Drakaki Describes Efforts to Leverage Immunotherapy in Urothelial Carcinoma

Alexandra Drakaki, MD

New and emerging trials focusing on immunotherapy and novel biomarkers may soon yield useful information that could be used to optimize treatment for patients with urothelial carcinoma, according to Alexandra Drakaki, MD, an assistant professor of medicine in urology and hematology/oncology at the University of California, Los Angeles.

In MORPHEUS-mUC, a phase 1/b2 open-label, multicenter, umbrella trial, investigators are evaluating the safety and efficacy of multiple immunotherapy-based treatment combinations in patients with locally advanced/metastatic urothelial carcinoma who have progressed on a platinum-containing chemotherapy. In stage 1 of the trial, the PD-L1 inhibitor atezolizumab (Tecentriq) will be administered either as a monotherapy or in combination with: enfortumab vedotin-ejfv (Padcev), niraparib (Zejula), magrolimab (formerly Hu5F9-G4), isatuximab-irfc (Sarclisa), linagliptin (Tradjenta), or tocilizumab (Actemra).^1,2 In stage 2 of the trial, investigators will examine atezolizumab plus either enfortumab vedotin or linagliptin, unless these combinations fail to show activity in the first portion of the trial.

"The aim of the trial is to find the right combination where we can enhance immune system [response], tumor infiltration, and immune cell activation," said Drakaki. "We are interested to find out what the mechanisms are in patients who develop resistance and how we can modify our future combinations [accordingly]. The beauty of the study is that if you have arms that are not seeing an efficacy signal, [you can] close them and [open] new ones [that] have clinical data to suggest [that another combination could be] the right one."

Within the same field, another study assessed the effects of immune checkpoint inhibitors on the immune microenvironment in patients with metastatic urothelial carcinoma who progressed on checkpoint inhibitors.³ To do this, investigators obtained samples from the primary or metastatic tumor prior to treatment with these inhibitors which were paired with samples collected from metastatic sites following treatment. Using the NanoString PanCancerIO360 panel for main genes of interest, including MAGEA3/6, CD274, HLADP, HLAA, B2M, and PDCD1, differential mRNA expression was evaluated.

Investigators found that the MAGEA3/6 mRNA expression was unchanged in post-treatment samples and immune cell localization genes CPA3, TPSAB1/B2, HDC, and MS4A2 were significantly downregulated post-treatment.

In an interview with OncLive, Drakaki discussed the ongoing research efforts being made in urothelial cancer, unmet needs and challenges faced in the space, and work that is generating further interest in the field.

OncLive: Could you provide some background to the MORPHEUS-mUC trial?

Drakaki: MORPHEUS-mUC is a phase 1/b2 umbrella study. In this [research], we are focusing on patients with metastatic urothelial cancer who progressed after platinum-based chemotherapy. As you may know, it is an adaptive study design and it is being sponsored by [Roche Group's] Genentech. It is a great partnership between Genentech and high-tier institutions throughout the world, including Greece, Spain, United Kingdom, France, South Korea, and the United States.

What is the study examining?

Cancer immunotherapy is trying to enable preexisting immunity to mount an effective cancer immune response. With the MORPHEUS-mUC trial, we have patients [who] are going to be randomized into 6 arms. We're going to have the control arm that will be testing atezolizumab, which is a PD-L1 inhibitor. The other combination arms will include atezolizumab plus a drug that is a targeted therapy or chemotherapy and targets specific pathways. Those drugs will include agents targeting CD47, CD38, DPP-4, nectin-4, PARP, [and IL-6R].

Patients who are enrolled on the study will start in stage 1 of the trial. They will be randomized into 1 of the 6 arms. Then, at the time of progression, if they have a good performance status, there is no safety concern, and there is available tissue, they will undergo biopsy. Then, we will be able to go to stage II of this trial in which [patients] will be randomized either to atezolizumab with enfortumab vedotin, which we know was approved [by the FDA] recently, or will be randomized to atezolizumab and linagliptin.

What are the goals of this trial?

The primary end point of the study is objective response rate (ORR) [and] secondary end points are progression-free survival (PFS) and overall survival (OS). We are interested in evaluating 12-month OS. Of course, we are also interested in safety, so we want to see [what] the immunity-related [adverse events (AEs) are] and frequency of these events. Additionally, we are looking into the biomarker analysis. We will be very focused on patients who are not responding and will try to find out why this is happening. The way we selected the different arms is based on the knowledge we got from prior immunotherapy trials with the IMvigor [trials] where atezolizumab was given to patients with urothelial cancer. There is already some background rationale to support the use of these current combinations.

Could you elaborate on the patients who are eligible for enrollment on the trial?

It would be great if colleagues around the world reach out to us so that we can direct them to the institutions where the study is open. As I mentioned, this trial is being done in Spain, Greece, France, the United Kingdom, South Korea, and the United States. Patients who are progressing on platinum-based therapy and are immunotherapy naive will have the option to be enrolled in the MORPHEUS-mUC trial. We are also going to potentially add arms where patients are pretreated with immunotherapy. We are not there yet, but this is something we are discussing. We are available to answer questions and are happy to guide our colleagues to where patients can be treated.

When are data from this trial expected to be published?

So far, the study is running and we do not have any safety concerns. No new safety signals have emerged that we need to be worried about. It is too early to start interpreting the data, but we hope in upcoming meetings we will be able to start discussing some of the combinations and responses [observed] in our patients.

Could you speak to your work regarding targets for immunotherapy?

This work started at UCLA and it is a great collaborative effort with colleagues at Memorial Sloan Kettering [Cancer Center], Columbia [University Herbert Irving Comprehensive Cancer Center], and City of Hope. This work is being supported by Kite Pharma, [a subsidiary of] Gilead Sciences. Specifically, we looked at the differential expression of specific proteins in MAGE-A3/A6, which is a melanoma-associated antigen-A that belongs to the family of CD8 cancer/testis antigens. Those proteins tend to be expressed in different cancer types, but not in normal tissue and that is why it is a great target for immunotherapy.

What we did with our colleagues is, we took patients with metastatic urothelial cancer who had been treated with immune checkpoint inhibitors, and we had tissue collected before and after treatment. We took the tissue and ran a 730 immune-related gene panel. We focused specifically on proteins that are related to antigen presentation and immune activation. One of our genes of interest was MAGE-A3/A6 and we found that it was very stable before and after immune checkpoint inhibitors, so that makes it an attractive target for immunotherapy. Right now, Kite-Gilead is running an engineered T-cell receptor therapy for MAGE-A3/A6, so all of this work we have done these past couple years provides the rationale for this trial. This trial is ongoing, so we hope in future meetings to have more data to share.

What is the biggest unmet need in this space?

The importance of this trial is to try and get more treatments available to our patients. We have immune checkpoint inhibitors and newer drugs are coming out, such as antibody-drug conjugates like enfortumab vedotin, and sacituzumab govitecan (Trodelvy) may be the next to come. We also have erdafitinib (Balversa). All of these drugs induce some responses; however, at some point, patients progress. As such, we are all interested to see how we can utilize the knowledge from the chimeric antigen receptor (CAR) therapies and T-cell receptor therapies to understand how we can best utilize them for patients with metastatic urothelial cancer. Hopefully, that approach will be the next breakthrough [in the space].

What are some of the challenges faced with regard to biomarkers and patent selection for immunotherapy?

A big challenge that we have as genitourinary oncologists when taking care of patients with urothelial cancer is that we do not know how to select our patients. All these immunotherapies and novel therapies we are using have some efficacy but also have toxicity. In an ideal world, we want to see a patient, identify their specific characteristics, and know based on those characteristics what drug they will respond to and which drugs will come with less toxicities. From all the studies that we are running, whether they are sponsored by pharmaceutical companies or they are driven by investigators, we try to do molecular and biomarker testing to try and identify the right biomarkers to guide us, how to select patients who are going to respond [to a certain treatment], and how to select patients so they experience less AEs from those given therapies.

Are any other research efforts being done in urothelial cancer that you find particularly interesting?

We are in a period where many first-line trials are ongoing. All of us who got involved in the study designs or conducted the trials in our institution are waiting to start getting the data out. [By understanding] how we're going to be treating our first-line patients, we'll then get more data [to inform us on] what to do in the second- and third-line settings. As you know, enfortumab vedotin was recently approved in the third-line setting, so we are about to run a first-line trial where enfortumab vedotin will be combined with pembrolizumab (Keytruda). We are very excited to see how that will impact response rates and how we treat our patients.

Another important twist to how we treat our patients is by using these drugs earlier in disease treatment. We are opening fascinating neoadjuvant trials where agents are being used in patients who are cisplatin eligible or ineligible. Adjuvant immunotherapy [trials are also ongoing. We saw some data from the atezolizumab study, but we need to look deeper into who the patients were who experienced benefit from adjuvant atezolizumab versus those who did not. Of course, the AMBASSADOR [trial] is still enrolling. We are also waiting to hear more about the use of nivolumab (Opdivo) in the adjuvant setting. Exciting studies are happening and, hopefully within the next year or 2, we can start using the information from these trials to [better] treat our patients.

References

1. A study evaluating the efficacy and safety of multiple immunotherapy-based treatment combinations in patients with locally advanced or metastatic urothelial carcinoma after failure with platinum-containing chemotherapy (MORPHEUS mUC). ClinicalTrials.gov. Updated May 6, 2020. Accessed May 13, 2020. www.clinicaltrials.gov/ct2/show/NCTs03869190.
2. Drakaki A, Kalebasty AR, Lee J-L, et al. Phase Ib/II umbrella trial to evaluate the safety and efficacy of multiple 2L cancer immunotherapy (CIT) combinations in advanced/metastatic urothelial carcinoma (mUC): MORPHEUS-mUC. J Clin Oncol. 2020;38(suppl 6): TPS591. doi:10.1200/JCO.2020.38.6_suppl.TPS591
3. Faiena I, Funt SA, Astrow SH, et al. Differential expression of melanoma-associated antigen A3/6 and associated immune molecules prior to and post treatment with immune checkpoint inhibitors (ICI) in patients with mUC. J Clin Oncol. 2020;38(suppl 6): 433. doi:10.1200/JCO.2020.38.6_suppl.433