Treatment Outcome and Clinical Characteristics of HER2 Mutated Advanced Non-Small Cell Lung Cancer Patients in China

Abstract

Background

Say cancer is the emperor of all maladies, lung cancer may be the king of all cancers, with the highest mortality rate and a rather high incidence in both sex. 5-year survival rate of lung cancer was only 19%. In 2019, there will be an estimated 228150 new patients with lung and bronchus tumor in the United States, as estimated deaths of 142670[1]. Non-small cell lung cancer(NSCLC) makes up the major part in lung carcinoma. The battle against NSCLC was a long, tough one until the discovery of small-molecule tyrosine kinase inhibitors (TKIs) in 2000s, regarded as “targeted therapy”. Two decades later, TKIs targeting epidermal growth factor receptors (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) and B-Raf proto-oncogene serine/threonine kinase (BRAF) have now been developed and put into practice[2-5], while those who do not harbor these mutations have a choice between traditional chemotherapy and immunotherapy as standard of care. However, a minority in lung cancer patients are drawing more attention, who have driver mutations other than the forgoing ones, such as RET, HER2 and so on. These patients pitifully cannot benefit from targeted therapies and still struggling with side effects of chemo agents. 

HER2 mutations was identified as a unique mutation in NSCLC. Unlike HER2 gene amplification commonly seen in breast cancer and gastric cancer, HER2 mutations possess a different molecular pattern in lung cancer samples, that is, in-frame insertions in exon 20. According to information from COSMIC websites and published papers, HER2 exon 20 in-frame insertions mainly have four patterns, A775_G776insYVMA, E770_A771insAYVM, P780_Y781insGSP and G776_V777insVGC[6].

In clinical practice, we found HER2 mutated lung cancer patients had dilemmas when choosing their treatment plans: they do harbor driver mutations but cannot take targeted drugs approved by food and drug administration; their counterparts in breast cancer can benefit from HER2 mono-antibodies like trastuzumab while they themselves cannot[7]; guideline-directed suggestions to their treatment were barely written. In real clinical scenario, the treatment varied from chemotherapy to targeted therapy, even immunotherapy. Patients’ compliance to the prescription was depressed because of intolerable side effects or minimal tumor responses. They usually jump from one kind of treatment to another, urging for any hope as a cure, adding on to the already heavy burden of the patient’s family. We clearly recognize that there is a need for investigating which therapy might benefit more for HER2 mutated advanced lung cancer patients.

Data on HER2 mutations in NSCLC is limited. Previous articles focused more on mutation patterns, while lacking information on treatment choice or the relation between therapy and prognosis. We retrospectively summarized information of HER2 mutated advanced NSCLC patients from China and analyzed their molecular patterns, clinical characteristics and treatment outcome.

Methods

Study design

A retrospectively collected, nation-wide study was designed to figure out the clinical features of HER2 mutated advanced non-small cell lung cancer patients, as well as the difference in between two main treatment regimens, chemotherapy and HER2 targeted therapy.

Patients

Between October 2012 and December 2018, information of 75 advanced NSCLC patients with HER2 mutations were collected from a web-based patient registry and hospital chart review, including patients from National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (information of patients’ frequently visited hospitals was presented in Supplementary Table1 S1). Clinicopathological characteristics were collected for analysis including gender, age at diagnosis, smoking history, histologic subtypes, clinical TNM stage, and variables of insertion mutations. Therapeutic outcomes were documented and retrospectively collected. Disease recurrence and survival outcomes were recorded according to follow-up clinic visits or telephone calls. This study was approved by Ethics Committee of National Cancer Center /National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Written informed consent was obtained from all patients.

HER2 Mutant Identifications

HER2 mutant identifications (exon17-26) were performed by next-generation sequencing. Either peripheral blood or tumor samples were used.

Statistical Analysis

The Kaplan-Meier method was used to calculate the curves for PFS. The Cox proportional hazards regression model was used to evaluate the impact of collected clinical variables on PFS. Significant differences were determined by the log-rank test. P value less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS® software, version 22.0 software (IBM Corp., Armonk, NY, USA).

Results

Seventy-five cases were diagnosed with de novo HER2 mutated advanced lung cancer, including 65 with in-frame insertion mutations, 8 with point mutations and 2 with gene amplifications. Among them, one squamous cell lung carcinoma with HER2 amplification were found. There were mainly 3 common subtypes of insertions detected in HER2 exon 20: c.2326_2327insTGT, p.Gly776delinsValCys, simplified as G776VC; c.2313_2324dupATACGTGATGGC, p.Ala775_Gly776insTyrValMetAla, simplified as YVMA; c.2330_2331insGGGCTCCCC, p.Val777_Gly778insGlySerPro, simplified as GSP. Patient number in each subgroup was 13, 38 and 7, respectively. HER2 mutation was mutually exclusive with other driver mutations of lung cancer in most cases, except for two patients harboring EGFR exon20 co-mutations. As Table 1 showed, forty HER2 mutated lung cancer patients also harbored other mutations in next-generation sequencing (NGS) results, of which 31 patients had TP53 co-mutations.

Among 75 patients, females were the majority with only 23 patients were male. Median age was 57 (range from 31 to 78). 21 patients had smoking history, and only 5 of them were heavy smokers. In thirty patients with documentary histological subtype information, half were poorly differentiated, another half were moderately or well differentiated. All patients were advanced or recurrent cancers, with 9 of them were unresectable stage IIIB (locally advanced) patients. Metastasis were also investigated. For 66 stage IV patients, 34 of them had oligometastasis, and metastasis to brain, liver, bone, lung was 12, 5, 22, 25, respectively. All these pre-treatment clinical characteristics were listed in Table2.

For univariate analysis of PFS1 (PFS of first-line treatment), all clinical characters mentioned above were analyzed. None had significant effect on the duration of response to drugs used in the first line setting. Table 3 showed the detailed results.

On treatment analysis, apart from 8 patients without available treatment information and 1 squamous cell lung cancer patient, 66 patients with treatment outcomes were analyzed. The median line of treatment for advanced patients was three. Afatinib, pyrotinib and poziotinib were regarded as one class of treatment named as HER2-TKI therapy. Chemotherapy included pemetrexed and platinum with or without anti-VEGF agents. Others included mono anti-vascular agents such as anlotinib and immune checkpoint inhibitors. Only first and second line treatment outcome were included in analysis. In the first line setting, patients received chemotherapy had longer progression free survival (PFS) than those accepted HER2-TKIs. The median PFS1 of HER2-TKIs and chemotherapy was 3.7 months (95% CI 2.3 to 5.0 months) and 5.5 months (95% CI 4.5 to 6.5 months), p=0.001. Similar difference was seen in the second line treatment as shown in Figure 1a; b. The median PFS2 of chemotherapy and HER2-TKIs was 4.2 months (95% CI 2.2 to 6.3 months) and 2.0 months (95% CI 0.8 to 3.3 months), p=0.031. In subgroup analysis, YVMA, the most common subtype of HER2 exon 20 insertions, possessed similar treatment response patterns compared to the population as a whole. As shown in Figure 2a; b, the median PFS1 for chemotherapy and HER-TKIs was 6.0 months (95% CI 5.3 to 6.8 months) and 2.6 months (95% CI 2.2 to 3.0 months) in YVMA subgroup, p=0.008. And the median PFS2 for chemotherapy and HER-TKIs was 4.2 months (95% CI 2.4 to 6.1 months) and 2.6 months (95% CI 0.1 to 5.1months) in this subgroup, p<0.001. While for non-YVMA insertions, chemotherapy brought 0.8 month longer PFS than HER2-TKIs, but there was no significant difference seen between the two groups (p=0.084). When taken together, survival (PFS1+PFS2) of HER2-TKIs plus chemotherapy were not affected by the sequential of the two agents (p=0.263), but shorter than two lines of chemotherapy as illustrated in Figure 3.

Discussion

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[8]. 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[9]. 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[10]. 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[11]. Another study compared the different responses to first-line chemotherapy, finding that YVMA had a PSF of 0.9 month shorter than the overall[12]. 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[7]. 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[13]. In another cohort involving 7 HER2 exon 20 insertion patients, 5 patients reached partial response or stable disease on T-DM1 treatment[14]. 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.

Conclusions

In conclusion, our study revealed that the most common HER2 mutations in advanced lung cancer were exon 20 insertions. HER2 mutated lung cancer patients were younger, mostly females, never or light smokers, histologically adenocarcinomas dominated. Compared to existed HER2-TKIs, chemotherapy might bring more benefit to HER2 mutated advanced lung cancer, especially the most common type of HER2 exon 20 insertions, A775_G776insYVMA.

Abbreviations

ALK: anaplastic lymphoma kinase; BRAF: B-Raf proto-oncogene serine/threonine kinase; EGFR: epidermal growth factor receptors; HER2: Human epidermal growth factor receptor2; NGS: next-generation sequencing; NSCLC: Non-small cell lung cancers; ORR: Objective response rate; PFS: Progression free survival; RET: Ret Proto-Oncogene; ROS1: ROS proto-oncogene 1 receptor tyrosine kinase; TKIs: tyrosine kinase inhibitors; TNM: Tumor Node Metastasis; TP53: Tumor protein P53; T-DM1: Ado-trastuzumab emtansine; VEGF: vascular endothelial growth factor

Declarations

Ethics, consent and permissions

The study protocol was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (18-070/1648) and informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Authors’ contributions

FX and GY contributed equally in preparing and conducting this research. HX, LY followed the patient survival data. WQ collected part of patient information. JL and YW designed and coordinated the research in the whole process. All authors read and approved the final manuscript.

Acknowledgments

Not Applicable.

References

1. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2019. CA Cancer J Clin 2019, 69(1):7-34.
2. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England journal of medicine 2004, 350(21):2129-2139.
3. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. The New England journal of medicine 2013, 368(25):2385-2394.
4. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB et al: Crizotinib in ROS1-rearranged non-small-cell lung cancer. The New England journal of medicine 2014, 371(21):1963-1971.
5. Planchard D, Besse B, Groen HJM, Souquet PJ, Quoix E, Baik CS, Barlesi F, Kim TM, Mazieres J, Novello S et al: Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. The Lancet Oncology 2016, 17(7):984-993.
6. Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, Juric D, Quinn DI, Moreno V, Doger B et al: HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 2018, 554(7691):189-194.
7. Gatzemeier U, Groth G, Butts C, Van Zandwijk N, Shepherd F, Ardizzoni A, Barton C, Ghahramani P, Hirsh V: Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Annals of oncology : official journal of the European Society for Medical Oncology 2004, 15(1):19-27.
8. Arcila ME, Chaft JE, Nafa K, Roy-Chowdhuri S, Lau C, Zaidinski M, Paik PK, Zakowski MF, Kris MG, Ladanyi M: Prevalence, Clinicopathologic Associations, and Molecular Spectrum of ERBB2 (HER2) Tyrosine Kinase Mutations in Lung Adenocarcinomas. Clinical Cancer Research 2012, 18(18):4910-4918.
9. Pillai RN, Behera M, Berry LD, Rossi MR, Kris MG, Johnson BE, Bunn PA, Ramalingam SS, Khuri FR: HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer 2017, 123(21):4099-4105.
10. Eng J, Hsu M, Chaft JE, Kris MG, Arcila ME, Li BT: Outcomes of chemotherapies and HER2 directed therapies in advanced HER2-mutant lung cancers. Lung cancer (Amsterdam, Netherlands) 2016, 99:53-56.
11. Peters S, Curioni-Fontecedro A, Nechushtan H, Shih JY, Liao WY, Gautschi O, Spataro V, Unk M, Chih-Hsin Yang J, Lorence RM et al: Activity of Afatinib in Heavily Pretreated Patients With ERBB2 Mutation-Positive Advanced NSCLC: Findings From a Global Named Patient Use Program. J Thorac Oncol 2018, 13(12):1897-1905.
12. Wang Y, Zhang S, Wu F, Zhao J, Li X, Zhao C, Ren S, Zhou C: Outcomes of Pemetrexed-based chemotherapies in HER2-mutant lung cancers. BMC cancer 2018, 18(1):326.
13. Mazieres J, Barlesi F, Filleron T, Besse B, Monnet I, Beau-Faller M, Peters S, Dansin E, Fruh M, Pless M et al: Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Annals of oncology : official journal of the European Society for Medical Oncology 2016, 27(2):281-286.
14. Hotta K, Aoe K, Kozuki T, Ohashi K, Ninomiya K, Ichihara E, Kubo T, Ninomiya T, Chikamori K, Harada D et al: A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non-Small Cell Lung Cancer. J Thorac Oncol 2018, 13(2):273-279.
15. Cappuzzo F, Soo R, Hochmair M, Schuler M, Lam KC, Stehle G, Cseh A, Lorence RM, Linden S, Forman ND et al: Global named patient use program of afatinib in advanced non-small-cell lung carcinoma patients who progressed following prior therapies. Future oncology (London, England) 2018, 14(15):1477-1486.
16. Dziadziuszko R, Smit EF, Dafni U, Wolf J, Wasag B, Biernat W, Finn SP, Kammler R, Tsourti Z, Rabaglio M et al: Afatinib in non-small cell lung cancer with HER2 mutations: results of the prospective, open-label phase II NICHE trial of European Thoracic Oncology Platform (ETOP). J Thorac Oncol 2019.
17. Lai WV, Lebas L, Barnes TA, Milia J, Ni A, Gautschi O, Peters S, Ferrara R, Plodkowski AJ, Kavanagh J et al: Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study. European Journal of Cancer 2019, 109:28-35.
18. Liu Z, Wu L, Cao J, Yang Z, Zhou C, Cao L, Wu H, Shen H, Jin M, Zhang Y et al: Clinical characterization of ERBB2 exon 20 insertions and heterogeneity of outcomes responding to afatinib in Chinese lung cancer patients. OncoTargets and therapy 2018, 11:7323-7331.
19. Oh IJ, Hur JY, Park CK, Kim YC, Kim SJ, Lee MK, Kim HJ, Lee KY, Lee JC, Choi CM: Clinical Activity of Pan-HER Inhibitors Against HER2-Mutant Lung Adenocarcinoma. Clinical lung cancer 2018, 19(5):e775-e781.
20. Wang Y, Jiang T, Qin Z, Jiang J, Wang Q, Yang S, Rivard C, Gao G, Ng TL, Tu MM et al: HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib. Annals of oncology : official journal of the European Society for Medical Oncology 2019, 30(3):447-455.
21. Kris MG, Camidge DR, Giaccone G, Hida T, Li BT, O'Connell J, Taylor I, Zhang H, Arcila ME, Goldberg Z et al: Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. Annals of oncology : official journal of the European Society for Medical Oncology 2015, 26(7):1421-1427.
22. Liu S, Li S, Hai J, Wang X, Chen T, Quinn MM, Gao P, Zhang Y, Ji H, Cross DAE et al: Targeting HER2 Aberrations in Non-Small Cell Lung Cancer with Osimertinib. Clinical cancer research : an official journal of the American Association for Cancer Research 2018, 24(11):2594-2604.

Tables

Table 1 co-mutation patterns of HER2 mutated lung cancer

Table 1. Forty advanced lung cancer patients who harbored more than one mutation were included in this table (HER2 mutations: a: point mutation; b: YVMA; c: G776VC; d: GSP; e: others). “Q” represented mutations found in that gene. The most frequently mutated gene was TP53 mutation, with 77.5% patients harboring.

Table 2 Clinical characteristics of HER2 mutated advanced lung cancer patients

Table 2. Clinical characteristics of HER2 mutated advanced and recurrent non-small cell lung cancer patients. If not specifically written, the percentage was calculated by the number of patients in the subgroup divided by the whole.

Table 3 Univariate analysis on clinical features on treatment responses (Cox regression model)

Table 3. Univariate analysis showed no significant impact of all clinical parameters on first-line treatment outcome.