SUMMARY: 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 25% of patients with NSCLC who present with early Stage (IāIIIA) disease. These patients are often treated with platinum-based neoadjuvant or adjuvant chemotherapy to eradicate micrometastatic disease and decrease the risk of recurrence. However, conventional neoadjuvant or adjuvant chemotherapy provides only a 5% absolute improvement in Overall Survival (OS) at 5 years and 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 (PDāL1) expression.
Nivolumab (OPDIVOĀ®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor which is highly expressed on activated T cells, and blocks its interaction with PD-L1 or PD-L2 on tumor cells, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. Combining cytotoxic chemotherapy with a PD 1 inhibitor therapy may augment the antitumor immune response through cell-death induced increased tumor antigenicity and reduction of Treg mediated immune suppression.
In the CheckMate 816 Phase III trial, neoadjuvant Nivolumab plus platinum-doublet chemotherapy in earlier stage resectable NSCLC resulted in a marked improvement in pathologic Complete Response rate, with a statistically significant improvement in the Event Free Survival among those receiving Nivolumab plus chemotherapy group, compared to those receiving chemotherapy alone.
CheckMate 77T, a multicenter, randomized, double-blind, Phase III trial, conducted to evaluate the efficacy of perioperative Nivolumab + chemotherapy in patients with resectable NSCLC. In this study, 461 patients (N=461) with untreated, resectable Stage IIA (more than 4 cm)-IIIB (N2) NSCLC were randomly assigned 1:1 to receive Nivolumab 360 mg IV every 3 weeks plus four cycles of histology-based platinum doublet chemotherapy followed by surgery, and adjuvant Nivolumab 480 mg IV every 4 weeks for 1 year (N=229), or placebo IV every 3 weeks plus four cycles of histology-based platinum doublet chemotherapy followed by surgery and adjuvant placebo IV every 4 weeks for 1 year (N=232). Enrolled patients had no prior systemic anticancer treatment and no EGFR or ALK mutations. Patients were stratified according to histology, disease stage, and tumor PD-L1 expression (less than 1% versus 1% or more) and patients with brain metastasis were excluded. The median age was 66 years, and both treatment groups were well balanced. Approximately two-thirds had Stage III disease, more than 50% of patients had tumor PD-L1 expression of 1% or more, and about 40% of patients had PD-L1 expression less than 1%. Approximately 90% were current or former smokers and majority of patients (75%) received Carboplatin-based chemotherapy. Surgery was performed within 6 weeks following the last dose of neoadjuvant therapy and radiologic restaging. The Primary endpoint of this study was Event Free Survival (EFS) according to Blinded Independent Central Review. Secondary endpoints included Overall Survival, pathologic Complete Response, Major Pathologic Response (10% or less of viable tumor cells remaining at time of surgery), and Safety. The researchers presented the data from the first interim prespecified analysis of Event-Free Survival.
At a median follow-up of 25.4 months, approximately 78% in the Nivolumab/chemotherapy group and 77% in the placebo/chemotherapy group were able to undergo definitive surgery. Lobectomy was the most common type of surgery performed and about 90% of patients had a complete resection. Nivolumab plus chemotherapy significantly improved Event-Free Survival, compared to placebo plus chemotherapy (median Not Reached versus 18.4 months respectively; HR=0.58; P=00025). This represented a 42% improvement in Event-Free Survival among those treated with Nivolumab plus chemotherapy. The 12-month Event-Free Survival rate was 73% versus 59%, respectively and the 18-month Event-Free Survival rate was 70% versus 50%. The pathologic Complete Response rates as well as Major Pathologic Response rates were significantly higher with Nivolumab plus chemotherapy, compared to placebo plus chemotherapy (25.3% versus 4.7% and 35.4% versus 12.1% repectively). Surgery related adverse events were similar in both treatment groups at 12%.
The researchers concluded that CheckMate 77T met its primary endpoint and is the first Phase III perioperative study that builds on the current standard of care, neoadjuvant Nivolumab plus chemotherapy. Patient with early stage resectable NSCLC now have three different treatment options: 1) Neoadjuvant therapy followed by surgery 2) Surgery followed by adjuvant therapy, and 3) Now perioperative therapy, which includes neoadjuvant therapy, surgery, and adjuvant therapy. Circulating tumor DNA and other biomarkers may identify patients who are cured with chemoimmunotherapy and in whom adjuvant therapy can be avoided.
CheckMate 77T: Phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage IIāIIIb NSCLC. Cascone T, Awad M, Spicer J, et al. ESMO Congress 2023. Abstract LBA1. Presented on October 21, 2023.
