Saturday, June 15, 2024

Malignant Pleural Mesothelioma: FDA Grants Priority Review to Merck’s KEYTRUDA® Application for First-Line Treatment

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Malignant pleural mesothelioma is the focus as Merck, known as MSD outside the United States and Canada, announced that the U.S. Food and Drug Administration (FDA) has accepted for priority review a new supplemental Biologics License Application (sBLA) for KEYTRUDA® (pembrolizumab).This application seeks approval for KEYTRUDA in combination with chemotherapy as a first-line treatment for patients with unresectable advanced or metastatic malignant pleural mesothelioma. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of September 25, 2024.

The sBLA is based on data from the pivotal Phase 2/3 IND.227/KEYNOTE-483 trial. Results from the final analysis of the study, presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that KEYTRUDA combined with chemotherapy significantly improved overall survival (OS), reducing the risk of death by 21% (HR=0.79 [95% CI, 0.64-0.98]; two-sided p-value=0.0324), with a median OS of 17.3 months (95% CI, 14.4-21.3) compared to 16.1 months (95% CI, 13.1-18.2) for chemotherapy alone.

KEYTRUDA Plus Chemotherapy Shows Significant Improvement in Progression-Free Survival for Malignant Pleural Mesothelioma

KEYTRUDA plus chemotherapy demonstrated a significant improvement in progression-free survival (PFS) (HR=0.80 [95%CI, 0.65-0.99], two-sided p-value = 0.0372; median PFS 7.13 months versus 7.16 months respectively) and objective response rate (ORR) compared to chemotherapy alone. At 12 months, the estimated PFS rate was 26% for the combination therapy versus 17% for chemotherapy alone. The ORR was significantly higher for the combination therapy versus chemotherapy alone (62% versus 38%, p<0.0001). The safety profile of KEYTRUDA plus chemotherapy in this study was consistent with previously reported studies.

“Malignant pleural mesothelioma is typically diagnosed in advanced stages when curative surgery is not an option, and progresses quickly,” said Dr. Gregory Lubiniecki, vice president of oncology clinical research at Merck Research Laboratories. “We continue to evaluate KEYTRUDA in new and difficult-to-treat tumors and look forward to working with the FDA to help bring KEYTRUDA as a potential treatment option to certain patients with advanced malignant pleural mesothelioma.”

IND.227/KEYNOTE-483 is a randomized, open-label Phase 2/3 trial (ClinicalTrials.gov, NCT02784171) sponsored and conducted by the Canadian Cancer Trials Group (CCTG) in collaboration with the National Cancer Institute of Naples (NCIN) and the Intergroupe Francophone de Cancérologie Thoracique (IFCT). Merck provided KEYTRUDA and support for the trial. The trial evaluated KEYTRUDA plus chemotherapy versus chemotherapy alone for the treatment of patients with unresected advanced pleural mesothelioma. The study’s primary endpoint was OS, and secondary endpoints included PFS and ORR as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) modified for mesothelioma, safety, and quality of life. The Phase 3 part of the trial enrolled 440 patients who were randomized to receive:

  • KEYTRUDA (200 mg intravenously [IV] every three weeks [Q3W] for up to 35 cycles) plus pemetrexed (500 mg/m2 Q3W for six cycles) and cisplatin (75 mg/m2 Q3W for six cycles; carboplatin substitution [AUC 5-6 Q3W for six cycles] was permitted), or
  • Pemetrexed and cisplatin (carboplatin substitution was permitted) alone.

Malignant mesothelioma is a type of cancer that starts in the linings of certain parts of the body, including the chest, abdomen, heart, and testicles. In 2022, more than 30,000 new cases of mesothelioma were diagnosed worldwide, and there were over 25,000 deaths from the disease. While the incidence of malignant mesothelioma has gradually declined in the U.S., ongoing use of and exposure to asbestos globally has led to increasing rates of this aggressive disease. Pleural mesothelioma, which develops in the lining of the lungs, is the most common form of malignant mesothelioma, accounting for about 75% of all cases. This form of mesothelioma often progresses rapidly, and the five-year survival rate is only 12%.

Malignant Pleural Mesothelioma

KEYTRUDA for Malignant Pleural Mesothelioma: Enhancing Immune Response to Fight Tumor Cells

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that enhances the body’s immune system to detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which can affect both tumor and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program, with over 1,600 trials studying KEYTRUDA across various cancers and treatment settings. The KEYTRUDA clinical program aims to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefiting from the treatment, including exploring several different biomarkers.

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  • Non-Small Cell Lung Cancer
    • KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
    • KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.
    • KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:
      • Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
      • Metastatic.
    • KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations before receiving KEYTRUDA.
    • KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node-positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
    • KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC.

KEYTRUDA can cause severe and fatal immune-mediated adverse reactions, which may affect any organ system or tissue, and can occur at any time during or after treatment. It is crucial to monitor patients closely for symptoms and signs that may indicate immune-mediated adverse reactions and to initiate appropriate management promptly.

Merck’s application for KEYTRUDA in combination with chemotherapy for the treatment of unresectable advanced or metastatic malignant pleural mesothelioma represents a significant step forward in addressing the needs of patients with this aggressive and challenging disease. The priority review granted by the FDA underscores the potential impact of this treatment on patient outcomes and highlights the importance of continued research and innovation in the field of oncology.

Resource: Businesswire, May 29, 2024

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