Represents the first PD-1 inhibitor plus ADC regimens for this patient population
RAHWAY, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA® (pembrolizumab) and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) in combination with Padcev® (enfortumab vedotin-ejfv), as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, for the treatment of adult patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. These approvals represent the first PD-1 inhibitor plus ADC regimens for this patient population.
These approvals are based on data from the Phase 3 KEYNOTE-905 trial (also known as EV-303), which was conducted in collaboration with Pfizer and Astellas. Results, which were presented at the recent European Society for Medical Oncology (ESMO) Congress, showed that after a median follow-up of 25.6 months, KEYTRUDA plus Padcev, as perioperative treatment, demonstrated a statistically significant 60% reduction in the risk of event-free survival (EFS) events versus surgery alone in patients with MIBC who are not eligible for or declined cisplatin-based chemotherapy (HR=0.40 [95% CI, 0.28-0.57]; p<0.0001; 48/170 [28%] versus 95/174 [55%]; median EFS not reached [NR] [95% CI, 37.3-NR] versus 15.7 months [95% CI, 10.3-20.5]). KEYTRUDA plus Padcev also demonstrated a statistically significant 50% improvement in overall survival (OS) versus surgery alone (HR=0.50 [95% CI, 0.33-0.74]; p=0.0002; 38/170 [22%] versus 68/174 [39%]; median OS NR [95% CI, NR-NR] vs 41.7 [95% CI, 31.8-NR]). The trial demonstrated a statistically significant difference in pathologic complete response (pCR) rate (57.1% [95% CI: 49.3, 64.6] vs. 8.6% [95% CI: 4.9, 13.8]; p<0.0001). The effectiveness of KEYTRUDA QLEX for its approved indications has been established based upon evidence from the adequate and well-controlled studies conducted with KEYTRUDA and additional data from MK-3475A-D77 comparing the pharmacokinetic, efficacy, and safety profiles of KEYTRUDA QLEX and KEYTRUDA.
KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients. 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 or KEYTRUDA QLEX, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, other transplant (including corneal graft) rejection. Additionally, fatal and other serious complications can occur in patients who receive allogenic hematopoietic stem cell transplantation (HSCT) before or after treatment. Consider the benefit vs risks for these patients. Treatment of patients with multiple myeloma with a PD-1/PD-L1-blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials due to the potential for increased mortality. 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 or KEYTRUDA QLEX. Based on the severity of the adverse reaction, KEYTRUDA and KEYTRUDA QLEX should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA and KEYTRUDA QLEX can also cause severe or life-threatening infusion-related reactions. Based on their mechanism of action, KEYTRUDA and KEYTRUDA QLEX can each cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.
“Pembrolizumab plus enfortumab vedotin is poised to address a critical unmet need,” said Dr. Matthew Galsky, Lillian and Howard Stratton Professor of Medicine, Director of Genitourinary Medical Oncology, Mount Sinai Tisch Cancer Center, and KEYNOTE-905 study investigator. “Half of patients with MIBC may experience cancer recurrence even after having their bladder removed, and many of these patients are ineligible to receive cisplatin. These approvals, based on striking event-free and overall survival benefits, may represent an important practice-changing advance for these patients who’ve had no new options in decades.”
“Our company’s ongoing commitment to putting patients at the center of finding new innovations in cancer care has made the introduction of these new options a reality for patients who are truly in need,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “Moreover, we are honored to provide these patients who previously had only one option — surgery — with a choice to receive their immunotherapy either intravenously or subcutaneously.”
Study design and additional data supporting the approval
KEYNOTE-905, also known as EV-303, is an open-label, randomized, multi-arm, controlled Phase 3 trial (ClinicalTrials.gov, NCT03924895) evaluating perioperative KEYTRUDA, with or without Padcev, versus surgery alone in patients with MIBC who are either not eligible for or declined cisplatin-based chemotherapy. The trial enrolled 344 patients who were randomized 1:1 to receive either:
- Neoadjuvant KEYTRUDA 200 mg over 30 minutes as an intravenous infusion on Day 1 and enfortumab vedotin 1.25 mg/kg as an intravenous infusion on Days 1 and 8 of each 21 day cycle for 3 cycles prior to surgery, followed by adjuvant KEYTRUDA 200 mg over 30 minutes on Day 1 of each 21 day cycle for 14 cycles and adjuvant enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21 day cycle for 6 cycles (n=170).
- Immediate radical cystectomy (RC) and pelvic lymph node dissection (PLND) alone (n=174).
Treatment continued until completion of study medications, disease progression, not undergoing or refusal of RC and PLND, disease recurrence in the adjuvant phase, or unacceptable toxicity. Assessment of tumor status, including CT/MRI, was performed at baseline, within 5 weeks prior to RC and PLND, and at 6 weeks post radical cystectomy. Following RC and PLND, assessment of tumor status, including cystoscopy and urine cytology for patients who did not undergo surgery, was performed every 12 weeks up to 2 years, and every 24 weeks thereafter.
A total of 149 (88%) patients in the KEYTRUDA in combination with enfortumab vedotin arm and 156 (90%) patients in the RC and PLND alone arm underwent RC and PLND.
The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment.
The major efficacy outcome measure of this trial was EFS defined as the time from randomization to the first of: disease progression preventing curative surgery, failure to undergo surgery for participants with muscle invasive residual disease, incomplete surgical resection, local or distant recurrence after surgery, or death. OS and pCR rate as assessed by blinded independent pathology review were additional efficacy outcome measures.
For the 167 patients who received KEYTRUDA in the neoadjuvant phase, the median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 1.4 months (range: 1 day to 2.7 months) and the median number of cycles of KEYTRUDA was 3 (range: 1 to 3) out of the planned 3 cycles in the neoadjuvant phase. For the 96 patients who received KEYTRUDA in the adjuvant phase, the median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 8.5 months (range: 1 day to 12.9 months) and the median number of cycles of KEYTRUDA was 12 (range: 1 to 14) out of the planned 14 cycles in the adjuvant phase. Across the combined neoadjuvant and adjuvant phases (n=167), the median number of cycles of KEYTRUDA was 5 (range: 1, 17) out of the planned 17 cycles.
In KEYNOTE-905, the most common adverse reactions (≥20%) occurring in cisplatin-ineligible patients with MIBC treated with KEYTRUDA in combination with enfortumab vedotin (n =167) were rash (54%), pruritus (47%), fatigue (47%), peripheral neuropathy (39%), alopecia (35%), dysgeusia (35%), diarrhea (34%), constipation (28%), decreased appetite (28%), nausea (26%), urinary tract infection (24%), dry eye (21%), and weight loss (20%).
In the neoadjuvant phase of KEYNOTE-905, serious adverse reactions occurred in 27% (n=167) of patients; the most frequent (≥2%) were urinary tract infection (3.6%) and hematuria (2.4%). Fatal adverse reactions occurred in 1.2% of patients, including myasthenia gravis and toxic epidermal necrolysis (0.6% each). Additional fatal adverse reactions were reported in 2.7% of patients in the post-surgery phase before adjuvant treatment started, including sepsis and intestinal obstruction (1.4% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of patients; the most frequent (>1%) were rash (2.4%, including generalized exfoliative dermatitis), increased alanine aminotransferase, increased aspartate aminotransferase, diarrhea, dysgeusia, and toxic epidermal necrolysis (1.2% each). Of the 167 patients in the KEYTRUDA in combination with enfortumab vedotin arm who received neoadjuvant treatment, 7 (4.2%) patients did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were acute myocardial infarction, bile duct cancer, colon cancer, respiratory distress, urinary tract infection, and two deaths due to myasthenia gravis and toxic epidermal necrolysis (0.6% each).
Of the 146 patients who received neoadjuvant treatment with KEYTRUDA in combination with enfortumab vedotin and underwent radical cystectomy, 6 (4.1%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding 8 weeks) due to adverse reactions.
In the adjuvant phase of KEYNOTE-905, serious adverse reactions occurred in 43% (n=100); the most frequent (≥2%) were urinary tract infection (8%); acute kidney injury and pyelonephritis (5% each); urosepsis (4%); and hypokalemia, intestinal obstruction, and sepsis (2% each). Fatal adverse reactions occurred in 7% of patients, including urosepsis, intracranial hemorrhage, death, myocardial infarction, multiple organ dysfunction syndrome, and pseudomonal pneumonia (1% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 28% of patients; the most frequent (>1%) were diarrhea (5%), peripheral neuropathy, acute kidney injury, and pneumonitis (2% each).
About KEYTRUDA® (pembrolizumab) injection, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help 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 may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.
About KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) injection for subcutaneous use
KEYTRUDA QLEX is a fixed-combination drug product of pembrolizumab and berahyaluronidase alfa. Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody and berahyaluronidase alfa enhances dispersion and permeability to enable subcutaneous administration of pembrolizumab. KEYTRUDA QLEX is administered as a subcutaneous injection into the thigh or abdomen, avoiding the 5 cm area around the navel, over one minute every three weeks (2.4 mL) or over two minutes every six weeks (4.8 mL).
Selected KEYTRUDA® (pembrolizumab) and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) Indications in the U.S.
Urothelial Cancer
KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer.
KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma:
- who are not eligible for any platinum-containing chemotherapy, or
- who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
KEYTRUDA and KEYTRUDA QLEX in combination with enfortumab vedotin, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, are each indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy.
KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
See additional selected KEYTRUDA and KEYTRUDA QLEX indications in the U.S. after the Selected Important Safety Information.
Selected Important Safety Information for KEYTRUDA and KEYTRUDA QLEX
Contraindications
KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients.
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA and KEYTRUDA QLEX are monoclonal antibodies that belong to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA or KEYTRUDA QLEX in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA and KEYTRUDA QLEX require interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients. Immune-mediated pneumonitis occurred in 5% (13/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including fatal (0.4%), Grade 3 (2%), and Grade 2 (1.2%) adverse reactions.
Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.
Immune-Mediated Colitis
KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.
Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients. Immune-mediated colitis occurred in 1.2% (3/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.8%) and Grade 2 (0.4%) adverse reactions.
Hepatotoxicity and Immune-Mediated Hepatitis
KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients. Immune-mediated hepatitis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%) adverse reactions.
KEYTRUDA With Axitinib or KEYTRUDA QLEX With Axitinib
KEYTRUDA and KEYTRUDA QLEX, when either is used in combination with axitinib, can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib or KEYTRUDA QLEX and axitinib, and consider administering corticosteroids as needed.
With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
KEYTRUDA and KEYTRUDA QLEX can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA and KEYTRUDA QLEX depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Adrenal insufficiency occurred in 2% (5/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.4%) and Grade 2 (0.8%) adverse reactions.
Hypophysitis
KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA,
including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Thyroid Disorders
KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity.
Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.
Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients.
Contacts
Media Contacts:
Julie Cunningham
(617) 519-6264
Marian Cutler
(973) 517-0519
Investor Contacts:
Peter Dannenbaum
(732) 594-1579
Steven Graziano
(732) 594-1583
