Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q (original) (raw)

• Journal List
• [Ann Oncol](/pmc/?term=%22Ann Oncol%22[journal])
• PMC6927318

Ann Oncol. 2019 Nov; 30(11): 1821–1830.

K L Jhaveri,1 X V Wang,2 V Makker,3 S -W Luoh,4 E P Mitchell,5 J A Zwiebel,6 E Sharon,7 R J Gray,8 S Li,8 L M McShane,9 L V Rubinstein,10 D Patton,11 P M Williams,12 S R Hamilton,13 B A Conley,14 C L Arteaga,15 L N Harris,14 P J O’Dwyer,16 A P Chen,17 and K T Flaherty18

K L Jhaveri

1Department of Medicine, Memorial Sloan-Kettering Center, New York

X V Wang

2Biostatistics, E-A Biostatistical Center, Boston

V Makker

3Gynecologic Medical Oncology Service, Memorial Sloan-Kettering Cancer Center, New York

S -W Luoh

4Knight Cancer Institute, Oregon Health Science University, Portland

E P Mitchell

5Medical Oncology, Thomas Jefferson University, Philadelphia

J A Zwiebel

6Investigational Drug Branch, Division of Cancer Treatment and Diagnosis

E Sharon

7Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda

R J Gray

8Department of Biostatistics, Dana Farber Cancer Institutes, Boston

S Li

8Department of Biostatistics, Dana Farber Cancer Institutes, Boston

Find articles by S Li

L M McShane

9Biometric Research Branch, National Cancer Institute, Bethesda

L V Rubinstein

10Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institute of Health, Bethesda

D Patton

11Center for Biomedical, Informatics & Information Technology, National Cancer Institute, Bethesda

P M Williams

12Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick

S R Hamilton

13Department of Pathology, University of Texas MD Anderson Cancer Center, Houston

B A Conley

14Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda

C L Arteaga

15Department of Internal Medicine, University of Texas Southwestern, Dallas

L N Harris

14Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda

P J O’Dwyer

16University of Pennsylvania, Philadelphia

A P Chen

17CTEP, National Cancer Institute, Bethesda

K T Flaherty

18Cancer Center, Massachusetts General Hospital, Boston, USA

1Department of Medicine, Memorial Sloan-Kettering Center, New York

2Biostatistics, E-A Biostatistical Center, Boston

3Gynecologic Medical Oncology Service, Memorial Sloan-Kettering Cancer Center, New York

4Knight Cancer Institute, Oregon Health Science University, Portland

5Medical Oncology, Thomas Jefferson University, Philadelphia

6Investigational Drug Branch, Division of Cancer Treatment and Diagnosis

7Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda

8Department of Biostatistics, Dana Farber Cancer Institutes, Boston

9Biometric Research Branch, National Cancer Institute, Bethesda

10Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institute of Health, Bethesda

11Center for Biomedical, Informatics & Information Technology, National Cancer Institute, Bethesda

12Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick

13Department of Pathology, University of Texas MD Anderson Cancer Center, Houston

14Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda

15Department of Internal Medicine, University of Texas Southwestern, Dallas

16University of Pennsylvania, Philadelphia

17CTEP, National Cancer Institute, Bethesda

18Cancer Center, Massachusetts General Hospital, Boston, USA

Correspondence to: Dr. Komal L. Jhaveri, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Tel: +1-646-888-5145; Fax: +1-646-888-4917; E-mail: gro.ccksm@kirevahj

Copyright © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Abstract

Background

The National Cancer Institute—Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in _HER2_-amplified histologies other than breast and gastroesophageal tumors.

Methods

Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed.

Results

Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0–9; unknown in one patient). Median HER2 CN was 17 (range 7–139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay.

Conclusion

T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.

Keywords: _HER2_-amplified, T-DM1, NCI-MATCH, NGS

Introduction

The ‘National Cancer Institute - Molecular Analysis for Therapy Choice’ (NCI-MATCH) trial is a national signal-finding precision medicine study that incorporates genomic testing to direct refractory cancer patients to molecularly targeted treatments. The NCI-MATCH is a single protocol (EAY131) which incorporates nearly 40 phase II treatment subprotocols (Clinical Trials.gov, NCT02465060).

To date, the vast majority of precision medicine trials have relied upon next-generation sequencing (NGS) assays of archival tumor tissue to determine the genomic profile of a tumor. A unique feature of the NCI-MATCH trial is that it incorporated a centralized validated assay that analyzed freshly acquired samples collected at over 1100 sites and used four Clinical Laboratory Improvement Amendments (CLIA)-accredited NCI-MATCH network laboratories that were harmonized for assay concordance. Targeted NGS was performed using the Ion Torrent Oncomine AmpliSeq™ panel of 143 genes and was supplemented with Phosphatase and tensin homolog (PTEN), MutS homolog (MSH) and MutL homolog (MLH) immunohistochemistry (IHC). All assays were performed in CLIA laboratories under an Investigational Device Exemption (IDE).

One of the genes on the panel was the ERBB2 (HER2) gene that encodes a member of the ERBB family of receptor tyrosine kinases and is a key proto-oncogene in solid tumors [1, 2]. HER2 amplification is a critical oncogenic driver event found in approximately 15% to 20% of breast and gastroesophageal cancers [3, 4]. To that end, successful application of _HER2_-directed therapies has improved the overall survival (OS) of patients with early and advanced HER2 positive (overexpressed and/or amplified) breast cancer [5–9]. In gastric cancer, the addition of trastuzumab to chemotherapy in the metastatic setting led to an improvement in OS and established a new standard of care for these patients [4, 10, 11]. HER2 amplifications also occur in a variety of other solid tumors including lung, bladder, endometrial cancers for which no _HER2_-directed therapy is currently approved [12–20]. In one large cohort, the overall frequency of HER2 amplification was 2% across multiple tumors (excluding breast, gastric and gastroesophageal cancers) with considerable variation by individual tumor type [21, 22] (Figure 1). Furthermore, HER2 amplification may also be implicated in chemoresistance and overall poor survival in lung, bladder, cervical, endometrial and ovarian cancers, which underscores the unmet need for effective HER2 directed therapies for these patients [23–26].

ERBB2 amplification frequency: all tumors excluding breast and gastric/gastroesophageal junction tumors. This plot includes solid tumors (467/28 106 samples and 442/25 637 patients) with a minimum of 50 sequenced tumors and ERBB2 amplification > 0% using MSK-IMPACT assay. The numbers in the parentheses are the total number of sequenced tumors. (cBioPortal.org).

Ado-trastuzumab emtansine or T-DM1 is an antibody drug conjugate (ADC) linking trastuzumab coupled via a noncleavable thioether linker to 3–4 molecules of the maytansine derivative DM1. It is currently approved for the treatment of _HER2-_amplified and/overexpressed metastatic breast cancer based on the progression-free and OS benefit in the second- and third-line metastatic settings, respectively [6, 27]. The objective response rate (ORR) in _HER2-_amplified and/overexpressed gastric and metastatic breast cancer in the second-line setting was 21% and 44%, respectively [6]. This treatment subprotocol (EAY131- Q) of the NCI-MATCH protocol is investigating the activity of T-DM1 in _HER2_-amplified nonbreast and nongastric or gastroesophageal junction solid tumors.

Methods

Patient eligibility and assays

The NCI-MATCH master protocol included patients with solid tumors, lymphomas and multiple myeloma whose disease had progressed following at least one line of standard systemic therapy or for whom no standard therapy was available. Participation occurred in two phases: screening phase and treatment phase. As part of the screening phase, consented patients underwent a fresh tumor biopsy. Analysis was then performed using a centralized, customized Thermo Fisher Oncomine AmpliSeq™ NGS panel and PTEN immunohistochemistry for expression of PTEN under an IDE submitted to the investigational new drug application held by NCI [28, 29]. Patients whose tumors contained amplification of ERRB2 of more than copy number (CN) 7 (validated limit of detection) by NGS and for whom all other eligibility requirements from the master protocol were met (supplementary data, available at Annals of Oncology online) were offered participation in this subprotocol.

For this treatment subprotocol, key eligibility requirements included any solid tumor except breast or gastric/gastroesophageal junction cancer and presence of measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria [30]. Additional eligibility requirements included Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, absolute neutrophil count of ≥1500/μl, platelet count ≥100,000/μl, hemoglobin concentration ≥9 g/dl, as well as adequate kidney and liver function. Patients with prior HER2 therapies (approved or investigational) and a left ventricular ejection fraction of <50% were excluded (supplementary data, available at Annals of Oncology online).

The study was approved by the NCI Central Institutional Review Board and is listed in clinicaltrials.gov (NCT02465060).

Treatment and evaluation

Patients were treated with the standard intravenous dosing of T- DM1, that is 3.6 mg/kg every 3 weeks for a 21-day cycle, until toxicity or progression. Imaging was performed every three cycles for the first 33 cycles and every four cycles thereafter.

Statistical methodology and end point analysis

The primary end point was ORR, defined as a complete or partial response, consistent with RECIST version 1.1 criteria for solid tumors. Allowing for 10% ineligibility rate, the accrual goal was 35 patients. However, additional patients were allowed to enroll for an additional 6 months or until the activation of another subprotocol for this population, provided outcome data were unavailable on at least 31 patients. The proposed design had the operating characteristics of at least 92% power to distinguish an ORR of 25% from a null of 5% with one-sided Type 1 error of 1.8%. T-DM1 would be declared promising and worthy of further study if ≥5/31 (16%) patients achieved ORR. Secondary end points included progression-free survival (PFS) at 6 months, PFS and OS. Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed.

Results

Thirty-eight patients with a tumor ERBB2 CN of >7 were assigned and enrolled on this subprotocol arm. These patients received at least one dose of treatment and were included in the safety analysis. Two patients did not meet other treatment eligibility criteria by central review leaving a final cohort of 36 eligible patients that were included in the efficacy analysis (Figure 2). The first patient was enrolled for treatment on 19 November 2015 and the last patient was enrolled on March 20, 2017. Baseline characteristics are listed in Table 1. Median age was 64 (range 39–80 years). Median number of prior treatment regimens in the metastatic setting was 3 (range 0–9; unknown for one patient). Median ERBB2 CN was 17 (range 7–139). Twenty-two different tumor types enrolled to this subprotocol (Table 1).

Table 1.

Patient demographics

Efficacy

As of the data lock for analysis on 9 March 2019, the ORR was 2/36 (5.6%) with 90% confidence interval (90% CI, 1.0% to 16.5%). In addition, 17 patients had stable disease as best response (SD, 47.2%), while 13 patients had progressive disease (36.1%). Four patients were not evaluable for response due to death before first assessment scan or timing of assessments. The 6-month PFS rate was 23.6% (90% CI 14.2% to 39.2%). Median treatment duration was four cycles (range 1–37). The median PFS was 3.1 months (90% CI 2.1–4.4 months) (Figure 3C). Thirty deaths have been reported, with a median OS of 8.4 (90% CI 4.7–11.8) months.

(A) Efficacy: Best% change from baseline (n = 28). Four patients had PD based on new lesions but data for the target lesions are not available so not included in this plot. (B) Treatment Duration in patients who achieved SD or PR. (C) Kaplan–Meier curve for progression-free survival. GYN, gynecological; CI, confidence interval; GI, gastrointestinal.

Some reduction in tumor size was seen in 17 patients (Figure 3). Of the seven patients with more than 30% reduction in the sum of diameters of measurable tumors, two patients with salivary gland cancers (one patient each with mucoepidermoid carcinoma of the parotid gland and squamous cell carcinoma of the parotid gland) were confirmed to be partial responders (Figure 3A). Of note, the patient with parotid gland squamous cell carcinoma who achieved a PR remains on therapy at 23.7 months and the duration of treatment response for the patient with mucoepidermoid carcinoma of the parotid gland was 9 months. A subset of patients achieved SD for >6 months including patients with gynecological and colorectal cancers (Figure 3B).

Safety

All patients who received at least one dose of the study drug were included in the safety analysis. No new safety signals were seen with T-DM1 with expected and known side-effects of fatigue, nausea, elevated liver enzymes and thrombocytopenia which were predominantly grade 1 and 2 (Common Terminology Criteria for Adverse Events (CTCAE) v5.0) (Table 2). There were no deaths related to T-DM1.

Table 2.

Treatment-related toxicities in patients who started treatment (n = 38)

Correlative analyses

There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay (Figure 4).The CN for the two partial responders was 139 and 21, respectively. In a linear model, there was an estimated tumor shrinkage of 24.5% (95% CI 42.6% to 6.4%) with each doubling of CN (P = 0.01).

Correlation of best % change by ERBB2 copy number gain (n = 28). PR, partial response; SD, stable disease; PD, progressive disease.

The most common co-occurring mutation was a missense TP53 mutation seen in 89% of the patients which is higher than expected. For instance, in HER2-enriched primary breast cancer, the prevalence of TP53 mutation was 70% [31] and TP53 mutations were more than fourfold enriched in MSK-IMPACT compared with TCGA (29% versus 7%) [22]. This might suggest that our cohort enriched for patients with more clinically aggressive disease [22]. The presence and nature of other co-occurring mutations in a given disease type in this cohort was as expected. For example, 73% (8/11) of colorectal patients had a frameshift/nonsense APC mutation without any concurrent RAS mutation. Interestingly, one patient with rectal adenocarcinoma had a co-occurring missense ERBB2 V777L mutation and achieved tumor shrinkage (Figure 5). Of note, responses with T-DM1 have been reported in HER2 mutant lung cancer [32]. Only seven patients had a co-occurring PIK3CA mutation. Overall, the presence of any specific co-occurring genomic alteration did not correlate with outcome, but this analysis was limited by the overall cohort size and small number of responders.

Co-occurring genomic alterations with HER2 amplification using the NCI-MATCH assay color coded by variant type (left): copy number variant (purple), single nucleotide variant (red), indel (pink) and number of variants (top) for each eligible patient along with information regarding histology and best response on treatment (bottom): partial response (PR), stable disease (SD), progression of disease (PD), unevaluable (UE).

Paired pre- and posttreatment biopsy in a patient with colon adenocarcinoma, who had an unconfirmed PR and progressed after seven months, showed no differences in the genetic alterations captured by our screening test. Interestingly, sequencing of a posttreatment biopsy from the patient with mucoepidermoid carcinoma of parotid gland, with a pretreatment HER2 CN of 21.06, revealed loss of the HER2 amplification but persistence of a frameshift TP53 mutation.

Discussion

Molecular profiling and genomically guided therapies have been implemented in routine clinical practice for many cancers, e.g. non-small-cell lung cancer, melanoma, gastrointestinal stromal tumors, basal cell carcinomas, and others [33–35]. However, many tumor types have a low incidence of targetable molecular alterations (usually <5%) which makes tumor-directed biomarker selected drug development studies challenging. One approach has been to utilize ‘basket trials’ that determine eligibility by the presence of a biomarker rather than a tumor type [36–38]. The NCI-MATCH trial is unique in that it systematically leveraged a centralized assay to explore many treatment arms in parallel from patients at over 1000 clinical sites under a master protocol. This report concerns the subprotocol evaluating T-DM1, an ADC for _HER2-_amplified nonbreast and nongastric/gastroesophageal junction cancers.

The ORR (5.6%) in this subprotocol did not meet the prespecified threshold for ORR (defined as ≥5 responses in 31 patients or 16%). While this is disappointing, there are several possible reasons for this apparent low response rate. First, this treatment subprotocol enrolled heavily pretreated patients with multiple unique histologies and a clinically aggressive phenotype (as demonstrated by enrichment for TP53 mutations in 89% of patients; Figure 5). It is possible that response may be histology dependent. Moreover, response evaluation using RECIST v1.1 was available in only 77% (28/36) patients. Despite that, confirmed and durable partial responses were seen in two out of the three salivary gland tumors. Notably, complete and partial responses have been reported in 90% (9/10 patients) salivary gland cancers in another phase II multihistology basket trial of T-DM1 in _HER2-_amplified solid tumors [39]. This warrants further study of T-DM1 in salivary gland tumors in larger dedicated trials. Additionally, there were 4 unconfirmed partial responses and 13 others that achieved disease stabilization (SD: 17/36 [47%]) including a subset of patients with colorectal and ovarian cancers that had SD of >6 months, which is in line with what has been reported with other anti-HER2 therapies and T-DM1, respectively, in other multihistology basket trials [40, 41].

The evaluation of HER2 status by HER2 protein overexpression by immunohistochemistry (IHC 3+) is established as an accepted alternative to assessment of gene amplification by FISH [2, 4, 5]. However, in breast cancer, the criteria for HER2 positivity as defined using the American Society of Clinical Oncology/College of American Pathologists clinical practice guidelines based on IHC and/or FISH, are slightly different than the criteria for HER2 positivity in gastroesophageal adenocarcinomas [42, 43]. Hence, it is certainly possible that HER2 positivity using IHC and/or FISH could each apply to only some tumor types. ERBB2 amplification can also be reliably determined by NGS. Notably, amplification calls using the hybrid capture-based MSK-IMPACT NGS assay had an overall concordance of 98% when compared with IHC and/or FISH [44, 45]. Similarly, the sensitivity of HER2 amplifications calls using the NCI MATCH assay was > 92% based on orthogonally validated tests including FISH. However, screening the target using NGS does not account for spatial heterogeneity. It is well known that the sensitivity to treatment is higher when HER2 is highly expressed or amplified [46, 47]. To that end, a trend for tumor shrinkage with T-DM1 was associated with higher levels of gene CN as determined by the NCI-MATCH assay in this subprotocol. Furthermore, a patient with mucoepidermoid tumor of the parotid gland, with an HER2 CN of 21 at baseline, who remained on therapy for 9 months before progression, had a post progression biopsy that showed no HER2 amplification. It is possible that loss of HER2 amplification is related to spatial heterogeneity, i.e. biopsy of a HER2 negative subclone, but could also be explained as a resistance mechanism to T-DM1 therapy. Loss of HER2 amplification as a mechanism of resistance to _HER2-_directed therapy has been previously demonstrated in breast and gastric cancer [48–50]. Alternative attractive strategies such as cell-free circulating tumor DNA (ctDNA)-based NGS can provide a real-time profile of a tumor’s genomic landscape in a dynamic (serial) fashion, attempting at the same time to recapitulate tumor heterogeneity and treatment response and resistance mechanisms [47, 51].

Lastly, newer ADCs with more potent payloads and bystander effects might further improve responses in HER2 expressing tumors [52]. For example, DS‐8201a, another _HER2_‐targeting ADC, with a novel topoisomerase I inhibitor and high drug‐to‐antibody ratio of 7 to 8 : 1 which is higher than that of T-DM1 (3.5), has shown broader antitumor activity preclinically and activity in HER2 overexpressing solid tumors, and is also being evaluated in tumors with low HER2 expression [40].

In conclusion, this treatment subprotocol of _HER2_-amplified nonbreast and nongastric/gastroesophageal junction tumors treated with ado-trastuzumab emtansine did not meet the predefined threshold of ORR in this heavily pretreated tumor agnostic cohort, despite the established activity and approval of this therapy for _HER2_-amplified metastatic breast cancer. However, the activity in _HER2_-amplified salivary gland tumors, seen in this subprotocol and other trials, warrants further investigation of the efficacy of treatment with this agent or other novel antibody drug conjugates for these tumors in larger trials.

Supplementary Material

mdz291_Suuplementary_Data

Acknowledgements

This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748) and the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, U10CA180794, UG1CA233302, UG1CA233290, UG1CA233341, UG1CA233329, UG1CA233180, NCI P30 CA142543. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Disclosure

KJ: consultant or advisory board: Novartis, Spectrum Pharmaceuticals, ADC Therapeutics, Pfizer, BMS, Jounce Therapeutics, Taiho Oncology, Synthon and Lily Pharmaceuticals; research funding (to the institution): Novartis, Clovis Oncology, Genentech, AstraZeneca, ADC Therapeutics, Novita Pharmaceuticals, Debio Pharmaceuticals, Pfizer and Zymeworks. VM: consultant/advisory board: Eisai, Merck, Karyopharm, IBM Watson; research funding (to the institution): Astra Zeneca, Eisai, Merck, Lilly Pharmaceuticals, Karyopharm, Takeda, Genentech. S-WL: consultant or advisory board: PDX Pharmaceuticals. EPM: honoraria from Sanofi; consultant or advisory board: Genentech; research funding (to the institution): Genentech and Sanofi. RJG: research funding: Abbott Molecular, Agios, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech/Roche, Genomic Health, Genzyme, GlaxoSmithKline, Janssen-Ortho, Millennium, Novartis, Onyx, Pfizer, Sanofi, Sequenta, Syndax. PMW: patents, royalties, other intellectual property—co-inventor of the DLBCL cell of origin patent recently filed by the NIH. SH: grant support: National Cancer Institute; consultant or advisory board: Bristol-Myers Squibb, Guardant, HalioDx, Loxo-Oncology, Merck, Thermo Fisher Scientific, Centers for Medicare and Medicaid Services, and Fred Hutchinson Cancer Research Center. CLA: grant support: Pfizer, Lilly, Radius, PUMA Biotechnology, Bayer, Takeda, Symphogen; advisory board/steering committee: Daiichi Sankyo, ABBVIE, Novartis, Lilly, Sanofi, Radius, Taiho Oncology, PUMA Biotechnology, Merck, H3Biomedicine, Symphogen, OrigiMed, Immunomedics, Petra Pharma, G1 Therapeutics, Athenex; stock options: Provista, Y-TRAP. LNH: patents, royalties, other intellectual property—Philips Healthcare. POD: consultant or advisory role: Bristol-Myers Squibb, Five Prime Therapeutics, Forty Seven, Genentech; research funding: Amgen, Bayer, BBI Healthcare, Bristol-Myers Squib, Celgene, Five Prime Therapeutics, Forty Seven, Genentech, GlaxoSmithKlin, Merck, Mirati Therapeutics, Novartis, Pfizer, Pharmacyclics. KTH: stock and other ownership interests: Clovis Oncology, Loxo, Strata Oncology, X4 Pharma; consultant or advisory board: Adaptimmune, Aeglea Biotherapeutics, Amgen, Asana Biosciences, Bristol-Myers Squibb, Genentech, Incyte, Lilly, Loxo, Merck, Novartis, Oncoceutics, Roche, Sanofi, Shattuck Labs, Tolero Pharmaceuticals; research funding: Novartis and Sanofi. All remaining authors have declared no conflicts of interest.

References

1. Slamon DJ, Clark GM, Wong SG. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235(4785): 177–182. [PubMed] [Google Scholar]

2. Slamon DJ, Godolphin W, Jones LA. et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244(4905): 707–712. [PubMed] [Google Scholar]

3. Wolff AC, Hammond ME, Hicks DG. et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. JCO 2013; 31(31): 3997–4013. [PubMed] [Google Scholar]

4. Bang YJ, Van Cutsem E, Feyereislova A. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of _HER2_-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376(9742): 687–697. [PubMed] [Google Scholar]

5. Slamon DJ, Leyland-Jones B, Shak S. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344(11): 783–792. [PubMed] [Google Scholar]

6. Verma S, Miles D, Gianni L. et al. Trastuzumab emtansine for _HER2_-positive advanced breast cancer. N Engl J Med 2012; 367(19): 1783–1791. [PMC free article] [PubMed] [Google Scholar]

7. Hudis CA.Trastuzumab–mechanism of action and use in clinical practice. N Engl J Med 2007; 357(1): 39–51. [PubMed] [Google Scholar]

8. Geyer CE, Forster J, Lindquist D. et al. Lapatinib plus capecitabine for _HER2_-positive advanced breast cancer. N Engl J Med 2006; 355(26): 2733–2743. [PubMed] [Google Scholar]

9. Baselga J, Cortes J, Kim SB. et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012; 366(2): 109–119. [PMC free article] [PubMed] [Google Scholar]

11. Janjigian YY, Werner D, Pauligk C. et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis. Ann Oncol 2012; 23(10): 2656–2662. [PubMed] [Google Scholar]

12. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014; 511: 543–550. [PMC free article] [PubMed] [Google Scholar]

13. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507: 315–322. [PMC free article] [PubMed] [Google Scholar]

14. Kris MG, Johnson BE, Berry LD. et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014; 311(19): 1998–2006. [PMC free article] [PubMed] [Google Scholar]

15. Kandoth C, Schultz N, Cherniack AD. et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013; 497(7447): 67–73. [PMC free article] [PubMed] [Google Scholar]

16. Grushko TA, Filiaci VL, Mundt AJ. et al. An exploratory analysis of HER-2 amplification and overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2008; 108(1): 3–9. [PMC free article] [PubMed] [Google Scholar]

17. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474: 609–615. [PMC free article] [PubMed] [Google Scholar]

18. Gao J, Aksoy BA, Dogrusoz U. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013; 6(269): pl1. [PMC free article] [PubMed] [Google Scholar]

19. Cerami E, Gao J, Dogrusoz U. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012; 2(5): 401–404. [PMC free article] [PubMed] [Google Scholar]

20. Yan M, Parker BA, Schwab R, Kurzrock R.. HER2 aberrations in cancer: implications for therapy. Cancer Treat Rev 2014; 40(6): 770–780. [PubMed] [Google Scholar]

21. Cheng DT, Prasad M, Chekaluk Y. et al. Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing. BMC Med Genomics 2017; 10(1): 33. [PMC free article] [PubMed] [Google Scholar]

22. Zehir A, Benayed R, Shah RH. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 2017; 23(6): 703–713. [PMC free article] [PubMed] [Google Scholar]

23. Al-Saad S, Al-Shibli K, Donnem T. et al. Clinical significance of epidermal growth factor receptors in non-small cell lung cancer and a prognostic role for HER2 gene copy number in female patients. J Thorac Oncol 2010; 5: 1536–1543. [PubMed] [Google Scholar]

24. Schneider SA, Sukov WR, Frank I. et al. Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome. Mod Pathol 2014; 27(5): 758–764. [PubMed] [Google Scholar]

25. Morrison C, Zanagnolo V, Ramirez N. et al. HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. JCO 2006; 24(15): 2376–2385. [PubMed] [Google Scholar]

26. English DP, Roque DM, Santin AD.. HER2 expression beyond breast cancer: therapeutic implications for gynecologic malignancies. Mol Diagn Ther 2013; 17(2): 85–99. [PMC free article] [PubMed] [Google Scholar]

27. Krop IE, Kim SB, Martin AG. et al. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated _HER2_-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 2017; 18(6): 743–754. [PubMed] [Google Scholar]

28. Lih CJ, Harrington RD, Sims DJ. et al. Analytical validation of the next-generation sequencing assay for a nationwide signal-finding clinical trial: molecular analysis for therapy choice clinical trial. J Mol Diagn 2017; 19(2): 313–327. [PMC free article] [PubMed] [Google Scholar]

29. Khoury JD, Wang WL, Prieto VG. et al. Validation of immunohistochemical assays for integral biomarkers in the NCI-MATCH EAY131 clinical trial. Clin Cancer Res 2018; 24(3): 521–531. [PMC free article] [PubMed] [Google Scholar]

30. Eisenhauer EA, Therasse P, Bogaerts J. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2): 228–247. [PubMed] [Google Scholar]

31. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490: 61–70. [PMC free article] [PubMed] [Google Scholar]

32. Li BT, Shen R, Buonocore D. et al. Ado-trastuzumab emtansine for patients with _HER2_-mutant lung cancers: results from a phase II Basket Trial. J Clin Oncol 2018; 36(24): 2532–2537. [PMC free article] [PubMed] [Google Scholar]

33. Shepherd FA, Rodrigues Pereira J, Ciuleanu T. et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353(2): 123–132. [PubMed] [Google Scholar]

34. Chapman PB, Hauschild A, Robert C. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26): 2507–2516. [PMC free article] [PubMed] [Google Scholar]

35. Sekulic A, Migden MR, Lewis K. et al. Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC. J Am Acad Dermatol 2015; 72: 1021–1026 e1028. [PubMed] [Google Scholar]

36. Hyman DM, Piha-Paul SA, Won H. et al. HER kinase inhibition in patients with _HER2_- and _HER3_-mutant cancers. Nature 2018; 554(7691): 189–194. [PMC free article] [PubMed] [Google Scholar]

37. Hyman DM, Smyth LM, Donoghue MTA. et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol 2017; 35(20): 2251–2259. [PMC free article] [PubMed] [Google Scholar]

38. Hyman DM, Puzanov I, Subbiah V. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 2015; 373(8): 726–736. [PMC free article] [PubMed] [Google Scholar]

39. Li BT, Shen R, Offin M. et al. Ado-trastuzumab emtansine in patients with HER2 amplified salivary gland cancers (SGCs): results from a phase II basket trial. In: Presented at the Annual ASCO Meeting 2019. [Google Scholar]

40. Tsurutani J, Doi T, Iwata H. et al. Updated results of phase 1 study of DS-8201a in patients with HER2 expressing non-breast, non-gastric malignancies. Ann Oncol 2017; 28(Suppl 5). [Google Scholar]

41. Li BT, V M, Buonocore D. et al. A multi-histology basket trial of ado-trastuzumab emtansine in patients with HER2 amplified cancers. In: Presented at the Annual ASCO meeting 2018.

42. Bartley AN, Washington MK, Colasacco C. et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. JCO 2017; 35(4): 446–464. [PubMed] [Google Scholar]

43. Wolff AC, Hammond MEH, Allison KH. et al. HER2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update Summary. JOP 2018; 14(7): 437–441. [PubMed] [Google Scholar]

44. Razavi P, Chang MT, Xu G. et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell 2018; 34: 427–438 e426. [PMC free article] [PubMed] [Google Scholar]

45. Ross DS, Zehir A, Cheng DT. et al. Next-generation assessment of human epidermal growth factor receptor 2 (ERBB2) amplification status: clinical validation in the context of a hybrid capture-based, comprehensive solid tumor genomic profiling assay. J Mol Diagn 2017; 19(2): 244–254. [PMC free article] [PubMed] [Google Scholar]

46. Nuciforo P, Thyparambil S, Aura C. et al. High HER2 protein levels correlate with increased survival in breast cancer patients treated with anti-HER2 therapy. Mol Oncol 2016; 10(1): 138–147. [PMC free article] [PubMed] [Google Scholar]

47. Siravegna G, Sartore-Bianchi A, Nagy RJ. et al. Plasma HER2 (ERBB2) copy number predicts response to HER2-targeted therapy in metastatic colorectal cancer. Clin Cancer Res 2019; 25(10): 3046–3053. [PubMed] [Google Scholar]

48. Mittendorf EA, Wu Y, Scaltriti M. et al. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin Cancer Res 2009; 15(23): 7381–7388. [PMC free article] [PubMed] [Google Scholar]

49. Li G, Guo J, Shen BQ. et al. Mechanisms of acquired resistance to trastuzumab emtansine in breast cancer cells. Mol Cancer Ther 2018; 17(7): 1441–1453. [PubMed] [Google Scholar]

50. Sanchez-Vega F, Hechtman JF, Castel P. et al. EGFR and MET amplifications determine response to HER2 inhibition in _ERBB2_-amplified esophagogastric cancer. Cancer Discov 2019; 9(2): 199–209. [PMC free article] [PubMed] [Google Scholar]

51. Page K, Guttery DS, Fernandez-Garcia D. et al. Next generation sequencing of circulating cell-free DNA for evaluating mutations and gene amplification in metastatic breast cancer. Clin Chem 2017; 63(2): 532–541. [PMC free article] [PubMed] [Google Scholar]

52. Jhaveri K.MARIANNE: impact on current treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer and implications for the future. JCO 2017; 35(2): 127–130. [PubMed] [Google Scholar]

Articles from Annals of Oncology are provided here courtesy of Oxford University Press