Enfortumab Vedotin Plus Pembrolizumab Shows Promise in Urothelial Cancer

Christopher J. Hoimes, MD

More than 70% of patients with cisplatin-ineligible locally advanced urothelial cancer had objective responses to the investigational antibody-drug conjugate enfortumab vedotin plus pembrolizumab (Keytruda), a preliminary clinical evaluation showed.

Responses to enfortumab vedotin and pembrolizumab occurred quickly and irrespective of PD-L1 expression status. The combination’s safety profile appeared to be manageable and tolerable and was similar to previous trials of single-agent enfortumab vedotin, Christopher J. Hoimes, MD, of Case Western Reserve/Seidman Cancer Center, reported at the 2019 ESMO Congress.

“There is a high unmet need for effective and tolerable therapies in first-line cisplatin-ineligible patients with locally advanced and metastatic urothelial cancer,” said Hoimes. “Enfortumab vedotin plus pembrolizumab demonstrates encouraging activity in this population. Enfortumab vedotin plus pembrolizumab has the potential to become a platinum-free option for cisplatin-ineligible locally advanced and metastatic urothelial cancer patients in the first-line setting.”

The study population described by Hoimes has a historical response rate of about 40% with standard-of-care regimens consisting of gemcitabine and carboplatin. The patients have limited treatment options that are associated with poor durability, tolerability, and survival, he said. Recently, PD-1/PD-L1 inhibitors have shown promising durability in patients whose tumors exhibited high PD-L1 expression.

Enfortumab vedotin targets nectin-4, a protein that is highly and uniformly expressed by urothelial cancer and certain other solid tumors. In an early clinical trial, treatment with single-agent enfortumab vedotin led to a 44% objective response rate, including complete responses in 12% of patients with locally advanced/metastatic urothelial cancer that had progressed on platinum-based chemotherapy and PD-1/L1 inhibitors. The agent had a manageable and tolerable safety profile.

The encouraging activity of single-agent enfortumab vedotin supported its evaluation in the first-line setting, said Hoimes.

Several lines of evidence provided a rationale for combining enfortumab vedotin with pembrolizumab. The anti—nectin-4 antibody is linked to the microtubule disruptor monomethyl auristatin E, which induces immunogenic cell death (ICD). ICD results in the release of innate immune-activating molecules that stimulate antigen presenting-cell activation and presentation of tumor antigens to T cells. The T-cells then mount an antigen-specific response, which PD-1/L1 inhibitors have been shown to augment.

Hoimes reported findings from a dose escalation/expansion study involving patients with cisplatin-ineligible urothelial cancer. The dose-escalation phase included patients (n = 5) with cisplatin ineligibility in the first- or second-line setting. The expansion phase limited enrollment to patients (n = 40) with newly diagnosed disease. Patients received enfortumab vedotin on days 1 and 8 of 3-week cycles, and pembrolizumab was administered on day 1 of each cycle.

The primary endpoints were adverse events and laboratory abnormalities. Secondary endpoints included dose-limiting toxicities, objective response rate, disease control rate, duration of response, and overall survival.

The 45 patients had a median age of 69, and men accounted for 80% (n = 36) of the study population. The primary tumor location was lower tract in 69% (n = 31), and metastatic sites consisted of lymph nodes only in 4 patients, and visceral disease in the remaining 41, including liver metastases in 15 patients. PD-L1 expression status by combined composite score was <10 in 19 patients, ≥10 in 13, and not evaluable/not available in 13.

Median treatment duration was 6.0 months and median number of treatment cycles was 7.0.

The combination of enfortumab vedotin and pembrolizumab led to objective responses in 32 (71%) patients, including complete responses in 6 (13%). Ten (22%) additional patients had stable disease as best results, leading to a clinical benefit rate of 93%. Two patients were not evaluable for response status, leaving just 1 patient with progressive disease as best response. All but 3 evaluable patients had some degree of tumor shrinkage.

Hoimes said 91% of objective responses were observed at the first assessment (week 9), and the median time to response was 2.0 months. Duration of response ranged from 1 to 10.5 months and ongoing, and 22 of 32 responding patients remained on treatment.

Treatment-related adverse events (TRAEs) occurring in ≥20% of patients included fatigue (49%), alopecia (47%), peripheral sensory neuropathy (47%), diarrhea (40%), decreased appetite (33%), dysgeusia (31%), nausea (29%), pruritus (27%), maculopapular rash (27%), weight loss (22%), and anemia (20%). The most common grade ≥3 TRAEs were increased lipase (13%), fatigue (9%), and maculopapular rash (7%).

TRAEs of special interest for enfortumab vedotin (peripheral neuropathy, rash, and non-fasting hyperglycemia) occurred at rates similar to those observed in studies of single-agent enfortumab vedotin. Immune-mediated adverse events requiring systemic steroids affected 9 patients and were grade ≥3 severity in 5 cases.

Earlier this month, the FDA granted a priority review designation to a biologics license application (BLA) for enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting. Under the Prescription Drug User Fee Act, the FDA will make a decision on the BLA by March 15, 2020.

Hoimes C, Rosenberg J, Srinivas S, et al. EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. Presented at: 2019 ESMO Congress; Barcelona, Spain; September 27 to October 1, 2019. Abstract 901O.

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