SUMMARY: The FDA on October 16, 2023, approved KEYTRUDA® (Pembrolizumab) with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of single-agent KEYTRUDA® as post-surgical adjuvant treatment for resectable (tumors 4 cm or more or node positive) Non-Small Cell Lung Cancer (NSCLC). Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.
Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.
Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2.
The present FDA approval was based on the KEYNOTE-671 trial, which is a randomized, double-blind, placebo-controlled, Phase III trial, conducted to evaluate whether a perioperative approach of combined neoadjuvant Pembrolizumab plus Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, would improve efficacy as compared with neoadjuvant Cisplatin-based chemotherapy and resection alone, in patients with resectable Stage II or III NSCLC. This study included patients with pathologically confirmed, resectable Stage II, IIIA, or IIIB (N2 disease-with involvement of 1 or more ipsilateral mediastinal lymph nodes or subcarinal lymph node) NSCLC. Eligible patients were randomly assigned in a 1:1 ratio to receive neoadjuvant Pembrolizumab 200 mg IV (N=397) or placebo (N=400) once every 3 weeks, each of which was given with Cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant Pembrolizumab 200 mg IV or placebo once every 3 weeks for up to 13 cycles. The median age was 64 years, 70% had Stage III disease, about 44% had N2 nodal stage, 57% has nonsquamous histology and 43% had squamous histology, about 36% had less than 1% PD-L1 Tumor Proportion Score (TPS), whereas 30% of patients had tumors with a TPS of 1-49% and 33% had TPS of 50% or more. The dual Primary end points were Event-Free Survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death), and Overall Survival (OS). Secondary end points included major pathological response, pathological Complete Response, and Safety.
The researchers reported the efficacy and safety data from the prespecified first interim analysis. The median follow-up was 25.2 months. The Event-Free Survival (EFS) at 24 months was 62.4% in the Pembrolizumab group and 40.6% in the placebo group. The median EFS was not reached in the Pembrolizumab group and was 17.0 months in the placebo group (HR=0.58; P<0.001). The EFS benefit with Pembrolizumab was consistent across all subgroups examined. The estimated 24-month Overall Survival was 80.9% in the Pembrolizumab group and 77.6% in the placebo group and this was not statistically significant (P=0.02) at this first interim analysis.
A major pathological response occurred in 30.2% of the patients in the Pembrolizumab group and in 11.0% of those in the placebo group (P<0.0001) and a pathological Complete Response occurred in 18.1% and 4.0%, respectively (P<0.0001). An exploratory analysis showed that the Event-Free Survival benefit was noted in the Pembrolizumab group regardless of whether participants had a major pathological response or a pathological Complete Response. The benefit with Pembrolizumab therapy appeared to be similar across both squamous and nonsquamous histologies. Approximately 45% of the patients in the Pembrolizumab group and 37% in the placebo group had treatment-related adverse events of Grade 3 or higher.
It was concluded that among patients with resectable Stage II, IIIA, or IIIB (N2 stage) NSCLC, the addition of Pembrolizumab to neoadjuvant Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, led to a significant improvement in Event-Free Survival, major pathological response, and pathological Complete Response, as compared with neoadjuvant chemotherapy alone followed by surgery. It should be noted that this trial was not designed to assess the relative contribution of adjuvant Pembrolizumab.
Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. Wakelee H, Liberman M, Kato T, et al., for the KEYNOTE-671 Investigators. N Engl J Med 2023;389:491-503.
