ADCs Change the Game for Cancer Treatment

DNA molecule: © Design Cells - stock.adobe.com

Antibody-drug conjugates (ADCs) are a promising class of drugs revolutionizing cancer therapy. ADCs combine the targeting power of antibodies with potent cell-killing drugs. This precise approach minimizes damage to healthy tissues, a major drawback of traditional chemotherapy.

ADCs have led to significant advancements, particularly in HER2-positive breast cancer and several ADCs are now FDA-approved, with many more under development for various cancers.

While challenges remain in optimizing their design and managing adverse effects (AEs), ADCs offer a powerful and evolving weapon in the fight against cancer.

Enfortumab Vedotin

Enfortumab vedotin (Padcev) is an ADC that targets Nectin-4, a protein overexpressed in several different malignancies, including bladder cancer cells.

As a single-agent, enfortumab vedotin demonstrated promising results in clinical trials, including the phase 1 dose-escalation study EV-101 (NCT02091999). Enfortumab vedotin led to an overall response rate (ORR) of 43% and a median overall survival (OS) of over a year (12.3 months).¹ Enfortumab vedotin alone led to AEs including fatigue, hair loss, appetite loss, dysgeusia, nausea, peripheral sensory neuropathy, pruritus, and diarrhea. However, the incidence of AEs was manageable, with most being low-grade.

“There was a single-arm registration trial, at least in the US, of a post-platinum and immune checkpoint inhibitor. It looked to have a high response rate that led to the initial accelerated approval,” said Scott T. Tagawa, MD, MS, FACP, FASCO, professor of medicine and urology at Weill Cornell Medicine, and an attending physician at NewYork-Presbyterian – Weill Cornell Medical Center, in an interview with Targeted Oncology^TM.

EV-201 (NCT03219333) is a 2-cohort phase 2 study of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma (mUC) previously treated with anti–PD-1/PD-L1 therapy who had prior platinum-based chemotherapy (cohort 1) or who were platinum-naïve and cisplatin-ineligible (cohort 2). Results for both cohorts showed that enfortumab vedotin led to favorable clinical activity compared to historical outcomes with standard care.^2,3

The head-to-head EV-301 study (NCT03474107) then added to this research by showing enfortumab vedotin to have the ability to prolong OS and progression-free survival (PFS) among patients with UC vs those given standard chemotherapy.⁴

“In the EV-301 study in the same patient population, post-platinum, post-immune checkpoint inhibitor, [enfortumab vedotin] was superior in all aspects,” explained Tagawa. “Towards the end of that, there were some combinations that were studied. The EV-103 study [NCT03288545] looked at multiple combinations of [enfortumab vedotin].”

In cohort K of EV-103, experts evaluated enfortumab vedotin or enfortumab vedotin plus pembrolizumab (Keytruda; EVP) as a first-line therapy for patients who were cisplatin-ineligible with locally advanced or mUC.5 Patients were randomly assigned in 1:1 ratio and given enfortumab vedotin as a monotherapy on days 1 and 8, or in combination with pembrolizumab on day 1 of the 3-week cycles.

Enfortumab vedotin alone led to an ORR of 45.2% (95% CI, 33.5-57.3) and with EVP, the ORR was 64.5% (95% CI, 52.7-75.1). Safety findings showed that treatment-related AEs consisted of skin reactions (67.1%) and peripheral neuropathy (60.5%) in the EVP arm.⁵

These results led to the FDA granting an accelerated approval to the combination in April 2023 for the treatment of patients with cisplatin-ineligible mUC.

“That regimen also was given accelerated US FDA approval, followed on the heels by the EV-302 study,” said Tagawa.

In EV-302, EVP resulted in significantly better outcomes compared with chemotherapy as a treatment for patients with untreated locally advanced or mUC.6 The safety profile of the combination was consistent with what was observed in previous reports.

Specifically, the median OS was 31.5 months (95% CI, 25.4-not reached) in the EVP arm vs 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm (HR, 0.47; 95% CI, 0.38-0.58; P < .00001). A significant improvement in PFS was also seen with EVP vs chemotherapy at 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5), resulting in a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.38-0.54; P < .00001).⁶

EVP is currently the standard first-line treatment for cisplatin-ineligible patients with locally advanced or mUC. However, enfortumab vedotin monotherapy may be an option for select patients who are not candidates for the combination regimen.

“That is now the standard of care as the combination,” explained Tagawa. “There are some patients that probably will still receive [enfortumab vedotin as a] single-agent, but [the combination] has moved forward.”

Clinical trials are ongoing to evaluate enfortumab vedotin in combination with other therapies for UC.

“Future development [of enfortumab vedotin] is not only with other drugs, but also in the perioperative setting. It is possible that in the future, the majority of patients will receive this for early-stage disease and not necessarily for late-stage disease if they have already received it,” continued Tagawa.

Hodgkin lymphoma cells: © Dr_Microbe - stock.adobe.com.jpg

Loncastuximab Tesirine

The CD19-directed loncastuximab tesirine-lpyl (Zynlonta) gained an FDA orphan drug designation in 2017⁷ and was granted accelerated approval in April 2021 for patients with large B-cell lymphoma. The approval was supported by the LOTIS-2 study (NCT03589469), which enrolled 145 patients who were relapsed/refractory to at least 2 prior treatments. A response rate of 48% was reported.⁸

“Based on the efficacy data, it shows good efficacy at this late line of treatment. It is also convenient; it is off the shelf. We do not have concern about any cytokine release syndrome or neurotoxicity. This is a good option at this line of therapy,” Nelson S. Yee, MD, PhD, RPh, medical oncologist at Penn State Health, told Targeted Oncology^TM.

Loncastuximab tesirine is also being investigated for the treatment of marginal zone lymphoma (MZL). Initial data from the phase 2 study (NCT05296070) show that 13 of 15 patients with MZL achieved a complete response (CR) and 1 patient achieved a partial response. Further, all responses were maintained at the time of the data cutoff, and the safety profile was consistent with previous reports.⁹

Tisotumab Vedotin

Tisotumab vedotin (Tivdak) gained its FDA accelerated approval in September 2021¹⁰ with traditional approval following in April 2024.¹¹ The agent was evaluated in the phase 3 innovaTV 301 trial (NCT04697628) that enrolled 502 patients with recurrent or metastatic cervical cancer who had received 1 or 2 prior systemic regiments with or without bevacizumab (Avastin) and/or an anti-PD(L)-1 agent.

“In this study, the primary outcome was overall survival. The 2 treatment arms were the experimental drug tisotumab vedotin vs traditional chemotherapy, investigators’ choice chemotherapy. What we found here is that those women who were treated with the experimental drug had a 30% decreased risk of death vs those treated with the traditional therapy,” said Brian Slomovitz, MD, director of gynecologic oncology at Mount Sinai Medical Center and primary investigator of innovaTV 301, in an interview with Targeted Oncology^TM.

“We saw similar changes, as well, in the progression-free survival… [with a] 33% decrease in progression-free survival. We saw a response rate that was approximately 3 to 4 times higher in the tisotumab vedotin arm vs chemotherapy. [For] the safety profile, there were no new safety signals to make us concerned that something else was going to come up,” Slomovitz continued.

Tisotumab vedotin is also being investigated in combinations with other agents for the treatment of cervical cancer.

“As far as combinations go, we are exploring them,” Slomovitz explained. “There are earlier trials looking to [combine] tisotumab vedotin with a series of combinations, including carboplatin with pembrolizumab and other agents. At this point, I think the results of this study will make us further explore to see if some of the future directions will include combination therapy, but for now, based on the current landscape, it will be a good treatment option in the second or third line [for] patients, these patients who recur.”

Mirvetuximab Soravtansine

Mirvetuximab soravtansine-gynx (Elahere) is a folate receptor alpha (FR⍺)-targeted ADC for the treatment of ovarian cancer. It gained accelerated approval from the FDA in November 2022 and full approval in March 2024 for patients with platinum-resistant disease and high FR⍺ expression who have received 1 to 3 prior lines of treatment.¹²

Data from the phase 3 MIRASOL trial (NCT04209855) presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting showed that the median OS was 16.46 months (95% CI, 14.46-24.57) with mirvetuximab soravtansine compared with 12.75 months (95% CI, 10.91-14.36) with investigator’s choice of chemotherapy (HR, 0.67; 95% CI, 0.50-0.88; P = .0046). The median PFS was 5.62 (95% CI, 4.34-5.95) vs 3.98 months (95% CI, 2.86-4.47), respectively (HR, 0.65; 95% CI, 0.52-0.81; P <.0001).¹³

“These data we consider to be practice-changing and position mirvetuximab soravtansine to be the new standard of care for tumors that are FRα-high and platinum-resistant for women with ovarian cancer,” lead study author Kathleen N. Moore, MD, associate director of clinical research at Stephenson Cancer Center, director of the Oklahoma TSET phase I program, and professor in the Section of Gynecologic Oncology at The University of Oklahoma College of Medicine, said during a presentation of the data at the ASCO meeting.

“When we are talking about overall survival benefit in ovarian cancer, these patients have a long-term chronic disease. The ability to demonstrate an overall survival benefit in clinical trials is difficult, and almost unheard of in recent ovarian cancer clinical trials. This is exciting data coming out of this phase 3 trial in the platinum-resistance space, [and] that is certainly going to change our standard of care,” said Eirwen M. Miller, MD, gynecologic oncologist at Allegheny Health Network, in an interview with Targeted Oncology^TM.

A close-up of a red cell with a red blood cell in the background: © Bipul Kumar - stock.adobe.com

Inotuzumab Ozogamicin

While inotuzumab ozogamicin (Besponsa) has been in development since 1991, stemming from the same collaboration responsible for gemtuzumab ozogamicin (Mylotarg),14 the first FDA approval for inotuzumab did not come until March 2024, when the agent was approved for pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL).¹⁵

The approval was supported by findings from a phase 2 study (NCT02981628) evaluating 53 pediatric patients. Twenty-two patients achieved a CR (42%; 95% CI, 28.1%-55.9%), and the median duration of CR was 8.2 months (95% CI, 2.6-not evaluable). Among patients who achieved a CR, the minimal residual disease negativity rate was 95.5% (n = 21; 95% CI, 77.2%-99.9%) based on flow cytometry.¹⁵

“[Inotuzumab ozogamicin] has rapidly revolutionized the treatment of Philadelphia chromosome-positive ALL in the sense that we now have chemotherapy-free regimens for these patients. Now, we're avoiding transplant for most of them,” Nicholas J. Short, MD, told Targeted Oncology^TM. Short is an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.

REFERENCES:

1. Rosenberg J, Sridhar SS, Zhang J, et al. EV-101: A phase I study of single-agent enfortumab vedotin in patients with nectin-4-positive solid tumors, including metastatic urothelial carcinoma [published correction appears in J Clin Oncol. 2022 May 20;40(15):1711]. J Clin Oncol. 2020;38(10):1041-1049. doi:10.1200/JCO.19.02044

2, 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. 2019;37(29):2592-2600. doi: 10.1200/JCO.19.01140.

3. Yu EY, Petrylak DP, O'Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):872-882. doi: 10.1016/S1470-2045(21)00094-2.

4. Powles T, Rosenberg J Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi: 10.1056/NEJMoa2035807.

5. O'Donnell PH, Milowsky MI, Petrylak DP, et al. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2023;41(25):4107-4117. doi: 10.1200/JCO.22.02887

6. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117

7. Developing products for rare diseases & conditions. FDA. Accessed May 21, 2024. https://tinyurl.com/7mttuawk

8. Drug trials snapshot: Zynlonta. FDA. Updated July 20, 2023. Accessed May 21, 2024. https://tinyurl.com/3dk58c7k

9. ADC Therapeutics announces initial data from investigator-initiated phase 2 clinical trial of Zynlonta in patients with relapsed/refractory marginal zone lymphoma. News release. ADC Therapeutics. May 6, 2024. Accessed May 21, 2024. https://tinyurl.com/3yfbxnyx

10. FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. News release. FDA. September 21, 2021. Accessed May 21, 2024. https://tinyurl.com/56j8tncy

11. FDA approves tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. News release. FDA. April 29, 2024. Accessed May 21, 2024. https://tinyurl.com/5xwc4z7z

12. FDA approves mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. News release. FDA. March 22, 2024. Accessed May 21, 2024. https://tinyurl.com/y67xwybh

13. Moore KN, Angelergues A, Konecny GE, et al. Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal or fallopian tube cancers with high folate receptor-alpha (FRα) expression. J Clin Oncol. 2023;41(suppl 17)LBA5507. doi:10.1200/JCO.2023.41.17_suppl.LBA5507

14. Inotuzumab ozogamicin. Pharma Intelligence. Accessed May 21, 2024. https://tinyurl.com/yc6p7569

15. FDA approves inotuzumab ozogamicin for pediatric patients with acute lymphoblastic leukemia. News release. FDA. March 6, 2024. Accessed May 21, 2024. https://tinyurl.com/2u7ydj82