Sonpavde Provides Overview of New Research That Advances Urothelial Cancer Treatments

During an interview with <em>Targeted Oncology</em>, Guru P. Sonpavde, MD highlights the extensive research around checkpoint inhibition and chemotherapy combinations and how these regimens are advancing bladder cancer treatment.

Guru P. Sonpavde, MD

A series of studies of newer treatments and newer approaches to traditional treatments for patients with urothelial cancer presented during the 2019 ASCO Annual Meeting reveal a host of active regimens to manage the disease.

Research highlighting new agents include the antibody—drug conjugate enfortumab vedotin, which was shown in the phase II EV-201 trial to have a response rate of 44% in patients with previously treated locally advanced or metastatic urothelial cancer. Another study, the randomized, phase II Borealis-2 study investigated apatorsen (OHX-427) plus docetaxel alone in platinum-resistant urothelial cancer.

Other research highlighted at the meeting focused on optimizing treatment with standard therapies, such as the SWOG-S314 trial, which was a randomized phase II study of the gene expression model COXEN as a predictive biomarker for treatment with neoadjuvant chemotherapy for muscle-invasive bladder cancer. Also, a retrospective analysis compared outcomes of treatment with neoadjuvant chemotherapy of gemcitabine and cisplatin in comparison with dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin).

Data from these studies and others show the ways that researchers are trying to move the bar to improve patient outcomes. Going forward Guru P. Sonpavde, MD, says that further research is focusing on the combination of immunotherapy and chemotherapy in the urothelial cancer space, especially for patients who are eligible to receive cisplatin. “The combination of checkpoint inhibition and platinum-based chemotherapy is feasible and looks promising. The phase III trials are going to look at [these combinations] in the cisplatin-eligible space.”

During an interview withTargeted Oncology, Sonpavde, bladder cancer director,Genitourinary Oncology, Dana-Farber Cancer Institute, highlights the extensive research around checkpoint inhibition and chemotherapy combinations and how these regimens are advancing bladder cancer treatment.

TARGETED ONCOLOGY: What bladder cancer research was presented at this meeting that you think are the most practice changing?

SONPAVDE:I think at this meeting, one of the major highlights was the data regarding enfortumab vedotin, that's an antibody—drug conjugate that targets Nectin-4, an additional molecule on the surface of bladder cancer cells. These come on the heels of the approval of erdafitinib (Balversa), which was approved just a few months ago forFGFR3orFGFR2alterations, that includes mutation and fusions.

Now comes the data with enfortumab vedotin, which was a non-randomized phase II trial with around 125 patients that essentially confirms the earlier data from the phase Ib trial. [It showed that] in patients that were post-platinum and post—PD-1/PD-L1 inhibitors [had] an approximate response rate of 40%. What was also impressive is that there was a complete response rate of 9%, and there were robust responses in patients with liver metastases.

So, we look forward to the use of this drug, and we'll hopefully be able to use it soon based on these data. And, there is a confirmatory phase III trial that is ongoing comparing enfortumab versus chemotherapy in the post-platinum plus post—PD-1 exposed patients.

Next, I want to highlight a novel strategy of switch maintenance therapy, which was a randomized phase II trial presented by the Hoosier Cancer Network. These were patients who had finished first-line platinum-based chemotherapy (with 4 cycles at least) and had stable disease or better after platinum-based chemotherapy. The normal strategy is to wait for patients to progress and then deliver a second-line therapy. But, in this study, the patient underwent a switch maintenance strategy comparing pembrolizumab (Keytruda) versus placebo in this setting. It was very promising that the results showed an improvement in progression-free survival—going from 5.5 months median to approximately 8 months median. The survival was not an endpoint that was primary in this study. There was also a crossover of patients from placebo to pembrolizumab [allowed] at progression.

It bodes well for the ongoing phase III trial that is looking at avelumab (Bavencio), a PD-L1 inhibitor, compared with [standard of care] in the other arm.

The third trial that I want to highlight is a phase III trial, this is not practice-changing, but it still informs us regarding further drug development. This was a trial conducted by the Alliance Group and the Inter Group in the United States that compared first-line cisplatin gemcitabine combined with either placebo or bevacizumab (Avastin), which is a VEGF ligand inhibitor. The bottom line is the primary endpoint, survival, was not extended by adding bevacizumab to cisplatin-based chemotherapy. The median survival was around 14 months in both arms. There was a modest improvement in progression-free survival, which was not the primary endpoint, but the hazard ratio was 0.77. The bottom line is this combination of bevacizumab with cisplatin-based chemotherapy did not move the bar up, and cisplatin/gemcitabine [continues to be the standard of care] or other regimens (like MVAC) are also reasonable.

We'll wait and see what happens with the combination of checkpoint inhibitors with cisplatin-based chemotherapy. Those data [will come] hopefully in the near future.

Four, I wanted to highlight a randomized phase II trial that compared gemcitabine/cisplatin (GC), given for 4 cycles versus dose-dense MVAC for 4 cycles, in patients in the neoadjuvant space of muscle-invasive bladder cancer. This trial had a primary endpoint of trying to prospectively look at a gene expression score called COXEN to predict whether patients benefitted from the GC regimen or the dose-dense MVAC regimen. That was the primary endpoint. [However] the COXEN code did not quite predict for response to GC or response to MVAC. Surprisingly, when they looked at both arms together, the score that was supposed to predict pathologic response to GC seemed to have some impact in the overall population.

What I was more interested in was the comparison of GC versus dose-dense MVAC. There's always been some controversy in this area. Historically, MVAC has been the regimen used based on a positive phase III trial, but we have all used GC in the community because it's more tolerable and easier to deliver.

In this study, the pathologic complete response rate was similar with GC or dose-dense MVAC—in the mid 30% range. Of course, this a randomized phase II trial, not a phase III trial. It's somewhat reassuring that what we've been doing in the community for a long time (using GC) might be reasonable. [But], we also want to wait and see how the progression-free survival and overall survival look.

TARGETED ONCOLOGY: What can community oncologist take away from these data?

SONPAVDE: Going forward, what do we do with [these data]. There are trials now trying to combine cisplatin-based chemotherapy with PD-1 and PD-L1 inhibitors in the neoadjuvant space. I have been involved in a phase III trial sponsored by Bristol-Myers Squibb which is looking at GC as a standard arm in the neoadjuvant space compared with GC plus nivolumab, a PD-1 inhibitor. There's [also] a third arm in which we plan to combine GC plus nivolumab plus an IDO1 inhibitor, which also enhances the immune state by inhibiting the IDO1 enzyme, which increases the levels of tryptophan in the environment by inhibiting it's conversion to kynurenine.

We'll wait and see the results of this phase III trial and other phase III trials that are going [on] in the cisplatin-eligible space. Also, in the cisplatin-ineligible space, there are trials looking at an immunotherapy [only] approach, so, a chemotherapy-free approach for cisplatin-ineligible patients [for whom] there is nothing approved at the moment.

TARGETED ONCOLOGY: What impact has the approval of erdafitinib had on this patient population?

SONPAVDE: Erdafitinib is a pan FGFR-specific potent tyrosine kinase inhibitor, given orally. One of the unique things about its approval, [which was] in the post-platinum space. This approval was not in patients that were exposed to both platinum and PD-1. They may or may have not been exposed to a PD-1/PD-L1 inhibitor. [This is] in the post-platinum space for patients who hadFGFR3mutations or fusions (FGFR2alterations are not that common in advanced bladder cancer). Overall, when you look atFGFR3alterations, it occurs in 15 to 20% in metastatic urothelial carcinoma. It appears to be a little more common in upper tract urothelial carcinoma than bladder cancer.

[Another] unique thing about the development of this drug is that in the phase II trial, they had a dose-escalation strategy. [That was] if the pharmaceutical dynamic endpoint of hyperphosphatemia was not met within a couple of weeks, they would increase the dose from 8 mg a day to 9 mg a day.

TARGETED ONCOLOGY: Can you explain the dose-escalation strategy?

SONPAVDE: In the phase II trial, they have a dose-escalation strategy. [The strategy holds] that if the pharmaceutical dynamic endpoint of hyperphosphatemia was not met within a couple of weeks, [there would be an increase in the] dose from 8 mg a day to 9 mg a day. This is a unique strategy that has not been done a lot in oncology.

The dose-escalation strategy might have led to better dosing in more patients. The drug is active with a response rate in the 35% to 40% range in this patient population. The duration of response was a median of around 6 months.

TARGETED ONCOLOGY: Having become aquatinted with some of this new research, what is your overall take on the combination of checkpoint inhibitors and platinum-based chemotherapy for patient with urothelial cancer?

SONPAVDE: The combination of checkpoint inhibition and platinum-based chemotherapy is feasible and looks promising. The phase III trials are going to look at [these combinations] in the cisplatin-eligible space. In the cisplatin-ineligible space, there's a different strategy looking at immunotherapy alone, without a chemotherapy backbone. [This is] because the standard right now in that space is going directly to radical cystectomy.

TARGETED ONCOLOGY: What is the rationale behind some of this research?

SONPAVDE: Data that led to these trials [show] that checkpoint inhibitors by themselves are active in the neoadjuvant space. Atezolizumab (Tecentriq) and pembrolizumab have both been looked at in the neoadjuvant space by themselves with a pathologic complete response in the 30% to 40% range, which is very promising. The combination of pembrolizumab and GC was presented at ESMO last year, and pathologic complete response rate was around 45%.

TARGETED ONCOLOGY: Were there any unique adverse effects associated witherdafitinib in this patient population?

SONPAVDE: There are some unique toxicities with this agent. One is the hyperphosphatemia, but it's very manageable with chelating agents and dietary changes. There is some hand-foot syndrome, again, it was manageable, and most of these [adverse] effects were grade 1 and 2, not grade 3 or 4. The third, [adverse effect] that's somewhat unique, and oncologists haven't been exposed to this with other agents, is eye toxicity of central serous retinopathy (CSR). This causes a central vision defect and an ophthalmologist needs to be involved for patients that get on this drug. I would recommend that an ophthalmologist get involved very early on to monitor the patients and [there] should be some kind of testing in the oncology clinic to look for central visual defects.