ADCs rise to become SOC in key solid tumors

Enhertu overtakes Kadcyla and becomes the standard of care… pushes into first-line

Padcev + Keytruda challenges Bavencio+chemotherapy combo as first-line therapy in bladder cancer

Major antibody-drug conjugates (ADCs) are rapidly becoming standard-of-care (SOC) therapies across solid tumors, reshaping treatment paradigms.

 

Daiichi Sankyo and AstraZeneca’s Enhertu (trastuzumab deruxtecan) has displaced Kadcyla (trastuzumab emtansine) as the new SOC in HER2-positive breast cancer.

 

Enhertu is also validating potential as a first-line therapy in combination with the targeted therapy Perjeta (pertuzumab).

 

In urothelial carcinoma, Astellas’ Padcev (enfortumab vedotin) is rising rapidly.

 

Padcev monotherapy has already become SOC in second-line settings, and in first-line disease, Padcev + Keytruda (pembrolizumab) is now a preferred regimen in the NCCN guidelines, overtaking Bavencio (avelumab) + chemotherapy as the dominant option.

 

Merck's existing immuno-oncology drug ‘Bavencio (avelumab)’ + chemotherapy, has been used as the SOC for urothelial carcinoma, but the introduction of Padcev significantly increased the likelihood of this position changing.

 

Enhertu aims to become SOC across HER2-mutated solid cancers Enhertu is a next-generation ADC composed of a monoclonal antibody that has the same structure as trastuzumab, which binds to receptors overexpressed on cancer cells and a highly potent Topo I inhibitor payload, linked via a tumor-selective cleavable linker.

 

ADCs are anticancer drugs manufactured by linking an antibody that binds to a specific target antigen on the surface of cancer cells with a drug that has cell-killing (cytotoxic) properties (payload).

 

ADCs act selectively on cancer cells by using the selectivity of antibodies to their targets and the killing activity of drugs to increase therapeutic efficacy while minimizing side effects.

 

In a head-to-head study, Enhertu nearly doubled progression-free survival (PFS) compared to Kadcyla.

 

Enhertu and Kadcyla use the same trastuzumab backbone but with a different microtubule inhibitor payload.

 

Unlike Kadcyla, which uses a microtubule inhibitor monomethyl auristatin E (MMAE) as its payload, Enhertu utilizes a topoisomerase I inhibitor.

 

This difference led to a starkly contrasting efficacy.

 

As a result, companies in Korea and abroad are actively pursuing ADC development using topoisomerase I inhibitor payloads.

 

Among later-stage drugs, ‘Datroway (datopotamab)’ and ‘Trodelvy (sacituzumab govitecan)’ have adopted topoisomerase I inhibitor payloads.

 

However, Enhertu's ambition extends beyond second-line HER2-positive breast cancer.

 

It has shown potential not only as the second-line SOC for HER2-positive breast cancer but also as a first-line therapy, demonstrating efficacy across various solid tumors.

 

Enhertu has established its efficacy in combination with Roche's Perjeta.

 

Perjeta is one of the drugs used in the so-called ‘THP regimen (taxane + Herceptin + Perjeta)’, which serves as the standard first-line treatment for HER2-positive breast cancer.

 

The Phase III DESTINY-Breast09 trial compared the efficacy and safety of Enhertu plus Perjeta versus THP therapy in 1,157 patients with previously untreated HER2-positive breast cancer.

 

Patients were randomized in a 1:1:1 ratio to the Enhertu + placebo group (387 patients), the Enhertu + Perjeta group (383 patients), or the THP therapy group (387 patients).

 

The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR).

 

Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety.

 

During a median follow-up of 29 months (interim data cutoff February 26, 2025), the PFS in the Enhertu+Perjeta group was 40.7 months, longer than the 26.9 months in the THP therapy group.

 

The ORR was 85.1% in the Enhertu+Perjeta group and 78.6% in the THP therapy group.

 

DOR was 39.2 months in the Enhertu+Perjeta group and 26.4 months in the THP therapy group, showing a difference.

 

The OS data were immature at the time of cutoff.

 

In addition to breast cancer, Enhertu has been approved for gastric cancer and non-small cell lung cancer.

 

In April last year, it also received accelerated approval from the U.S.

 

Food and Drug Administration (FDA) for all HER2-positive solid tumors that lack alternative treatment options.

 

Its potential is now being explored in cancers with limited treatment options, such as colorectal cancer and biliary tract cancer.

 

Padcev seeks to become first-line SOC in urothelial carcinoma in combination with an immune-oncology drug Astellas’ Padcev is pushing toward first-line SOC in combination with Keytruda.

 

That position had long been held by Bavencio plus chemotherapy.

 

Bavencio is a relatively mild agent and has advantages for use in elderly patients and long-term administration.

 

But Padcev’s clinical results are being regarded as groundbreaking.

 

In the Phase III EV-302/KEYNOTE-A39 study, Padcev + Keytruda achieved a median overall survival (OS) of 31.5 months in previously untreated urothelial carcinoma patients.

 

This represented a significant difference compared to the 16.1 months observed in the control group(chemotherapy).

 

Although differences existed in the control group and clinical design, the median OS for the Bavencio maintenance therapy arm was 29.7 months.

 

This represents an extension of over 9 months compared to the 20.5 months observed in the control group receiving maintenance therapy alone.

 

However, patients were randomized after receiving approximately 4 months or more of prior treatment (4-6 cycles) with gemcitabine plus cisplatin or carboplatin combination therapy.

 

Accordingly, the NCCN guidelines recommend Padcev + Keytruda as a Category 1 first-line therapy in locally advanced or metastatic urothelial carcinoma.

 

For second-line or later settings, Padcev monotherapy is the preferred therapy, and for third-line or later, it is recommended as a Category 1 preferred therapy.

 

Padcev also demonstrated efficacy in muscle-invasive bladder cancer, where radical cystectomy is the SOC, presenting new possibilities.

 

The combination therapy of Padcev plus Keytruda demonstrated statistically significant improvements in event-free survival (EFS), overall survival (OS), and pathological complete response rate (pCR) compared to radical cystectomy+pelvic lymph node dissection (RC+PLND) alone.

 

This study is the first randomized Phase III trial demonstrating a clear survival benefit from pre- and post-operative combination therapy in patients with cisplatin-ineligible, muscle-invasive bladder cancer who are eligible for surgery.

 

Padcev is an ADC targeting Nectin-4, composed of a Nectin-4-specific fully human monoclonal antibody and MMAE.

 

Padcev chose MMAE as the payload due to its synergistic effect with PD-1.

 

Nectin-4 is overexpressed in urothelial carcinoma cells compared to normal tissue, providing high selectivity for cancer cells.

 

After binding, it enters the cell and releases MMAE to induce cell death.

 

When combined with PD-1 inhibitors like Keytruda, the cytotoxicity of MMAE synergizes with the immune activation from PD-1 inhibition, maximizing antitumor activity.

 

Despite its aggressive nature, metastatic urothelial carcinoma has had no first-line treatment options beyond chemotherapy for 30 years, creating a significant unmet need.

 

Before Padcev monthearpy, the response rate to immune-oncology drugs was only 13-28% regardless of PD-L1 status, and a significant number of patients experienced disease progression within 3 months of treatment.

 

Therefore, whether Padcev + Keytruda becomes the new standard of care (SOC) in the first-line treatment space is now a matter of intense interest.

 

Recently, this combination therapy cleared the first hurdle for reimbursement in Korea by passing the Cancer Disease Deliberation Committee, taking a significant step closer to commercialization in Korea.