Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study

Lai, W. Victoria; Lebas, Louisiane; Barnes, T.; Milia, Julie; Ni, Ai; Gautschi, Oliver; Peters, Solange; Ferrara, Roberto; Kavanagh, John; Sabari, Joshua K.; Clarke, Stephen; Pavlakis, Nick; Drilon, Alexander; Rudin, Charles M.; Arcila, Maria E.; Leighl, Natasha B.; Shepherd, Frances A.; Kris, Mark G.; Mazières, Julien; Li, Bob T.

doi:10.1016/j.ejca.2018.11.030

Cited by 67 publications

(54 citation statements)

References 27 publications

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“…The demographics and outcomes of the patients in our study are in line with previously reported studies of HER2 ‐mutant lung cancers . Consistent with previously published literature, our data show that patients with brain metastases were younger at diagnosis than patients without brain metastases, regardless of driver mutations .…”

Section: Discussionsupporting

confidence: 91%

“…The demographics and outcomes of the patients in our study are in line with previously reported studies of HER2-mutant lung cancers. 3,4,33,34 Consistent with previously published literature, our data show that patients with brain metastases were younger at diagnosis than patients without brain metastases, regardless of driver mutations. 35 We found that the likelihood of having brain metastases at the baseline diagnosis in patients with HER2-mutant lung cancers was comparable to the frequency in patients with KRAS-mutant lung cancers and trended toward being lower than the incidence in patients with EGFR-mutant lung cancers.…”

Section: Figurementioning

confidence: 65%

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Frequency and outcomes of brain metastases in patients with HER2‐mutant lung cancers

Offin

Feldman

et al. 2019

Cancer

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Background Mutations in human epidermal growth factor receptor 2 (HER2; also known as ERBB2) are found in approximately 2% of lung adenocarcinomas. The frequency and clinical course of brain metastases in this oncogenic subset are ill defined. Methods Baseline and subsequent development of brain metastases was evaluated in consecutive patients with HER2‐mutant (n = 98), epidermal growth factor receptor (EGFR)–mutant (n = 200), and KRAS‐mutant lung cancers (n = 200). Results At metastatic diagnosis, the odds ratio (ORs) for brain metastases was similar for patients whose tumors harbored HER2 mutations (19%) in comparison with patients with KRAS mutations (24%; OR for HER2 vs KRAS, 0.7; P = .33) but lower compared to patients with EGFR mutations (31%; OR for HER2 vs EGFR, 0.5; P = .03). Patients with lung cancer and HER2 mutations developed more brain metastases on treatment than patients with KRAS mutations (28% vs 8%; hazard ratio [HR], 5.2; P < .001) and trended more than patients with EGFR mutations (28% vs 16%; HR, 1.7; P = .06). Patients with HER2 YVMA mutations also developed more brain metastases on treatment than patients with KRAS mutations (HR, 5.9; P < .001). The median overall survival (OS) was shorter for patients with HER2‐mutant (1.6 years; P < .001) or KRAS‐mutant lung cancers (1.1 years; P < .001) than patients with EGFR‐mutant lung cancers (3.0 years). Brain metastases occurred in 47% of patients with HER2‐mutant lung cancers, which imparted shorter OS (HR, 2.7; P < .001). Conclusions These data provide a framework for brain imaging surveillance in patients with HER2‐mutant lung cancers and underpin the need to develop HER2‐targeted agents with central nervous system activity.

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Section: Discussionsupporting

confidence: 91%

Section: Figurementioning

confidence: 65%

Frequency and outcomes of brain metastases in patients with HER2‐mutant lung cancers

Offin

Feldman

et al. 2019

Cancer

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“…Neither of them was effective for A775_G776insYVMA , the predominant HER2 variant in lung cancer. Notably, responses to afatinib in HER2 YVMA insertions have been described in some studies , whereas there also are reports of rapid disease progression after the treatment of afatinib in patients with identical mutations . In our study, two out of 14 patients carrying A775_G776insYVMA stayed on afatinib for more than 6 months.…”

Section: Discussionmentioning

confidence: 50%

Mutation Variants and Co-Mutations as Genomic Modifiers of Response to Afatinib in HER2-Mutant Lung Adenocarcinoma

et al. 2019

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Background Human epidermal growth factor receptor 2 (HER2)‐mutant lung cancer remains an orphan of specific targeted therapy. The variable responses to anti‐HER2 therapies in these patients prompt us to examine impact of HER2 variants and co‐mutations on responses to anti‐HER2 treatments in lung cancer. Patients and Methods Patients with stage IV/recurrent HER2‐mutant lung cancers identified through next‐generation sequencings were recruited from seven hospitals. The study comprised a cohort A to establish the patterns of HER2 variants and co‐mutations in lung cancer and a cohort B to assess associations between HER2 variants, co‐mutations, and clinical outcomes. Results The study included 118 patients (cohort A, n = 86; cohort B, n = 32). Thirty‐one HER2 variants and 35 co‐mutations were detected. Predominant variants were A775_G776insYVMA (49/118, 42%), G778_P780dup (11/118, 9%), and G776delinsVC (9/118, 8%). TP53 was the most common co‐mutation (61/118, 52%). In cohort B, objective response rates with afatinib were 0% (0/14, 95% confidence interval [CI], 0%–26.8%), 40% (4/10, 14.7%–72.6%), and 13% (1/8, 0.7%–53.3%) in group 1 (A775_G776insYVMA, n = 14), group 2 (G778_P780dup, G776delinsVC, n = 10), and group 3 (missense mutation, n = 8), respectively (p = .018). Median progression‐free survival in group 1 (1.2 months; 95% CI, 0–2.4) was shorter than those in group 2 (7.6 months, 4.9–10.4; hazard ratio [HR], 0.009; 95% CI, 0.001–0.079; p < .001) and group 3 (3.6 months, 2.6–4.5; HR, 0.184; 95% CI, 0.062–0.552; p = .003). TP53 co‐mutations (6.317; 95% CI, 2.180–18.302; p = .001) and PI3K/AKT/mTOR pathway activations (19.422; 95% CI, 4.098–92.039; p < .001) conferred additional resistance to afatinib. Conclusion G778_P780dup and G776delinsVC derived the greatest benefits from afatinib among HER2 variants. Co‐mutation patterns were additional response modifiers. Refining patient population based on patterns of HER2 variants and co‐mutations may help improve the efficacy of anti‐HER2 treatment in lung cancer. Implications for Practice Human epidermal growth factor receptor 2 (HER2)‐mutant lung cancers are a group of heterogenous diseases with up to 31 different variants and 35 concomitant genomic aberrations. Different HER2 variants exhibit divergent sensitivities to anti‐HER2 treatments. Certain variants, G778_P780dup and G776delinsVC, derive sustained clinical benefits from afatinib, whereas the predominant variant, A775_G776insYVMA, is resistant to most anti‐HER2 treatments. TP53 is the most common co‐mutation in HER2‐mutant lung cancers. Co‐mutations in TP53 and the PI3K/AKT/mTOR pathway confer additional resistance to anti‐HER2 treatments in lung cancer. The present data suggest that different HER2 mutations in lung cancer, like its sibling epidermal growth factor receptor, should be analyzed independently in future studies.

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“…Among small molecule TKIs, afatinib was most widely used in China in recent years, with PFS ranging from 2.9 to 6 months. 20,[24][25][26][27] Poziotinib, neratinib and pyrotinib had similar PFS, with 4.5-5.5 months, 5.5 and 6.4 months, respectively. 9,28,29 Dacomitinib and Osimertinib had weaker effects on this population, either with a short PFS or being invalid in cell line experiments.…”

Section: Discussionmentioning

confidence: 94%

“…This could mean that trastuzumab or T‐DM1 might be beneficial to a minority of patients. Among small molecule TKIs, afatinib was most widely used in China in recent years, with PFS ranging from 2.9 to 6 months . Poziotinib, neratinib and pyrotinib had similar PFS, with 4.5–5.5 months, 5.5 and 6.4 months, respectively .…”

Section: Discussionmentioning

confidence: 99%

Treatment outcome and clinical characteristics of HER2 mutated advanced non‐small cell lung cancer patients in China

Gao

et al. 2020

Thoracic Cancer

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Background HER2 mutation is found in 1%–2% of lung cancer patients. Studies comparing chemotherapy to HER2‐TKIs are limited. This study aimed to investigate the molecular and clinical patterns of HER2 mutations in advanced non‐small cell lung cancer (NSCLC), and compare the different outcomes between chemotherapy and HER2‐TKIs. Methods Advanced or recurrent non‐small cell lung cancer patients with de novo HER2 mutations (N = 75) were included in this study. Molecular information, clinical features, and treatment outcomes were retrospectively collected from a web‐based patient registry and hospital chart review. Results Between October 2012 and December 2018, 65 patients with in‐frame insertion mutations, eight with point mutations and two with gene amplification were found. The most common subtypes of insertion mutations were A775_G776insYVMA, G776delinsVC, and V777_G778insGSP. HER2 mutated patients were mostly young‐aged, females, never or light smokers, with adenocarcinoma. Chemotherapy achieved better outcomes than HER2‐TKIs (median PFS: 5.5 vs. 3.7 months in the first‐line setting and 4.2 vs. 2.0 months in the second‐line setting, P = 0.001 and 0.031, respectively). In particular for the most common subtype, YVMA insertions, PFS was significantly longer in chemotherapy than HER2‐TKIs both in the first‐line (6.0 vs. 2.6 months, P = 0.008) and the second‐line (4.2 vs. 2.6 months P < 0.001). Conclusions HER2 mutated lung cancer patients were younger, mostly females, never or light smokers, with histologically diagnosed adenocarcinomas. Compared with afatinib, chemotherapy might bring more benefit to HER2 mutated advanced lung cancer patients, especially the most common type of HER2 exon 20 insertions, A775_G776insYVMA subtype. Key points Chemotherapy achieved better outcomes than afatinib for Chinese HER2 mutated advanced NSCLC patients, especially for the most common subtype, YVMA insertions.

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Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study

Cited by 67 publications

References 27 publications

Frequency and outcomes of brain metastases in patients with HER2‐mutant lung cancers

Frequency and outcomes of brain metastases in patients with HER2‐mutant lung cancers

Mutation Variants and Co-Mutations as Genomic Modifiers of Response to Afatinib in HER2-Mutant Lung Adenocarcinoma

Treatment outcome and clinical characteristics of HER2 mutated advanced non‐small cell lung cancer patients in China

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