FDA Approves Expanded Indication For KEYTRUDA Plus Padcev For The First-Line Treatment Of Adult Patients With Locally Advanced Or Metastatic Urothelial Cancer

Author: Happy Mohamed | December 16, 2023 07:38pm

Approval is based on results from the Phase 3 KEYNOTE-A39 trial, which demonstrated a superior overall survival benefit with KEYTRUDA plus Padcev versus platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin) in these patients

Approval expands the use of KEYTRUDA plus Padcev for locally advanced or metastatic urothelial cancer regardless of cisplatin eligibility

Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Merck's anti-PD-1 therapy, in combination with Padcev (enfortumab vedotin-ejfv), an antibody-drug conjugate, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. The FDA approved this application nearly five months ahead of the PDUFA goal date of May 9, 2024.

The approval is based on data from the Phase 3 KEYNOTE-A39 trial (also known as EV-302) in 886 patients with locally advanced or metastatic urothelial cancer, which was conducted in a research collaboration with Pfizer (previously Seagen) and Astellas. In the trial, KEYTRUDA plus enfortumab vedotin demonstrated a statistically significant improvement in the trial's major efficacy endpoints of overall survival (OS) and progression-free survival (PFS) versus platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin). KEYTRUDA plus enfortumab vedotin reduced the risk of death by 53% (HR=0.47 [95% CI, 0.38-0.58]; p<0.0001) versus platinum-based chemotherapy. Median OS was 31.5 months (95% CI, 25.4-not reached) for KEYTRUDA plus enfortumab vedotin versus 16.1 months (95% CI, 13.9-18.3) for platinum-based chemotherapy. KEYTRUDA plus enfortumab vedotin reduced the risk of disease progression or death by 55% (HR=0.45 [95% CI, 0.38-0.54]; p<0.0001) versus platinum-based chemotherapy. Median PFS was 12.5 months (95% CI, 10.4-16.6) for KEYTRUDA plus enfortumab vedotin versus 6.3 months (95% CI, 6.2-6.5) for platinum-based chemotherapy.

The trial also demonstrated a statistically significant improvement in objective response rate (ORR) in patients randomized to receive KEYTRUDA plus enfortumab vedotin compared with patients randomized to receive platinum-based chemotherapy. The ORR was 68% (95% CI, 63-72) for KEYTRUDA plus enfortumab vedotin versus 44% (95% CI, 40-49) for platinum-based chemotherapy (p<0.0001). For KEYTRUDA plus enfortumab vedotin, the complete response (CR) rate was 29% and the partial response (PR) rate was 39%, and for platinum-based chemotherapy, the CR rate was 12% and the PR rate was 32%. Efficacy results (OS, PFS and ORR) were consistent across all stratified patient subgroups.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see "Selected Important Safety Information" below.

"Advanced bladder cancer is a common cause of cancer-related death," said Dr. Thomas Powles, primary investigator of KEYNOTE-A39, professor of Genitourinary Oncology and director, Barts Cancer Center. "The overall survival benefit seen in the KEYNOTE-A39 trial demonstrates the potential for KEYTRUDA in combination with enfortumab vedotin to impact the first-line treatment of patients with locally advanced or metastatic urothelial cancer. In my opinion, this is a meaningful advancement over platinum-based chemotherapy in the systemic treatment of these patients."

"The landmark findings from the KEYNOTE-A39 trial are the first positive Phase 3 results combining a PD-1 inhibitor and an antibody-drug conjugate as first-line treatment for patients with locally advanced or metastatic urothelial cancer. This combination has the potential to change the treatment paradigm in advanced urothelial cancer and to help these patients live longer," said Dr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. "Today's approval reinforces the value of advancing novel combinations with KEYTRUDA to provide these patients with a treatment option."

Results from KEYNOTE-A39 were presented at the European Society for Medical Oncology Congress 2023 as late-breaking data during a Presidential Symposium session. KEYTRUDA plus enfortumab vedotin was previously approved under the FDA's accelerated approval program for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who are not eligible to receive cisplatin-containing chemotherapy based on data from the KEYNOTE-869 trial (also known as EV-103) dose escalation cohort, Cohort A and Cohort K, which was conducted in collaboration with Pfizer and Astellas. In accordance with accelerated approval regulations, continued approval was contingent upon verification and description of clinical benefit; these accelerated approval requirements have been fulfilled with the data from KEYNOTE-A39.

This approval was reviewed under the FDA's Real-Time Oncology Review program, which aims to improve the efficiency of the review process of applications to ensure that treatments are available to patients as early as possible.

Study design and additional data supporting the approval

KEYNOTE-A39 is an open-label, multicenter, randomized, active-controlled Phase 3 trial (ClinicalTrials.gov, NCT04223856) evaluating KEYTRUDA plus enfortumab vedotin compared to platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin) for the treatment of patients with locally advanced or metastatic urothelial cancer who received no prior systemic therapy for locally advanced or metastatic disease. Patients randomized to the chemotherapy arm were allowed to receive maintenance immunotherapy. The trial enrolled 886 patients who were randomized (1:1) to receive either:

• KEYTRUDA 200 mg over 30 minutes on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle. KEYTRUDA was given approximately 30 minutes after enfortumab vedotin. Treatment was continued until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, KEYTRUDA was continued for up to two years, or;
• Gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle with cisplatin 70 mg/m2 or carboplatin (AUC 4.5 or 5) on Day 1 of a 21-day cycle. Treatment was continued until disease progression or unacceptable toxicity for up to 6 cycles.

Randomization was stratified by cisplatin eligibility, PD-L1 expression and presence of liver metastases.

The major efficacy outcome measures were OS and PFS as assessed by blinded independent central review (BICR) according to RECIST v1.1. Additional outcome measures included ORR as assessed by BICR.

Among patients who received KEYTRUDA and enfortumab vedotin (n=440), the median duration of exposure to KEYTRUDA was 8.5 months (range: 9 days to 28.5 months). Fatal adverse reactions occurred in 3.9% of patients receiving KEYTRUDA plus enfortumab vedotin, including acute respiratory failure (0.7%), pneumonia (0.5%) and pneumonitis/interstitial lung disease (ILD) (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; the serious adverse reactions in ≥2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%) and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (≥20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%) and urinary tract infection (21%).

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