Next Steps in Bladder Cancer Include Chemoimmunotherapy, Targeted Agents, and ADCs

Guru Sonpavde, MD

While there are 5 single-agent checkpoint inhibitors approved for the second-line treatment of patients with metastatic urothelial cancer, and 2 in the frontline space, ongoing studies of combining immunotherapy with chemotherapy have the potential to further improve patient outcomes, explained Guru Sonpavde, MD.

For example, the phase III KEYNOTE-361 study (NCT02853305) is evaluating the efficacy and safety of pembrolizumab (Keytruda) with or without chemotherapy compared with chemotherapy alone in patients with advanced or metastatic urothelial carcinoma.

“The metastatic [bladder cancer] setting is mostly an incurable disease—chemotherapy plus PD-1/PD-L1 inhibitors provide an advance,” said Sonpavde. “[Single-agent PD-1/PD-L1 inhibitors] improve outcomes for many patients, but we don’t think they cure most patients. So, patients should be referred to trials to gain access to promising new agents in every setting you can think of.”

Beyond PD-1/PD-L1 inhibitors, other agents are impacting the paradigm. In April 2019, the FDA granted an accelerated approval to erdafitinib (Balversa) for the treatment of adult patients with locally advanced or metastatic bladder cancer with an FGFR3 or FGFR2 alteration that has progressed on platinum-containing chemotherapy.

Additionally, the antibody-drug conjugates (ADCs) enfortumab vedotin and sacituzumab govitecan have both demonstrated clinical activity in patients with advanced disease in phase II and I/II studies, respectively.^1,2

In an interview during the 2019 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Sonpavde, the bladder cancer director at Dana-Farber Cancer Institute, discussed the current use of immunotherapy and the numerous strategies in development.

OncLive: How would you define the most recent advances in bladder cancer?

Sonpavde: The most recent advance has been the approval of erdafitinib, which is a specific pan-FGFR inhibitor in patients who are progressing with metastatic disease post-platinum chemotherapy. This is approved in patients with somatic mutations in FGFR3 or FGFR2, based on a companion assay.

The data with erdafitinib showed that the agent is active in these patients with FGFR2 and FGFR3 alterations in the post-platinum setting. The overall response rate (ORR) [with erdafitinib] is in the 35% to 40% range, with a median duration of response of approximately 6 months. This is clearly an advance and the first biologic, targeted agent for patients with metastatic urothelial carcinoma.

What are the key developments with immunotherapy?

At the moment, we are unveiling some key phase III data in the first-line setting. What we have is 5 agents approved in the post-platinum setting, and we have 2 agents approved in the first-line setting in patients who are cisplatin-ineligible with high PD-L1 expression in the tumor, or in platinum-ineligible patients. The drugs approved [in the first-line setting] are atezolizumab and pembrolizumab in patients regardless of PD-L1 expression.

What are the key data from trials that have recently read out?

We are still unveiling data from phase III frontline trials; these trials are going with the theme of combining checkpoint inhibitors with PD-L1 plus CTLA-4 inhibition. The other strategy is platinum-based chemotherapy plus PD-1/PD-L1 inhibition. We are waiting to see what the results from those studies are. There is a strategy to look at PD-1/PD-L1 inhibitors alone versus chemotherapy in the first-line setting, and we haven’t yet seen the data.

However, what we know from PD-L1—low patients is that single-agent atezolizumab (Tecentriq) or pembrolizumab was inferior to chemotherapy with carboplatin/gemcitabine. Therefore, in PD-L1–low patients, the FDA changed the label for these patients to allow the approval of them to be only in patients who are PD-L1 high and cisplatin-ineligible. For patients who are PD-L1 low, we still have to administer gemcitabine/carboplatin in the first-line, cisplatin-ineligible setting.

Are there agents under investigation to target PD-L1—low patients?

There are trials being planned in that patient population. We will wait and see what happens with the combination of chemotherapy and PD-1/PD-L1 inhibitors and that is also being looked at in these ongoing phase III trials in both cisplatin-eligible and -ineligible patients.

There are other trials looking at a different strategy. There is an Intergroup trial for cisplatin-ineligible patients comparing cisplatin/gemcitabine with or without bevacizumab (Avastin) or placebo. We will wait and see what the data are from that trial.

Yet another strategy being looked at in one trial is essentially the “kitchen sink” strategy combining durvalumab (Imfinzi) and tremelimumab—a PD-L1 inhibitor and a CLTA-4 inhibitor—plus platinum-based chemotherapy, compared with chemotherapy, or chemotherapy plus PD-L1 inhibition alone.

How is immunotherapy used following disease progression, specifically durvalumab?

There are 5 agents approved in patients progressing on platinum-based chemotherapy, and the one agent with phase III level 1 data is pembrolizumab. However, there are 4 other agents approved and durvalumab is one of them. With durvalumab, the data are somewhat similar in terms of activity. It is difficult to compare these agents across trials, and durvalumab was approved based on a large nonrandomized phase II trial, in which the responses seen were similar to other agents and were durable. The toxicity profile is similar, in the 10% to 15% range of grade 3 or higher toxicities. Durvalumab is clearly an important agent in these patients in the post-platinum setting and provides yet another option for these patients.

How do you approach patient selection with the 5 checkpoint inhibitors?

The easy answer to that question is that the only agent with level 1 evidence is pembrolizumab. That is proven in the phase III KEYNOTE-045 trial, in which pembrolizumab was superior to chemotherapy regardless of PD-L1 expression. All the other agents are approved based on nonrandomized phase II data, showing responses in the 15% to 25% range, with durability of responses. Atezolizumab, as you may know, could not be shown to be superior to chemotherapy in the phase III trial. The first step was looking at PD-L1—high patients with atezolizumab, in which this was not statistically better than chemotherapy. Really, at the moment, the easy answer to that question is pembrolizumab because those data were shown in a phase III trial.

Could you discuss the early promise of sacituzumab govitecan?

Sacituzumab govitecan is an ADC that targets a membrane antigen and is combined with an irinotecan compound, which has significant activity in patients who progress on platinum-based chemotherapy, with responses seen in approximately one-third of patients. The toxicity profile was quite manageable, with myelosuppression and diarrhea being seen. This is an agent that might serve a useful purpose in this patient population. We’ll wait and see if these data could lead to potential early approval. The drug is being looked at in larger data sets, so we will wait for those trials.

There have also been data with enfortumab vedotin. Could you discuss these findings?

Enfortumab vedotin is also an ADC it has the toxin [monomethyl auristatin E], and this agent has shown significant activity in patients who following platinum-based therapy, as well as have been exposed to prior PD-1/PD-L1 inhibitors. Responses were seen in approximately 35% to 40% of patients, and it is generally a tolerable agent. The toxicities tend to be sometimes a skin rash and sometimes manageable neurotoxicity. Overall, the ORR with this agent in this population fulfills a big unmet need and we’re hoping that this agent will also become available to us sometime in the future.

What are other exciting and emerging approaches?

We wait for confirmatory phase III trials with enfortumab vedotin and the FGFR inhibitors—that includes erdafitinib—and there is yet another FGFR inhibitor rogaratinib being looked at in a phase III trial in previously treated patients. There are exciting combinations with immunotherapy drugs being looked at.

There are also interesting studies looking at the adjuvant setting after radical cystectomy, looking at PD-1/PD-L1 inhibitors as adjuvant therapy to improve cure rates. Even more exciting is neoadjuvant therapy where phase III trials have launched combining platinum-based chemotherapy plus PD-1/PD-L1 inhibition. Also, trials are being launched in cisplatin-ineligible patients, in the neoadjuvant space, where we have nothing at the moment approved. These patients go straight to radical cystectomy.

In the neoadjuvant space, what looks promising are a couple of phase II trials that looked at pembrolizumab or atezolizumab alone. The pathologic complete responses looked somewhat promising in the 30% to 40% range. That was very promising, so we’ll wait and see what happens with these agents. Phase III trials are being planned.

What are the biggest challenges in the paradigm?

Bladder cancer is a highly heterogeneous disease; there are many pathways and many molecules driving the disease. There is not a dominant target that sticks out. That has been a big challenge in improvement cure rates. The challenges have been addressed partly with immunotherapy; since this is a cancer with a high mutation burden, immunotherapy has brought these advances that we had not had for a long time. The combinations of immunotherapy drugs might provide a bigger increment than what we have seen so far. There are lots of phase I trials ongoing looking at these exciting combinations, and we have many of them open at Dana-Farber Cancer Institute. I hope they will take us to the next level.

References

1. Seattle Genetics and Astellas Announce Positive Topline Results from Pivotal Trial of Enfortumab Vedotin in Locally Advanced or Metastatic Urothelial Cancer. Seattle Genetics. Published March 28, 2019. https://bit.ly/2OuyERy. Accessed March 28, 2019.
2. Tagawa S, Faltas BM, Lam ET, et al. Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): results from a phase I/II study. J Clin Oncol. 2019;37(suppl 7S; abstr 354). meetinglibrary.asco.org/record/170545/abstract.