or T-DM1 had an objective response rate (ORR) of 50.9% and PFS of 4.8 months in HER2 exon 20 mutated patients. In another cohort involving 7 HER2 exon 20 insertion patients, 5 patients reached partial response or stable disease on T-DM1 treatment. That could mean that trastuzumab or T-DM1 might be beneficial to these minority. Among small molecule TKIs, afatinib was most widely used in China in recent years, with PFS ranging from 2.9 to 6 months[11, 15-18]. Poziotinib, neratinib and pyrotinib had similar PFS, with 4.5-5.5 months, 5.5 months and 6.4 months, respectively[6, 19, 20]. Dacomitinib and Osimertinib was inferior in this population, either with a short PFS or invalid in cell lines experiments[21, 22].
Our study collected information from wide-spread geographical parts of China, discussing the different outcomes of treatment among HER2 mutated advanced lung cancer patients. We drew the conclusion that for HER2 mutated advanced non-small cell lung cancer patients, chemotherapy would bring more benefit than available tyrosine kinase inhibitors, especially in the most common subtype of exon 20 insertions. Nevertheless, limited by the retrospective information collection, some important parameters were missed out. In patients lacking tumor tissue samples, we accepted NGS outcomes from peripheral blood samples. Treatment was rich in their variety, so it was no easy task to categorize them appropriately. Patients’ samples were sent to different centers for analysis, so we could not summarize the relevance between mutation abundance and the response to treatment. A prospective study is warranted to explore the efficacy of chemotherapy and different TKIs in HER2 mutated lung cancer patients, and a standardized platform to test the mutant alleles should be more convincible.