Real-World Treatment Patterns in Patients With HER2-Amplified Metastatic Colorectal Cancer: A Clinical-Genomic Database Study

Authors:
John H. Strickler Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina

Search for other papers by John H. Strickler in
Current site
Google Scholar
PubMed
Close
 MD
,
Ling-I Hsu Seagen Inc., Bothell, Washington

Search for other papers by Ling-I Hsu in
Current site
Google Scholar
PubMed
Close
 MPH, PhD
,
Phoebe Wright Seagen Inc., Bothell, Washington

Search for other papers by Phoebe Wright in
Current site
Google Scholar
PubMed
Close
 PharmD
,
Michael Stecher Seagen Inc., Bothell, Washington

Search for other papers by Michael Stecher in
Current site
Google Scholar
PubMed
Close
 MD
,
Muriel F. Siadak Seagen Inc., Bothell, Washington

Search for other papers by Muriel F. Siadak in
Current site
Google Scholar
PubMed
Close
 MD
,
Maria Corinna Palanca-Wessels Seagen Inc., Bothell, Washington

Search for other papers by Maria Corinna Palanca-Wessels in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Junhua Yu Guardant Health, Inc., Redwood City, California

Search for other papers by Junhua Yu in
Current site
Google Scholar
PubMed
Close
 PhD
,
Nicole Zhang Guardant Health, Inc., Redwood City, California

Search for other papers by Nicole Zhang in
Current site
Google Scholar
PubMed
Close
 MPH
,
Carin R. Espenschied Guardant Health, Inc., Redwood City, California

Search for other papers by Carin R. Espenschied in
Current site
Google Scholar
PubMed
Close
 MS
,
Kathryn Lang Guardant Health, Inc., Redwood City, California

Search for other papers by Kathryn Lang in
Current site
Google Scholar
PubMed
Close
 MD
, and
Tanios S. Bekaii-Saab Division of Hematology/Oncology, Mayo Clinic, Phoenix, Arizona

Search for other papers by Tanios S. Bekaii-Saab in
Current site
Google Scholar
PubMed
Close
 MD
Restricted access

Background: HER2 amplification (HER2+) occurs in approximately 3% of patients with metastatic colorectal cancer (mCRC). Despite the recent addition of HER2-directed therapies to treatment recommendations in the NCCN Guidelines, until more recently there were no FDA-approved treatments. This study examined real-world treatment patterns in patients with HER2+ mCRC in the United States before and after the emerging awareness of HER2-directed therapies in 2018. Methods: This was a retrospective observational study of patients with HER2+ mCRC from the GuardantINFORM database, which contains claims data for patients with Guardant360 genomic testing results. Patients were aged ≥18 years, were diagnosed with mCRC between January 2014 and September 2020, and had confirmed ERBB2 amplification via the blood-based Guardant360 test. Treatment patterns and real-world time to next treatment (rwTTNT) were evaluated. Results: This study included 142 patients with a median age of 59 years; 31 (21.8%) patients with ERBB2 amplifications also had ERBB2 mutations. Treatment patterns were heterogeneous and evolved over time; before 2018, the most common regimen prescribed after detection of ERBB2 amplification was anti-VEGF therapy with or without chemotherapy (31.6%; n=25), and after 2018, HER2-directed therapies were the most commonly prescribed (36.5%; n=23). Median rwTTNT among the overall cohort was 8.4 months (95% CI, 6.5–10.0); rwTTNT was numerically longer in patients who received HER2-directed therapy compared with those who received non–HER2-directed therapies (11.0 months [95% CI, 6.3–12.3] vs 7.2 months [95% CI, 5.8–9.6]). Conclusions: This real-world study of the largest clinically annotated dataset of patients with HER2+ mCRC showed that many patients do not receive HER2-directed therapy despite its inclusion in NCCN Guidelines, with heterogeneous treatment patterns suggesting that standard of care remains undefined and targeted therapy remains underutilized. Greater awareness of the unmet need in this patient population, together with new effective therapies, will facilitate strategies for improved, targeted treatment approaches.

Submitted September 3, 2022; final revision received March 9, 2023; accepted for publication March 15, 2023.

Author contributions: Study concept and design: All authors. Data analysis: Hsu, Yu, Zhang, Espenschied, Lang. Data interpretation: All authors. Writing—original draft: Strickler, Hsu, Zhang, Bekaii-Saab. Manuscript preparation—review and editing: All authors.

Disclosures: Dr. Strickler has disclosed serving as a principal investigator for AbbVie, Amgen, AStar D3, Bayer, BeiGene, Curegenix, Daiichi-Sankyo, Eli Lilly, Erasca, Leap Therapeutics, Roche/Genentech, and Seagen; and serving on an advisory board for AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Pfizer, Roche/Genentech, Seagen, Takeda, and Viatris. Dr. Hsu has disclosed owning stock in Seagen. Dr. Stecher has disclosed receiving grant/research support from, being employed by, and owning stock/having ownership interest in Seagen. Dr. Siadak has disclosed being employed by and owning stock/having ownership interest in Seagen. Dr. Palanca-Wessels has disclosed receiving grant/research support from Seagen; holding an executive position, serving on a governing board, or being employed by Seagen; and owning stock/ownership interest in Seagen. N. Zhang has disclosed being employed by and owning stock in Guardant Health. C. Espenschied has disclosed being employed by and owning stock in Guardant Health. Dr. Bekaii-Saab has disclosed receiving grant/research support from Seattle Genetics and Pfizer; serving as a consultant for Pfizer, Seattle Genetics, and Merck; and serving on a data safety monitoring board for Merck. The remaining authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This study was sponsored by Seagen Inc., in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Correspondence: Tanios S. Bekaii-Saab, MD, Division of Hematology/Oncology, Mayo Clinic, 5881 East Mayo Boulevard, Phoenix, AZ 85054. Email: bekaii-saab.tanios@mayo.edu

Supplementary Materials

    • Supplemental Materials (PDF 417 KB)
  • Collapse
  • Expand
  • 1.

    Global Cancer Observatory. Colorectal cancer. Accessed November 3, 2021. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/10_8_9-Colorectum-fact-sheet.pdf

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

    SEER. Cancer stat facts: colorectal cancer. Accessed November 3, 2021. Available at: https://seer.cancer.gov/statfacts/html/colorect.html

  • 3.

    Verdaguer H, Saurí T, Macarulla T. Predictive and prognostic biomarkers in personalized gastrointestinal cancer treatment. J Gastrointest Oncol 2017;8:405417.

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

    Benson AB III, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 3.2022. Accessed January 27, 2023. To view the most recent version, visit https://www.nccn.org

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

    Sartore-Bianchi A, Amatu A, Porcu L, et al. HER2 positivity predicts unresponsiveness to EGFR-targeted treatment in metastatic colorectal cancer. Oncologist 2019;24:13951402.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Sartore-Bianchi A, Trusolino L, Martino C, et al. 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;17:738746.

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

    Meric-Bernstam F, Hurwitz H, Raghav K, et al. 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;20:518530.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Siena S, Di Bartolomeo M, Raghav K, et al. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial. Lancet Oncol 2021;22:779789.

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

    Nakamura Y, Okamoto W, Kato T, et al. Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial. Nat Med 2021;27:18991903.

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

    Benson AB III, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer. Version 4.2022. Accessed January 27, 2023. To view the most recent version, visit https://www.nccn.org

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Tucatinib tablets, oral use. Prescribing information. Seagen; 2023. Accessed January 27, 2023. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213411s004lbl.pdf

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

    Odegaard JI, Vincent JJ, Mortimer S, et al. Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies. Clin Cancer Res 2018;24:35393549.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Zill OA, Banks KC, Fairclough SR, et al. The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients. Clin Cancer Res 2018;24:35283538.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373383.

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

    Greally M, Kelly CM, Cercek A. HER2: an emerging target in colorectal cancer. Curr Probl Cancer 2018;42:560571.

  • 16.

    Mehta R. The role of HER2 testing in advanced colorectal cancer. Curr Colorectal Cancer Rep 2018;14:184191.

  • 17.

    Ross JS, Fakih M, Ali SM, et al. Targeting HER2 in colorectal cancer: the landscape of amplification and short variant mutations in ERBB2 and ERBB3. Cancer 2018;124:13581373.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Takegawa N, Yonesaka K. HER2 as an emerging oncotarget for colorectal cancer treatment after failure of anti-epidermal growth factor receptor therapy. Clin Colorectal Cancer 2017;16:247251.

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

    Bikov KA, Mullins CD, Seal B, et al. Algorithm for identifying chemotherapy/biological regimens for metastatic colon cancer in SEER-Medicare. Med Care 2015;53:e5864.

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

    Yezefski TA, Le D, Chen L, et al. Comparison of treatment, cost, and survival in patients with metastatic colorectal cancer in western Washington, United States, and British Columbia, Canada. JCO Oncol Pract 2020;16:e425432.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Meric-Bernstam F, Johnson AM, Dumbrava EEI, et al. Advances in HER2-targeted therapy: novel agents and opportunities beyond breast and gastric cancer. Clin Cancer Res 2019;25:20332041.

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

    Sawada K, Nakamura Y, Shitara K. Development of HER2-targeted therapies for gastrointestinal cancer. Eur Oncol Haematol 2020;16:2938.

  • 23.

    Guarini C, Grassi T, Pezzicoli G, et al. Beyond RAS and BRAF: HER2, a new actionable oncotarget in advanced colorectal cancer. Int J Mol Sci 2021;22:6813.

  • 24.

    Qiu MZ, He CY, Xu RH. Relationship of HER2 Alteration and MSI Status in Colorectal Adenocarcinoma. Lippincott Williams & Wilkins; 2021.

  • 25.

    Benson AB III, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2.2019. To view the most recent version, visit https://www.nccn.org

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Strickler J, Cercek A, Siena S, et al. Primary analysis of MOUNTAINEER: a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC. Ann Oncol 2022;33(Suppl 4):S375376. Abstract LBA-2.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Tosi F, Sartore-Bianchi A, Lonardi S, et al. Long-term clinical outcome of trastuzumab and lapatinib for HER2-positive metastatic colorectal cancer. Clin Colorectal Cancer 2020;19:256262.e2.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Raghav K, Loree JM, Morris JS, et al. Validation of HER2 amplification as a predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer. JCO Precis Oncol 2019;3:113.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Mariani S, Bertero L, Osella-Abate S, et al. Extreme assay sensitivity in molecular diagnostics further unveils intratumour heterogeneity in metastatic colorectal cancer as well as artifactual low-frequency mutations in the KRAS gene. Br J Cancer 2017;117:358366.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Van Cutsem E, Lenz HJ, Köhne CH, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015;33:692700.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    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;25:30463053.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Patelli G, Tosi F, Amatu A, et al. Strategies to tackle RAS-mutated metastatic colorectal cancer. ESMO Open 2021;6:100156.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 3401 3401 85
PDF Downloads 2372 2372 87
EPUB Downloads 0 0 0