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, NJ, USA I June 03, 2023 I 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.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
Urothelial Carcinoma
KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):
- 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, as a single agent, is indicated for the treatment of 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.
Microsatellite Instability-High or Mismatch Repair Deficient Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:
- in combination with platinum- and fluoropyrimidine-based chemotherapy, or
- as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Cervical Cancer
KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
Endometrial Carcinoma
KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Tumor Mutational Burden-High Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.
Triple-Negative Breast Cancer
KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Merck’s focus on cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
SOURCE: Merck
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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, NJ, USA I June 03, 2023 I 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.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
Urothelial Carcinoma
KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):
- 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, as a single agent, is indicated for the treatment of 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.
Microsatellite Instability-High or Mismatch Repair Deficient Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:
- in combination with platinum- and fluoropyrimidine-based chemotherapy, or
- as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Cervical Cancer
KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
Endometrial Carcinoma
KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Tumor Mutational Burden-High Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.
Triple-Negative Breast Cancer
KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Merck’s focus on cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
SOURCE: Merck
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