Looking Toward the Future of Immunotherapy in Bladder Cancer

Joaquim Bellmunt MD, PhD

The rapid approval of checkpoint inhibitors has provided a wealth of new treatment options for patients with metastatic bladder cancer; however, physicians are now challenged with determining the optimal sequencing of these agents. Community oncologists can refer to 2 pivotal trials for guidance, according to Joaquim Bellmunt, MD, PhD.

In 2-year follow-up findings from the KEYNOTE-045 trial, pembrolizumab (Keytruda) showed sustained improvements in overall survival (OS) versus standard chemotherapy in the frontline setting.

The median OS was significantly longer in those who received pembrolizumab compared with those who received chemotherapy at 10.3 versus 7.3 months, respectively (HR, 0.70;P<.0002).¹Progression-free survival (PFS) did not significantly differ between the 2 arms at 2.1 months versus 3.3 months, respectively (HR, 0.96;P= .32).

Based on the initial data from this trial, pembrolizumab was approved by the FDA in May 2017 as a frontline therapy for patients with locally advanced or metastatic urothelial carcinoma (mUC) who are ineligible for cisplatin-containing chemotherapy. Pembrolizumab also received an indication for patients with locally advanced or mUC with disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Atezolizumab (Tecentriq) is also approved as a frontline treatment for cisplatin-ineligible patients with locally advanced or mUC. In a cohort of the phase II IMvigor210 trial, results showed that the overall response rate with the PD-L1 inhibitor was 23.5% (95% CI, 16.2-32.2), including a complete response rate of 6.7%.2 The frontline approval followed its indication as a treatment for patients with locally advanced or mUC whose disease progressed during or after platinum-based chemotherapy, or <12 months of receiving platinum-containing chemotherapy, either before or after surgery.

However, in May 2018, the FDA issued a drug safety notification warning against the use of frontline single-agent immune checkpoint inhibition for patients with urothelial carcinoma who are considered biomarker-negative; these are patients with PD-L1—low expressing platinum-eligible disease. A similar warning was issued by the European Medicines Agency, both following data demonstrating lower OS with pembrolizumab and atezolizumab versus platinum-based chemotherapy in these patients.

Despite that there have not been any head-to-head trials, Bellmunt, who is the director of the Bladder Cancer Center at Dana-Farber Cancer Institute and a professor of Medicine at Harvard Medical School, said pembrolizumab should be the frontline option followed by atezolizumab in the second-line setting for patients with metastatic bladder cancer.

In an interview withTargeted Oncology, Bellmunt provided insight on how to navigate the complex treatment paradigm of metastatic bladder cancer.

TARGETED ONCOLOGY:What are the latest advances in the treatment of patients with metastatic bladder cancer?

Bellmunt:We have a wealth of new opportunities for patients. In fact, we have seen that in the span of just 1 year, there have been 7 FDA approvals for immunotherapy agents in this space. Five drugs were approved for second-line treatment for patients who progress on platinum-based chemotherapy; two of these drugs were approved for the frontline treatment of patients who are ineligible for chemotherapy.

TARGETED ONCOLOGY:Which checkpoint inhibitor should be the first choice for treatment?

Bellmunt:We have no head-to-head comparisons. The approvals were based mainly on phase I and II clinical trials where we saw the responses were highly durable. The survival benefit also made it worth it to use these agents. We need to move on to the era of phase III trials, and we currently have 2 of these ongoing. We can say the only one that has demonstrated a clear survival advantage is the KEYNOTE-045 trial, which compared pembrolizumab with standard chemotherapy for second-line treatment. This trial showed superiority for the checkpoint inhibitor versus chemotherapy. The quality of life was also much better for the patients who received immunotherapy.

The other trial was the [phase II] IMvigor210 study, which tested the use of atezolizumab against chemotherapy in a similar design. Atezolizumab did a great job, matching what we saw in [other] phase II studies. However, in the phase III [IMvigor211] trial, there was no statistically significant difference.

So, based on this evidence, we can say that the first option is pembrolizumab. However, we have atezolizumab, durvalumab (Imfinzi), avelumab (Bavencio), and nivolumab (Opdivo). These are certainly options [in the second-line setting], too.

TARGETED ONCOLOGY:Is the goal to move away from chemotherapy or is it here to stay?

Bellmunt:We initially thought that immunotherapy would replace chemotherapy, but we have seen that only about 20% of patients respond to immunotherapy. Moreover, only half of the patients who respond have durable responses, and so we have huge room for improvement. We are only benefitting a small percentage of patients [with this treatment approach]. In diseases such as lung cancer and kidney cancer, we have seen that combining chemotherapy with immunotherapy—or 2 different types of immunotherapy&mdash;can improve patient outcomes.

The future for bladder cancer, specifically for frontline treatment, will probably be in combinations. We cannot forget that chemotherapy is an active way of treating these patients. We might enhance this [activity through the use of] combination [regimens].

TARGETED ONCOLOGY:What is your advice for managing immune-related adverse events (AEs)?

Bellmunt:Although these AEs are not frequently seen, when you are using single-agent immunotherapy, you can have an unexpected AE become life-threatening, which obviously is a major threat to the patient. The first thing is that you need to know the AEs are there; they can happen in any patient. We have no predictive biomarkers of which patients will develop an AE. We need to know that if we find an AE pretty soon in the disease history, we can stop therapy and implement steroids.

TARGETED ONCOLOGY:What are the next steps for research in metastatic bladder cancer?

Bellmunt:The next steps are with combination therapy. Combinations need to be explored in new trials with select patients who are enriched with biomarkers. We do not have a final answer in terms of biomarkers, but we need to prospectively design trials in which patients are enriched with tumor mutational burden and PD-L1 staining. We could also be genomically profiling the patients before they undergo treatment. The future involves biomarker-driven trials and combinations.

References:

1. Bellmunt J, De Wit R, Vaughn DJ, et al. Two-year follow-up from the phase 3 KEYNOTE-045 trial of pembrolizumab (pembro) vs investigator&rsquo;s choice (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer (UC) [ASCO abstract 410].J Clin Oncol. 2018;36(suppl 6; abstr 410). doi: 10.1200/JCO.2018.36.6_suppl.410.
2. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.Lancet. 2017;389(10064):67-76.