Timing of immunotherapy in stage IV non-small cell lung cancer.

8544 Background: Excluding oncogene-driven disease, a combination of cytotoxic chemotherapy and immune checkpoint inhibitor (i.e., anti-PD1/PDL1 inhibitors) became a standard management in stage IV non-small cell lung cancer (NSCLC) in 2017. Cases with a positive driver oncogene such as EGFR, however, need to be treated with rather appropriate targeted therapy. In routine practice, a lengthy turnaround time of molecular analysis to rule out oncogenes makes the chemo-immunotherapy combination a challenge. In addition, unexpected toxicities when immunotherapy and targeted therapy are combined or sequenced have been reported. Because of these restrictions many oncologists often initiate traditional chemotherapy alone for the first few cycles until molecular result becomes available so that they can modify the first-line therapy accordingly. This practice pattern to delay initiation of immunotherapy may lead to inferior cancer outcome. Keynote-189, an international phase III trial defining the role of additive pembrolizumab to first-line chemotherapy, demonstrated an overall survival advantage of chemo-immunotherapy combination over chemotherapy alone regardless of PDL1 status. In the arm of chemotherapy alone, an approximately 40% of patients received immunotherapy as second-line therapy. Despite the cross-over of the arms, this study showed a statistically significant difference in OS, suggesting the importance of early exposure to immunotherapy. Impact of delayed administration of immunotherapy in the first-line therapy is unknown. Methods: Using NCDB, a total of 99,008 patients diagnosed in 2017-2018 as stage IV NSCLC were screened. Eligible patients must have been treated with multi-agent chemotherapy as first-course of therapy. Those with neuroendocrine pathology, those who were exposed to immunotherapy prior to chemotherapy were excluded. They were assigned to a group of: (1) those who received immunotherapy within 30 days of chemotherapy, (2) 30-61 days of chemotherapy, or (3) chemotherapy alone. Those who have died within 2 months of diagnosis were excluded. Results: A total of 3291, 237, and 4309 were selected for group 1, 2, 3 for the analysis, respectively. Median OS was 14.5, 9.5, and 10.0 months for the group 1,2, 3, respectively. The significant difference in OS was observed between group 1 and 2 (HR= 0.74, 95% CI: 0.64-0.87, p=0.0003) and between group 1 and 3 (HR=0.73, 95%CI 0.70-0.78, p<0.0001). There is no difference in OS between group 2 and 3. Multivariate analysis demonstrated that group 1 has a significantly prolonged OS over group 2. The significant OS difference between group 1 and 2 was confirmed by propensity-score matching analysis (N=237 each, HR=0.73, 95%CI: 0.59-0.90, p=0.004). Conclusions: This retrospective study using one of the largest cancer databases suggests that delay of immunotherapy when used in combination with chemotherapy have detrimental effect in survival outcome.