Emerging therapies with new mechanisms of action are offering more diverse therapeutic options for bladder cancer patients.

Historically, for patients with metastatic bladder cancer, the only viable treatment option was chemotherapy. In this patient population, where up to 50% of patients are ineligible for effective cisplatin-based therapies, treatment options are severely limited1. Thus, there is a significant unmet need for novel therapies for patients who have either progressed following chemotherapy and immunotherapy or who have failed to respond.

The diversity of the clinical pipeline discussed at ASCO 19 highlighted how the bladder cancer market is finally catching up with other indications and offering drugs with a multitude of different mechanisms of action. Several abstracts stood out showcasing the beneficial effects that such emerging therapies could offer bladder cancer patients:

FIERCE-22: FGFR3 inhibitor Vofatamab shows promising overall response rates in metastatic bladder cancer

Following the recent FDA approval of the small molecule inhibitor, Balversa (erdafitinib), targeted treatments are entering the fore. As such, the results of the Phase Ib/II FIERCE-22 trial were of interest at ASCO 2019. FIERCE-22 is investigating the use of Vofatamab (a pan-FGFR inhibitor) in combination with Keytruda (pembrolizumab) in wild-type patients with platinum-refractory metastatic urothelial carcinoma (mUC). The objective response rate (ORR) was 30% and the combination was well tolerated. Of interest, was the response to Vofatamab which appeared to be enriched in tumours that are of the luminal subtype, typically immunologically “cold”2. These results hint that Vofatamab might work synergistically with Keytruda to elicit an anti-tumour immune response.

Diversification of drug classes was not the only aspect explored at ASCO 2019, the timing of treatments in relation to the stage of disease was also discussed.

HCRN GU14-182: Keytruda as a maintenance treatment following first-line chemotherapy in metastatic bladder cancer patients

The HCRN GU14-182 trial focuses on providing deeper responses and improving progression free survival (PFS) in mUC patients who have received chemotherapy by administering Keytruda as a maintenance treatment. This way, the duration of administration of chemotherapy is shortened, reducing the toxic effects of the treatment in this vulnerable patient group. Patients were randomised to receive maintenance Keytruda or placebo, and those on placebo could switch to Keytruda. Compared to placebo, Keytruda showed a significantly longer median PFS of 5.4 months, compared to 3.2 months with placebo. Objective response rates were 22% and 12% on Keytruda and placebo respectively3. More mature OS data is required from a Phase III trial for confirmation should Keytruda attempt to cement itself as a maintenance treatment in mUC. It also calls into question the matter of treatment sequencing – if an immune checkpoint inhibitor is used in the earlier stage of disease, will it limit future treatment options? Given the already restricted list of drugs approved as second-line treatments in mUC, using an immune checkpoint inhibitor as a maintenance treatment is something to be carefully considered.

EV-201: The pivotal Phase II trial of Enfortumab Vedotin shows impressive ORR rates in patients who have progressed following chemotherapy and immunotherapy

Perhaps the most ground-breaking and stimulating results in bladder cancer from ASCO were those of the pivotal Phase II EV-201 trial evaluating Enfortumab Vedotin. Data from patients who had progressed following both chemotherapy and immunotherapy were presented; Enfortumab Vedotin achieved an impressive ORR of 42% with 9% complete response (CR)4. These results are of significance, because there is a lack of effective treatments for patients who have progressed following both chemotherapy and immunotherapy. Thus, the consensus amongst key opinion leaders in the field is that Enfortumab Vedotin is a very promising treatment that caters to an unmet need. Enfortumab Vedotin also represents yet another entirely new class of drug to treat bladder cancer – antibody drug conjugates (ADCs). Such results show the potential for this drug class, should additional effective bladder tumor biomarkers be identified.

RC-48: An ADC using HER2 as a target files for Investigational New Drug

A peek at the use of HER2 as a target in bladder cancer was also delivered at ASCO 2019. Chinese company, Remegen, announced results of a Phase II trial investigating RC-48 – a HER2-targeting ADC – in patients with metastatic urothelial cancer who had received previous treatment with chemotherapy and had visceral metastasis. The ORR was an impressive 60.5% in HER2-positive patients with ≥1 prior systemic treatment, and the data is being used to support an investigational new drug application to the FDA in the latter half of 20195.

These abstracts highlight the sheer pace of the developing market in bladder cancer. A greater understanding of bladder cancer at the molecular level has propelled a shift towards targeting specific biomarkers, reflected in the number of small molecule inhibitors entering the pipeline, as well as the introduction of ADCs targeting commonly overexpressed proteins such as HER2 and Nectin-4. Hopefully this diversification of treatment options can lead to an increase in patient survival in the future and although there remains a lot of progress to be made, research is certainly taking a step in the right direction.

  1. Galsky, M.D., Hahn, N.M., Rosenberg, J., Sonpavde, G., Hutson, T., Oh, W.K., Dreicer, R., Vogelzang, N., Sternberg, C.N., Bajorin, D.F. and Bellmunt, J., 2011. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. Journal of Clinical Oncology, 29(17), pp.2432-2438.
  2. Siefker-Radtke AO et al. FIERCE-22: Clinical activity of vofatamab (V) a FGFR3 selective inhibitor in combination with pembrolizumab (P) in WT metastatic urothelial carcinoma, preliminary analysis. DOI: 10.1200/JCO.2019.37.15_suppl.4511 Journal of Clinical Oncology 37, no. 15_suppl (May 20 2019) 4511-4511.
  3. Galsky MD et al. Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients (pts) with metastatic urothelial cancer (mUC): HCRN GU14-182. J Clin Oncol 37, 2019 (suppl; abstr 4504).
  4. Petrylak DP et al. EV-201: Results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. J Clin Oncol 37, 2019 (suppl; abstr LBA4505).
  5. Sheng X et al. A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma. DOI: 10.1200/JCO.2019.37.15_suppl.4509 Journal of Clinical Oncology 37, no. 15_suppl (May 20 2019) 4509-4509.

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