New drug Padcev alone or in combination with Keytruda for bladder cancer

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The first innovative drug for bladder cancer! The new ADC drug Padcev alone or in combination with Keytruda has a significant effect!

New drug Padcev alone or in combination with Keytruda for bladder cancer.  Seattle Genetics Company (Seagen) and Astellas (Astellas) recently jointly announced the latest results of two clinical trials for the treatment of urothelial cancer (UC) with an antibody-conjugated drug (ADC) Paddev (enfortumab vedotin). Monotherapy (EV-201 study [NCT03219333] cohort 2) and Padcev combined with anti-PD-1 therapy Keytruda (corrida, pembrolizumab) (EV-103 study [NCT03288545] cohort A) treatment cannot accept cisplatin Patients with locally advanced or metastatic UC undergoing chemotherapy.

The EV-201 cohort 2 is the first study to report objective remission data of patients with advanced UC who have progressed after anti-PD-(L)1 immunotherapy. These patients cannot receive cisplatin chemotherapy due to their physical condition. Data show that with a median follow-up of 16 months, many patients continue to benefit from Padcev treatment.

This is an important finding because the treatment options for these patients are very limited. The EV-103 cohort A was carried out in patients with newly diagnosed locally advanced or metastatic UC. The data showed that after 2 years of follow-up, the platinum-free regimen of Padvev+Keytruda has a long-lasting effect.

Bladder cancer-(Image source-medscape.com)

Urothelial carcinoma (UC) is the most common type of bladder cancer, accounting for approximately 90% of bladder cancer cases. Padcev is a first-in-class ADC drug that targets a cell surface protein that is highly expressed in bladder cancer. The drug is a combination of enfortumab, a human IgG1 monoclonal antibody targeting connexin-4 (Nectin-4), and the cytotoxic agent MMAE (monomethyl auristatin E, a microtubule disrupting agent). . Nectin-4 is a therapeutic target highly expressed in a variety of solid tumors including urothelial carcinoma (UC). In the drug, the ADC link technology comes from Seattle Genetics, and the target identification is completed by Astellas.

In December 2019, Padcev received accelerated approval from the U.S. FDA for the treatment of patients with locally advanced or metastatic urothelial cancer (UC), specifically: it has received a PD-1/L1 inhibitor in the past and is in neoadjuvant /Adjuvant therapy or patients who have received a platinum-containing chemotherapy regimen in the treatment of locally advanced or metastatic disease.

Padcev is the first ADC drug approved for the treatment of UC and the first drug approved for locally advanced or metastatic UC patients who have previously received platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor. In March of this year, Padcev applied for listing in the European Union and Japan. If approved, the drug will become the first ADC drug for UC in Europe and Japan.

The latest analysis of EV-201 cohort 2:

This cohort evaluated Padcev treatment in patients with locally advanced or metastatic UC who had previously received PD-1/PD-L1 inhibitors, had not received platinum-containing chemotherapy in locally advanced or metastatic cases, and were not suitable for cisplatin chemotherapy.

The median follow-up time was 16 months. Among patients treated with Padcev, the confirmed objective response (ORR) was 51% (95% CI: 39.8-61.3), and the complete response rate (CR) was 22%. The median time to response (DOR) was 13.8 months (95%CI: 6.4-not reached). The median progression-free survival (PFS) was 6.7 months (95%CI: 5.0-8.3), and the median overall survival (OS) was 16.1 months (95%CI: 11.3-24.1).

The most common treatment-related adverse events (TRAE) of all grades were alopecia (51%), peripheral sensory neuropathy (49%) and fatigue (34%). The most common grade 3 or higher TRAE was neutropenia (9%), macular papules (8%) and fatigue (7%). Special concerns of grade 3 or higher include skin reactions (17%), peripheral neuropathy (8%), and hyperglycemia (6%). Researchers previously reported that 4 deaths among patients 75 years of age and older with multiple coexisting diseases were related to treatment.

According to the preliminary analysis of EV-201 cohort 2, the US FDA recently prioritized a supplementary application for Padcev. The relevant data was published in The Lancet Oncology this month.

The latest analysis of EV-103 cohort A:

The study evaluated Padcev+Keytruda as the first-line treatment for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). In the dose escalation and expansion cohort A, Padvev+Keytruda combination therapy is used for the first-line treatment of patients with la/mUC. These patients are not suitable for platinum-containing chemotherapy, have not previously received systemic therapies for the treatment of locally advanced or metastatic disease, and are not in the process. The group received platinum-containing adjuvant/neo-adjuvant therapy in the first 12 months.

The main outcome indicator of this analysis is safety. The median follow-up time was 24.9 months. Long-term analysis showed that the safety was basically consistent with the results of previous studies, and no new safety signals were observed. The most common TRAEs were peripheral sensory neuropathy (55.6%), fatigue (51.1%) and hair loss (48.9%). The most common TRAEs of grade 3 and above were elevated lipase (17.8%) and macular papules (11.1%). And fatigue (11.1%). TRAEs of grade 3 or higher that are of concern include skin reactions (20%), hyperglycemia (8.9%), and peripheral neuropathy (4.4%). A previous death report may be related to research treatment (multiple organ dysfunction syndrome).

As mentioned earlier, the results showed that the objective response rate (ORR) assessed by the investigator was 73.3% (95% CI: 58.1-85.4), and 15.6% of patients achieved CR. The median PFS was 12.3 months (95%CI: 8.0, not reached). Long-term follow-up showed that the median DOR was 25.6 months (95%CI: 8.3, not reached), and the median OS was 26.1 months (95%CI: 15.7, not reached).

In 2020, the US FDA granted Padcev and Keytruda a breakthrough drug designation (BTD) for the treatment of unresectable locally advanced or metastatic urothelial carcinoma (UC). The FDA last year approved a breakthrough treatment plan for the combination of PADCEV and KEYTRUDA to treat patients with unresectable locally advanced or metastatic urothelial cancer. These patients are not suitable for first-line treatment with cisplatin-based chemotherapy.

(source:internet, reference only)

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