HER2-mutant Lung Cancers Research Articles

Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer

IntroductionNo definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment. MethodsWe retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS). ResultsSixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 – 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0–22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21–34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2–23.9; p = 0.019). ConclusionChemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.

3D layered co-culture model enhances Trastuzumab Deruxtecan sensitivity and reveals the combined effect with G007-LK in HER2-positive non-small cell lung cancer

Human epidermal growth factor receptor 2 (HER2) aberrations are observed in various cancers. In non-small cell lung cancer, genetic alterations activating HER2, mostly exon 20 insertion mutations, occur in approximately 2–4% of cases. Trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate has been approved as the first HER2-targeted drug for HER2-mutant lung cancer. However, some cases are not responsive to T-DXd and the primary resistant mechanism remains unclear. In this study, we assessed sensitivity to T-DXd in JFCR-007, a patient-derived HER2-mutant lung cancer cell line. Although JFCR-007 was sensitive to HER2 tyrosine kinase inhibitors, it showed resistance to T-DXd in attachment or spheroid conditions. Accordingly, we established a three-dimensional (3D) layered co-culture model of JFCR-007, where it exhibited a lumen-like structure and became sensitive to T-DXd. In addition, an in-house inhibitor library screening revealed that G007-LK, a tankyrase inhibitor, was effective when combined with T-DXd. G007-LK increased the cytotoxicity of topoisomerase-I inhibitor, DXd, a payload of T-DXd and SN-38. This combined effect was also observed in H2170, an HER2-amplified lung cancer cell line. These results suggest that the proposed 3D co-culture system may help in evaluating the efficacy of T-DXd and may recapitulate the tumor microenvironment.

Population pharmacokinetics of trastuzumab deruxtecan (T-DXd) in subjects with HER2-mutant and HER2-overexpressing non-small cell lung cancer (NSCLC).

e20537 Background: T-DXd is a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, approved globally at the dose of 5.4 mg/kg in HER2-positive or HER2-low breast cancer (BC) and HER2-mutant (HER2m) NSCLC1,2. The aim of the analysis was to characterize the populaton pharmacokinetics (PopPK) of T-DXd and its released payload, deruxtecan (DXd), in HER2m or HER2-overexpressing (HER2-OE) NSCLC subjects using data across tumor types (BC, NSCLC and others) from 12 Phase 1 to 3 studies with T-DXd doses ranging from 0.8-8.0 mg/kg. Methods: Analysis wasperformed using nonlinear mixed-effects modeling methods in NONMEM (version 7.4.3), similar to the previous analysis in HER2-positive BC1. Covariate effects were explored on the PK parameters of T-DXd and DXd. Results: Analysis included data across 1822 subjects, including 346, 1128, and 348 subjects with NSCLC, BC, and other cancers, respectively. The PK of T-DXd and DXd were adequately described by a PopPK model, judging by standard model diagnostics3. Covariate effects on T-DXd and DXd steady-state area under the concentration-time curve (AUC) were not clinically meaningful (within 0.8 to 1.25 AUC ratio interval for tested covariate level versus reference), except for subjects with high body weight (e.g., 90 kg; 95th percentile) showing a 31% and 37% higher T-DXd and DXd AUC, respectively, relative to typical subject with 58 kg body weight (median).The T-DXd and DXd AUC were also similar across subjects with BC, HER2m or HER2-OE NSCLC, with the same T-DXd dose. T-DXd and DXd AUC in NSCLC subjects were similar across subjects with mild hepatic or mild or moderate renal impairment (vs. normal counterparts), region (Asia, North America, Europe, and rest of the world), and race-country (Asian-Japan, Asian-Non-Japan, and Non-Asian) groups. Conclusions: T-DXd and DXd exposures were similar across subjects with BC and HER2m or HER2-OE NSCLC, as well as across hepatic function, renal function, region, and race-country groups within NSCLC supporting the use of 5.4 mg/kg dose (approved dose in BC) in HER2m or HER2-OE NSCLC from PK perspective. Reference: Enhertu [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2022. Enhertu [summary of product characteristics]. Daiichi Sankyo Europe GmbH, Munich; 2022 Yin O et al. Clin Pharmacol Ther. 2021;109(5):1314-1325. Clinical trial information: NCT04644237 , NCT03505710 .

MA13.10 Trastuzumab Deruxtecan in Patients with HER2-Mutant Metastatic Non-Small Cell Lung Cancer: Primary Results of DESTINY-Lung02

MA13.10 Trastuzumab Deruxtecan in Patients with HER2-Mutant Metastatic Non-Small Cell Lung Cancer: Primary Results of DESTINY-Lung02

High risks adverse events associated with trastuzumab emtansine and trastuzumab deruxtecan for the treatment of HER2-positive/mutated malignancies: a pharmacovigilance study based on the FAERS database

ABSTRACT Background T-DM1 and T-DXd are two promising antibody-drug conjugates for treating advanced HER2-positive breast cancer and HER2-mutated lung cancer. Understanding the differences in the adverse events (AEs) profile of both drugs may help clinicians make an appropriate treatment decision. Research design and methods All data obtained from the FDA Adverse Event Reporting System (FAERS) database from Q1 2004 to Q3 2022 underwent disproportionality analysis and Bayesian analysis to detect and assess the AE signals of T-DM1 and T-DXd for comparison. Results A total of 2,113 and 1,269 AE reports associated with T-DM1 and T-Dxd, respectively, were retrieved from FAERS database, in which, respondents were mostly elderly women. Their statistical differences (p < 0.001), poses high incidence of thrombocytopenia, including cardiotoxicity (p < 0.05) for T-DM1, while myelosuppression, interstitial lung disease (ILD), and pneumonitis for T-DXd. Splenomegaly, nodular regenerative hyperplasia, hepatic cirrhosis, portal hypertension, neuropathy peripheral, and spider nevus, are particular to T-DM1. Similarly, febrile neutropenia, pneumocystis jirovecii pneumonia, neutrophil count decreased, and KL-6 increased, are unique to T-DXd. Conclusions T-DXd is more likely to induce ILD/pneumonia and myelosuppression than T-DM1, whereas T-DM1 has higher risk of hepatotoxicity, cardiotoxicity, and thrombocytopenia than T-DXd. T-DM1-related hepatotoxicity may need redefinition. Clinicians may need to balance the benefits and risks of antibody-drug conjugates treatment for certain patients.

LBA55 Trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutant metastatic non-small cell lung cancer (NSCLC): Interim results from the phase 2 DESTINY-Lung02 trial

In DESTINY-Lung01, T-DXd 6.4 mg/kg (a HER2-targeting antibody-drug conjugate) showed durable activity in pts with previously treated HER2-mutant (HER2m) NSCLC (Li et al. N Engl J Med 2022). DESTINY-Lung02 assessed the benefit-risk profile of T-DXd doses 5.4 and 6.4 mg/kg in pts with previously treated HER2m metastatic NSCLC (NCT04644237). Here we report interim results for DESTINY-Lung02. This was a blinded, randomized, non-comparative, phase 2 trial. Pts were randomized 2:1 to T-DXd 5.4 or 6.4 mg/kg Q3W, respectively. The primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR) by BICR, confirmed disease control rate (cDCR) and safety. The prespecified early cohort (PEC; pts randomized ≥4.5 months [mo] before data cutoff [DCO]) was defined to include pts with postbaseline tumor assessments. The safety analysis set (SAS) was all randomized pts who received ≥1 dose of T-DXd. The study was not powered to statistically compare the doses. At DCO (03/24/2022), 52 and 28 pts in the PEC were randomized and 101 and 50 pts in the SAS were treated with T-DXd 5.4 or 6.4 mg/kg, respectively. Median follow-up duration was 5.6/5.4 mo and 3.8/3.9 mo. In the PEC, cORR was 53.8% (95% CI, 39.5-67.8%) and 42.9% (95% CI, 24.5-62.8%) in pts receiving T-DXd 5.4 or 6.4 mg/kg, respectively (Table). Treatment-emergent adverse events (TEAEs) were higher with T-DXd 6.4 mg/kg vs 5.4 mg/kg in the PEC and SAS (median treatment duration: 4.7/5.5 mo and 3.3/3.7 mo). In the SAS, any-grade adjudicated drug-related interstitial lung disease occurred in 5.9% and 14.0% of pts receiving T-DXd 5.4 or 6.4 mg/kg, respectively.Table: LBA55T-DXd in HER2m NSCLCResponse (PEC)5.4 mg/kg n = 526.4 mg/kg n = 28cORR†, n (%)95% CI28 (53.8)39.5-67.812 (42.9)24.5-62.8Complete response (CR)1 (1.9)1 (3.6)Partial response (PR)27 (51.9)11 (39.3)Stable disease (SD)19 (36.5)14 (50.0)Progressive disease2 (3.8)1 (3.6)Nonevaluable (NE)3 (5.8)1 (3.6)cDCR‡, n (%)95% CI47 (90.4)79.0-96.826 (92.9)76.5-99.1DoR, median (95% CI), moNE (4.2-NE)5.9 (2.8-NE)Safety (SAS), %n = 101n = 50Drug-related TEAEsAll-grade92.1100Grade ≥331.758.0Assoc. w/Dose Reduction9.926.0Drug Discontinuation7.916.0Dose Interruption13.930.0†Proportion of pts w/ confirmed CR or PR by BICR.‡Proportion of pts w/ confirmed CR, PR, or SD by BICR. Open table in a new tab †Proportion of pts w/ confirmed CR or PR by BICR. ‡Proportion of pts w/ confirmed CR, PR, or SD by BICR. DESTINY-Lung02 demonstrated clinically meaningful activity with T-DXd 5.4 mg/kg and 6.4 mg/kg in pts with previously treated HER2m NSCLC in the PEC, with a more favorable safety profile with T-DXd 5.4 mg/kg.

SY20-3 Development of treatment for HER2 or EGFR exon 20 insertion mutation-driven NSCLC

Mutations in human epidermal growth factor receptor 2 (ERBB2; HER2) are the major reason for the development of approximately 3% of non-squamous non-small cell lung cancer (NSCLC) cases, of which about half of the cases are due to insertions in exon 20. Patients with these mutations generally tend to be younger, female, and have a poor prognosis. To date, various drugs have been tested as targeted therapies for HER2-mutated NSCLC, but no drugs have been approved. Our phase 2 trial of trastuzumab-emtansine (T-DM1), an anti-HER2 antibody-drug conjugate, initially showed some response in HER2-mutated lung cancer.

Afatinib combined with anlotinib in the treatment of lung adenocarcinoma patient with novel HER2 mutation: a case report and review of the literature

BackgroundHER2 is a member of the ERBB family of receptor tyrosine kinases, and HER2 mutations occur in 1–4% of non-small cell lung cancer (NSCLC) as an oncogenic driver mutation. We found a rare mutation of HER2 p.Asp769Tyr in NSCLC.Case presentationWe presented a case of a 68-year-old nonsmoking male patient with brain metastasis from lung adenocarcinoma harboring a rare mutation of HER2 p.Asp769Tyr. After multiple lines of treatment, he obtained a durable response (10 months) to afatinib and anlotinib.ConclusionWe reported for the first time that afatinib and anlotinib have successfully treated lung adenocarcinoma with HER2 p.Asp769Tyr mutation. This finding can provide an insight into the optimal treatment of lung adenocarcinoma patients with novel mutations. Additionally, we summarized the efficacy of targeted therapy for HER2 mutant lung cancer in this article.

Activity and mechanism of acquired resistance to tarloxotinib in HER2 mutant lung cancer: an in vitro study.

BackgroundHER2 (ERBB2) activating mutations are present in 2–3% of lung adenocarcinomas; however, no targeted therapy is approved for HER2-altered lung cancers. A novel pan-HER inhibitor, tarloxotinib, is designed to release the active form (tarloxotinib-E) under hypoxic conditions in tumor tissues after being administered as a prodrug. Following the evaluation of the in vitro activity of tarloxotinib-E in HER2-mutant cells, we explored the mechanisms of resistance to tarloxotinib-E in these cells.MethodsGrowth inhibitory assays were performed with tarloxotinib-E and its prodrug using Ba/F3 cells expressing one of six HER2 mutations or wild-type (WT) HER2, in addition to H1781 cells with HER2 exon 20 insertions. Resistant clones were established from N-ethyl-N-nitrosourea (ENU)-treated HER2-mutant Ba/F3 cells and H1781 cells by chronic exposure to tarloxotinib-E.ResultsTarloxotinib-E showed potent activity against HER2-mutant Ba/F3 cells and H1781 cells. Furthermore, the half maximal inhibitory concentration (IC50) of tarloxotinib (inactive form) for WT HER2 was 180 times higher than that of tarloxotinib-E, indicating a wide therapeutic window of tarloxotinib. We established 30 resistant clones with secondary mutations of HER2 by ENU mutagenesis, all of which harbored C805S in exon 20. In the analysis of H1781 cells that acquired resistance to tarloxotinib-E, we found that increased HER3 expression was the molecular mechanism of tarloxotinib-E resistance.ConclusionsTarloxotinib-E exhibited potent activity against cell line models with HER2 mutations. We identified a secondary C805S HER2 mutation and HER3 overexpression as the mechanisms of acquired resistance to tarloxotinib-E.

MA11.03 Trastuzumab Deruxtecan in HER2-Mutated Metastatic Non-Small Cell Lung Cancer (NSCLC): Interim Results of DESTINY-Lung01

Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. In a phase 1 trial, patients with HER2-mutated non-small cell lung cancer (NSCLC) who received T-DXd had a confirmed objective response rate (ORR) of 72.7% (8/11) (Tsurutani et al, Cancer Discov 2020). DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase 2 study of T-DXd in patients with non-squamous NSCLC overexpressing HER2 or containing a HER2-activating mutation. We report data for the cohort with HER2-activating mutations after a median follow-up of 8.0 mo (range, 1.4-14.2 mo). This abstract was previously presented at ASCO 2020. Patients were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was confirmed ORR (complete response [CR] + partial response [PR]) by independent central review (ICR). Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety. Updated data to be presented at the meeting. At data cutoff (25 Nov 2019), 42 patients (64.3% female) had received T-DXd. Median age was 63.0 years (range, 34-83 years; < 65 y, 59.5%); 45.2% had CNS metastases; ECOG performance status was 0 in 23.8% of patients and 1 in 76.2%. HER2 mutations were predominantly in the kinase domain (90.5%). Most patients (90.5%) had prior platinum-based chemotherapy and 54.8% had anti–PD-1 or –PD-L1 treatment. The median number of prior treatment lines was 2 (range, 1-6). Median treatment duration was 7.75 mo (range, 0.7-14.3 mo); 45.2% of patients remained on treatment. Confirmed ORR by ICR among the 42 patients was 61.9% (95% CI, 45.6%-76.4%). At data cutoff, median DOR was not reached, and 16 of 26 responders remained on treatment. DCR was 90.5% (95% CI, 77.4%-97.3%) and estimated median PFS was 14.0 mo (95% CI, 6.4-14.0 mo). All patients (42/42) had treatment-emergent adverse events (TEAEs); 64.3% were grade ≥ 3 (52.4% drug-related), including decreased neutrophil count (26.2%) and anemia (16.7%). There were 5 cases (11.9%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (all grade 2, no grade ≥ 3) and 1 case of grade 1 ILD is pending adjudication. TEAEs led to dose interruption in 25 patients (59.5%), dose reduction in 16 patients (38.1%), and treatment discontinuation in 10 patients (23.8%). T-DXd demonstrated promising clinical activity with high ORR and durable responses in patients with HER2-mutated NSCLC. The safety profile was generally consistent with previously reported studies.

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): Interim results of DESTINY-Lung01.

9504 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. In a phase I trial, patients (pts) with HER2-mutated NSCLC who received T-DXd had a confirmed objective response rate (ORR) of 72.7% (8/11) (Tsurutani et al, WCLC 2018). DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase II study of T-DXd in pts with non-squamous NSCLC overexpressing HER2 or containing a HER2-activating mutation. We report data for the cohort with HER2 mutations after a median follow-up of 8.0 mo (range, 1.4-14.2 mo). Methods: Pts were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was confirmed ORR (complete response [CR] + partial response [PR]) by ICR. Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety. Results: At data cutoff (25 Nov 2019), 42 pts (64.3% female) had received T-DXd. Median age was 63.0 years (range, 34-83 years; &lt; 65 y, 59.5%); 45.2% had central nervous system metastases; ECOG performance status was 0 in 23.8% of pts and 1 in 76.2%. HER2 mutations were predominantly in the kinase domain (90.5%). Most pts (90.5%) had prior platinum-based chemotherapy and 54.8% had anti–PD-1 or –PD-L1 treatment; median number of prior treatment lines was 2 (range, 1-6). Median treatment duration was 7.75 mo (range, 0.7-14.3 mo); 45.2% of pts remained on treatment. Confirmed ORR by ICR among the 42 pts was 61.9% (95% CI, 45.6%-76.4%); median DOR was not reached at data cutoff; 16 of 26 responders remained on treatment at data cutoff; DCR was 90.5% (95% CI, 77.4%-97.3%); estimated median PFS was 14.0 mo (95% CI, 6.4-14.0 mo). All pts (42/42) had treatment-emergent adverse events (TEAEs); 64.3% were grade ≥ 3 (52.4% drug-related), including decreased neutrophil count (26.2%) and anemia (16.7%). There were 5 cases (11.9%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (all grade 2, no grade ≥ 3) and 1 case of grade 1 ILD is pending adjudication. TEAEs led to dose interruption in 25 pts (59.5%), dose reduction in 16 pts (38.1%), and treatment discontinuation in 10 pts (23.8%). Conclusions: T-DXd demonstrated promising clinical activity with high ORR and durable responses in pts with HER2-mutated NSCLC. The safety profile was generally consistent with previously reported studies. Clinical trial information: NCT03505710 .

The efficacy of afatinib in patients with HER2 mutant non-small cell lung cancer: a meta-analysis.

BackgroundErb-b2 receptor tyrosine kinase 2 (ErbB2/HER2) mutation has been found in approximately 2–4% of non-small cell lung cancer (NSCLC) patients and has been identified as one of carcinogenic mutations. Afatinib, a member of irreversible HER family inhibitor, has been investigated by a number of literatures, yet whose therapeutic efficiency remains uncertain in NSCLC with HER2 mutation. To elucidate the clinical efficacy and safety of afatinib in treating HER2 mutant NSCLC, we integrated and reanalyzed the data from current available studies.MethodsWe conducted a systematic literature search for published articles regarding afatinib treating HER2-mutant lung cancer. Eight studies met the inclusion and exclusion criteria. The main outcomes were the objective response rate (ORR) and disease control rate (DCR).ResultsNinety-five patients with HER2 mutations were identified from eight studies. The pooled ORR was 21% (95% CI: 11–34%) and the pooled DCR was 66% (95% CI: 57–76%). The patients harboring A775-G776ins YVMA mutation, the most common subtype of HER2 exon 20 mutation, derived greater clinical benefit. Most adverse events were grade 1–2, except a case of fatal acute renal injury, possibly related to afatinib.ConclusionsAfatinib monotherapy demonstrated frustrating anti-tumor activity with tolerable toxicity in HER2 mutant NSCLC. Based on current available data, we do not recommend the regular application of afatinib in NSCLC with HER2 mutations unless the response heterogeneity with specific genomic variant of HER2 mutation was further clarified.

Conformational Landscapes of HER2 Exon 20 Insertions Explain Their Sensitivity to Kinase Inhibitors in Lung Adenocarcinoma.

HER2 exon 20 insertion (ex20ins) is one of the most intractable problems in lung cancer. Most ex20ins are resistant to available EGFR or pan-HER tyrosine kinase inhibitors (TKIs), with the exception of a few mutants. However, the mechanism for TKI response and resistance of HER2 ex20ins remains poorly understood. Next-generation sequencing-based genomic profiling data of 4139 patients with lung cancer were interrogated for HER2 ex20ins. Structural modeling and molecular dynamics simulations of common HER2 ex20ins were carried out to provide insights into the mechanism of activation and response heterogeneity of ex20ins. Molecular docking was performed to predict affinity to TKIs. Therapeutic decisions for patients were made on the basis of the results of genomic profiling. From 155 HER2-mutant lung cancer cases, Y772_A775dup and G778_P780dup were identified in 74 (47.7%) and 18 (11.6%) cases, respectively. Molecular dynamics simulations revealed that HER2 ex20ins led to ligand-independent kinase activation by changing the conformational landscape of HER2 kinase and restricting kinase conformation in the active state. G778_P780dup had a three-amino acid extension in the αC-β4 loop and retained the HER2-characteristic G776 and G778. Compared with Y772_A775dup, it had less restriction on kinase conformational sampling and higher affinity to afatinib, dacomitinib, pyrotinib, and poziotinib. Treating lung adenocarcinomas carrying G778_P780dup with these inhibitors led to sustained tumor responses in six of the 10 patients. The kinase conformational landscape dictated by the length of the αC-β4 loop and residues at HER2 776 and 778 position explains TKI sensitivity in ex20ins. This finding could guide therapeutic decisions with currently available therapies and future drug development strategies.

Clinical outcomes of patients with HER2-mutant advanced lung cancer: chemotherapies versus HER2-directed therapies.

Background:Lung cancer is now the leading cause of cancer mortality worldwide for both men and women. In non-small cell lung cancer (NSCLC), matching a specifically targeted drug to the identified driver mutation in each patient resulted in dramatically improved therapeutic efficacy, often in conjunction with decreased toxicity. Mutations in HER2 have been identified as an oncogenic driver gene for NSCLC. This retrospective study was conducted to better understand the clinical outcomes of advanced lung cancer patients harboring HER2 mutations treated with chemotherapies and HER2-targeted agents, as well as the optimal clinical choice.Methods:Patients who were diagnosed with advanced lung cancer (stage IIIB/IV) and had undergone molecular testing at Zhongshan Hospital, Fudan University, Shanghai, China from April 2016 to December 2018 were reviewed. For patients that had HER2 mutant advanced lung cancer, we analyzed their clinical and molecular features and clinical outcomes, including overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and objective response rate (ORR).Results:We identified 44 patients harboring HER2 mutations. Their median age was 56 years, with the majority being women (n = 24), never smokers (n = 32), and having the adenocarcinoma genotype (n = 42). Amongst the HER2 mutations present, a 12 base pair in-frame insertion in exon 20 with p.771insAYVM was the most common subtype in patients with known detail variants of HER2 mutation (9/27). The median OS from the date of advanced disease diagnosis was 9.9 months with 24 deaths, and a median follow-up of 12.7 months for survivors. For patients with a known HER2 exon 20 insertion mutation, OS tended to be superior (though not statistically) in the first-line HER2-TKI group to that in the group receiving chemotherapy (10.8 versus 9.8 months, p = 0.40). However, patients that received first-line chemotherapy had a median PFS of 5.9 months, numerically longer than that of the HER2-TKI group (4.6 months, p = 0.63). Patients who received HER2-targeted therapy as first-line therapy had an improved OS (10.8 versus 10.1 months, p = 0.30) and PFS (4.6 versus 2.8 months, p = 0.36) relative to those who received HER2-targeted therapy as subsequent-line therapy, although they did not meet the threshold for statistical significance. Furthermore, patients with AYVM mutation were associated with poor clinical outcomes.Conclusion:Pemetrexed-based chemotherapy remains an important component of care for patients with HER2-mutant NSCLC. HER2-TKI given as an initial therapy may bring more clinical benefits than when given as a subsequent-line therapy. Refining the patient population based on patterns of HER2 variants may help improve the efficacy of anti-HER2 treatment in lung cancer. Developing highly effective and tolerable HER2-targeted agents is urgently needed for this population.

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

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 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. 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. 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. 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.

P2.14-10 Identification of Frequent, Activating HER2 Mutations and HER2 Inhibitor Response and Resistance in Canine Lung Cancer

Naturally occurring primary canine lung cancers share clinical and pathologic features with human never-smoker lung cancer, but their genetic and biologic underpinnings have been unknown. We mapped the genomic landscape of canine lung cancer, discovering somatic HER2 (ERBB2) mutations in ∼38% of canine pulmonary adenocarcinomas (cPACs). We describe our genomic findings, effects of HER2 mutations on cell signaling and HER2 inhibitor response/resistance, and results of pharmacokinetic (PK) studies of the HER2 inhibitor neratinib in healthy dogs. We performed multi-platform genomic analysis of 92 primary canine lung tumors or cell lines. We evaluated HER2 signaling by Western blot. Neratinib and lapatinib responses were assessed in HER2-mutant and wild-type cPAC cell lines in vitro. HER2-mutant cell lines were continuously treated with IC50 neratinib doses to select for drug resistance, then evaluated for resistance mutations. Neratinib tolerability and PK were evaluated in healthy, mixed-breed, middle-aged dogs given a single 6 mg/kg oral neratinib dose with or without maropitant citrate or loperamide. Plasma samples for PK were collected pre-dose and timepoints from 0.5-24h after dosing. Canine lung cancers exhibited low tumor mutation burden. HER2 was the most commonly mutated gene in cPACs, occurring in ∼38%, but was absent from canine adenosquamous or squamous cell carcinomas. HER2 hotspot V659E transmembrane domain (TMD) mutations were most common and comparable to activating TMD mutations in human cancer. HER2 V659E correlated with constitutive phosphorylation of Akt in cPAC cell lines. HER2 V659E lines displayed hypersensitivity to neratinib and lapatinib relative to wild-type lines. Continuous treatment of HER2-mutant cell lines led to rapid development of resistance. Characterization of resistance-driving alterations is ongoing, as are efficacy studies in mouse xenografts. A dose of 6 mg/kg neratinib in healthy dogs showed that neratinib was tolerable and achieved therapeutic levels from IC50 studies. Evaluation of neratinib tolerability and efficacy in dogs bearing HER2-mutant lung cancer is ongoing. HER2 TMD mutations are common in otherwise low-mutation-burden primary canine lung cancers. They confer constitutive HER2 signaling and HER2 inhibitor response in cell lines. Dosing and tolerability studies in healthy dogs have shown that therapeutically relevant doses are achievable. Study of HER2 inhibitor response/resistance in cell lines and mouse xenografts is ongoing as is clinical evaluation of neratinib activity in dogs with spontaneous lung cancer. These data offer immediate diagnostic and therapeutic opportunities for pet dogs and bear implications for comparative understanding of human never-smoker lung cancers and other HER2-mutant cancers.

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

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. 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). 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 (1.6years; P<.001) or KRAS-mutant lung cancers (1.1years; P<.001) than patients with EGFR-mutant lung cancers (3.0years). Brain metastases occurred in 47% of patients with HER2-mutant lung cancers, which imparted shorter OS (HR, 2.7; P<.001). 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.

Abstract 3705: Identification of frequent HER2 activating mutations in canine primary pulmonary adenocarcinoma

Abstract Spontaneous primary canine lung cancers are aggressive malignancies that are increasingly common in dogs. They share clinicopathologic features with human lung cancers in never-smokers, but their genetic underpinnings are unknown. As never-smoker lung cancer incidence increases in humans, a need exists for improved biologic understanding and development of new models to fuel translational research. Here, we describe for the first time the detailed clinical and genetic features of primary canine lung cancers through case review and multi-platform sequencing of 90 primary canine lung tumors and cell lines. We performed multi-platform genomic profiling including whole exome sequencing (WES), amplicon panel-based sequencing of 250 regions of 51 cancer genes, and single nucleotide polymorphism (SNP) array-based analysis of tumors and matched constitutional DNA. We profiled 76 cPAC, 11 canine pulmonary adenosquamous carcinomas (cPASC) and three canine pulmonary squamous cell carcinomas (cPSCC). The median age at the time of diagnosis was 11 year old. The most common affected pure breed was the Labrador retriever (19%). Five cPACs assessed by WES displayed low mutation burden with a median of 64 somatic single nucleotide variants (SNVs), 19 somatic copy number variants (CNVs), and 1 structural variant (SV), and frequent C&amp;gt;T substitutions (80%) at NpCpG trinucleotides, a common mutation signature seen across human and canine cancers. Based on WES and amplicon sequencing, we discovered somatic, coding HER2 (ERRB2) point mutations in 37% of cPAC, but none in cPASC or cPSCC. Additional recurrently mutated genes in cPAC included CDKN2A/B (~40%), TP53 (~12%), K/HRAS (~7%), SMAD4 (~5%), and PTEN (~5%). In cPASC, KRAS and TP53 were the most frequently mutated genes (18% each). In cPSCC, no recurrently mutated genes were identified, but individual somatic coding mutations were found in BRAF and PTPN11. The majority (93%) of HER2 mutations were hotspot V659E, located on the transmembrane domain (TMD), and comparable to activating mutations at this same site in human cancer. We were able to detect this mutation not only in biopsied tumors, but also in the plasma of 33% (2/6) of dogs with localized V659E-positive tumors. Other somatic HER2 mutations identified were similarly located in the HER2 juxtamembrane domain and TMD including A664T and K676E. HER2 point mutations occurred in the absence of significant focal amplification (assessed by WES and SNP array) or overexpression (assessed by qRT-PCR and IHC). We also showed that HER2 mutation correlated with constitutive phosphorylation of Akt in cPAC cell lines. Furthermore, HER2 V659E-mutant lines displayed hypersensitivity to the HER2 kinase inhibitors neratinib (IC50, 23nM) and lapatinib (IC50, 168nM) relative to HER2 wild-type cell lines (IC50, &amp;gt;2500nM). These data bear implications for comparative understanding of HER2-mutant lung cancer across species. Citation Format: Gwendolen Lorch, Karthigayini Sivaprakasam, Victoria Zissman, Nieves Perdigones, Tania Contente-Cuomo, Alexandra Nazareno, Salvatore Facista, ShukMei Wong, Winnie Liang, Joseph M. Amann, Sara L. Sinicropi-Yao, Michael J. Koenig, Krista La Perle, Timothy G. Whitsett, Muhammed Murtaza, Jeffrey Trent, David P. Carbone, William P. Hendricks. Identification of frequent HER2 activating mutations in canine primary pulmonary adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3705.

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

IntroductionHER2 mutations occur in 1–3% of lung adenocarcinomas. With increasing use of next-generation sequencing at diagnosis, more patients with HER2-mutant tumours present for treatment. Few data are available to describe the clinical course and outcomes of these patients when treated with afatinib, a pan-HER inhibitor. MethodsWe identified patients with metastatic or recurrent HER2-mutant lung adenocarcinomas treated with afatinib among seven institutions across Europe, Australia, and North America between 2009 and 2017. We determined the partial response rate to afatinib, types of HER2 mutations, duration of response, time on treatment, and survival. ResultsWe collected information on 27 patients with stage IV or recurrent HER2-mutant lung adenocarcinomas treated with afatinib. Of 23 patients evaluable for response, three partial responses were noted (13%, 95% confidence interval [CI] 4–33%). In addition, 57% of patients (13/23) had stable disease, and 30% (7/23) had progressive disease. We documented partial responses in patients with HER2 exon 20 insertions, including two with YVMA insertion and one with VAG insertion. Two patients with partial responses were previously treated with trastuzumab and pertuzumab. Median duration of response to afatinib was 6 months (range 5–10); median time on treatment was 3 months (range 1–30) and median overall survival from the date of diagnosis of metastatic or recurrent disease was 23 months (95% CI 18–53 months). ConclusionsAfatinib is modestly active in patients with HER2-mutant lung adenocarcinomas, including responses after progression on prior HER2-targeted therapies. However, investigations into the biology of HER2-mutant lung adenocarcinomas and development of better HER2-directed therapies are warranted.

P088 Distribution of Different HER2 Mutations and Their Impact on Clinical Responses to Afatinib in HER2-Mutant Lung Cancer

P088 Distribution of Different HER2 Mutations and Their Impact on Clinical Responses to Afatinib in HER2-Mutant Lung Cancer