Antibody-Drug Conjugates Carve Out Space in Urothelial Carcinoma Landscape

Monoclonal antibodies (mAbs) have played a key role in the development of personalized oncology and have proven antitumor activity through multiple mechanisms, including direct transmembrane signaling leading to apoptosis, complement mediated cytotoxicity, antibody-dependent cellular cytotoxicity, and inhibiting tumor vasculature and stroma.^1-4 However, mAbs are rarely effective in killing tumor cells on their own.⁵ This has led investigators to hypothesize that increased potency may be achieved through the addition of a cytotoxic drug forming an antibody-drug conjugate (ADC).

ADCs are composed of 3 parts: an antibody, a linker, and a cytotoxic agent also known as payload (Figure). An ideal antigen target is one that is highly and consistently expressed on malignant cells but has limited expression on normal cells, leading to less systemic toxicity. The stereotypic mAb should have high immunoaffinity to the antigen and be internalized into the cell sufficiently, as the goal is to have enough cytotoxic agent released within the tumor cell,^1,6 though some products may drop payload in the stroma as well. To facilitate this cytotoxic release inside the cell, a linker is required. A linker functions as a connection between the mAb and the cytotoxin. Creating a linker, cleavable or noncleavable, that is stable in the circulation but released once inside the tumor cell or at the target site is critical to the success of the ADC.^1,7,8 If all steps in the process of delivering an ADC work with 50% efficiency, only 1% to 2% of the payload delivered will reach the tumor cell.^9,10

This emphasizes the necessity of the cytotoxic drug's being highly potent. The most common cytotoxins in use are auristatins, maytansines, and calicheamicins. They induce apoptotic cell death, the former 2 by targeting the cell cycle and the latter by inducing DNA damage.^1-4

Several urothelial carcinoma (UC) surface proteins have been identified as potential targets for the development of ADCs, based on their abundant expression and their involvement in tumor growth, invasion, metastatic progression, and/or treatment resistance. In this review, we provide an overview of the current status in the clinical development of ADCs for UC and discuss the most promising clinical data for ADC monotherapy as well as combinations with other anticancer agents.

Figure. Structure of an Antibody-Drug Conjugate

ADCs in Various Phases of Clinical Development in UC

Enfortumab Vedotin

Enfortumab vedotin-ejfv (Padcev) is a fully human mAb developed by conjugating a human anti-nectin-4 antibody to the antimicrotubule agent MMAE.11 The safety of enfortumab vedotin was initially assessed in the phase 1 EV-101 study (NCT02091999) in 155 patients with metastatic UC (mUC) who were either previously treated with chemotherapy and/or a checkpoint inhibitor (CPI) or were unfit for cisplatin.¹² In total, 112 patients received the recommended phase 2 dose (RP2D) of 1.25 mg/kg. Enfortumab vedotin was generally well tolerated, with half of patients reporting grade 2 or lower fatigue as the most common treatment-related adverse event (TRAE). The most common severe AEs (grade ≥ 3) included anemia, hyponatremia, urinary tract infection, and hyperglycemia, all of which were less than 10%. Investigators reported 4 fatal TRAEs, including respiratory failure, urinary tract obstruction, diabetic ketoacidosis, and multiorgan failure.¹²

Preliminary results from EV-101 were particularly encouraging, with an objective response rate (ORR) of 33%. Investigators subsequently confirmed these data in the phase 2 EV-201 study (NCT03219333), which consisted of 2 cohorts: patients with mUC who were previously treated with both platinum chemotherapy and PD-1 or PD-L1 inhibitor (cohort 1), and patients unfit for cisplatin and previously treated only with PD-1 or PD-L1 inhibitor (cohort 2).¹³ After a median follow-up of 10.2 months, the ORR in the 125 patients of cohort 1 was 44%, including 12% complete responses (CR), with a median duration of response of 7.6 months. No new safety concerns were raised, and fatigue, peripheral neuropathy, decreased appetite, and dysgeusia were the most common AEs.¹³ These results led to the drug’s accelerated approval by the FDA (Table ).¹⁴ With long-term follow-up (median, 22.3 months), the median overall survival (OS) was 12.4 months in cohort 1 of the EV-201 trial.¹⁵

The confirmatory phase 3 EV-301 study (NCT03474107) compares enfortumab vedotin as a single agent with second-line chemotherapy of either docetaxel, paclitaxel, or vinflunine in a similar patient population following platinum-based chemotherapy and CPI. In a press release, results were reported as positive, with a 30% reduction in risk of death (HR, 0.70; 95% CI, 0.56-0.89; P = .001). Enfortumab vedotin also significantly improved progression-free survival (PFS), a secondary end point, with a 39% reduction in risk of disease progression or death (HR, 0.61; 95% CI, 0.50-0.75; P < .00001).¹⁶ These phase 3 results may lead to full approval in the United States and initial approval in other countries.

The activity of enfortumab vedotin monotherapy in patients with advanced UC has generated great interest in combining it with other approved therapies to further improve responses and outcomes. Several expansion cohorts of the phase 1/2 EV-103 study (NCT03288545) include combinations of enfortumab vedotin plus pembrolizumab (Keytruda) in the first- and second-line treatment of patients who are cisplatin-ineligible; plus cisplatin; plus carboplatin; plus gemcitabine; or plus pembrolizumab and platinum chemotherapy, respectively. Of the data reported so far, the combination of enfortumab vedotin with pembrolizumab as first-line therapy led to an ORR of 73% in 45 previously untreated patients with mUC who were ineligible for cisplatin-based chemotherapy. The median PFS was 12.3 months and the median duration of response has not yet been reached, with more than half of responses lasting a year or longer.¹⁷

The combination was well tolerated overall, with 26 (57.8%) grade 3 or higher TRAEs, the most common of which were increased lipase, fatigue, maculopapular rash, diarrhea, and anemia. The most common TRAEs of any grade included fatigue, alopecia, and sensory neuropathy in up to half of patients.¹⁷

Table. Approval Snapshot

Sacituzumab Govitecan

Sacituzumab govitecan-hziy (Trodelvy) is an ADC consisting of a mAb that internalizes after binding to a trophoblast cell surface antigen 2 (Trop-2)-specific epitope and releases its conju- gated cytotoxic chemotherapeutic agent SN-38, the active metabolite of irinotecan, with a half- life in serum of approximately 24 hours.^18,19 Trop- 2 is overexpressed on most epithelial tumor types, especially urothelial carcinoma. Sacituzumab govitecan breaks the ADC stereotype: In addition to intracellular tumor release, the agent uses a hydrolysable linker, has a higher drug-to-antibody ratio, and less potent toxin designed to be released in the tumor microenvironment.

The earliest clinical evidence of activity of sacituzumab govitecan in mUC was reported in a small group of 6 patients who were treated as part of the initial phase 1 study on different advanced epithelial cancers.²⁰ There were 2 partial responders, with a 38% reduction in target lesions as best response. Of 6 treated patients, 3 had a clinically significant response (PFS, 6.7-8.2 months; OS, 7.5 + to 11.4 + months).²⁰ This led to an expanded UC cohort that included 45 patients and reported an ORR of 31%, including in patients with liver metastases and in platinum- and CPI-resistant tumors. In the intention-to-treat (ITT) population, the median PFS was 7.3 months, with durable responses. Specifically, the median duration of response was 12.9 months and OS was 16.3 months.21 Overall, treatment was well tolerated and the most common severe (grade ≥ 3) toxicities were diarrhea (69%), neutropenia (51%), anemia (33%), and febrile neutropenia (7%).²¹

In light of the drug’s significant activity in this phase 2 UC expanded cohort of the IMMU-132- 01 basket study (NCT01631552), an international, open-label phase 2 study was initiated (TROPHY U-01; NCT03547973). Interim results from the first 35 patients with mUC in cohort 1, who progressed after both platinum-based chemotherapy and CPI, showed an ORR of 29% including 25% in patients with liver involvement.²² These combined results coupled with a clinical unmet need for this patient population led to the FDA granting the drug a breakthrough designation. Final results in 113 patients confirmed sacituzumab govitecan’s meaningful efficacy with a centrally confirmed ORR of 27% (25% in patients with liver metastases), median duration of response lasting 5.9 months, and clinical benefit rate of 37%. Median PFS and OS were 5.4 months and 10.5 months, respectively.²³ The safety profile was consistent with prior reports, and patients experienced key TRAEs at grade 3 or higher, including neutropenia (35%), anemia (14%), febrile neutropenia (10%), and diarrhea (10%). A confirmatory phase 3 TROPiCS-04 study (NCT04527991) is underway.

HER2-Targeting ADCs

ADCs targeting HER2 are a rational therapeutic strategy in patients with UC with HER2 over- expression. The anti-HER2 ADC RC48 demonstrated significant clinical activity in 43 patients with HER2-positive (IHC 2+ or 3+) mUC in the phase 2 setting.^24,25 Although the majority of patients had visceral disease and were heavily pretreated, investigators observed an ORR of 60.5%.24 RC48 had a manageable safety profile, with the most common grade 3 or higher AEs including leukopenia (11.4%), neutropenia (11.4%), numbness (11.1%), and fatigue (5.6%), which resolved with dose reduction and supportive care.²⁵ Based on this preliminary activity, investigators are expected to initiate a global phase 3 clinical trial for RC48. In addition, an open-label, single-arm, phase 1b/2 study (NCT04264936) is evaluating the safety and pharmacokinetics of combining RC48 with the anti–PD-1 mAb JS001 in patients with mUC.

Fam-trastuzumab deruxtecan-nxki (Enhertu) is a HER2-targeting ADC currently being combined with nivolumab (Opdivo) in a phase 1b study (NCT03523572) in patients with advanced breast or UC with tumors expressing HER2. Another HER2-targeting ADC currently under investigation in UC is A166. The amino acid sequence is identical to trastuzumab and is linked to the MMAF derivative Duostatin-5 as payload.²⁶ An ongoing phase 1/2 trial (NCT03602079) is examining the agent in patients with HER2-expressing or amplified advanced solid tumors including UC and prostate cancer who progressed on or did not respond to available standard therapies. Among the first 23 patients examined, data showed manageable toxicity with reversible grade 1 to 3 ophthalmic toxicities (mainly keratitis, blurry vision) and grade 1 to 2 peripheral neuropathy, anemia, leukopenia, and thrombocytopenia. Additionally, a preliminary efficacy assessment in 8 evaluable patients was promising (4 partial responses; 75% disease control rate).²⁶

Other Avenues to Explore

Tisotumab vedotin was the first-in-human anti-tissue factor ADC tested for safety and pre- liminary efficacy in the multicenter phase 1/2 dose-escalation and dose-expansion innovaTV 201 study (NCT02001623), in nontarget-selected patients with relapsed, advanced, or metastatic cancer of different primaries, including mUC and prostate.²⁷ Investigators established 2 mg/kg as the highest-tolerated dose, given the dose-limiting toxicities of grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever. Other grade 3 or higher AEs included fatigue (10%), anemia (5%), abdominal pain (4%), hypokalemia (4%), conjunctivitis (3%), hyponatremia (3%), and vomiting (3%).²⁷ Tisotumab vedotin achieved a 15.6% ORR across all tumor types, with a 26.7% ORR in the 15 patients with bladder UC in the study. This was the highest ORR of all histologies treated.

Patients with nonmuscle-invasive bladder UC, refractory to or intolerant of bacillus Calmette-Guérin (BCG), may also benefit from ADC therapy targeted against the epithelial cell adhesion molecule (EpCAM). Investigators of the first phase 1 study of the anti-EpCAM ADC oportuzumab monatox tested ascending doses ofthedrugfor6consecutiveweeksviabladder instillation.²⁸ A subsequent phase 2 study enrolled 46 patients, who underwent 1 induction cycle of 6 (cohort 1) or 12 (cohort 2) weekly intravesical instillations of oportuzumab monatox 30 mg, followed by up to 3 maintenance cycles of 3 weekly administrations every 3 months. A significant proportion of the study population (44%) achieved a CR, with 16% remaining disease-free after a follow-up of 18 to 25 months. Patients tolerated treatment well, with only mild to moderate, reversible bladder AEs (eg, discomfort, pain, spasm, infections, hematuria, incontinence, and retention).²⁹

In August 2018, the FDA granted oportuzumab monatox a fast track designation for the treatment of BCG-unresponsive, high-grade nonmuscle-in- vasive bladder cancer and the drug is currently in the follow-up stage of a phase 3 registration trial (NCT02449239). Preliminary phase 3 results in 89 patients showed a complete response rate of 40% in patients with carcinoma in situ with a median duration of response of 9.4 months.³⁰ The recurrence-free rates of the 38 evaluable patients at 3, 6, 12, and 24 months were 71%, 58%, 50%, and 37%, respectively, and the median time to recurrence was 13.2 months.³⁰ Overall, responders at 3 months remained recurrence-free for 34 months compared with 20.7 months for nonresponders. The preliminary OS rate was 96% at 2 years. A combination trial with durvalumab (Imfinzi) is also ongoing (NCT03258593).

Summary

ADCs have already impacted the clinical management of patients with UC with the accelerated approval of enfortumab vedotin in December 2019, which has more recently demonstrated benefit in a randomized confirmatory trial. Two additional ADCs have early data that may also lead to clinical availability. Other ADCs against similar as well as different targets are in development and there is excitement about drug combinations, in particular regarding immune checkpoint inhibitors. Ongoing and new studies are testing safety and efficacy in early stages of disease.

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