Updated Trials at ESMO Reveal New Frontline Combo in Urothelial Carcinoma

Treatment options for patients with metastatic urothelial carcinoma (mUC) are sparse. After platinum-based chemotherapy such as cisplatin and carboplatin have been exhausted, targeted therapy options have been explored with some success. Yet there remains a serious unmet need. The recent clinical trials exploring targeted therapy combinations presented during the 2023 European Society for Medical Oncology (ESMO) Congress offered encouraging results.

In particular, findings of the frontline regimen of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) in the phase 3 EV-302 trial (NCT04223856) excited oncologists during the presentation of data.¹

EV-302 Trial

Thomas Powles, MD, MBBS, MRCP, a professor of genitourinary oncology and director of the Barts Cancer Centre at St Bartholomew’s Hospital in London, England, reported that previously untreated patients with locally advanced or mUC demonstrated a statistically significant improvement in overall survival (OS) vs chemotherapy when administered the targeted combination (enfortumab vedotin-ejfv and pembrolizumab; EVP arm). Further, Powles said that the combination led to a reduced risk of death by 53% compared with chemotherapy.¹

The median OS was 31.5 months (95% CI, 25.4-not reached) in the EVP arm compared with 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm (HR, 0.47; 95% CI, 0.380.58; P < .00001). The OS benefit was seen regardless of the patient’s PD-L1 status or the presence of visceral metastases, and the findings were consistent regardless of whether the patient was treated with cisplatin or carboplatin.¹

Treatment with the combination also led to a significant improvement in progression-free survival (PFS) versus chemotherapy. The median PFS was 12.5 months (95% CI, 10.4-16.6) with EVP compared with 6.3 months (95% CI, 6.2-6.5) with chemotherapy. This resulted in a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.38-0.54; P < .00001). The PFS benefit was sustained across all prespecified subgroups, such as those defined by cisplatin eligibility, PD-L1 status, and visceral metastases.¹

“This is the first time [in urothelial carcinoma] we’ve managed to beat chemotherapy in the first-line setting for overall survival, despite multiple previous attempts. Enfortumab vedotin and pembrolizumab showed significant decrease in the risk of death and a decrease in the risk of progression compared with chemotherapy. These results support enfortumab vedotin plus pembrolizumab as a standard of care in this setting,” Powles said, who is also lead for solid tumour research at Queen Mary University of London, during the presentation.¹

In the EVP arm, 30.5% of patients had the primary tumor located in the upper tract and 69% had the tumor located in the lower tract. The rates were 23.4% and 76.4%, respectively, in the chemotherapy arm. Fifty-four percent of patients in each arm were cisplatin eligible and 72% had visceral metastases. Of note regarding PD-L1 status, investigators reported that 58% of patients in each arm had high expression (combined positive score [CPS] ≥ 10), with the remaining 42% having low expression (CPS < 10).¹

Patients were randomly assigned 1:1 to standard-of-care chemotherapy consisting of gemcitabine plus cisplatin or carboplatin for a maximum of 6 cycles (n = 444) or enfortumab vedotin (1.25 mg/kg intravenously [IV]) on days 1 and 8 and pembrolizumab (200 mg IV) on day 1 of 3-week cycles (n = 442; FIGURE1). The maximum number of pembrolizumab cycles allowed was 35, and there was no maximum number of cycles for enfortumab vedotin. The coprimary end points were OS and PFS, per blinded independent central review.¹ The confirmed objective response rate (ORR) was 67.7% in the EVP arm compared with 44.4% in the chemotherapy arm. The ORR in the EVP arm consisted of a complete response (CR) rate of 29.1% and a partial response (PR) rate of 38.7%. The stable disease (SD) rate was 18.8%, and the progressive disease (PD) rate was 8.7%. In the chemotherapy arm, the ORR consisted of a CR rate of 12.5% and a PR rate of 32%. The SD rate was 33.8%, and the PD rate was 13.6%.¹

The median number of cycles received was 12 (range, 1-46) for EVP and 6 (range, 1-6) for chemotherapy. Overall, 67% of patients in the EVP arm and 45.7% of patients in the chemotherapy arm remained on the study at the time of the analysis. In the EVP arm, 34.6% of patients discontinued treatment due to progressive disease compared with 16.4% of patients in the chemotherapy arm. Adverse event (AE)–related discontinuations occurred in 21.9% and 14.0% of the 2 arms, respectively. Regarding subsequent immunotherapy in the chemotherapy arm, 59% received a PD-1/ L1 inhibitor and 30% of patients received maintenance avelumab (Bavencio).¹

“The safety profile of EVP was generally manageable, with no new safety signals observed,” Powles said. “Hematological toxicity was more prominent with chemotherapy, [whereas] peripheral neuropathy, rash, and hyperglycemia are adverse events of special interest with EVP.”

The safety data showed that 56% of patients receiving EVP and 70% of patients in the chemotherapy arm experienced grade 3 or higher treatment-related AEs (TRAEs). Serious TRAEs occurred in 27.7% vs 19.6% of the arms, respectively.¹

In April 2023, the FDA granted an accelerated approval to pembrolizumab plus enfortumab vedotin for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.²

Double Antibody-Drug Conjugates

Also presented at the 2023 ESMO Congress were the results of the phase 1 DAD trial of the double antibody-drug conjugates (ADCs) sacituzumab govitecan (Trodelvy; SG) and enfortumab vedotin in the second-line setting (NCT04724018).³ With their benefits as single agents in mUC, established efforts to optimize the efficacy of the ADCs were explored in this trial.

Bradley McGregor, MD, director of clinical research at the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, explained the rationale for the trial, given each agent’s different targets, non-overlapping payload toxicities, and preclinical synergy observed with antimicrotubule agents, in general.³

The results demonstrated that the combination offered an acceptable safety profile with an ORR of 71% (90% CI, 51%-87%) that included 2 complete responses, 13 partial responses, and 2 cases of progressive disease in patients with treatment-refractory UC.³

Overall, the 24 patients with mUC enrolled in the trial had an ECOG performance status of 1 or 0, had progressed on platinum-based chemotherapy and immunotherapy or were cisplatin ineligible, and had received 1 prior line of therapy. The combination doses were given on days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity.

To determine feasibility and safety, the combination doses were adjusted based on the incidence of dose-limiting toxicities during the first cycle and during 4 prespecified dose levels.

After 2 patients experienced febrile neutropenia, prophylactic granulocyte colony-stimulating factor (G-CSF) was permitted, resulting in 18 patients receiving G-CSF. Regarding toxicity, 70% of patients experienced grade 3 or higher AEs, with a grade 5 pneumonitis possibly related to EV during the second cycle.³

With a median follow-up of 19 months, 11 of 15 responses are ongoing. Further exploration involving double ADCs in the treatment refractory or treatment-naive setting is continuing, McGregor noted.³

THOR Trial

Findings from the phase 3 THOR trial (NCT03390504) evaluated the pan–FGFR inhibitor, erdafitinib (Balversa), in patients with mUC with susceptible FGFR3/2 alterations who have progression after receiving platinum-containing chemotherapy.⁴ The trial determined whether erdafitinib conveyed an OS advantage vs chemotherapy in patients with this molecular subtype after 1 to 2 prior therapies, including anti–PD-L1. Findings were simultaneously published in the New England Journal of Medicine.⁵

A total of 266 patients were randomly assigned to receive either 8 mg of erdafitinib once a day (n = 136) or investigator’s choice of chemotherapy (docetaxel or vinflunine) every 3 weeks (n = 130) until disease progression or toxicity intolerance. The primary end point was OS, and secondary end points were PFS, ORR, and safety.⁴

After a median follow-up of 15.9 months, patients in the erdafitinib arm had a median OS that was significantly longer (12.1 months) than patients in the chemotherapy arm (7.8 months) as well as a 36% lower chance of death (HR, 0.64; 95% CI, 0.47-0.88; P = .005). Median PFS was also longer in the treatment arm (5.6 months) vs the control arm (2.7 months; HR, 0.58; 95% CI, 0.44-0.78; P < .001).⁴ The incidence of grade 3 or 4 treatment-related adverse events was similar in the 2 groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). TRAEs that led to death were less common with erdafitinib (0.7%) than with chemotherapy (5.4%).⁴

The most frequently reported TRAEs were hyperphosphatemia (79%), diarrhea (55%), and stomatitis (46%) in patients treated with erdafitinib. In the chemotherapy group, the most frequently reported TRAEs were anemia (28%), alopecia (21%), and nausea (20%).⁴

The OS benefit was consistent across clinically relevant subgroups, including age, FGFR alteration type (mutations vs fusions), and primary tumor location (upper vs lower tract). However, lead author Yohann Loriot, MD, PhD, director of the Bladder Cancer Program at Gustave Roussy, Université Paris-Saclay, in Villejuif, France, cautioned that the subgroup analysis should be interpreted carefully because the study was not designed to assess treatment effects in subgroups and patients in some subgroups were limited.⁴

Non-Muscle Invasive Bladder Cancer

In the BCG-unresponsive, high-risk non– muscle-invasive bladder cancer (NMIBC) setting, TAR-200, an intravesical chemotherapy delivery system, achieved a CR rate per central review of 76.7% (95% CI, 57.790.1) in the open-label, phase 2b SunRISe-1 trial (NCT04640623).

At a median follow-up of 48 weeks (range, 12-121), 21 (91%) of the 23 CRs remained ongoing and the median duration of response (DOR) was not reached. Eleven of the complete responders had a DOR of at least 6 months (10 of 11 ongoing) and 6 had a DOR of at least 12 months (all ongoing). At the time of analysis, none of the complete responders had received radical cystectomy.⁶

“TAR-200 provides sustained and durable response. The efficacy and safety data from SunRISe-1 support the ongoing investigations of TAR-200 in patients with BCG-unresponsive, high-risk NMIBC,” said first author Andrea Necchi, MD, associate professor at Vita-Salute Raffaele University and chief of the Division of Genitourinary Medical Oncology at San Raffaele Hospital and Scientific Institute in Milan, Italy.

Patients were randomly assigned to 3 treatment arms: cohort 1 received TAR-200 every 3 weeks for up to 24 weeks, then every 12 weeks until week 96 (year 2), plus cetrelimab every 3 weeks through week 78; cohort 2 received TAR-200 only, at the same dose as cohort 1; and cohort 3 received cetrelimab alone, at the same dose as cohort 1. The most recent amendment to the study design added a fourth cohort consisting of patients with BCG-unresponsive, high-risk NMIBC with papillary tumors only (no carcinoma in situ [CIS] component) and who received TAR-200 monotherapy.⁶

CRs were measured by cystoscopy, central cytology, and central pathology at week 24 and week 48. The primary end point is CR, with secondary end points including DOR, overall survival, quality of life, safety, and tolerability.⁶

During the conference, Necchi only shared data from cohort 2 participants, who received TAR-200 monotherapy. There were 54 patients in the cohort with a median age of 71 years (range, 40-85). The majority were men (77.8%), White (68.5%), and had an ECOG performance status of 0 (96.3%). Nicotine use data showed that 55.6% of the patients were former users, 35.1% were never-users, and 9.3% were current users.⁶

The tumor stage was CIS only for 66.7% of patients and CIS plus papillary disease for 33.3% of patients. The median number of prior doses of BCG was 12 (range, 7-42). The median time from last BCG treatment to CIS diagnosis was 3.0 months (range, 0.2-22.4). The majority of patients (94.4%) declined to receive radical cystectomy, and the remaining patients (5.6%) were not eligible for the surgery.⁶

The safety population included all 54 patients. Most AEs were grade 2 or less. More than half (53.7%) of patients had at least 1 TRAE and 7.4% of patients had at least 1 TRAE of grade 3 or higher. Discontinuations due to TRAEs occurred in 2 patients. There were no patient deaths on the trial.⁶

After many years in which platinum- based chemotherapy was established as the standard of care in mUC, findings presented during the 2023 ESMO Annual Meeting have demonstrated a new combination of targeted therapies offering clinicians and patients renewed hope in this difficult to treat cancer type.