Is HER2 Still a Worthwhile Therapeutic Target for Urothelial Bladder Cancer?

Whenever the term, HER2, is mentioned, people immediately think, “breast cancer.” With the regulatory approvals of trastuzumab and ado-trastuzumab emtansine, oncologists now have multiple approaches to address HER2 amplified breast cancers. However, HER2 overexpression in gastric cancer has also led to a demonstration of trastuzumab treatment benefit in that disease. We’ve often heard about HER2 amplification in urothelial bladder cancer, yet it seems as if we’ve had no major advances in this area.

Molecular alterations in HER2 occur in up to 20-30% of bladder cancer patients and the alterations are most commonly amplifications, although mutations occasionally occur.1 As a result, multiple HER2 targeting-agents, with varying mechanism of action, have been tested in advanced urothelial bladder cancer with modest results.

Trastuzumab, a monoclonal antibody against HER2, was combined with carboplatin, paclitaxel, and gemcitabine and administered to patients with HER2 overexpression.2 Although the objective response rate was 70%, 22.7% suffered cardiac toxicity, with a 4.5% grade 3 cardiotoxicity rate. Additionally, there were 2 therapy-related deaths. Another trial, randomized patients to gemcitabine with either cisplatin or carboplatin plus/minus trastuzumab.3 There was no difference in the primary endpoint of progression-free survival, with the trastuzumab arm patients at a median of 8.2 months vs. the control median at 10.2 months. However, combinations of trastuzumab with pertuzumab have revealed 3 of 12 (25%) patients to respond to the combination, with all responders harboring HER2 amplification.4

Lapatinib is a tyrosine kinase inhibitor of both HER2 and epidermal growth factor receptor (EGFR), currently, FDA approved for metastatic breast cancer. Only 1 urothelial bladder cancer patient (3%) had a partial response in an initial open-label, single-arm trial.5 A randomized discontinuation trial in HER2-amplified solid tumors, saw 0 of 9 bladder cancer patients respond to lapatinib.6 Lapatinib has also been combined with cytotoxic chemotherapy. A 59% response rate was found when lapatinib was administered with gemcitabine and cisplatin7 and 1 of 15 patients had a complete response when lapatinib was combined with docetaxel;8 both trials were in previously platinum-treated populations. Finally, lapatinib was tested as maintenance therapy in a post-chemotherapy, randomized phase 3, double-blinded controlled trial.9 There was no improvement in progression-free or overall survival. Of note, none of these trials were designed to distinguish between specific effects on HER2 vs. EGFR.

Other pan-kinase inhibitors have been tested as well. Neratinib is an irreversible inhibitor of EGFR, HER2, and HER4 that is FDA approved for adjuvant therapy for HER2 overexpressing breast cancers. Unfortunately, limited activity was observed in a small number of urothelial cancer patients in a basket trial.10 Afatinib inhibits EGFR, HER2, HER3, and HER4 and has regulatory approval for EGFR-mutated non-small cell lung cancer. In urothelial bladder cancer, 5 of 23 (21.7%) patients met the primary endpoint of 3-month progression-free survival, falling short of the 30% goal.11 All 5 patients, who met the primary endpoint, harbored either HER2 amplification or HER3 mutation. As a result, efforts are now ongoing to identify HER2 and HER3 altered patients and treat them with afatinib in a molecularly selected trial (see actively accruing trial list below).

Multiple antibody-drug conjugates are being developed to target HER2 in urothelial bladder cancer. Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is FDA approved for HER2 positive breast cancer. Clinical trials testing T-DM1 in urothelial bladder cancer have completed enrollment, and results are forthcoming. At the 2019 American Society of Clinical Oncology meeting, results were presented with RC48-ADC in HER2 positive patients with advanced urothelial carcinoma.12 This antibody-drug conjugate trial enrolled 43 patients and demonstrated an impressive objective response rate of 60.5%. This has prompted further investigation (see actively accruing trial list below). DS-8201a is another antibody-drug conjugate targeting HER2, with early signs of impressive efficacy in breast and gastric cancer, that is being combined with nivolumab in an ongoing trial of breast and bladder cancer patients.

It is clear that HER2 is a feasible target for urothelial bladder cancer. Although there have been early attempts with minimal to modest success, having the right drugs, or combinations of agents, is often the key. Therefore, we should confidently enroll patients aggressively onto this next wave of trials in an optimistic, yet very rational attempt to further improve patient outcomes.

Clinical Trials Targeting HER2 in Advanced Urothelial Bladder Cancer

  • Afatinib for HER2 or HER3 altered patients (NCT02780687)
  • Afatinib in a molecularly matched trial of multiple agents (NCT02795156)
  • RC48-ADC for HER2 overexpressing patients (NCT03809013)
  • RC48-ADC for HER2 negative patients (NCT04073602)
  • DS8201a in combination with nivolumab (NCT03523572)
  • PRS-343 (bispecific antibody to HER2/41BB) (NCT03330561)

Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine,  Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center

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  12. Sheng X et al. A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma. Journal of Clinical Oncology. 37, 2019 (suppl; abstr 4509). DOI: 10.1200/JCO.2019.37.15