Enfortumab Vedotin Emerging as Post-Immunotherapy Option in Bladder Cancer

Jonathan E. Rosenberg, MD

Enfortumab vedotin may be a safe, well-tolerated option for patients with locally advanced or metastatic urothelial cancer who are previously treated with immunotherapy, an area for which the current alternative is platinum-based chemotherapy, explained Jonathan E. Rosenberg, MD.

“Single-agent chemotherapy might be an option for some of those patients, but [enfortumab vedotin] may be a very good alternative,” said Rosenberg, chief of the Genitourinary Cancer Service at Memorial Sloan-Kettering Cancer Center. He presented updated data from the phase I EV-101 study with enfortumab vedotin at the 2018 ASCO Annual Meeting.

The antibody-drug conjugate enfortumab vedotin consists of an anti—Nectin-4 monoclonal antibody attached to vedotin, a microtubule-disrupting agent MMAE, using proprietary linker technology from Seattle Genetics, the drug’s manufacturer.

In March, the FDA granted breakthrough therapy designation to enfortumab vedotin for the treatment of patients who previously received checkpoint inhibitors for locally advanced or metastatic urothelial cancer. The designation was based on interim results from a phase I dose-escalation/dose-expansion trial showing an overall response rate (ORR) of 41% (95% CI, 29.3-53.2), including 3 (4%) complete responses and 26 (37%) partial responses.¹

The trial included 71 evaluable patients who received treatment with enfortumab vedotin 3 out of 4 weeks in a 28-day cycle until there was no further clinical benefit. In updated results presented at ASCO, the data showed that in patients who previously received a checkpoint inhibitor or had liver metastases, the ORR was 40% and 39%, respectively.²

Investigators are exploring the ADC in the ongoing, pivotal phase II EV-201 trial (NCT03219333).³ Investigators hope to recruit 100 platinum-treated patients as well as 100 platinum-naïve and cisplatin-ineligible patients at 57 sites in 8 countries. Eligible patients must have unresectable, locally advanced or metastatic urothelial carcinoma and have received previous treatment with a checkpoint inhibitor.

The agent is also being evaluated in combination with either pembrolizumab (Keytruda) or atezolizumab (Tecentriq) in the phase I EV-103 trial (NCT03288545).

OncLive: What was the rationale for the phase I trial?

In an interview with OncLive^®, Rosenberg, lead investigator for the phase II study and the updated phase I results, discussed the promise of enfortumab vedotin in patients with bladder cancer who previously received a checkpoint inhibitor, and reflected on the rapid pace of change in the urothelial cancer landscape.Rosenberg: Enfortumab vedotin is an antibody-drug conjugate that targets a molecule that's overexpressed in about 93% of bladder cancers. When it's infused into patients, it circulates throughout the body but it's taken up in cells that express Nectin-4, the target of the molecule. Vedotin is released in the lysosome through cleavage by proteases, the cytotoxic then kills the cancer cell through antimicrotubular activity. That's the proposed mechanism of action. Nectin-4 is also expressed in the skin at low levels, so skin toxicity can be an on-target toxicity of the drug.

That provided the rationale for the phase I study. That study did an initial dose escalation and identified the recommended phase II dose, which is 1.25 mg/kg. The data that are presented [at the 2018 ASCO Annual Meeting] are the data from the dose expansion at 1.25 mg/kg.

More than 110 patients were included in that cohort, the majority of whom had received prior checkpoint inhibitor therapy as well as prior platinum-based chemotherapy. These are patients for whom there isn't a real standard in the United States. The ORR in that study was 41% which was quite impressive compared with historical controls of taxane monotherapy, which are in the 10% to 15% range, at best.

What have you learned about the toxicity profile of enfortumab vedotin?

In addition, the estimated progression-free survival is more than 5 months and the median overall survival (OS), which is an estimated value based on the Kaplan-Meier curves, is about 13 months. In historical context, we expect a 6- to 10-month OS in this patient population. These are quite promising results for an early-phase study, and provided the rational for the ongoing, pivotal phase II study.Fatigue, anemia, and rash were all common side effects. The rates of grade 3 or higher individual side effects are very low—on average less than 6%. Severe hypoglycemia was identified in a very small fraction of patients; this was a serious adverse event, and the protocols were modified to deal with this. It appears that it might be related to treatment but we're not totally sure at the moment.

What can you tell us about the ongoing phase II trial?

However, on average, patients tolerate it very well and, when it works, they can stay on treatment for many months. I believe the longest person I have on study is about 16 months, and I know people who have gone on longer than that. For patients for whom the treatment works, it is [generally] well tolerated and they are experiencing durable remissions.We're very excited that the phase II study is accruing very well. [If the data between the phase I and II trials are similar] it should lead to a new drug approval in bladder cancer.

Would an approval include both populations?

It's a single-arm study looking at patients who have had checkpoint inhibitor and platinum-based chemotherapy in cohort 1. In cohort 2 are patients who are cisplatin ineligible and who have had a checkpoint inhibitor but not chemotherapy for metastatic disease. There are 2 different patient populations within the same study.It depends on the results. For patients who are refractory to both checkpoint inhibitor and platinum-based chemotherapy, there isn't another option; this truly is an unmet need. If the data are similar with a tolerable toxicity profile or a good response rate—if we're seeing good durability of response and good OS—I suspect it will get accelerated approval pending a phase III trial.

The first-line cisplatin-ineligible patient population just got more complicated with the announcement from the Independent Data Monitoring Committee of 2 randomized, phase III trials saying that checkpoint monotherapy is inferior in patients with low PD-L1¬—expressing tumors, so those trials are now only accruing PD-L1–high expressing patients.

How this affects the entire landscape for first-line, cisplatin-ineligible patients is not at all clear at the moment. The European Medicines Agency restricted the labels of pembrolizumab and atezolizumab to PD-L1—high tumors in cisplatin-ineligible patients. The FDA hasn't done something similar yet, but they may. All of that plays into the design of ongoing or planned frontline cisplatin-ineligible trials.

There have been some new agents introduced for urothelial cancer lately. How would you describe the past few years in this landscape?

However, in patients who had a checkpoint inhibitor and aren't candidates for cisplatin, if they receive enfortumab vedotin, the hope and expectation is that it will be a very active drug and could potentially support an indication in that as well. This is because it's still an unmet need, particularly in the PD-L1—low population and, frankly, for this cohort of people who progressed after immunotherapy.We have had a long drought until about 3 years ago and now we've got 5 immune checkpoints approved in bladder cancer; we have a lot of options for our patients. However, the majority of our patients, unfortunately, do not respond to immunotherapy. It's exciting to hear that these are agents that are active in post-checkpoint patients or, perhaps with erdafitinib in people who have very low response rates to immunotherapy due to the tumor microenvironment and the association of FGFR3 mutation with immunotherapy resistance, which seems to be emerging from some of the checkpoint inhibitor trials.

We're developing drugs now that complement the drugs we have. There may be opportunities for combining them, and there is a phase Ib study going on of enfortumab vedotin and a checkpoint inhibitor. Hopefully we'll see that this combination is promising. We hope that there will be synergy, but even if there's just additive activity, it might be quite useful.

It's been very exciting. It's totally changed how we think about the disease and how we think about patients. We are thinking about sequencing therapies in ways we previously hadn't. When you only have 1 treatment, there's not much to sequence. [We're thinking about] combinations versus sequential therapy versus timing of starting immunotherapy versus targeted agents.

It's our time in bladder cancer, finally. We really have laid the groundwork with The Cancer Genome Atlas work that, in the past year, published a much larger update showing much broader landscape of alterations in urothelial cancer. There is a better understanding of the tumor microenvironment in bladder cancer such that we can now think about why the patients who don't respond to immunotherapy might respond to other agents and rationally design clinical trials.

A lot of work has been done getting specimens from patients on these trials and interrogating them in depth and identifying novel targets and novel pathways that are associated with immunotherapy resistance—either acquired or primary. We're poised to take advantage of all this knowledge right now, and that's paying off for us and our patients.

References

1. Petrylak DP, Perez RP, Zhang J, et al. A phase I study of enfortumab vedotin: updated analysis of patients with metastatic urothelial cancer. J Clin Oncol. 2017;35 (suppl; abstr 106).
2. Rosenberg JE, Sridhar SS, Zhang J, et al. Updated results from the enfortumab vedotin phase 1 (EV-101) study in patients with metastatic urothelial cancer (mUC). J Clin Oncol. 2018;36 (suppl; 4504).
3. Rosenberg JE, Heath EI, O’Donnell PH, et al. EV-201 Study: a single-arm, open-label, multicenter study of enfortumab vedotin for treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor therapy. J Clin Oncol. 2018;36 (suppl; abstr TPS4590).