HER2-positive Gastroesophageal Cancer Research Articles

460P Real-world study of ramucirumab and paclitaxel as ≥2nd-line therapy in patients with HER2-positive gastroesophageal cancer

460P Real-world study of ramucirumab and paclitaxel as ≥2nd-line therapy in patients with HER2-positive gastroesophageal cancer

Pembrolizumab Plus Trastuzumab and Chemotherapy for HER2-Positive Gastric or Gastro-oesophageal Junction Adenocarcinoma

he combination of pembrolizumab, and trastuzumab chemotherapy has long been investigated in the treatment of HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. HER2-positive gastric or gastroesophageal junction adenocarcinoma refers to cancers that overexpress the human epidermal growth factor receptor 2 (HER2), which is associated with more aggressive tumor behavior. Pembrolizumab is a monoclonal antibody that targets the programmed cell death protein 1 (PD-1) receptor, a checkpoint protein on immune cells. By blocking PD-1, pembrolizumab helps unleash the immune system to target and attack cancer cells. Trastuzumab is another monoclonal antibody that specifically targets HER2-positive cancer cells. It has been a standard treatment for HER2-positive breast cancer and has been explored in HER2-positive gastric and gastroesophageal junction cancers. Janjigian and colleagues revealed the interim analysis of a randomized, phase 3 KEYNOTE-811 trial which involved 168 medical centers in 20 countries worldwide. They found that compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumors with a PD-L1 combined positive score of 1 or more. They stated that the overall survival follow-up is ongoing and will be reported at the final analysis. Lancet. 2023 Dec 9;402(10418):2197-2208. doi: 10.1016/S0140-6736(23)02033-0.

Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial

Evidence for the efficacy of combined PD-1 and HER2 blockade with chemotherapy on progression-free and overall survival in HER2-positive gastro-oesophageal cancer is scarce. The first interim analysis of the randomised, phase 3 KEYNOTE-811 study showed a superior objective response with pembrolizumab compared with placebo when added to trastuzumab plus fluoropyrimidine and platinum-based chemotherapy. Here, we report results from protocol-specified subsequent interim analyses of KEYNOTE-811. The randomised, phase 3 KEYNOTE-811 trial involved 168 medical centres in 20 countries worldwide. Patients aged 18 years or older with locally advanced or metastatic HER2-positive gastro-oesophageal junction adenocarcinoma, without previous first-line treatment, were randomly assigned (1:1) by an integrated interactive voice-response and web-response system to intravenous pembrolizumab 200 mg or placebo, both to be combined with standard chemotherapy (fluoropyrimidine and platinum-based therapy) plus trastuzumab every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxic effects, or investigator or participant-initiated withdrawal. Randomisation used a block size of four and was stratified by region, PD-L1 status, and chemotherapy. Dual primary endpoints were progression-free and overall survival, analysed by intention to treat. Safety was assessed in all randomly assigned patients who received at least one dose of study treatment according to the treatment received. KEYNOTE-811 is registered with ClinicalTrials.gov (NCT03615326) and is active but not recruiting. Between Oct 5, 2018, and Aug 6, 2021, 698 patients were assigned to pembrolizumab (n=350) or placebo (n=348). 564 (81%) were male and 134 (19%) were female. At the third interim analysis, 286 (82%) of 350 patients in the pembrolizumab group and 304 (88%) of 346 in the placebo group who received treatment had discontinued treatment, mostly due to disease progression. At the second interim analysis (median follow-up 28·3 months [IQR 19·4-34·3] in the pembrolizumab group and 28·5 months [20·1-34·3] in the placebo group), median progression-free survival was 10·0 months (95% CI 8·6-11·7) in the pembrolizumab group versus 8·1 months (7·0-8·5) in the placebo group (hazard ratio [HR] 0·72, 95% CI 0·60-0·87; p=0·0002). Median overall survival was 20·0 months (17·8-23·2) versus 16·9 months (15·0-19·8; HR 0·87 [0·72-1·06]; p=0·084). At the third interim analysis (median follow-up 38·4 months [IQR 29·5-44·4] in the pembrolizumab group and 38·6 months [30·2-44·4] in the placebo group), median progression-free survival was 10·0 months (8·6-12·2) versus 8·1 months (7·1-8·6; HR 0·73 [0·61-0·87]), and median overall survival was 20·0 months (17·8-22·1) versus 16·8 months (15·0-18·7; HR 0·84 [0·70-1·01]), but did not meet prespecified criteria for significance and will continue to final analysis. Grade 3 or worse treatment-related adverse events occurred in 204 (58%) of 350 patients in the pembrolizumab group versus 176 (51%) of 346 patients in the placebo group. Treatment-related adverse events that led to death occurred in four (1%) patients in the pembrolizumab group and three (1%) in the placebo group. The most common treatment-related adverse events of any grade were diarrhoea (165 [47%] in the pembrolizumab group vs 145 [42%] in the placebo group), nausea (154 [44%] vs 152 [44%]), and anaemia (109 [31%] vs 113 [33%]). Compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumours with a PD-L1 combined positive score of 1 or more. Overall survival follow-up is ongoing and will be reported at the final analysis. Merck Sharp & Dohme.

Combining chemotherapy, trastuzumab, and immune-checkpoint inhibitors in HER2-positive gastro-oesophageal cancer

Combining chemotherapy, trastuzumab, and immune-checkpoint inhibitors in HER2-positive gastro-oesophageal cancer

Comparative analysis of the molecular profile and tumor immune microenvironment (TIME) of human epidermal growth factor receptor 2 (HER2) low (L)- versus high (H)-expressing gastroesophageal cancers (GEC).

287 Background: Addition of immune checkpoint blockade to anti-HER2 therapy has improved outcomes in HER2-positive GEC. Anti-HER2 antibody-drug conjugates have shown activity in some HER2-L tumors in other tumor types. We aimed to compare the molecular profile and TIME of HER2-L and HER-H GEC. Methods: 8678 GEC (gastric, GE junction, and esophageal) adenocarcinoma and squamous cell carcinoma samples were analyzed by next-generation sequencing (NGS) of RNA (whole transcriptome, NovaSeq), DNA (592 genes, NextSeq, or whole exome sequencing, NovaSeq), and immunohistochemistry (IHC, Caris Life Sciences, Phoenix, AZ). Cohorts were stratified by IHC HER2 values of 0 (non-expressors), 1-2+ (HER2-L), or 3+ (HER2-H) and compared using X2 or Fisher-Exact. Statistical significance was determined as P-value adjusted for multiple comparisons (q < 0.05). Microenvironment cell population (MCP) counter was used to quantify immune cell infiltration. Results: Tumor were grouped into HER2 non-expressors (N = 5217), L (N = 2660), and H (N = 801). Mutations of TP53 (72% vs 92%) and amplification of MYC (4% vs 7%), CCNE1 (7% vs 12%), CCND3 (2% vs 4%), CDK6 (3% vs 6%), SMARCE1 (2% vs 25%) and RARA (3% vs 24%) were significantly lower in HER2-L compared to HER2-H (q < 0.05). ARID1A (14% vs 9%), PIK3CA (8% vs 3%), KRAS (9% vs 2%), GNAS (2% vs 0.3%), KMT2D (6% vs 1%), CDH1 (5% vs 1%), and ATM (4% vs 1%) mutations were significantly higher in HER2-L compared to HER2-H (q < 0.05). HER2-L was associated with more TMB-H (9.3% vs. 5%; q<0.05), MSI-H (4.7% vs. 0.6%; q<0.05), and a trend towards higher PD-L1 expression than in HER2-H (80.8% vs 76.1%, p < 0.05 but q > 0.05). Immuno-oncology (IO)-related gene expression inversely correlated with HER2 expression with lowest expression of PDCD1LG2, CD274, CTLA4, PDCD1, HAVCR2, CD80, IFNG, LAG3, and CD86 in HER2-H (q < 0.05). HER2-L had significantly higher median immune infiltration of B cells (fold change [FC]: 1.22), T cells (FC: 1.16), CD8+ T cells (FC: 1.56), NK cells (FC: 1.12), neutrophils (FC: 1.10), cytotoxic lymphocytes (FC: 1.36), and myeloid dendritic cells (FC: 1.34), compared to HER2-H (q < 0.05). HER2 non-expressors showed similar immune cell infiltrates compared to HER2-H. HER2-H was associated with lower T-cell inflamed scores and IFN gamma signature when compared to HER2-L and non-expressors (q < 0.05). Conclusions: To our knowledge, this study is the first and largest comparison of molecular profile and TIME in HER2-expressing GEC. We demonstrated distinct molecular and TIME profiles with higher immunogenic profiles in HER-L as compared to HER2-H. IO-related gene expression and TIME cell distribution differences in HER2-H GEC suggest that response to IO and HER2 therapy combinations is likely related to HER2-targeted treatment effect on TIME rather than baseline immunogenicity of the tumor.

HER2-Positive Gastroesophageal Cancers Are Associated with a Higher Risk of Brain Metastasis.

Brain metastasis from gastroesophageal adenocarcinomas (GOCs) is a rare but a devastating diagnosis. Human epidermal growth factor receptor 2 (HER2) is a prognostic and predictive biomarker in GOCs. The association of HER2 with GOC brain metastasis is not known. We performed a retrospective analysis of patients with GOCs with known HER2 status between January 2015 and November 2021. HER2 was assessed on either the primary tumour or metastasis by immunohistochemistry or in situ hybridization. The diagnosis of brain metastasis was made on standard imaging techniques in patients with symptoms or signs. HER2 results were available for 201 patients, with 34 patients (16.9%) HER2 positive. A total of 12 patients developed symptomatic brain metastasis from GOCs, of which 7 (58.3%) were HER2 positive. The development of symptomatic brain metastasis was significantly higher in the HER2-positive GOCs (OR8.26, 95%CI 2.09-35.60; p = 0.0009). There was no significant association of HER2 status and overall survival in patients with brain metastasis. Although the rate of brain metastasis remains low in GOCs, the incidence of symptomatic brain metastasis was significantly higher in patients with HER2-positive tumours.

Abstract 6376: Effect of MET tyrosine kinase inhibitors on MET amplified gastro-esophageal cancer cells

Abstract Background: Many studies have suggested that MET protein overexpression or MET amplification plays a critical role in the progression of gastro-esophageal cancer (GC) and negatively affects survival in patients with GC. However, the criteria used to define overexpression of MET protein have differed among many studies, and in contrast to the initial phase II studies, the phase III trials failed to show any clinical benefit from anti-MET therapies in GCs, even in patients with MET-positive disease. Several studies have used consistent criteria to define MET amplification on FISH, and recent MET inhibitor trials for MET amplified cancers have been successful. Furthermore, hyperactivation of MET pathway are known to reduce the growth-inhibitory effect of trastuzumab in HER2 positive GC. Currently, there is no FDA approved MET inhibitors for GC. Capmatinib and savolitinib, which are selective MET inhibitors, has been evaluated for various MET positive cancers. The aim of this study was to test these MET inhibitors on MET amplified gastro-esophageal cancer (GC) cells. Material and Methods: Among a total of 37 GC cells in our lab, the following cells were positive for MET by copy number amplification (CNV > 10): SNU-620, ESO51, MKN-45, SNU-5 and OE-33. We assessed cytotoxic response of these GC cells to capmatinib or savolitinib alone by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay and anchorage independent growth in soft agar. Western blots were performed to assess the cellular activity of capmatinib or savolitinib in MET signal pathway. Xenograft studies were performed to evaluate in vivo therapeutic efficacy of savolitinib with MKN-45 cells. Results: Savolitinib and capmatinib showed anti-proliferative activity against MET amplified GC cell lines in dose-dependent manner. There was no inhibitory effect on GC cells without MET amplification, such as SNU-216 and SNU-1750. Savolitinib inhibited phosphorylation of MET and down-stream signaling pathway, such as AKT or ERK, in MET amplified GC cells. We observed that treatment with savolitinib induced a significant decrease in the number of colonies formed in soft agar. In addition, Savolitinib exhibited dose-responsive anti-tumor efficacy in xenograft model with MKN-45 GC cells. Furthermore, the combination of Trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in OE-33 cells, which is positive for both HER2 and MET, and resistant to trastuzumab alone. Conclusion: Collectively, these data support that targeting MET with Savolitinib and capmatinib efficiently suppresses the growth of MET amplified GC cells. Moreover, MET inhibitor could synergize with trastuzumab to induce the therapeutic effect on the HER2 and MET amplified GC cells. Further studies are warranted to test this concept in clinical setting. Citation Format: Jin-Soo Kim, Sungyoul Hong, Mi Young Kim. Effect of MET tyrosine kinase inhibitors on MET amplified gastro-esophageal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6376.

Therapeutic Advances and Challenges in the Management of HER2-Positive Gastroesophageal Cancers.

Gastroesophageal cancer is one of the most common cancers in the world, with a high rate of mortality. While there has been significant progress over the past decade, particularly with the addition of anti-HER2 therapies to platinum-based chemotherapy agents in the advanced setting, the prognosis remains poor and the treatment options for this disease entity remain limited. In this review, we discuss the current therapeutic landscape for HER2-positive gastroesphageal cancer and the seminal clinical trials that have shaped our approach to this disease entity. In addition, we highlight some of the challenges to the understanding and management of this disease, specifically discussing the breadth of molecular diversity and intratumoral heterogeneity of HER2 expression that impact the clinical efficacy and prognosis. Furthermore, we discuss the potential role of next-generation sequencing (NGS) and circulating-tumor DNA (ctDNA) as complementary tools to immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) to guiding clinical decision making. Finally, we highlight promising clinical trials of new treatment regimens that will likely reshape the therapeutic approach to this disease entity.

Comparative effectiveness and tolerability of targeted agents combined with chemotherapy in patients with HER2-positive gastroesophageal cancer: A network meta-analysis.

Background:Gastric cancer (GC) or gastroesophageal junction (GEJ) cancer with HER2 overexpression is highly invasive, with a poor prognosis. With the development of new targeted agents, which agents have ideal therapeutic effects must be determined. This network meta-analysis analyzed the effectiveness and tolerability of targeted agents combined with chemotherapy in HER2-positive GC/GEJ cancer.Methods:Public databases were searched from the date of inception to October 22, 2020. Randomized controlled trials (RCTs) on targeted agent-related regimens for HER2-positive advanced GC or GEJ cancer were included. Subgroup analyses based on publication language, first-line treatment, second/third-line treatment, and HER2 staining intensity were performed.Results:In total, 13 articles were included. The trastuzumabderuxtecan (TraD) and pertuzumab plus trastuzumab and chemotherapy (PerTraChemo) regimens were considered to have high effectiveness but low tolerability. In the subgroup analysis, PerTraChemo still had high effectiveness with low tolerability as the first-line therapy. As the second- or third-line therapy, TraD and lapatinib plus chemotherapy (LapChemo) had high effectiveness and moderate tolerability. In terms of overall survival (OS) time, PerTraChemo had a relative advantage in the immunohistochemistry (IHC) 2+/in situ hybridization (ISH)+ population, whereas TraD, PerTraChemo, and trastuzumab plus chemotherapy (TraChemo) had a relative advantage in the IHC3+ population.Conclusion:TraD had relative advantages as the second- or third-line therapy and in the IHC3 + population. PerTraChemo is a potential first-line therapy, but it requires further confirmation because the JACOB phase III clinical trial failed to confirm the superiority of PerTraChemo over TraChemo with regard to OS.

PD-L1 and HER2 Expression in Gastroesophageal Cancer: a Matched Case Control Study

Immunotherapy with check-point inhibitors serves as a promising treatment strategy in patients with upper gastrointestinal (GI) tumors. Human epidermal growth factor receptor 2 (HER2) is the only identified therapeutic target in upper GI tumors, whose potential interaction with programmed death-ligand 1 (PD-L1) is unknown. The aim of this study was the investigation of PD-L1 and HER2 in upper GI tumors. We retrospectively identified patients with HER2 positive gastroesophageal cancers and matched them with a HER2 negative group. We investigated the tumor specimens for HER2 status and PD-L1 expression, with the following assessments being performed: i) staining of tumor cells in terms of tumor proportion score (TPS), ii) staining for tumor-associated immune cells (TAIs), iii) interface pattern and iv) combined positive score (CPS). Both HER2 positive and negative group consisted of 59 patients. Expression of PD-L1 in TAIs and interface pattern were associated with a favorable outcome (p = 0.02, HR = 0.8; p = 0.04, HR = 0.39; respectively) in patients with localized disease, whereas TPS was associated with an unfavorable outcome in patients with advanced tumor (p = 0.02, HR = 1.4). These effects were HER2 independent. PD-L1 expression in its different assessment is equally observed in HER2 positive and negative patients. Future studies will show whether dual inhibition of HER2 and PD-L1 improves survival of this selected patient population.

Survival of patients with metastatic HER2 positive gastro-oesophageal cancer treated with second-line chemotherapy plus trastuzumab or ramucirumab after progression on front-line chemotherapy plus trastuzumab

BackgroundThe role of continuing anti-HER2 therapy beyond progression on front-line therapy in patients with metastatic HER2 positive gastro-oesophageal cancer (GEC) is unclear. Continued chemotherapy plus trastuzumab (CT) has never been compared with the current standard second-line treatment, chemotherapy plus ramucirumab (CR).MethodsThe Flatiron Health electronic health record derived database, a nationwide database comprising patient-level structured and unstructured data, curated via technology-enabled abstraction, was reviewed for patients with metastatic HER2 positive GEC who received first-line CT, followed by second-line CT or CR. Survival from second-line therapy (SST) and time to next therapy or death (TTNTD) were compared using Kaplan-Meier curves and logrank analysis.Results133 patients with metastatic HER2 positive GEC who received first-line CT were identified. 32 received second-line CR and 101 received CT. Median SST for patients treated with CT versus CR was 10.2 months (IQR 5.1–20.8) and 6.8 months (IQR 2.4–20.2), respectively (p=0.29). Median TTNTD for second-line CT versus CR was 4.9 months (IQR 2.8–9.8) and 5.1 months (IQR 2.3–7.5), respectively (p=0.65). Patients who received second-line CT were more likely to receive a multiagent chemotherapy backbone (76% vs 3%, p≤0.001).ConclusionsThis analysis showed no significant difference in SST for patients treated with second-line CT versus CR. Further studies are needed to clarify the role of trastuzumab in the second line, especially in patients with confirmed retention of HER2 positivity following progression.

Survival of patients with metastatic HER2 positive gastroesophageal cancer treated with second-line chemotherapy plus trastuzumab or ramucirumab after progression on frontline chemotherapy plus trastuzumab.

69 Background: Optimal second line treatment for patients with metastatic HER2 positive gastroesophageal cancer (Her2GE) is unknown. A retrospective study has suggested continuation of chemotherapy with trastuzumab (CT), as compared to chemotherapy alone, may improve outcomes. However, CT has never been compared to the current standard second-line treatment of chemotherapy plus ramucirumab (CR). Methods: The Flatiron Health EHR-derived database, a nationally representative database comprising patient-level structured and unstructured data, curated via technology-enabled abstraction, was reviewed for patients with metastatic Her2GE who received CT in the first line setting, followed by either second line CT or CR. Survival from second line therapy (SST) and time to next therapy or death (TTNTD) were compared using Kaplan-Meier curves and Log-Rank analysis. Demographics between treatment groups were compared using standard T tests and chi-squared analysis. Results: 135 patients were identified, of whom 34 received second-line CR and 101 received CT. Median SST for patients treated with CT was 10.2 months (m) [interquartile range (IQR) 5.1-20.8] and 6.8 m (IQR 3.2-20.2) for those treated with CR, p = 0.39. Median TTNTD for patients treated with CT versus CR was 4.9 m (IQR 2.8-9.8) and 4.8 m (IQR 2.3-7.5), respectively (p = 0.53). There was no difference between patients who received CT or CR in regards to average age (63 vs. 62, p = 0.72), average duration of first-line therapy (7.8 m vs. 9.1 m, p = 0.36), or percentage of patients with ECOG > 1 (15% vs. 22%, p = 0.50). Patients who received CT were more likely to receive a multiagent chemotherapy backbone (76% vs. 3%, p ≤ 0.001). Conclusions: This data suggest a non-significant trend towards increased SST for patients treated with second line CT versus CR. Further studies are needed to clarify optimal second-line treatment for this patient population.

Outcomes for advanced HER2 positive gastroesophageal cancer by anatomical location: Experience from the Princess Margaret Cancer Centre.

Outcomes for advanced HER2 positive gastroesophageal cancer by anatomical location: Experience from the Princess Margaret Cancer Centre.

Patterns of recurrence and outcomes after curative resection of locally advanced HER2-positive gastroesophageal cancer (HPGEC).

147 Background: Literature on recurrence and outcomes of HPGEC is scarce. The aim of this study was to determine pattern of recurrence and outcomes after curative intent surgery for locally advanced HPGEC. Methods: A retrospective database was used to identify consecutive patients with gastroesophageal adenocarcinomas undergoing curative intent resection between 2011 and 2016 at the Princess Margaret Cancer Centre. Clinico-demographic data were extracted from the electronic health record. Patterns of relapse are classified as nonvisceral (defined as recurrences in the bone, peritoneal or both), visceral (not nonvisceral, including the brain), or both. Time to relapse (TTR) and overall survival (OS) were calculated from date of histologic diagnosis. Results: Of 45 patients with HPGEC, 78% were male, and 91% were non-Asian. Median age was 64.4 years (interquartile range [IQR] 53, 70); 60% were gastroesophageal junction, 24% were gastric, and 16% were esophageal adenocarcinomas; 31% were poorly differentiated tumors while 68% had clinical or pathological node positive disease. Complete R0 resection occurred in 93%, and 84% had received perioperative therapy (31% with perioperative chemotherapy; 40% with pre-operative chemoradiation; 9% with post-operative chemoradiation). With a median follow-up time of 26.0 months. relapse rate of HPGEC at last follow-up was 78%. Among first relapses, 94% were distant, while 6% were local recurrences. Among distant relapses, visceral recurrences occurred in 85%, nonvisceral in 3%, and 12% patients had both visceral and nonvisceral recurrences. None had peritoneal only recurrence. Median TTR was 12.2 months (IQR 8.8, 23.5), while median post-recurrence survival was 9.7 months (IQR 4.7, 16.3). Of the entire cohort, 2-year OS was 53% and 3-year OS was 26%. Conclusions: More than three-quarters of patients with HPGEC experienced recurrence after curative intent multimodality therapy. Our results suggest that HPGEC rarely relapse with peritoneal only disease or local recurrence, thereby calling into question the utility for aggressive surveillance, pending verification from larger cohorts.

Outcomes for advanced HER2-positive gastroesophageal cancer by anatomical location: Experience from the Princess Margaret Cancer Centre.

131 Background: The landmark ToGA trial established trastuzumab (T) based therapy as the standard of care for advanced HER2+ gastric and gastroesophageal junction cancer. However, outcomes for T based therapy for HER2+ esophageal cancer have not been well characterized. Methods: We conducted a retrospective analysis of patients (pts) with HER2+ gastroesophageal cancer receiving T based therapy at our institution from 2011-2016. Distal esophagus ( < 35 cm) and Siewert type I/II tumours were defined as esophageal (E). Siewert type III and stomach tumours were defined as gastric (G). Trained abstractors collected pt demographics and treatment details. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of first T treatment. Chi-square tests, t-tests and Cox proportional hazards models were applied where appropriate. Results: We identified 87 pts with advanced HER2+ disease. 62% (n = 54) had de novo metastatic (M1) disease. 57 patients were treated with T based therapy, with median age 57 years (IQR 48-67), 91% baseline performance status 0-1, 19% female, and 7% Asian. 63% (n = 36) had E and 37% (n = 21) had G primary tumours. 67% (n = 38) presented with M1 disease. 33% (n = 19) underwent surgery with curative intent and received T based therapy at recurrence. Baseline characteristics were balanced between the E and G groups. Survival data were available for 51 patients. The E and G groups did not have significant differences in PFS (median 9.5 vs. 9.1 months, HR 0.89 (95% CI 0.44-1.80), p = 0.74) or in OS (median 15.8 vs. 14.2 months, HR 0.88 (95% CI 0.42-1.82), p = 0.73). 63% (n = 36) were treated with subsequent systemic therapy after progression on T, with 23 receiving one line, 9 receiving two lines and 4 receiving three additional lines of treatment. The number subsequent therapies received was similar between E and G groups. Conclusions: Although patients with distal esophagus tumours were not included in the ToGA trial, our analysis suggests that patients with E and G tumours had similar outcomes. Our contemporary cohort had comparable survival outcomes relative to patients receiving T in the ToGA trial (median PFS = 6.7 months, median OS = 13.8 months).

Lapatinib versus lapatinib plus capecitabine as second-line treatment in HER-2-overexpressing metastatic gastro-esophageal cancer (GC): A randomized phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

112 Background: HER2 amplification is present in a subgroup of gastroesophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-EGFR and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC. Methods: Patients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250 mg per day 1-21 plus capecitabine (CAP) 2000mg/m² on days 1-14 of a 21-day cycle or LAP 1500 mg monotherapy day 1-21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary endpoint was the objective response rate (ORR) as assessed by the investigator using RECIST 1.1 criteria. We aimed to include 38 pts per arm to show a response rate of >20% in either of the two arms. Results: 37 pts were enrolled (18 to LAP+CAP, 19 to LAP). Pts had received a median of three prior treatment lines, however, the treatment was intended to be tested as a second-line treatment. 12 pts in the LAP+CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% CI: 1.37 – 34.7), both in the LAP+CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38 to 61) days in the LAP group and 83 (95% CI: 42 to 86) days in the LAP+CAP group. Other secondary efficacy endpoints (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhea were higher with LAP+CAP (61%; 95% CI: 35 to 83) compared to 26% (95%CI 9 to 51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] vs. 17 [90%]). Conclusions: Lapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP+CAP was as expected with some more toxicity in the combination arm. Clinical trial information: NCT01145404.

HER2 positive gastroesophageal cancer in an Irish population.

e14687 Background: Gastroesophageal cancer is a major cause of cancer-related mortality. HER2 is overexpressed in ~ 7-34% of gastroesophageal (GE) adenocarcinomas. The ToGA study, established the benefit of trastuzumab in combination with chemotherapy in HER2 positive metastatic GE tumours. In this study, 22% of patients were HER2 positive {immunohistochemistry (IHC)3+ or fluorescence insitu hybridization (FISH)(+)}. Potential heterogeneity of HER2 amplification, overexpression, and incomplete membrane staining of HER2 by IHC leaves some ambiguity in HER2 testing and definition of HER2 positive GE tumours. We report a multi-center Irish experience by examining HER2 status by IHC and FISH in GE tumours. Methods: HER2 testing was performed on adenocarcinoma biopsy or resection specimens of patients with early stage and metastatic GE tumors between 2008 - 2011. We defined HER2 positive as IHC3+ or FISH(+) {HER2:17ch ≥ 2}. In addition, age, gender, smoking history, histology, stage of disease, treatment, and survival data were recorded. Results: A total of136 Caucasian patients with early stage and metastatic GE cancers were identified. Median age was 69 yrs (ranging from 25 – 96). Data available for analysis was conducted from 111 patients with 10% FISH(+). There are 73 patients with early stage and 38 with metastatic disease. Five metastatic cases (13%) were FISH(+) (of whom 3 IHC3+, 1 IHC2+, 1 IHC1+), 33 cases were FISH(-). Sites of metastatic disease in the FISH(+) cohort were liver, peritoneal, and bone metastasis. In the FISH(-) group, sites of metastatic disease were predominantly liver. Interestingly CNS disease is seen exclusively in the FISH(-) cohort. Of the early stage patients, only 6 patients (8.2%) were FISH(+) (of whom 3 IHC3+, 2 IHC2+, 1 IHC1+). With respect to tumour heterogeneity of HER2 amplification, in IHC3+, 82% were FISH(+), IHC2+, 17% were FISH(+) and IHC1+, 6% were FISH(+). There was 100% concordance between IHC0 and FISH(-). Conclusions: HER2 positive GE adenocarcinomas in the analyzed cohort displays similar pattern of heterogeneity in IHC staining and FISH positivity but with lower incidence (10%) of HER2 amplification than was reported in the ToGA study. Further data on location, histological pattern and survival will be reported.

HER2 status of gastric and gastroesophageal cancer (GC) patients assessed by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and high-resolution array comparative genomic hybridization (aCGH).

4103 Background: The ToGA study established the benefit of trastuzumab in HER2-positive GC. Accurate HER2 molecular assessment is crucial for patient selection for trastuzumab therapy. It is estimated by the ASCO/CAP that ∼20% of HER2 breast cancer (BC) testing is inaccurate. aCGH is a reliable, sensitive, and high-resolution method that characterizes gene copy number alternations present in tumors. aCGH is increasingly used as a research tool to help identify HER2-positive BC patients. Potential heterogeneity of HER2 amplification and incomplete membrane staining of HER2 by IHC leaves ambiguity of HER2 positivity in GC. We examined HER2 status by IHC, FISH, and aCGH in MSKCC GC patients with the aim to better define HER2-positive GC. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor specimens of patients with GC were HER2 tested by FISH (PathVysion, Abbott-Vysis) and IHC (4B5, Ventana) at MSKCC and aCGH on Agilent 244K feature arrays at Cold Spring Harbor Laboratory. IHC and FISH results were scored according to the ASCO/CAP guidelines for BC. Age, gender, histology, stage, therapy, and survival were also recorded. Results: 100 patients with advanced GC have been studied. 22 women, 78 men. Median age 59. Median survival is 14 months, independent of HER2 status. aCGH analysis is ongoing; results are available on 22 patients (14 FISH positive, 5 FISH negative, 3 FISH equivocal), of which 1 IHC3+/FISH+ pt was found to be HER2 negative by aCGH. Conclusions: 21% of GC are HER2 FISH positive. FISH concordance rate is 100% for IHC positive and 94% for IHC negative. aCGH analysis is feasible on FFPE GC tumor specimens. We note a 93% concordance rate between FISH and aCGH positivity in GC thus far; additional analysis is ongoing. N=100 IHC0-1+ negative IHC2+equivocal IHC3+positive aCGH positive* log2 ratio >1.3 aCGH negative* Total FISH Positive >2.2 HER2:CEP17 1 3 16** 13 1 21* Negative <1.8 HER2:CEP17 66 3 0 5 71 Equivocal 1.8-2.2 HER2:CEP17 3 1 0 3 4 * Analysis is ongoing. ** 1 pt FISH+/IHC not available, 1 pt IHC 3+/FISH test failure. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GenDx, Inc. GenDX, Inc.