SUMMARY: The FDA on March 4, 2022, approved OPDIVO® (Nivolumab) with platinum-doublet chemotherapy for adult patients with resectable Non Small Cell Lung Cancer (NSCLC) in the neoadjuvant setting. This represents the first FDA approval for neoadjuvant therapy for early stage NSCLC. The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 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.
Surgical resection with a curative intent is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease, unless medically unfit. These numbers are likely to increase with the implementation of Lung Cancer screening programs. These patients are often treated with platinum-based adjuvant chemotherapy/immunotherapy following surgical resection, 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.
CHECKMATE-816 is an open-label, multicenter, randomized Phase III study which evaluated OPDIVO® plus chemotherapy versus chemotherapy alone as neoadjuvant treatment in patients with resectable Stage IB to IIIA NSCLC. In this trial, 358 patients with clinical Stage IB to Stage IIIA resectable NSCLC, with an ECOG Performance Status of 0 to 1 and no known sensitizing EGFR mutations or ALK alterations, were randomly assigned 1:1 to receive OPDIVO® at a dose of 360 mg IV along with platinum-doublet chemotherapy every 3 weeks for 3 doses (N=179) or chemotherapy alone on the same schedule (N=179). Patients then underwent radiologic staging and surgical resection within 6 weeks of neoadjuvant therapy. They then had the option of adjuvant therapy with or without radiation therapy, and were followed up. Both treatment groups were well balanced with regards to age, sex, histology and smoking status. About two-thirds of the patients had Stage IIIA disease. The median patient age was 65 years and patients were stratified by cancer stage, gender and PD-L1 status (1% or higher versus less than 1%). Tumor Mutational Burden results were available for 50% of patients. The Primary end points of this study were pathologic Complete Response (pCR), defined as the absence of viable tumor cells in lung and lymph nodes, and Event Free Survival (EFS). Secondary endpoints include major pathological response and Overall Survival. Key exploratory endpoints included feasibility of surgery and surgery-related adverse events.
The pCR rate was 24% in the OPDIVO® plus chemotherapy group and 2.2% in the chemotherapy alone group. The pCR improvement was noted with the OPDIVO® plus chemotherapy combination regardless of disease stage and irrespective of radiologic downstaging. Overall, 83% of patients assigned to OPDIVO® plus chemotherapy and 78% of patient’s assigned to chemotherapy alone achieved R0 resection, with 10% versus 74% median residual viable tumor cells noted in the primary tumor bed respectively. Lung-sparing surgery (lobectomy) was performed in 77% of patients assigned to OPDIVO® plus chemotherapy versus 61% among those assigned to chemotherapy alone. The median EFS was 31.6 months in the OPDIVO® plus chemotherapy group and 20.8 months for those receiving chemotherapy alone (HR=0.63; P=0.0052).
The authors concluded that CheckMate 816 is the first Phase III trial to show a benefit for neoadjuvant immunotherapy plus platinum-doublet chemotherapy in earlier stage resectable NSCLC, with marked improvement in pathologic Complete Response rate, without any meaningful increase in toxicity or decrease in the feasibility of surgery. It is likely that the higher pathologic Complete Response rate may translate into higher cure rates, with longer follow up.
Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). Spicer J, Wang C, Tanaka F, et al. J Clin Oncol. 2021;39(suppl 15):8503. doi:10.1200/JCO.2021.39.15_suppl.8503
