Christopher Hoimes, MD
The first known clinical trial report of an antibody-drug conjugate was a phase 0/I pharmacodynamic and safety study of a conjugate that targeted carcinoembryonic antigen and delivered a payload of vinca alkaloid in eight patients with ovarian or colorectal cancer.1 This work built on the work of Ghose et al,2 who published a paper on immunochemotherapy for cancer with a chlorambucil-carrying antibody; they reported the results of their preclinical work and regression of metastatic melanoma nodules in one patient volunteer using a molecule that was a conjugation of “antimelanoma” serum globulin and chlorambucil.
Foundation of FDA Approval: Phase II and III Clinical Trials
Enfortumab vedotin-ejfv is one of the first antibody-drug conjugates for treatment of solid tumors to receive U.S Food and Drug Administration (FDA) designation. An initial accelerated approval was granted in 2019 based on results from the pivotal phase II EV-201 trial of enfortumab vedotin in patients with metastatic urothelial cancer who had experienced disease progression on prior platinum and anti–PD-1 therapy (cohort 1).3 Of 125 patients treated with enfortumab vedotin at 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle, 44% had a confirmed objective response, with 12% having a complete response.
The confirmatory global phase III EV-301 trial4 was recently reported by Powles and colleagues in The New England Journal of Medicine and reviewed in this issue of The ASCO Post. A total of 608 patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had prior therapy with a platinum regimen and an anti–PD-L1 agent were randomly assigned to receive enfortumab vedotin or investigator’s choice of docetaxel, paclitaxel, or vinflunine chemotherapy (standard of care), with the primary endpoint of overall survival. The 1:1 randomization led to well-matched characteristics of heavily pretreated patients, with ~80% harboring visceral disease, nearly one-third with liver metastasis, 15% with urothelial carcinoma that included a variant/mixed histology, and ~70% with no response to prior checkpoint immunotherapy.
In this population, compared with chemotherapy, enfortumab vedotin was associated with a hazard ratio (HR) for death of 0.70 (95% confidence interval [CI] = 0.56–0.89, P = .001) at a median follow-up of 11 months. Kaplan-Meier estimate curves for each of overall survival and progression-free survival diverged by the third month of therapy, with a median overall survival of 12.9 vs 9.0 months and a median progression-free survival of 5.6 vs 3.7 months (HR = 0.62, 95% CI = 0.51–0.75, P < .001).
Grade 3 or higher adverse events related to treatment occurred in about half of patients in each group. Common side effects noted with enfortumab vedotin included fatigue, rash, and neuropathy; the most common grade 3 or higher event was neutropenia. Treatment interruptions related to adverse events were more frequent with enfortumab vedotin (51%) than with chemotherapy (19%), although the rates of dose reduction and discontinuation were about the same for each group, ~30% and ~12%, respectively. Treatment-related events of special interest for enfortumab vedotin included dermatitis, peripheral neuropathy, and hyperglycemia, which occurred in 44%, 46%, and 6%, respectively. The efficacy and overall manageable toxicity profile of enfortumab vedotin shown in the EV-301 trial have led enfortumab vedotin monotherapy to become immediately practice-changing for patients with urothelial carcinoma in the postplatinum, post–PD-1/PD-L1 inhibitor setting.
Enfortumab vedotin delivers a payload of monomethyl auristatin E (MMAE), a tubulin-disrupting agent, to urothelial carcinoma, which overexpresses the nectin-4 surface receptor target of the monoclonal antibody. Just as important are the linker properties, which will not be discussed here apart from pointing out that it is protease cleavable and that ‘vedotin’ refers to MMAE+linker.
A selective targeting of metastatic urothelial cancer is an important mechanism of action. However, there is also preclinical evidence that the impact of the agent on the immune system may be as important. The antibody-drug conjugate induces tumor-cell endoplasmic reticulum stress, which causes the targeted cancer cells to emit danger signals and leads to an immunogenic cell death pathway that can enhance tumor-specific antigen recognition and antitumor immune response.
Potential in Earlier Disease Settings
Several trials are currently studying the potential of enfortumab vedotin to impact earlier disease settings.
EV-201 Cohort 2 has completed enrollment of patients to receive enfortumab vedotin monotherapy in the second-line, platinum-naive, post–PD-1/PD-L1 setting. EV-103 is a phase Ib/II multicohort trial studying enfortumab vedotin in combination with chemotherapy or pembrolizumab in the perioperative and first-line cisplatin-ineligible metastatic settings and is pending FDA review in the summer of 2021. To test whether there is enhanced antitumor activity when enfortumab vedotin is combined with PD-1 inhibition,5-7 the phase Ib/II EV103 Cohort A (ClinicalTrials.gov identifier NCT032888545) is examining the first-line use of enfortumab vedotin and pembrolizumab in cisplatin-ineligible patients with metastatic urothelial cancer; thus far, promising robust and durable clinical activity has been shown with the combination.8,9
As we explore the next steps with enfortumab vedotin in earlier disease settings, and in combinations, we will also gain familiarity with recognition and management of its side effect profile to better care for our patients with bladder cancer and upper tract urothelial cancers. Enfortumab vedotin represents a community of work in antibody-drug conjugates targeting cancer that has spanned decades and our patients can now benefit from this important treatment option.
Dr. Hoimes works in medical oncology at the Duke University School of Medicine, Durham, North Carolina.
DISCLOSURE: Dr. Hoimes has received honoraria from Seattle Genetics; has served as a consultant or advisor to Bristol Myers Squibb, Eisai, Genentech/Roche, Merck Sharp & Dohme, Prometheus Laboratories, Seattle Genetics, and 2bPrecise; has participated in a speakers bureau for Astellas Pharma, Bristol Myers Squibb, Eisai, Genentech/Roche, and Seattle Genetics; has received research funding from Merch Sharp & Dohme; and has held uncompensated relationships with 2bPrecise.
REFERENCES
1. Ford CH, Newman CE, Johnson JR, et al: Localisation and toxicity study of a vindesine-anti-CEA conjugate in patients with advanced cancer. Br J Cancer 47:35-42, 1983.
2. Ghose T, Norvell ST, Guclu A, et al: Immunochemotherapy of cancer with chlorambucil-carrying antibody. Br Med J 3:495-499, 1972.
3. Rosenberg JE, O’Donnell PH, Balar AV, et al: Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 37:2592-2600, 2019.
4. Powles T, Rosenberg JE, Sonpavde GP, et al: Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 384:1125-1135, 2021.
5. Gardai SJ, McPhillips KA, Frasch SC, et al: Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321-334, 2005.
6. Galluzzi L, Buqué A, Kepp O, et al: Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol 17:97-111, 2017.
7. Cao AT, Law CL, Gardai SJ, et al: Brentuximab vedotin-driven immunogenic cell death enhances antitumor immune responses, and is potentiated by PD1 inhibition in vivo. Cancer Res 77(suppl):5588, 2017.
8. Hoimes CJ, Rosenberg JE, Srinivas S, et al: EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. ESMO 2019 Congress. Abstract 4844. Presented September 28, 2019.
9. Rosenberg JE, Flaig TW, Friedlander TW, et al: Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. J Clin Oncol 38(suppl):441, 2020.
