Precision Medicine to Take Hold in Advanced Bladder Cancer

Parminder Singh, MD

Beyond the availability of checkpoint inhibitors for patients with advanced bladder cancer, investigators are continuing to search for synergistic combinations, targeted therapies, and biomarkers of response that will further propel the field forward, explained Parminder Singh, MD.

“The field is moving very fast with newer agents that are being approved,” said Singh. “Most likely, several new agents will receive regulatory approval this year as well. Our understanding of precision medicine in bladder cancer is going to expand very quickly over the next year or so. We need to be aware of and ready for that information.”

One promising therapeutic class in particular is antibody-drug conjugates (ADCs). In July 2019, a biologics license application was submitted to the FDA for enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and platinum-based chemotherapy.

Additionally, targeted agents are of interest in the space. In April 2019, the FDA granted an accelerated approval to erdafitinib (Balversa) for patients with locally advanced or metastatic bladder cancer with an FGFR3 or FGFR2 alteration that has progressed on platinum-based chemotherapy. This decision led to the first targeted therapy available for use in patients with metastatic bladder cancer.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Singh, a hematologist/oncologist at Mayo Clinic, discussed ongoing research in advanced urothelial cancer and the focus on incorporating precision medicine in the field.

OncLive: Is immunotherapy the standard treatment for platinum-ineligible patients?

Singh: Immunotherapy has been evaluated in patients who had progressed on chemotherapy as well as those who were chemotherapy-ineligible. At this point, the FDA has stated that patients who have a low PD-L1 expression should not receive immunotherapy as first-line therapy. However, patients who have high PD-L1 expression can receive immunotherapy as first-line treatment. All patients, after progression on chemotherapy, can receive a checkpoint inhibitor.

Could you discuss any ongoing work with biomarkers, such as PD-L1?

PD-L1 is a marker we are looking at; however, we don't have the conclusive data from the FDA [supporting its use as a marker for frontline immunotherapy eligibility]. Another marker, tumor mutational burden (TMB), is being looked at in trials, especially those evaluating atezolizumab (Tecentriq). In those studies, patients with [high] TMB had a good response rate to the agent; there is merit to this biomarker in bladder cancer.

Other tumor subtypes, such as basal and luminal subtypes, might come up in the future, according to their mRNA expression. As the data mature, we’ll have a better understanding of the applicability of these tests, which may have a role in predicting those who will respond to immunotherapy.

Could you discuss the research with ADCs?

We know that most patients who receive a checkpoint inhibitor will progress. In general, if you look across [checkpoint inhibitors, the response rate is about] 15% to 20%. There is clearly an unmet need in this space. ADCs, such as enfortumab vedotin and sacituzumab govitecan, have come into this space. Trials are ongoing.

Data with enfortumab vedotin, which were presented at the 2019 ASCO Annual Meeting, showed a remarkable response rate of around 44% in patients who had received prior immunotherapy and chemotherapy. Up to 12% of patients achieved a complete response (CR), which is very promising. I'm sure this molecule will move forward and become a definitive therapeutic option for this patient population.

Could you discuss the FDA approval of erdafitinib based on data from the phase II BLC2001 trial?

Erdafitinib was granted an accelerated approval by the FDA in April 2019 as a treatment for patients with an FGFR3 or FGFR2 mutation. This is a pan-FGFR inhibitor, which showed a response rate of approximately 33%. Moreover, 3% of patients had a CR with the agent. This molecule is being investigated further in a head-to-head phase III trial with immunotherapy and chemotherapy; that trial will solidify its approval in the space for patients who have this mutation.

What other agents are being explored?

Combination strategies are emerging in the field. Padmanee Sharma, MD, from The University of Texas MD Anderson Cancer Center, presented data on the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), which showed a response rate of about 40% in patients who received the 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab.

Immunotherapy is also being combined with other agents. There are trials combining immunotherapy and ADCs, as well as immunotherapy plus chemotherapy. The space is going to expand with combination strategies, as well as the newer molecules which are coming out.

Is there any rationale to explore combinations in the frontline setting?

The drugs that are getting approved in the advanced setting are already moving into the first-line space. We opened the SWOG 1806 trial, which is looking at the combination of chemotherapy with radiation and atezolizumab (Tecentriq) in localized bladder cancer. There are other clinical trials combining chemoimmunotherapy in the neoadjuvant space. It is clear that these molecules are going to move into earlier lines of therapy. There are also clinical trials combining FGFR3 molecules with chemotherapy in earlier-line settings. As our understanding of these newer molecules and our comfort level with these molecules improves, there will be a natural progression [of these agents] into early-stage disease; we'll see the field expand in that sense.

What should your colleagues working in this field be aware of?

This space is going to explode very fast with newer combination strategies. Newer translational research is coming out, which will help guide treatment options. We already know that TMB and PD-L1 expression have a role in predicting response to immunotherapy. Furthermore, FGFR3 mutations are going to help guide treatment in that subgroup of patients. There are also DNA damage repair mutations, which are going to show an association with chemotherapy response. Treatment is going to become more precision-based. We need to be aware of these upcoming changes as well as the strategies that are being explored to increase response rates. Treatments are going to become complicated, but patients are going to live longer. The burden will be on the oncologists to be aware of all these nuances when treating patients.

Given the potential of targeted therapy, should genomic testing be incorporated into routine practice?

Most medical oncologists are already using different platforms to test their patients, including FoundationOne or Caris Life Sciences. Newer platforms from Tempus are coming into the market. These platforms are giving us information regarding PD-L1 expression, TMB, and mutations in FGFR3. In addition to DNA damage repair mutations, these assays provide us with information on these markers. This has, more or less, already become standard of care.

The paradigm is going to change in the future with circulating tumor DNA (ctDNA). The technology is changing very fast. We may be doing this testing as we are treating our patients so that we can identify clones which are going to respond to different modalities. That's where the space is going to expand moving forward. Physicians are already doing baseline testing, but the field is going to move forward with sequential testing—especially with ctDNA.