Antibody-Drug Conjugates Continue to Transform the Oncology Landscape

Image of drugs administered through IV drip: © Trsakaoe - stock.adobe.com

Antibody-drug conjugates (ADCs) have shown significant promise. While they have been especially notable for the treatment of HER2-positive (HER2+) breast cancer and other HER2-expressing tumors, a multitude of targets across solid tumors and hematologic malignancies has allowed the treatment landscape to rapidly evolve.

ADCs are a revolutionary class of targeted cancer therapies that work to deliver cytotoxic agents directly to cancer cells, minimizing damage to healthy tissues. With the combination of the specificity of monoclonal antibodies and the potency of chemotherapy drugs, ADCs offer a highly effective treatment option for a number of malignancies.

Gemtuzumab Ozogamicin

Gemtuzumab ozogamicin (Mylotarg) was the first FDA-approved ADC.¹ In 2000, gemtuzumab ozogamicin was granted accelerated approval for patients over 60 years old with CD33-positive acute myeloid leukemia (AML) experiencing first relapse who were unsuitable for chemotherapy.

The FDA added a black box warning to the agent within a year of approval, as it was observed to increase risks of veno-occlusive disease in patients who had not undergone bone marrow transplantation. This increased frequency of veno-occlusive disease was later observed even in patients who had undergone transplantation.² In 2008, gemtuzumab ozogamicin was the subject of criticism due to the inadequacy of postmarketing surveillance.

In accordance with accelerated approval requirements, the phase 3 SWOG S0106 comparative controlled study (NCT00085709) commenced in 2004; however, the study ended in August 2009 before completion due to unfavorable toxicity. The fatal toxicity rate in the gemtuzumab combination arm was 5.7% vs 1.4% in the standard therapy group (P =.01). In 2010, gemtuzumab was voluntarily withdrawn from the market.

Despite this, in 2017, the FDA approved gemtuzumab ozogamicin for patients with relapsed or refractory CD33-positive AML in adults and children 2 years and older³ and in 2020, the FDA expanded the indication to include patients with newly diagnosed CD33-positive AML in patients 1 month and older.⁴ These approvals were supported by the French ALFA-0701 study (00927498). In this study, lower doses of gemtuzumab with standard chemotherapy were used, which resulted in longer survival and improved toxicity profiles.⁵

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

Brentuximab Vedotin

Brentuximab vedotin (Adcetris) was first approved by the FDA in 2011 in adult patients with classical Hodgkin lymphoma (cHL) after failure of autologous stem cell transplant or after failure of at least 2 prior multiagent chemotherapy regimens in patients who are not autologous transplant candidates.⁶ Since then, several other lymphoma indications have been added, including:

Adult patients with previously untreated stage III or IV cHL in combination with doxorubicin, vinblastine, and dacarbazine.

• Pediatric patients 2 years and older with previously untreated high-risk cHL in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus etoposide.
• Adult patients with cHL at high risk of relapse or progression as post autologous hematopoietic stem cell transplantation consolidation.
• Adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (CHP).
• Adult patients with sALCL after failure of at least 1 prior multiagent chemotherapy regimen.
• Adult patients with primary cutaneous ALCL or CD30-expressing mycosis fungoides who have received prior systemic therapy.⁷

The ECHELON studies are currently evaluating the agent in diffuse large B-cell lymphoma (DLBCL). In March 2024, findings from the phase 3 ECHELON-3 trial (NCT04404283) were announced and showed that brentuximab vedotin plus lenalidomide and rituximab (Rituxan) delivered a statistically significant improvement in overall survival (OS) compared with lenalidomide and rituximab plus placebo.⁸ In the ECHELON-2 study (NCT01777152), adding brentuximab vedotin to the CHP regimen nearly tripled progression-free survival (PFS) compared with the control arm. Compared with the control group, in the 5-year results, the treatment arm showed a PFS rate of 51.4% (95% CI, 42.8%-59.4%) vs 43.0% (95% CI, 35.8%-50.0%).⁹

“The classifications of T-cell lymphomas have become much more complex. Our understanding of the biology and ability to describe different subtypes has significantly increased our therapeutic options,” Steven M. Horwitz, MD, lymphoma specialist and cellular therapist at Memorial Sloan Kettering Cancer Center, said in a presentation of the ECHELON-2 data at the 41st Annual Chemotherapy Foundation Symposium Innovation Cancer Therapy for Tomorrow Conference in November 2023.⁹

T-DM1

For patients with HER2+ breast cancer, ado-trastuzumab emtansine (T-DM1; Kadcyla), was the first ADC to be approved in 2013, based on data from the KATHERINE study (NCT01772472).¹⁰

“T-DM1 is indicated for both adjuvant HER2+ disease and metastatic HER2+ disease in the adjuvant setting. It is specifically indicated for patients who have been treated neoadjuvantly and then have residual disease at the time of surgery based on the results of the KATHERINE study [NCT01772472],” Tanya Gupta, MD, medical oncologist in the Stanford University Department of Medicine, Division of Medical Oncology, told Targeted Oncology^TM.

In the study, adjuvant T-DM1 was associated with an improved median OS and invasive disease-free survival compared with adjuvant trastuzumab.¹⁰

T-DM1 was initially favored as a second-line therapy for metastatic HER2+ disease following progression on trastuzumab (Herceptin) and a taxane, based on the EMILIA trial (NCT00829166). However, it has been largely replaced by [fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd)] in this setting due to superior outcomes, according to Gupta.

“T-DXd is now the favored second-line therapy,” added Gupta.

T-DXd

T-DXd is a monoclonal antibody with the same amino acid sequence as trastuzumab (Herceptin),¹¹ which was first approved in 1998 to treat HER2+ metastatic breast cancer.¹² In 2019, the ADC was granted accelerated approval for the treatment of adult patients with unresectable or metastatic HER2+ breast cancer who had received 2 or more prior HER2-targeted therapies in the metastatic setting.

“DESTINY-Breast01 [NCT03248492] first demonstrated the efficacy of this drug... In this study, patients had received a median of 6 prior lines of therapy, and yet, still had a remarkable overall response rate [ORR] of just under 61%,” explained Gupta. “DESTINY-Breast02 [NCT03523585] was then the confirmatory phase 3 study, and then DESTINY-Breast03 [NCT03529110] compared T-DXd to T-DM1.”

It was the DESTINY-Breast03 study that established T-DXd as the go-to second-line therapy for advanced HER2+ disease as T-DXd outperformed T-DM1 in terms of PFS and ORR. The agent also showed potential for improved OS. T-DXd was approved in 2019 for HER2+ breast cancer.

“Specifically, in this study, T-DXd had a quadrupling of the median progression-free survival as compared with T-DM1. The median progression-free survival with T-DXd was just under 29 months as compared with being just under seven months with T-DM1, which is an extraordinary increase in median progression-free survival,” explained Gupta.

In HER2-low disease, DESTINY-Breast04 (NCT03734029) evaluated T-DXd vs physicians’ choice of chemotherapy. Here, T-DXd reduced the risk of death by 36% vs chemotherapy in this patient population, leading to the FDA approval for T-DXd for this indication.

The agent has also been studied for up to 2 decades in urothelial cancer. Separate from this space was the recent pan-tumor agnostic approval for T-DXd based on data from the DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831) trials, which included a cohort of patients with urothelial carcinoma who were HER2+.

“Now, our patients with refractory urothelial carcinoma have access to [T-DXd] if they have HER2+ disease,” 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 OncologyTM.

Small tumor cancer cells treatment cluster on the health tissue blood vessels: © Yuriy - stock.adobe.com

T-DXd also has an approval for second-line HER2-mutated non–small cell lung cancer (NSCLC) based on DESTINY-Lung01 (NCT03505710) which led to a median PFS of 8.2 months (95% CI, 6.0-11.9) and a median OS of 17.8 months (95% CI, 13.8-22.1) among the 91 patients enrolled.¹³ At a median duration of follow-up of 13.1 months (range, 0.7-29.1), the centrally confirmed ORR was 55% (95% CI, 44%-65%) and the median duration of response (DOR) was 9.3 months (95% CI, 5.7-14.7).

For safety, 46% of patients had grade 3 or higher drug-related adverse events (AEs), which most commonly was neutropenia (19%). Additionally, drug-related interstitial lung disease was seen in 26% of patients and resulted in death for 2 patients.

The phase 2 DESTINY-Lung02 trial (NCT04644237) then led to the accelerated approval of the agent.¹⁴ Among the 102 patients with previously treated, HER2-mutated, advanced or metastatic NSCLC treated with 5.4 mg/kg of the ADC, the confirmed ORR was 49.0% (95% CI, 39.0%-59.1%) per blinded independent central review (BICR) assessment.13 One percent of responders achieved a complete response, 48.0% had a partial response, 44.1% of patients had stable disease, and 3.9% had progressive disease.

Moreover, the disease control rate was 93.1% (95% CI, 86.4%-97.2%), the median DOR was 16.8 months (95% CI, 6.4-not evaluable), and the median time to initial response was 1.8 months (range, 1.2-7.0).

In August 2022, the FDA granted accelerated approval to T-DXd for adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received previous systemic therapy.

Polatuzumab Vedotin

Polatuzumab vedotin (Polivy) is a CD79b-directed ADC for the treatment of DLBCL. Following breakthrough therapy and orphan drug designations, in 2019, the FDA approved polatuzumab vedotin with bendamustine and rituximab (pola-BR) for patients with DLBCL that progressed or returned following at least 2 prior therapies.¹⁵

“I use [pola-BR] in patients who have more aggressive disease, so those patients who need a quicker response, who have bulky disease, as they are the patients that are most likely to use this regimen. [Now,] there are other options. For instance, you can think about [using] other approved agents such as loncastuximab [tesirine (Zynlonta)], [which is] a reasonable option. Another reasonable option is lenalidomide and tafasitamab [Monjuvi]. They are largely immunological based therapies, [and] I tend to use those regimens in patients that perhaps are primary refractory or don't have as aggressive disease. For those patients that you need a quick response in, then I tend to use the antibody-drug conjugate with [BR],” Ian W. Flinn, MD, PhD, hematologist-oncologist at Tennessee Oncology, told Targeted Oncology^TM.

In 2023, the FDA approved the agent with rituximab and CHP (R-CHP) for patients with previously untreated DLBCL not otherwise specified or high-grade B-cell lymphoma.¹⁶

In the POLARIX study (NCT03274492) that supported the 2023 approval, patients were randomized to receive polatuzumab plus R-CHP (pola-R-CHP) or R-CHOP for 6 cycles which each lasted 21 days. Both arms then received 2 additional cycles of rituximab alone. Investigator-assessed PFS was notably longer in the pola-R-CHP arm (HR, 0.73; 95% CI, 0.57-0.95; P =.0177). There was also an improvement in event-free survival in the pola-R-CHP arm (HR, 0.75; 95% CI, 0.58-0.96; P =.0244).

Sacituzumab Govitecan

Sacituzumab govitecan is a Trop2-directed ADC approved for patients with advanced triple-negative breast cancer who have received 2 or more prior systemic therapies, at least 1 of which was in the metastatic setting. It is also approved in hormone receptor (HR)+/HER2-negative advanced disease given prior endocrine therapy and at least 2 additional systemic therapies.¹⁷

The ADC was evaluated in the ASCENT trial (NCT02574455) where its safety and efficacy were compared with physicians' choice of chemotherapy. The primary end point was PFS by BICR in patients without brain metastases.¹⁸

“In that setting, sacituzumab was associated with an improvement and median PFS, as well as overall survival,” explained Gupta.

At a median follow-up of 17.7 months (range, 5.8-28.1), the median PFS in patients without brain metastases was 5.6 months (95% CI, 4.3-6.3) vs 1.7 months (95% CI, 1.5-2.6) in the investigational (n = 235) and chemotherapy (n = 233) arms, respectively (HR, 0.41; 95% CI, 0.32-0.52; P < .001). OS rates were 12.1 months (95% CI, 10.7-14.0) vs 6.7 months (95% CI, 5.8-7.7), respectively (HR, 0.48; 95% CI, 0.38-0.59; P < .001).¹⁹

“Sacituzumab has also been studied for HR+, HER2-advanced breast cancer. This was in the TROPiCS-02 study [NCT03901339], where sacituzumab was associated with an improvement in median PFS, along with median OS as compared with physicians’ choice of chemotherapy,” stated Gupta.

Along with its positive results in breast cancer, sacituzumab govitecan has been studied in urothelial carcinoma. TROPHY-U-01 (NCT03547973) was a phase 2 trial in patients with metastatic urothelial cancer who progressed after prior platinum-based treatment or checkpoint inhibition. Patients were treated with 10 mg/kg of sacituzumab on days 1 and 8 every 21 days.²⁰

Results from cohort 1 demonstrated promising response data with an ORR of 27.4% (95% CI, 19.5%-36.6%). The median DOR was around 7.2 months (95% CI, 4.7-8.6), and the median OS was 10.9 months (95% CI, 9.0-13.8). Additionally, the PFS was 5.4 months (95% CI, 3.5-7.2).

AEs with the ADC included the risk for neutropenia and neutropenic fever, gastrointestinal AEs like diarrhea, nausea, and vomiting, and fatigue and alopecia in some patients.

“For urothelial cancer, the TROPHY-U-01 study, cohort 1…had a better overall ORR than historical controls without randomization, adequate safety, and PFS, etc, although that is not really part of the label. But that led to accelerated US FDA approval,” explained Tagawa.

The TROPiCS-04 study (NCT04527991) is another trial exploring the use of sacituzumab govitecan in patients with metastatic urothelial carcinoma. The trial is fully accrued but has not yet been read out.²¹

“Many of us expect it to be read out in 2024. That is the confirmatory study that is designed to look at overall survival in a similar refractory patient population,” added Tagawa. “[This will] hopefully lead to full use US FDA approval, as well as expanded approval across different countries.”

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