Merck’s KEYTRUDA® (pembrolizumab) Plus Chemotherapy Before Surgery and Continued as a Single Agent After Surgery Reduced the Risk of Event-Free Survival Events by 42% Versus Pre-Operative Chemotherapy in Resectable Stage II, IIIA or IIIB NSCLC

Based on a subgroup analysis, improvement in event-free survival (EFS) with the KEYTRUDA-based regimen was consistent across all PD-L1 expression subgroups, histology and stage

Exploratory subgroup analysis showed a reduction in EFS events with the KEYTRUDA perioperative regimen for patients with or without pathological complete response (pCR) compared with the chemotherapy-placebo regimen

KEYNOTE-671 is the eighth positive pivotal study evaluating a KEYTRUDA-based regimen in earlier stages of cancer and the seventh positive pivotal study in lung cancer

RAHWAY, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced positive results from the pivotal Phase 3 KEYNOTE-671 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, as a perioperative treatment regimen, which includes treatment before surgery (neoadjuvant) and after surgery (adjuvant), for patients with resectable stage II, IIIA or IIIB non-small cell lung cancer (NSCLC). After a median follow-up of 25.2 months, neoadjuvant KEYTRUDA plus chemotherapy followed by resection and adjuvant single-agent KEYTRUDA significantly improved EFS, reducing the risk of disease recurrence, progression or death by 42% (HR=0.58 [95% CI, 0.46-0.72]; p<0.00001) for patients with resectable stage II, IIIA or IIIB NSCLC versus neoadjuvant placebo plus chemotherapy followed by adjuvant placebo. For patients who received the KEYTRUDA-based regimen, median EFS was not reached (95% CI, 34.1-NR) versus 17 months (95% CI, 14.3-22) for patients who received chemotherapy alone.

The trial is continuing to allow for additional follow-up of overall survival (OS), the other dual primary endpoint. A favorable trend in OS was observed for the KEYTRUDA regimen versus pre-operative chemotherapy (HR 0.73 [95% CI, 0.54-0.99]; p=0.02124); with only 177 events, these OS data are not mature and did not reach statistical significance at the time of this interim analysis. The safety profile of the KEYTRUDA regimen was consistent with the safety profile in earlier stages and metastatic NSCLC, with no new safety concerns identified. These results are being presented today during a clinical science symposium, The Promise of Neoadjuvant Immunotherapy Across Solid Tumors, at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA100) and are also being simultaneously published in the New England Journal of Medicine.

In a subgroup analysis, improvement in EFS with the KEYTRUDA regimen was consistent across PD-L1 expression subgroups, histology and stage. Treatment with the KEYTRUDA-based regimen reduced the risk of EFS events regardless of PD-L1 expression versus the chemotherapy-placebo regimen (tumor proportion score [TPS] ≥50% [n=266] HR=0.42 [95% CI, 0.28-0.65]; TPS 1-49% [n=242] HR=0.51 [95% CI, 0.34-0.75]; TPS <1% [n=289] HR=0.77 [95% CI, 0.55-1.07]). The KEYTRUDA-based regimen also improved EFS compared with the chemotherapy-placebo regimen regardless of histology (nonsquamous [n=453] HR=0.58 [95% CI, 0.43-0.78]; squamous [n=344] HR=0.57 [95% CI, 0.41-0.77]) and stage (stage II [n=239] HR=0.65 [95% CI, 0.42-1.01]; stage IIIA [n=442] HR=0.54 [95% CI, 0.41-0.72]; stage IIIB [n=116] HR=0.52 [95% CI, 0.31-0.88]).

While achieving pCR is a predictor of better outcomes, an exploratory subgroup analysis showed the reduction in EFS events with the KEYTRUDA perioperative regimen was observed for patients with or without pCR (with pCR: HR=0.33 [95% CI, 0.09-1.22]; without pCR: HR=0.69 [95% CI, 0.55-0.86]).

“Historically, more than half of people with earlier stages of non-small cell lung cancer that has been surgically removed will experience recurrence,” said Dr. Heather Wakelee, thoracic medical oncologist and professor of medicine at Stanford Medicine, president of the International Association for the Study of Lung Cancer and principal investigator for KEYNOTE-671. “Results showed that a pembrolizumab-based regimen before and after surgery significantly reduced the risk of recurrence, progression or death by 42 percent versus pre-operative chemotherapy, regardless of PD-L1 expression and with or without a pathological complete response. These event-free survival data are very encouraging and support the potential of this perioperative approach for patients with resectable stage II, IIIA or IIIB non-small cell lung cancer.”

“These compelling new results build on previous studies of KEYTRUDA in earlier stages of disease across certain types of cancer, including non-small cell lung cancer,” said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. “KEYNOTE-671 demonstrated statistically significant and clinically meaningful improvements in event-free survival for patients with stage II, IIIA or IIIB non-small cell lung cancer treated with the KEYTRUDA perioperative regimen compared with chemotherapy and surgery alone. We are working with the FDA and other global authorities to bring this new option to patients as quickly as possible.”

“These results are meaningful for the community of thoracic surgeons given the need for additional treatment options that can improve event-free survival for patients with resectable stage II, IIIA or IIIB non-small cell lung cancer,” said Dr. Jonathan Spicer, associate professor of surgery, McGill University, attending surgeon, division of thoracic and upper gastrointestinal surgery, Montreal General Hospital, McGill University Health Centre and KEYNOTE-671 investigator. “Notably, the results showed that the KEYTRUDA-based perioperative regimen did not impact the opportunity for a complete resection and improvements were seen regardless of if they achieved a pathological complete response or not.”

Merck previously announced that, based on these results, the U.S. Food and Drug Administration (FDA) has accepted a new supplemental Biologics License Application (sBLA) for KEYTRUDA for the treatment of patients with resectable stage II, IIIA, or IIIB (T3-4N2) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment. The FDA has set a Prescription Drug User Fee Act, or target action, date of October 16, 2023.

In addition to KEYNOTE-671, seven other pivotal trials evaluating a KEYTRUDA-based regimen in patients with earlier stages of cancer met their primary endpoint(s). These trials included: KEYNOTE-057 in Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer; KEYNOTE-629 in cutaneous squamous cell carcinoma; KEYNOTE-716 in stage IIB and IIC melanoma; KEYNOTE-054 in stage III melanoma; KEYNOTE-091 in stage IB, II or IIIA NSCLC; KEYNOTE-564 in renal cell carcinoma; and KEYNOTE-522 in triple-negative breast cancer.

The seven positive pivotal studies in lung cancer include: KEYNOTE-189, KEYNOTE-407, KEYNOTE-042, KEYNOTE-024, KEYNOTE-010, KEYNOTE-091 and KEYNOTE-671.

Merck has an extensive clinical development program in lung cancer and is advancing multiple registration-enabling studies, with research directed at earlier stages of disease and novel combinations. Key studies in earlier stages of NSCLC and small cell lung cancer (SCLC) include KEYNOTE-671, KEYNOTE-091, KEYNOTE-867, KEYLYNK-012, KEYVIBE-006 and KEYLYNK-013.

As announced, data spanning more than 25 different types of cancer are being presented from Merck’s broad oncology portfolio and investigational pipeline at the 2023 ASCO Annual Meeting. A compendium of Merck’s presentations and posters is available here.

Study design and additional data from KEYNOTE-671

KEYNOTE-671 is a randomized, double-blind Phase 3 trial (ClinicalTrials.gov, NCT03425643) evaluating neoadjuvant KEYTRUDA plus chemotherapy, followed by resection and adjuvant KEYTRUDA as a single agent, versus placebo plus neoadjuvant chemotherapy, followed by resection and adjuvant placebo, in patients with resectable stage II, IIIA or IIIB (T3-4N2) NSCLC. The trial’s dual primary endpoints are EFS and OS. Key secondary endpoints include pCR and major pathological response (mPR). The study enrolled 797 patients who were randomly assigned (1:1) to receive either:

• KEYTRUDA (200 mg intravenously [IV] every three weeks [Q3W] for up to four cycles) plus chemotherapy (cisplatin [75 mg/m², IV; given on Day 1 of each cycle] and either gemcitabine [1000 mg/m², IV; given on Days 1 and 8 of each cycle or pemetrexed [500 mg/m², IV; given on Day 1 of each cycle]) as neoadjuvant therapy prior to surgery, followed by KEYTRUDA (200 mg IV Q3W for up to 13 cycles) as adjuvant therapy post-surgery (n=397) for up to 13 cycles, or;
• Placebo (saline IV Q3W for up to four cycles) plus chemotherapy (cisplatin [75 mg/m², IV; given on Day 1 of each cycle] and either gemcitabine [1000 mg/m², IV; given on Days 1 and 8 of each cycle] or pemetrexed [500 mg/m², IV; given on Day 1 of each cycle]) as neoadjuvant therapy prior to surgery, followed by placebo (saline IV Q3W for up to 13 cycles) as adjuvant therapy post-surgery (n=400) for up to 13 cycles.

As previously announced, KEYNOTE-671 met the dual primary endpoint of EFS at the first interim analysis. At two years, 62.4% of patients treated with the KEYTRUDA regimen were alive and did not experience an EFS event compared to 40.6% of patients treated with the chemotherapy-placebo regimen.

The KEYTRUDA-based perioperative treatment regimen also demonstrated statistically significant and clinically meaningful improvements in key secondary endpoints of pCR and mPR. In the study, 18.1% of patients treated with the KEYTRUDA plus chemotherapy regimen achieved pCR versus 4% of patients treated with pre-operative chemotherapy (difference: 14.2% (95% CI: 10.1-18.7); p<0.00001). Additionally, treatment with the KEYTRUDA plus chemotherapy regimen resulted in a 30.2% mPR rate, meaning 10% or less or their tumor cells remained after receiving perioperative treatment, versus 11% with chemotherapy alone (difference: 19.2% [95% CI: 13.9-24.7]; p<0.00001).

Among patients treated with pre-operative KEYTRUDA plus chemotherapy, 80.6% underwent definitive surgery compared to 75.5% who received chemotherapy alone. Of these patients, 92% and 84% had a complete resection (R0 resection), respectively.

Treatment-related adverse events (TRAEs) occurred in 96.7% of patients receiving the KEYTRUDA regimen (n=396) and 95% of patients receiving the chemotherapy-placebo regimen (n=399); Grade 3-5 TRAEs occurred in 44.9% versus 37.3%, respectively. Treatment-related adverse events led to discontinuation of all study treatment in 12.6% of patients treated with the KEYTRUDA regimen and 5.3% treated with the chemotherapy-placebo regimen. Treatment-related adverse events led to death in 1.0% of patients receiving the KEYTRUDA regimen (n=4) and 0.8% of patients receiving the chemotherapy-placebo regimen (n=3). No new safety concerns were identified.

Immune-mediated adverse events (AEs) and infusion reactions of any grade occurred in 25.3% of patients receiving the KEYTRUDA regimen and 10.5% of patients receiving the chemotherapy-placebo regimen. Grade 3-5 immune-mediated AEs and infusion reactions occurred in 5.8% versus 1.5%, respectively. The most common of these events (occurring in ≥10% of patients) was hypothyroidism (11.1%) in patients receiving the KEYTRUDA regimen. Immune-mediated AEs and infusion reactions led to death in 0.3% of patients receiving the KEYTRUDA regimen (n=1) and no patients receiving the chemotherapy-placebo regimen. Immune-mediated AEs and infusion reactions that led to discontinuation of all study treatment occurred in 5.1% of patients receiving the KEYTRUDA regimen and 0.8% of patients receiving the chemotherapy-placebo regimen.

About lung cancer

Lung cancer is the leading cause of cancer death worldwide. In 2020 alone, there were more than 2.2 million new cases and 1.8 million deaths from lung cancer globally. Non-small cell lung cancer is the most common type of lung cancer, accounting for about 81% of all cases. In the U.S., the overall five-year survival rate for patients diagnosed with lung cancer is 25%, which is a 21% improvement over the last five years. Improved survival rates are due, in part, to reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, screening, early detection and improving treatment rates remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. Only 5.8% of people in the U.S. who are eligible were screened for lung cancer in 2021.

About Merck’s research in lung cancer

Merck is advancing research aimed at transforming the way lung cancer is treated, with a goal of improving outcomes for patients affected by this deadly disease. Through nearly 200 clinical trials evaluating more than 36,000 patients around the world, Merck is at the forefront of lung cancer research. In NSCLC, KEYTRUDA has five approved U.S. indications (see indications below) and is approved for advanced disease in more than 95 countries. Among Merck’s research efforts are trials focused on evaluating KEYTRUDA in earlier stages of lung cancer as well as identifying new combinations and coformulations with KEYTRUDA.

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 studying KEYTRUDA in earlier disease states, with approximately 20 ongoing registrational studies across multiple types of cancer.

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.

Selected KEYTRUDA^® (pembrolizumab) Indications in the U.S.

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 prior to receiving KEYTRUDA.

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.

See additional selected indications for KEYTRUDA in the U.S. after the Selected Important Safety Information

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the 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 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 depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires 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 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.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

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 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.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA 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.

KEYTRUDA With Axitinib

KEYTRUDA 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, 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 can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA 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.

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