First and only PD-1 inhibitor plus antibody-drug conjugate regimens approved for patients with MIBC regardless of cisplatin eligibility
Approvals based on Phase 3 KEYNOTE-B15 trial, combined with previous approvals based on Phase 3 KEYNOTE-905 trial, bring forward new options for these patients
RAHWAY, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the U.S. Food and Drug Administration (FDA) approved KEYTRUDA® (pembrolizumab) and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph), Merck’s anti-PD-1 therapies, each 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). These approvals represent the first and only PD-1 inhibitor plus antibody-drug conjugate (ADC) regimens approved for adults with MIBC regardless of cisplatin eligibility.
These approvals are based on data from the Phase 3 KEYNOTE-B15 trial (also known as EV-304), which was conducted in collaboration with Pfizer and Astellas and enrolled 808 patients. They also expand the previously approved indication based on the Phase 3 KEYNOTE-905 trial (also known as EV-303) for KEYTRUDA and KEYTRUDA QLEX, each in combination with Padcev, in the U.S. as treatment before and after surgery for adult patients with MIBC who are ineligible for cisplatin-based chemotherapy.
In KEYNOTE-B15, KEYTRUDA plus Padcev, given before and after surgery, demonstrated a statistically significant improvement in event-free survival (EFS), reducing the risk of EFS events (defined as disease progression, recurrence or death) by 47% (HR=0.53 [95% CI, 0.41-0.70]; p<0.0001; 87/405 [21%] versus 146/403 [36%]) in patients with MIBC who are eligible for cisplatin-based chemotherapy compared to neoadjuvant chemotherapy (gemcitabine and cisplatin) and surgery. Median EFS was not reached (NR) (95% CI, NR-NR) for perioperative KEYTRUDA plus Padcev versus 48.5 months (95% CI, 43.3-NR) for neoadjuvant chemotherapy and surgery. KEYTRUDA plus Padcev also demonstrated a statistically significant improvement in overall survival (OS), reducing the risk of death by 35% (HR=0.65 [95% CI, 0.48-0.89]; p=0.0029; 69/405 [17%] versus 99/403 [25%]) in these patients when compared to neoadjuvant chemotherapy and surgery. Median OS was NR (95% CI, NR-NR) for either regimen. The trial showed KEYTRUDA plus Padcev demonstrated a statistically significant improvement in pathologic complete response (pCR) rate compared to neoadjuvant chemotherapy (55.8% [95% CI: 50.8, 60.7] versus 32.5% [95% CI: 28.0, 37.3]; 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. KEYTRUDA and KEYTRUDA QLEX are associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions in any or multiple organs, which can occur during or after treatment, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, other transplant (including corneal graft) rejection; severe and life-threatening infusion or injection-related reactions; fatal and other serious complications in patients who receive allogeneic hematopoietic stem cell transplantation before or after beginning treatment; embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when KEYTRUDA or KEYTRUDA QLEX is added to a thalidomide analogue plus dexamethasone, which is not recommended outside of controlled trials. Immune-mediated adverse reactions listed here may not include all such possible severe or fatal reactions. For more information, see “Selected Safety Information” below.
“Today’s FDA approvals represent a meaningful development for patients who have muscle-invasive bladder cancer, as nearly half of these patients experience disease recurrence following bladder removal surgery,” said Dr. Matthew Galsky, Lillian and Howard Stratton professor of medicine, Icahn School of Medicine at Mount Sinai, director of genitourinary medical oncology, Mount Sinai Tisch Cancer Center. “This shift away from traditional cisplatin-based chemotherapy, which has been recommended for eligible patients for more than 20 years, provides important new treatment options for individuals with muscle-invasive bladder cancer regardless of cisplatin eligibility.”
“We’re expanding the use of KEYTRUDA and KEYTRUDA QLEX, each in combination with Padcev, for patients with muscle-invasive bladder cancer who are eligible for cisplatin-based chemotherapy with these approvals,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “The results from KEYNOTE-B15, together with KEYNOTE-905, highlight the potential of these new treatment options for patients regardless of cisplatin eligibility in the perioperative setting and mark a promising step forward in the treatment of muscle-invasive bladder cancer.”
Study design and additional data from KEYNOTE-B15 supporting this approval
KEYNOTE-B15, also known as EV-304, is an open-label, randomized, multicenter, active-control Phase 3 trial (ClinicalTrials.gov, NCT04700124) evaluating perioperative KEYTRUDA in combination with Padcev and surgery (radical cystectomy [RC] and pelvic lymph node dissection [PLND]) versus neoadjuvant chemotherapy (gemcitabine plus cisplatin) and surgery in patients with previously untreated MIBC who are eligible for cisplatin-based chemotherapy. The trial enrolled 808 patients who were randomized 1:1 to receive either:
- Neoadjuvant KEYTRUDA 200 mg intravenously on Day 1 and Padcev 1.25 mg/kg intravenously on Days 1 and 8 of each 21-day cycle for four cycles prior to surgery, followed by adjuvant KEYTRUDA 200 mg on Day 1 of each 21-day cycle for 13 cycles and adjuvant Padcev 1.25 mg/kg on Days 1 and 8 of each 21-day cycle for five cycles (n=405), or;
- Neoadjuvant gemcitabine 1000 mg/m2 on Days 1 and 8 and cisplatin 70 mg/m2 on Day 1 of each 21-day cycle for four cycles prior to surgery, followed by observation (n=403).
The major efficacy outcome measure was EFS as assessed by blinded independent central review (BICR), defined as the time from randomization to the first occurrence of the following events: 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. Additional efficacy outcome measures were OS and pCR rate as assessed by blinded independent pathology review.
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 five weeks prior to RC and PLND, and at six weeks post-RC. 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 two years and every 24 weeks thereafter.
A total of 351 (87%) patients receiving KEYTRUDA in combination with Padcev and 361 (90%) patients receiving gemcitabine with cisplatin underwent RC and PLND. A total of 25 (6%) of patients in the gemcitabine with cisplatin arm received adjuvant nivolumab.
The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment.
For the 403 patients who received KEYTRUDA in the neoadjuvant phase, the median duration of exposure to KEYTRUDA 200 mg every three weeks was 2.1 months (range: 1 day to 3.9 months) and the median number of cycles of KEYTRUDA was four (range: 1 to 4) out of the planned four cycles in the neoadjuvant phase. For the 262 patients randomized to receive KEYTRUDA in combination with Padcev and who received any adjuvant treatment, 249 patients received KEYTRUDA in the adjuvant phase. The median duration of exposure to KEYTRUDA 200 mg every three weeks was 8.3 months (range: 1 day to 18.9 months) and the median number of cycles of KEYTRUDA was 13 (range: 1 to 13) out of the planned 13 cycles for patients who received KEYTRUDA in the adjuvant phase. Across the combined neoadjuvant and adjuvant phases (n=403), the median number of cycles of KEYTRUDA was 10 (range: 1 to 17) out of the planned 17 cycles.
In the neoadjuvant phase of KEYNOTE-B15, serious adverse reactions occurred in 27% of patients who received KEYTRUDA in combination with Padcev. The most frequent (≥1.5%) serious adverse reactions were rash (3.2%), pneumonitis/interstitial lung disease (ILD) (2.2%) and diarrhea (1.7%). Fatal adverse reactions occurred in 1.7% of patients, including multiple organ dysfunction syndrome (0.5%) and COVID-19 pneumonia, cardiac arrest, pneumonia, septic shock and urosepsis (0.2% each). Additional fatal adverse reactions were reported in two patients in the post-surgery phase before adjuvant treatment started, including pneumonia and sepsis (one patient each).
Permanent discontinuation of KEYTRUDA in the neoadjuvant phase due to an adverse reaction occurred in 17% of patients. The most frequent (>1%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were rash (2.2%), increased alanine aminotransferase (ALT) and pneumonitis/ILD (1.7% each) and hepatitis (1.2%).
Adverse reactions leading to dose interruption of KEYTRUDA in the neoadjuvant phase occurred in 29% of patients. The most common adverse reactions (≥2%) leading to dose interruption of KEYTRUDA were rash (8%), increased ALT (3.7%), neutropenia (3.2%) and hyperglycemia (2.5%). Of the 403 patients who received neoadjuvant treatment with KEYTRUDA in combination with Padcev, 13 patients (3.2%) did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were multiple organ dysfunction syndrome (0.5%) and adenocarcinoma of colon, COVID-19 pneumonia, cardiac arrest, chronic obstructive pulmonary disease, coronary artery disease, glomerulonephritis, immune-mediated lung disease, myocarditis, pneumonia, pneumonitis and urosepsis (0.2% each).
Of the 351 patients who received neoadjuvant treatment with KEYTRUDA in combination with Padcev and underwent RC, 26 (7%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding eight weeks) due to adverse reactions.
In the adjuvant phase of KEYNOTE-B15, serious adverse reactions occurred in 35% of patients who received KEYTRUDA in the adjuvant phase; the most frequent (≥1.5%) serious adverse reactions were urinary tract infection (8%), sepsis (2.8%), diarrhea, hyperglycemia and pneumonitis/ILD (1.6% each). Fatal adverse reactions occurred in 3.2% of patients who received KEYTRUDA in the adjuvant phase, including death (0.8%) and cardiac arrest, duodenal ulcer perforation, acute pancreatitis, renal failure, small cell lung cancer and toxic shock syndrome (0.4% each).
Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 23% of patients who received KEYTRUDA in the adjuvant phase. The most frequent (>1%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were diarrhea and pneumonitis/ILD (2.4% each), rash (2%), and hyperglycemia and sepsis (1.2% each).
Adverse reactions leading to dose interruption of KEYTRUDA in the adjuvant phase occurred in 39% of patients who received KEYTRUDA in the adjuvant phase. The most common adverse reactions (≥2%) leading to dose interruption of KEYTRUDA were diarrhea (6%), urinary tract infection (5%), COVID-19 (3.6%), rash (2.8%) and nausea (2%).
Study design and additional data from KEYNOTE-905 supporting the previous 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 was conducted in collaboration with Pfizer and Astellas and enrolled 344 patients who were randomized 1:1 to receive either:
- Neoadjuvant KEYTRUDA 200 mg intravenously on Day 1 and Padcev 1.25 mg/kg intravenously on Days 1 and 8 of each 21-day cycle for three cycles prior to surgery, followed by adjuvant KEYTRUDA 200 mg on Day 1 of each 21-day cycle for 14 cycles and adjuvant Padcev 1.25 mg/kg on Days 1 and 8 of each 21-day cycle for six cycles (n=170).
- Immediate RC and PLND alone (n=174).
The major efficacy outcome measure was EFS as assessed by BICR, defined as the time from randomization to the first occurrence of the following events: 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. Overall survival and pCR rate as assessed by blinded independent pathology review were additional efficacy outcome measures.
In KEYNOTE-905, KEYTRUDA plus Padcev, given before and after surgery, demonstrated a statistically significant improvement in EFS, reducing the risk of EFS events by 60% (HR=0.40 [95% CI, 0.28-0.57]; p<0.0001; 48/170 [28%] versus 95/174 [55%]) compared to surgery alone in patients with MIBC who are not eligible for or declined cisplatin-based chemotherapy. Median EFS was not reached (NR) (95% CI, 37.3-NR) for perioperative KEYTRUDA plus Padcev versus 15.7 months (95% CI, 10.3-20.5) for surgery alone. KEYTRUDA plus Padcev also demonstrated a statistically significant improvement in OS, reducing the risk of death by 50% (HR=0.50 [95% CI, 0.33-0.74]; p=0.0002; 38/170 [22%] versus 68/174 [39%]) in these patients when compared to surgery alone. Median OS was NR (95% CI, NR-NR) for the regimen containing KEYTRUDA plus Padcev compared to 41.7 months (95% CI, 31.8-NR) for surgery alone. The trial showed KEYTRUDA plus Padcev demonstrated a statistically significant improvement in pCR rate compared to surgery alone (57.1% [95% CI: 49.3, 64.6] versus 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.
A total of 149 (88%) patients in the arm receiving KEYTRUDA in combination with Padcev and 156 (90%) patients in the RC and PLND alone arm underwent RC and PLND. A total of 29 (17%) of patients in the RC and PLND alone arm received adjuvant nivolumab.
The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment.
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 five weeks prior to RC and PLND and at six 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 two years and every 24 weeks thereafter.
For the 167 patients who received KEYTRUDA in the neoadjuvant phase, the median duration of exposure to KEYTRUDA 200 mg every three weeks was 1.4 months (range: 1 day to 2.7 months) and the median number of cycles of KEYTRUDA was three (range: 1 to 3) out of the planned three cycles in the neoadjuvant phase. For the 100 patients randomized to receive KEYTRUDA in combination with Padcev and who received any adjuvant treatment, 96 patients received KEYTRUDA in the adjuvant phase. The median duration of exposure to KEYTRUDA 200 mg every three 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 for patients who received KEYTRUDA in the adjuvant phase. Across the combined neoadjuvant and adjuvant phases (n=167), the median number of cycles of KEYTRUDA was five (range: 1 to 17) out of the planned 17 cycles.
In the neoadjuvant phase, serious adverse reactions occurred in 27% of patients receiving KEYTRUDA in combination with Padcev. The most frequent (≥2%) serious adverse reactions 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%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were rash (2.4%, including generalized exfoliative dermatitis), increased ALT, increased aspartate aminotransferase (AST), diarrhea, dysgeusia and toxic epidermal necrolysis (1.2% each).
Adverse reactions leading to dose interruption of KEYTRUDA in the neoadjuvant phase occurred in 20% of patients. The most common adverse reactions (≥2%) leading to dose interruption of KEYTRUDA were rash (4.8%) and neutropenia (2.4%). Of the 167 patients in the KEYTRUDA in combination with Padcev arm who received neoadjuvant treatment, seven (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 the 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 Padcev and underwent radical cystectomy, six (4.1%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding eight weeks) due to adverse reactions.
In the adjuvant phase, serious adverse reactions occurred in 45% of patients who received KEYTRUDA in the adjuvant phase; the most frequent (≥2%) serious adverse reactions were urinary tract infection (8%), acute kidney injury and pyelonephritis (5% each), urosepsis (4.2%), and hypokalemia, intestinal obstruction and sepsis (2.1% each). Fatal adverse reactions occurred in 7% of patients who received KEYTRUDA in the adjuvant phase, 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 29% of patients who received KEYTRUDA in the adjuvant phase. The most frequent (>2%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were diarrhea (5%) and peripheral neuropathy, acute kidney injury and pneumonitis (2% each).
Adverse reactions leading to dose interruption of KEYTRUDA in the adjuvant phase occurred in 40% of patients who received KEYTRUDA in the adjuvant phase. The most common adverse reactions (≥2%) leading to dose interruption of KEYTRUDA were rash (7%), urinary tract infection (6%), diarrhea (4%) and abdominal pain, COVID-19, fatigue, pruritus and pyelonephritis (2% each).
About bladder cancer
Bladder cancer is the eighth most common cancer worldwide, diagnosed in more than 635,000 patients each year globally. In the U.S., it is estimated there will be more than 84,000 new cases of bladder cancer diagnosed and more than 17,000 deaths from the disease in 2026. According to some clinical practice guidelines, about 25% of newly diagnosed bladder cancer cases are MIBC. The standard of care for patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery, which is shown to prolong survival. However, nearly half of patients who undergo this standard treatment experience recurrence. Additionally, up to half of patients with MIBC are not eligible to receive cisplatin and face limited treatment options, typically undergoing surgery alone.
About Merck’s research in genitourinary cancers
Merck is advancing research aimed at helping transform the treatment landscape and broaden options for people with genitourinary (GU) cancers, including bladder, kidney and prostate cancers. Globally, GU cancers account for an estimated 2.6 million new cancer diagnoses each year, equaling over 1 in 8 of all cancer incidences. Through a robust clinical development program with more than 50 ongoing clinical trials evaluating more than 22,000 patients around the world, Merck is investigating the potential of several portfolio medicines and pipeline assets, leveraging multiple novel combination strategies, across various stages of disease, to help address unmet needs in GU cancers.
About Merck’s early-stage cancer clinical program
Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is evaluating our portfolio of medicines and pipeline candidates in earlier disease states, with more than 30 ongoing registrational studies across multiple types of cancer.
About KEYTRUDA® (pembrolizumab) injection for intravenous use, 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 2,800 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, 165 mg + 2,000 units/mL
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.
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