Clinical Response to T-DM1 in HER2-Amplified, KRAS-Mutated Metastatic Colorectal Cancer

HER2 amplification has been identified in 2% to 3% of all colorectal cancers (CRCs). Although the prognostic role of HER2 amplification in metastatic CRC (mCRC) is unclear, studies have highlighted it as a therapeutic target. In addition, several studies have shown that HER2 amplification is implicated in the resistance to EGFR-targeted therapies. Other studies have provided scientific evidence to support the use of HER2-directed therapies in HER2-amplified CRC; however, thus far this benefit has been limited to the RAS wild-type population. There is an ongoing clinical need to identify novel means of targeting HER2 amplifications in the rare settings of HER2-amplified, RAS-mutated CRC. This case report presents a 58-year-old man with HER2-amplified mCRC and a KRAS G12D mutation whose disease progressed on all standard cytotoxic therapies as well as dual HER2 targeting using trastuzumab and pertuzumab. He subsequently derived a clinical benefit with metastatic lung disease regression on trastuzumab emtansine (T-DM1). He eventually experienced disease progression in the liver after 6 every-3-week cycles. The patient’s response and disease progression were associated with ongoing decline in the HER2 copy number on the circulating tumor DNA assay, suggesting that the mechanism of resistance was related to the loss of HER2 amplification or the emergence of non–HER2-amplified CRC clones. This represents the first report of clinical benefit with T-DM1 in KRAS-mutated HER2-amplified CRC.

Abstract

HER2 amplification has been identified in 2% to 3% of all colorectal cancers (CRCs). Although the prognostic role of HER2 amplification in metastatic CRC (mCRC) is unclear, studies have highlighted it as a therapeutic target. In addition, several studies have shown that HER2 amplification is implicated in the resistance to EGFR-targeted therapies. Other studies have provided scientific evidence to support the use of HER2-directed therapies in HER2-amplified CRC; however, thus far this benefit has been limited to the RAS wild-type population. There is an ongoing clinical need to identify novel means of targeting HER2 amplifications in the rare settings of HER2-amplified, RAS-mutated CRC. This case report presents a 58-year-old man with HER2-amplified mCRC and a KRAS G12D mutation whose disease progressed on all standard cytotoxic therapies as well as dual HER2 targeting using trastuzumab and pertuzumab. He subsequently derived a clinical benefit with metastatic lung disease regression on trastuzumab emtansine (T-DM1). He eventually experienced disease progression in the liver after 6 every-3-week cycles. The patient’s response and disease progression were associated with ongoing decline in the HER2 copy number on the circulating tumor DNA assay, suggesting that the mechanism of resistance was related to the loss of HER2 amplification or the emergence of non–HER2-amplified CRC clones. This represents the first report of clinical benefit with T-DM1 in KRAS-mutated HER2-amplified CRC.

HER2 amplification has been detected in 2% to 3% of all colorectal cancers (CRCs).1,2 The frequency increases up to 5% in KRAS/BRAF wild-type (WT) patients.24 HER2-amplified tumors are more frequently found in association with left-sided CRC and are uncommon in the setting of KRAS, NRAS, and BRAF mutations.57 Although the prognostic role of HER2 amplification in metastatic CRC (mCRC) is unclear, studies have highlighted it as a therapeutic target.1,3,8 In addition, several studies have shown that HER2 amplification is implicated in the resistance to EGFR-targeted therapies.1,4,9,10

Multiple studies have provided scientific evidence to support HER2-directed therapies in CRC.3,8 These studies interrogated dual HER2 targeting based on preclinical models showing minimal efficacy using trastuzumab or HER2 tyrosine kinase monotherapy.1,11 Although the HERACLES-A trial investigated trastuzumab + lapatinib in patients with KRAS-WT only,3 the MyPathway trial included patients with both RAS-WT and RAS-mutated.8 HERACLES-A and MyPathway showed significant clinical activity in patients with KRAS-WT tumors with response rates of 30% and 40%, progression-free survival (PFS) of 4.8 and 5.3 months, and overall survival of 10.6 and 14 months, respectively.3,8 Consistent with the preclinical data demonstrating resistance to dual HER2 targeting in the KRAS-mutated setting,12 MyPathway demonstrated a lack of clinical activity of trastuzumab + pertuzumab in KRAS-mutated, HER2-amplified CRC.8 There is an ongoing clinical need to identify novel means of targeting HER2 amplifications in the rare settings of HER2-amplified, RAS-mutated CRC. HER2-targeting immunoconjugates such as trastuzumab emtansine (T-DM1) or DS-8201 could hypothetically have clinical activity in HER2-amplified, RAS-mutated cancers given their unique mechanism that uses HER2-targeting antibodies as chemotherapy delivery vehicles to HER2-overexpressing cancers.

This report presents a 58-year-old man with HER2-amplified, KRAS G12D–mutated mCRC treated with T-DM1 who experienced disease progression on standard chemotherapy with 5-FU, oxaliplatin, irinotecan, and TAS-102, as well as dual HER2 targeting with trastuzumab and pertuzumab as part of a clinical trial.

Case Presentation

A man aged 58 years presented in February 2015 with the chief complaint of bloating, change in bowel movements, thinning of stools, and intermittent bleeding. Initial radiologic screening displayed a heterogeneous mass in the right lobe of the liver consistent with metastatic disease, along with irregular thickening of the rectosigmoid colon, implicating it as the primary tumor site. Colonoscopy revealed a mass at 12 cm from the anal verge. Histology showed a moderately differentiated invasive adenocarcinoma with mismatch repair proficiency. Next-generation sequencing was performed by FoundationOne and revealed HER2 (ERBB2) amplification (77 copies) in addition to KRAS G12D and TP53 E51fs*72 mutations.

Given the patient’s right liver–limited disease, he underwent 3 months of FOLFOX chemotherapy, which was complicated by grade 3 neuropathy, followed by right hepatectomy. This was followed by protracted chemoradiation to the pelvis and low anterior resection. No further adjuvant therapy was warranted. The patient remained in clinical remission for 5 months, when a PET/CT in comparison with the postsurgical CT scan revealed an FDG-avid enlarged right midabdominal mesenteric lymph node along with intense FDG uptake at the rectosigmoid anastomosis, supporting recurrent disease. Anastomotic reccurrence was proven via endoscopic biopsies. Given his HER2 amplification, prior disease progression after FOLFOX treatment, and refusal of further chemotherapy, the patient was enrolled on the pertuzumab + trastuzumab arm of the MyPathway clinical trial.8 His best response was stable disease, followed by clear progression after 5 months of treatment. The patient subsequently received a total 22 cycles of FOLFIRI with stable disease as the best response. He eventually experienced disease progression in the lungs and liver after 14 months of treatment, and was subsequently treated with trifluridine/tipiracil for 2 months, with radiographic progression.

Given the patient’s HER2-amplified, KRAS-mutated tumor and his progression on all standard therapies and on prior trastuzumab + pertuzumab, he was offered T-DM1 on compassionate grounds. Circulating tumor DNA (ctDNA) using Guardant360 and tumor HER2 immunohistochemistry (IHC) confirmed a high-plasma HER2 copy number (56.1) and an HER2 IHC of 3+. He was started on T-DM1 in January 2019. Clinical benefits were noted after the first cycle of T-DM1, with a decrease in pelvic pain and narcotic requirements. Treatment was well tolerated without any significant adverse effects. After 3 cycles of every-3-week T-DM1, imaging studies showed stable disease, with several tumors in the lungs exhibiting disease regression (Figure 1). In addition, ctDNA assay confirmed a decrease in mutation allele frequency (MAF) of all somatic mutations and in the HER2 copy number, consistent with disease regression. Unfortunately, disease progression occurred after cycle 6 of treatment, with an increase in hepatic metastases and pelvic disease while the patient’s lungs continued to show a mixed response. Despite disease progression, ctDNA assay indicated a significant ongoing decline in the HER2 copy number from 13.1 to 8.6 (Figure 2), with an increase in the MAF of multiple somatic tumor mutations (Figure 3). After disease progression, the patient was treated with FOLFOX rechallenge, which was poorly tolerated, and he enrolled in hospice care and died shortly afterward.

Figure 1.
Figure 1.

Radiographic response to T-DM1 in HER2-amplified, KRAS-mutated metastatic colorectal cancer. Baseline of (A) lung lesion 1 (14.6 × 8.8 mm) and (B) lung lesion 2 (17.3 × 13.7 mm). Status of (C) lung lesion 1 (11 × 7.4 mm) and (D) lung lesion 2 (15.1 × 10.3 mm) after 3 cycles of T-DM1.

Abbreviation: T-DM1, trastuzumab emtansine.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 2; 10.6004/jnccn.2019.7371

Figure 2.
Figure 2.

Biochemical response showing decreasing HER2 plasma copy number with T-DM1 treatment (baseline, 56.1; after 4 treatment cycles, 13.1; at time of progression after 6 cycles, 8.6) and abrupt increase in plasma copy number of KRAS (baseline, 0; after 4 treatment cycles, 0; at time of progression after 6 cycles, 2.6) and BRAF (baseline, 0; after 4 treatment cycles, 0; at time of progression after 6 cycles, 2.3) at time of progression on T-DM1.

Abbreviation: T-DM1, trastuzumab emtansine.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 2; 10.6004/jnccn.2019.7371

Figure 3.
Figure 3.

Increase in MAF of multiple somatic tumor mutations at time of disease progression on T-DM1 (KRAS G12D: baseline, 30.6%; after 4 treatment cycles, 25.9%; at time of progression after 6 cycles, 56.6%; TP53 E51fs: baseline, 48.3%; after 4 treatment cycles, 38.2%; at time of progression after 6 cycles, 76.5%; SMAD4 R361C: baseline, 48%; after 4 treatment cycles, 37.1%; at time of progression after 6 cycles, 76%).

Abbreviations: ctDNA, circulating tumor DNA; MAF, mutation allele frequency; T-DM1, trastuzumab emtansine.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 2; 10.6004/jnccn.2019.7371

Discussion

HER2 amplification is a key genetic driver occurring in approximately 2% to 3% of all CRCs.1,2 Although HER2-amplified, RAS-WT CRCs demonstrate relative resistance to anti-EGFR therapies, dual HER2 targeting has been met with clinical success whether using trastuzumab + lapatinib or trastuzumab + pertuzumab, which has resulted in endorsement of these 2 treatment strategies by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer.3,8,13 However, RAS-mutated, HER2-amplified CRCs do not seem to derive any clinical benefit from combinations of HER2-targeted therapies.8 We hypothesized that a HER2 immunoconjugate may result in antitumor activity through targeted cytotoxic drug administration that is independent of RAS status. This case report showed for the first time that the immunoconjugate T-DM1 can be associated with clinical benefits in KRAS-mutated, HER2-amplified CRC. The regression in multiple pulmonary metastases confirmed on-target activity of T-DM1. In addition, the major reduction in HER2 copy number on ctDNA even in the setting of disease resistance indicated debulking of the HER2-positive tumor with T-DM1. Concurrent increase in MAF was seen across all the somatic mutations at the time of resistance, which included KRAS, SMAD4, and TP53 (Figure 3). This was noted without the emergence of any new driver mutations. As such, we cannot attribute resistance to any of these individual mutations. Notably, KRAS and BRAF amplifications were also seen at the time of resistance (Figure 2). Whether these alterations conferred resistance to T-DM1 or reflected a higher burden of disease cannot be confirmed. Our findings are consistent with multiple other reports, across different tumor types, that link resistance to HER2 targeting to loss of HER2 expression.1417 T-DM1 treatment is known to decrease HER2 expression and amplification.17 HER2 overexpression is vital for the efficacy of T-DM1. Retrospective analysis of 2 phase II trials suggests that clinical response to T-DM1 is linked with HER2 levels.1820

HERACLES-RESCUE, a phase II clinical trial, is examining the response of patients with HER2-amplified mCRC treated with T-DM1 who had shown progression on anti-HER2 therapy (trastuzumab + lapatinib). The rationale of evaluating T-DM1 in HER2-amplified mCRC originates from testing CRC in patient-derived xenograft (PDX) models after patients experienced progression on trastuzumab + lapatinib in the HERACLES-A trial. These PDX models demonstrated tumor responses with T-DM1.21 The results from this clinical trial are currently awaited and may support our findings.

Another trial, the NCI-MATCH, investigated T-DM1 in a range of HER2-amplified cancers that were not exposed to prior HER2-targeted therapies. In a subgroup of CRCs, T-DM1 showed stable disease as the best response in 27% (3 of 11) of patients. However, the population was heterogeneous in the trial, making it difficult to infer a T-DM1 response against HER2-amplified, KRAS-mutated CRC.22

Conclusions

This report presents a patient with HER2-amplified, KRAS-mutated mCRC who achieved tumor shrinkage and clinical benefits after treatment with T-DM1. He received a total of 6 cycles of T-DM1. Although radiologic images showed modest tumor shrinkage, the patient achieved stable disease as the best response with 4 months of PFS. In comparison, the MyPathway trial reported a median PFS of 1.4 months in patients with KRAS-mutated treated using trastuzumab + pertuzumab.8 This case report provides further support for investigating HER2-targeting immunoconjugates in HER2-amplified, KRAS-mutated mCRC.

References

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    Meric-Bernstam F, Hurwitz H, Raghav KPS, . Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 2019;20:518–530.

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    Leto SM, Sassi F, Catalano I, . Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas. Clin Cancer Res 2015;21:5519–5531.

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    Seo S, Ryu MH, Park YS, . Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: results of the GASTric cancer HER2 reassessment study 3 (GASTHER3). Gastric Cancer 2019;22:527–535.

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    Kim C, Lee CK, Chon HJ, . PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer. Oncotarget 2017;8:113494–113501.

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    Kida K, Lee J, Liu H, . Changes in the expression of HER2 and other genes in HER2-positive metastatic breast cancer induced by treatment with ado-trastuzumab emtansine and/or pertuzumab/trastuzumab [abstract]. Cancer Res 2019;79(4 Suppl):Abstract P3-10-23.

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    LoRusso P, Krop IE, Burris HA, . Quantitative assessment of diagnostic markers and correlations with efficacy in two phase II studies of trastuzumab-DM1 (T-DM1) for patients (pts) with metastatic breast cancer (MBC) who had progressed on prior HER2-directed therapy [abstract]. J Clin Oncol 2010;28(Suppl):Abstract 1016.

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    Burris HA III, Rugo HS, Vukelja SJ, . Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011;29:398–405.

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    • PubMed
    • Search Google Scholar
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  • 20.

    Krop I, LoRusso P, Miller K, . A phase II study of trastuzumab-DM1 (T-DM1), a novel HER2 antibody–drug conjugate, in HER2+ metastatic breast cancer (MBC) patients previously treated with conventional chemotherapy, lapatinib and trastuzumab. Cancer Res 2009;69(24 Suppl):5090.

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    Siena S, Bardelli A, Sartore-Bianchi A, . HER2 amplification as a “molecular bait” for trastuzumab-emtansine (T-DM1) precision chemotherapy to overcome anti-HER2 resistance in HER2 positive metastatic colorectal cancer: the HERACLES-RESCUE trial [abstract]. J Clin Oncol 2016;34(Suppl):Abstract TPS774.

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    Jhaveri KL, Wang XV, Makker V, . Ado-trastuzumab emtansine (T-DM1) in patients with HER2 amplified tumors excluding breast and gastric/gastro-esophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) sub-protocol Q [published August 27, 2019]. Ann Oncol, doi: 10.1093/annonc/mdz291

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Submitted August 13, 2019; accepted for publication October 22, 2019.Disclosures: Dr. Fakih has disclosed that he receives honoraria, is a consultant, is a scientific advisor, and receives grant/research support from Amgen; is a scientific advisor for Array and Bayer; and receives grant/research support from AstraZeneca and Novartis. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.Correspondence: Marwan Fakih, MD, Department of Medical Oncology, City of Hope National Medical Center, Building 51, Room 112, 1500 East Duarte Street, Duarte, CA 91010. Email: mfakih@coh.org
  • View in gallery

    Radiographic response to T-DM1 in HER2-amplified, KRAS-mutated metastatic colorectal cancer. Baseline of (A) lung lesion 1 (14.6 × 8.8 mm) and (B) lung lesion 2 (17.3 × 13.7 mm). Status of (C) lung lesion 1 (11 × 7.4 mm) and (D) lung lesion 2 (15.1 × 10.3 mm) after 3 cycles of T-DM1.

    Abbreviation: T-DM1, trastuzumab emtansine.

  • View in gallery

    Biochemical response showing decreasing HER2 plasma copy number with T-DM1 treatment (baseline, 56.1; after 4 treatment cycles, 13.1; at time of progression after 6 cycles, 8.6) and abrupt increase in plasma copy number of KRAS (baseline, 0; after 4 treatment cycles, 0; at time of progression after 6 cycles, 2.6) and BRAF (baseline, 0; after 4 treatment cycles, 0; at time of progression after 6 cycles, 2.3) at time of progression on T-DM1.

    Abbreviation: T-DM1, trastuzumab emtansine.

  • View in gallery

    Increase in MAF of multiple somatic tumor mutations at time of disease progression on T-DM1 (KRAS G12D: baseline, 30.6%; after 4 treatment cycles, 25.9%; at time of progression after 6 cycles, 56.6%; TP53 E51fs: baseline, 48.3%; after 4 treatment cycles, 38.2%; at time of progression after 6 cycles, 76.5%; SMAD4 R361C: baseline, 48%; after 4 treatment cycles, 37.1%; at time of progression after 6 cycles, 76%).

    Abbreviations: ctDNA, circulating tumor DNA; MAF, mutation allele frequency; T-DM1, trastuzumab emtansine.

  • 1.

    Bertotti A, Migliardi G, Galimi F, . A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 2011;1:508–523.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Richman SD, Southward K, Chambers P, . HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials. J Pathol 2016;238:562–570.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Sartore-Bianchi A, Trusolino L, Martino C, . Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17:738–746.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Raghav KPS, Overman MJ, Yu RX, . HER2 amplification as a negative predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer [abstract]. J Clin Oncol 2016;34(Suppl):Abstract 3517.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Salem ME, Weinberg BA, Xiu J, . Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers. Oncotarget 2017;8:86356–86368.

  • 6.

    Stintzing S, Tejpar S, Gibbs P, . Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes. Eur J Cancer 2017;84:69–80.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Muzny DM, Bainbridge MN, Chang K, . Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330–337.

  • 8.

    Meric-Bernstam F, Hurwitz H, Raghav KPS, . Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 2019;20:518–530.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Yonesaka K, Zejnullahu K, Okamoto I, . Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med 2011;3:99ra86.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Bertotti A, Papp E, Jones S, . The genomic landscape of response to EGFR blockade in colorectal cancer. Nature 2015;526:263–267.

  • 11.

    Leto SM, Sassi F, Catalano I, . Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas. Clin Cancer Res 2015;21:5519–5531.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Kavuri SM, Jain N, Galimi F, . HER2 activating mutations are targets for colorectal cancer treatment. Cancer Discov 2015;5:832–841.

  • 13.

    Benson AB III, Venook AP, Al-Hawary MM, . NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 4.2019. Accessed 2019. To view the most recent version, visit NCCN.org.

  • 14.

    Seo S, Ryu MH, Park YS, . Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: results of the GASTric cancer HER2 reassessment study 3 (GASTHER3). Gastric Cancer 2019;22:527–535.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Li G, Guo J, Shen BQ, . Mechanisms of acquired resistance to trastuzumab emtansine in breast cancer cells. Mol Cancer Ther 2018;17:1441–1453.

  • 16.

    Kim C, Lee CK, Chon HJ, . PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer. Oncotarget 2017;8:113494–113501.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Kida K, Lee J, Liu H, . Changes in the expression of HER2 and other genes in HER2-positive metastatic breast cancer induced by treatment with ado-trastuzumab emtansine and/or pertuzumab/trastuzumab [abstract]. Cancer Res 2019;79(4 Suppl):Abstract P3-10-23.

    • Search Google Scholar
    • Export Citation
  • 18.

    LoRusso P, Krop IE, Burris HA, . Quantitative assessment of diagnostic markers and correlations with efficacy in two phase II studies of trastuzumab-DM1 (T-DM1) for patients (pts) with metastatic breast cancer (MBC) who had progressed on prior HER2-directed therapy [abstract]. J Clin Oncol 2010;28(Suppl):Abstract 1016.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Burris HA III, Rugo HS, Vukelja SJ, . Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011;29:398–405.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Krop I, LoRusso P, Miller K, . A phase II study of trastuzumab-DM1 (T-DM1), a novel HER2 antibody–drug conjugate, in HER2+ metastatic breast cancer (MBC) patients previously treated with conventional chemotherapy, lapatinib and trastuzumab. Cancer Res 2009;69(24 Suppl):5090.

    • Search Google Scholar
    • Export Citation
  • 21.

    Siena S, Bardelli A, Sartore-Bianchi A, . HER2 amplification as a “molecular bait” for trastuzumab-emtansine (T-DM1) precision chemotherapy to overcome anti-HER2 resistance in HER2 positive metastatic colorectal cancer: the HERACLES-RESCUE trial [abstract]. J Clin Oncol 2016;34(Suppl):Abstract TPS774.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Jhaveri KL, Wang XV, Makker V, . Ado-trastuzumab emtansine (T-DM1) in patients with HER2 amplified tumors excluding breast and gastric/gastro-esophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) sub-protocol Q [published August 27, 2019]. Ann Oncol, doi: 10.1093/annonc/mdz291

    • Search Google Scholar
    • Export Citation
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