Merck Keytruda gets US FDA approval for patients with resectable NSCLC in combo with chemotherapy as neoadjuvant treatment

Merck, known as MSD outside of the United States and Canada, announced that the US Food and Drug Administration (FDA) has approved Keytruda, Merck’s anti-PD-1 therapy, for the treatment of patients with resectable (tumours =4 centimeters [cm] or node positive) non-small cell lung cancer (NSCLC) in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. With this approval, Keytruda has six indications in NSCLC, across both metastatic and earlier stages of NSCLC.

The approval was based on data from the phase 3 KEYNOTE-671 trial evaluating Keytruda in combination with chemotherapy as neoadjuvant treatment followed by surgery and continued adjuvant treatment with Keytruda as a single agent, for patients with resectable stage II, IIIA or IIIB (N2) NSCLC per the American Joint Committee on Cancer eighth edition (AJCC 8th edition). In the study, the Keytruda regimen demonstrated statistically significant improvements in event-free survival (EFS) and overall survival (OS), the study’s dual primary endpoints, versus neoadjuvant placebo plus chemotherapy followed by adjuvant placebo alone. The EFS results, which were from the first interim analysis, were published in June 2023 in the New England Journal of Medicine. The detailed OS results will be presented at the European Society for Medical Oncology (ESMO) Congress 2023 in Madrid, Spain, on October 20, 2023.

Adverse reactions occurring in patients with resectable NSCLC receiving Keytruda in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as single agent adjuvant treatment, were generally similar to those occurring in patients across tumor types receiving Keytruda in combination with chemotherapy.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with Keytruda, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda (pembrolizumab). Based on the severity of the adverse reaction, Keytruda should be withheld or permanently discontinued and corticosteroids administered if appropriate. Keytruda can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman.

“There remains a need for treatment options to improve outcomes for patients with earlier stages of non-small cell lung cancer,” said Dr. Heather Wakelee, principal investigator for KEYNOTE-671, thoracic medical oncologist and professor of medicine at Stanford University and past president of the International Association for the Study of Lung Cancer (IASLC). “This important milestone has the potential to change the current treatment paradigm for resectable non-small cell lung cancer that is greater than four centimeters or has lymph node involvement, by offering an immunotherapy-based regimen that has demonstrated statistically significant improvements in overall survival and event-free survival compared to a placebo and chemotherapy regimen.”

“Keytruda continues to change the way non-small cell lung cancer is treated across earlier and metastatic disease regardless of PD-L1 expression,” said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. “This approval marks a pivotal moment for the lung cancer community by providing certain patients with earlier stages of non-small cell lung cancer and healthcare providers with an important new treatment option.”

The approval marks the sixth NSCLC indication for Keytruda. The five other indications for Keytruda in NSCLC include:

1) In combination with pemetrexed and platinum chemotherapy for the first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumour aberrations;

2) In combination with carboplatin and either paclitaxel or paclitaxel protein-bound for the first-line treatment of patients with metastatic squamous NSCLC;

3) As a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 [tumour proportion score (TPS) =1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumour aberrations and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic;

4) As a single agent for the treatment of patients with metastatic NSCLC whose tumours 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 tumour aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Keytruda; and

5) As a single agent for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a =4 cm), II, or IIIA NSCLC.

KEYNOTE-671 is a multicenter, randomized, double-blind, placebo-controlled phase 3 trial (ClinicalTrials.gov, NCT03425643) evaluating Keytruda in combination with neoadjuvant chemotherapy, followed by surgery and continued adjuvant treatment with Keytruda (pembrolizumab) as a single agent, versus placebo plus neoadjuvant chemotherapy, followed by resection and adjuvant placebo, in patients with resectable stage II, IIIA or IIIB (N2) NSCLC per the AJCC eighth edition. Patients were enrolled regardless of tumour PD-L1 expression. Patients with active autoimmune disease that required systemic therapy within two years of treatment, a medical condition that required immunosuppression or a history of interstitial lung disease or pneumonitis that required steroids were ineligible. Randomization was stratified by stage (II vs. III), tumor PD-L1 expression (TPS =50% or <50%), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia).

The study enrolled 797 patients who were randomly assigned (1:1) to receive either:

Neoadjuvant Keytruda 200 mg intravenously (IV) every three weeks on Day 1 in combination with cisplatin 75 mg/m2 IV on Day 1 and either pemetrexed 500 mg/m2 IV on Day 1 or gemcitabine 1000 mg/m2 IV on Days 1 and 8 of each 21-day cycle for up to four cycles. Within 4-12 weeks following surgery, Keytruda (200 mg) was administered every three weeks for up to 13 cycles, or; Neoadjuvant placebo IV every three weeks on Day 1 in combination with cisplatin 75 mg/m2 IV on Day 1 and either pemetrexed 500 mg/m2 IV on Day 1 or gemcitabine 1000 mg/m2 IV on Days 1 and 8 of each 21-day cycle for up to four cycles. Within 4-12 weeks following surgery, placebo was administered every three weeks for up to 13 cycles.

Treatment with Keytruda or placebo continued until completion of the treatment (17 cycles), disease progression that precluded definitive surgery, disease recurrence in the adjuvant phase, disease progression for those who did not undergo surgery or had incomplete resection and entered the adjuvant phase, or unacceptable toxicity. Assessment of tumour status was performed at baseline, Week 7, and Week 13 in the neoadjuvant phase and within four weeks prior to the start of the adjuvant phase. Following the start of the adjuvant phase, assessment of tumour status was performed every 16 weeks through the end of year 3, and then every six months thereafter. The trial was not designed to isolate the effect of Keytruda in each phase (neoadjuvant or adjuvant) of treatment.

The main efficacy outcome measures were OS and investigator-assessed EFS. Additional efficacy outcome measures were pathological complete response (pCR) rate and major pathological response (mPR) rate as assessed by blinded independent pathology review (BIPR).

Eighty-one percent of patients in the Keytruda in combination with platinum-containing chemotherapy arm had definitive surgery compared to 76% of patients in the placebo in combination with platinum-containing chemotherapy arm.

Lung cancer is the leading cause of cancer death worldwide. In 2020 alone, there were more than 2.2 million new cases and approximately 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 US, 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 advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, screening and early detection 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 US who are eligible were screened for 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 (pembrolizumab) has six approved US 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.

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