Investigational New Drugs

, Volume 30, Issue 2, pp 695–701 | Cite as

Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors

  • Matthew D. Galsky
  • Daniel D. Von Hoff
  • Marcus Neubauer
  • Thomas Anderson
  • Mark Fleming
  • Yasir Nagarwala
  • Janine M. Mahoney
  • Dawn Midwinter
  • Linda Vocila
  • Tal Z. Zaks
PHASE II STUDIES

Summary

Background: To explore the activity of lapatinib with a novel trial design focused on the drug target rather than on histology. Methods: Patients with HER2 amplified gastro-esophageal, bladder, ovarian, or uterine tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1,500 mg PO daily. The planned sample size was 250 patients with HER2 amplified tumors, with the goal of randomizing 100 patients with stable disease (SD) at week 12 to either lapatinib or placebo. Patients responding after 12 weeks continued on lapatinib; those who progressed were discontinued from study. The primary objectives were response rate after 12 weeks and the percentage of patients who remained progression free 12 weeks after randomization to placebo versus lapatinib. Secondary objectives were duration of response and determination of the incidence of HER2 amplification in multiple tumor types. Results: A total of 141 patients were screened and 32 patients with HER2 amplified tumors were enrolled. At week 12, 1 (3%) patient had a complete response, 9 (28%) had stable disease, 20 (63%) had progressive disease, and 2 (6%) were unknown. Only 7 patients with SD underwent randomization. The low response rate coupled with slow screening and enrollment led to early study closure. Conclusions: Basing trial eligibility on the presence of a genetic target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy is associated with modest activity. The target-specific histology-independent randomized discontinuation design still merits consideration for targets clearly implicated in “oncogene addiction”.

Keywords

Her-2 Bladder cancer Gastroesophageal cancer Ovarian cancer Lapatinib Randomized discontinuation 

Notes

Acknowledgements

NIH PO1 Grant #5PO1CA109522.

References

  1. 1.
    Millar AW, Lynch KP (2003) Rethinking clinical trials for cytostatic drugs. Nat Rev 3:540–545CrossRefGoogle Scholar
  2. 2.
    Cameron D, Casey M, Press M et al (2008) A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 112:533–543PubMedCrossRefGoogle Scholar
  3. 3.
    Geyer CE, Forster J, Lindquist D et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743PubMedCrossRefGoogle Scholar
  4. 4.
    Press MF, Finn RS, Cameron D et al (2008) HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res 14:7861–7870PubMedCrossRefGoogle Scholar
  5. 5.
    Hardwick RH, Shepherd NA, Moorghen M, Newcomb PV, Alderson D (1995) c-erbB-2 overexpression in the dysplasia/carcinoma sequence of Barrett’s oesophagus. J Clin Pathol 48:129–132PubMedCrossRefGoogle Scholar
  6. 6.
    Hetzel DJ, Wilson TO, Keeney GL, Roche PC, Cha SS, Podratz KC (1992) HER-2/neu expression: a major prognostic factor in endometrial cancer. Gynecol Oncol 47:179–185PubMedCrossRefGoogle Scholar
  7. 7.
    Lara PN Jr, Meyers FJ, Gray CR et al (2002) HER-2/neu is overexpressed infrequently in patients with prostate carcinoma. Results from the California Cancer Consortium Screening Trial. Cancer 94:2584–2589PubMedCrossRefGoogle Scholar
  8. 8.
    Miyamoto H, Kubota Y, Noguchi S et al (2000) C-ERBB-2 gene amplification as a prognostic marker in human bladder cancer. Urology 55:679–683PubMedCrossRefGoogle Scholar
  9. 9.
    Park DI, Yun JW, Park JH et al (2006) HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci 51:1371–1379PubMedCrossRefGoogle Scholar
  10. 10.
    El-Sahwi K, Bellone S, Cocco E et al (2010) In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma. Br J Cancer 102:134–143PubMedCrossRefGoogle Scholar
  11. 11.
    Gordon MS, Matei D, Aghajanian C et al (2006) Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J Clin Oncol 24:4324–4332PubMedCrossRefGoogle Scholar
  12. 12.
    Hussain MH, MacVicar GR, Petrylak DP et al (2007) Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol 25:2218–2224PubMedCrossRefGoogle Scholar
  13. 13.
    Kim JW, Kim HP, Im SA et al (2008) The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. Cancer Lett 272:296–306PubMedCrossRefGoogle Scholar
  14. 14.
    Konecny GE, Venkatesan N, Yang G et al (2008) Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells. Br J Cancer 98:1076–1084PubMedCrossRefGoogle Scholar
  15. 15.
    Van Cutsem E, Kang Y, Chung H et al (2009) Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. Proc Am Soc Clin Oncol 27Google Scholar
  16. 16.
    Wainberg ZA, Anghel A, Desai AJ et al (2010) Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. Clin Cancer Res 16:1509–1519PubMedCrossRefGoogle Scholar
  17. 17.
    Wulfing C, Machiels JP, Richel DJ et al (2009) A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma. Cancer 115:2881–2890PubMedCrossRefGoogle Scholar
  18. 18.
    Galsky MD, Zaks T, Hassani H et al (2009) Target-specific randomized discontinuation trial design: a novel approach in molecular therapeutics. Invest New DrugsGoogle Scholar
  19. 19.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  20. 20.
    Galsky MD, Mironov S, Iasonos A, Scattergood J, Boyle MG, Bajorin DF (2007) Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Investig New Drugs 25:265–270CrossRefGoogle Scholar
  21. 21.
    Kulke MH, Muzikansky A, Clark J et al (2006) A phase II trial of vinorelbine in patients with advanced gastroesophageal adenocarcinoma. Cancer Investig 24:346–350CrossRefGoogle Scholar
  22. 22.
    Peethambaram PP, Melisko ME, Rinn KJ et al (2009) A phase I trial of immunotherapy with lapuleucel-T (APC8024) in patients with refractory metastatic tumors that express HER-2/neu. Clin Cancer Res 15:5937–5944PubMedCrossRefGoogle Scholar
  23. 23.
    Zaks TZ, Rosenberg SA (1998) Immunization with a peptide epitope (p369–377) from HER-2/neu leads to peptide-specific cytotoxic T lymphocytes that fail to recognize HER-2/neu+ tumors. Cancer Res 58:4902–4908PubMedGoogle Scholar
  24. 24.
    Amado RG, Wolf M, Peeters M et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634PubMedCrossRefGoogle Scholar
  25. 25.
    Mellinghoff IK, Wang MY, Vivanco I et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024PubMedCrossRefGoogle Scholar
  26. 26.
    Havaleshko DM, Smith SC, Cho H et al (2009) Comparison of global versus epidermal growth factor receptor pathway profiling for prediction of lapatinib sensitivity in bladder cancer. Neoplasia (New York, NY) 11:1185–1193Google Scholar
  27. 27.
    Wolff AC, Hammond ME, Schwartz JN et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145PubMedCrossRefGoogle Scholar
  28. 28.
    Yano T, Doi T, Ohtsu A et al (2006) Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep 15:65–71PubMedGoogle Scholar
  29. 29.
    Simon R, Nocito A, Hubscher T et al (2001) Patterns of her-2/neu amplification and overexpression in primary and metastatic breast cancer. J Natl Cancer Inst 93:1141–1146PubMedCrossRefGoogle Scholar
  30. 30.
    Zidan J, Dashkovsky I, Stayerman C, Basher W, Cozacov C, Hadary A (2005) Comparison of HER-2 overexpression in primary breast cancer and metastatic sites and its effect on biological targeting therapy of metastatic disease. Br J Cancer 93:552–556PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Matthew D. Galsky
    • 1
  • Daniel D. Von Hoff
    • 2
  • Marcus Neubauer
    • 3
  • Thomas Anderson
    • 3
  • Mark Fleming
    • 3
  • Yasir Nagarwala
    • 4
  • Janine M. Mahoney
    • 4
  • Dawn Midwinter
    • 4
  • Linda Vocila
    • 2
  • Tal Z. Zaks
    • 5
  1. 1.Mount Sinai Medical Center/Tisch Cancer InstituteNew YorkUSA
  2. 2.Translational Genomics Research InstitutePhoenixUSA
  3. 3.Translational Oncology Program, US Oncology ResearchThe WoodlandsUSA
  4. 4.GlaxoSmithKlineCollegevilleUSA
  5. 5.ex-GlaxoSmithKlineCollegevilleUSA

Personalised recommendations