In the present study there was no association with OS
In the present study, there was no association with OS and development of irAE with 3-, 6-, and 9-month landmark analysis. Landmark analysis was utilized in order to minimize lead- time bias associated with time-dependent factors. Studies involving nivolumab treated aNSCLC patients utilized landmarks within the first weeks of therapy [13,14,29]. However, median time of onset of pembrolizumab induced irAE can occur many months after treatment ; based on the product monograph, median time to onset of nephritis is 5.1 months (range 12 days to 12.8 months). Treatment cessation due to irAE has been suggested as a marker of immune activation due to immune checkpoint inhibition . However, in this Quizartinib (AC220) retrospective series there was no difference in median overall survival amongst patients needing treatment interruption and those receiving pembrolizumab continuously.
With respect to irAE subtypes, we observed a weak association between development of pneumonitis and lower OS at the 9-month landmark. Unlike previous studies with pembrolizumab, no association between dermatitis or thyroid changes and OS were noted in this study [17,37]. Regarding nivolumab induced pneumonitis, retrospective studies have shown conflicting results regarding this irAE and patients outcomes. In an observational retrospective series involving Japanese patients, Fujimoto et al. correlated pneumonitis with improved PFS . In contrast, Suresh et al. found decreased OS using a Markov multi-state model amongst nivolumab recipients at an American institution . The authors of the latter study suggest that comorbid pulmonary conditions (i.e., chronic obstructive pulmonary disease) might differ in patient populations and explain the disparate results.
Conflict of interest
Acknowledgements This work was supported by the BC Cancer Foundation.
Introduction Multimodality therapy is the current standard of care for resectable stage III non-small cell lung cancer (NSCLC). Approximately 10% of all NSCLC cases present as stage IIIA-N2, and for these individuals, disease control and overall survival (OS) remain poor, with 5-year survival rates of 23% . Based on randomized trials and a meta-analysis demonstrating improved OS with the addition of induction chemotherapy (CT) plus surgery versus surgery alone, induction chemotherapy is a reasonable option for resectable stage IIIA-N2 NSCLC [2,3]. Induction CT also appears to have similar efficacy to neoadjuvant chemoradiation (CRT) [4,5]. Nodal response after induction chemotherapy is an important prognostic factor. A study by the Swiss SAKK group led to the conclusion that patients with nodal downstaging from N2 to N0-1 after induction CT had improved disease-free and OS in comparison to those with persistent N2 disease . A follow-up publication demonstrated local relapse rates of 30% amongst all comers with initially N2 disease, with approximately 50% of patients receiving adjuvant RT, but did not provide details about effect of RT on oncologic outcomes . The current National Comprehensive Cancer Network (NCCN) guidelines suggest induction CT, with or without radiation (RT), as an appropriate option for patients with resectable stage IIIA-N2 NSCLC . However, optimal adjuvant therapy is not well defined in this patient population and often left to the discretion of the treating physicians. Previous retrospective studies showed that pathological downstaging and lymph node ratio (LNR) in this clinical scenario were prognostic [, , ]. We sought to determine the importance of consolidative CT and RT with respect to OS in patients with clinical N2 (cN2) disease who undergo induction CT followed by surgery. We hypothesized that LNR and nodal response to induction CT would predict OS and predict the need for more aggressive adjuvant therapy.
Materials and methods
Discussion In ypN0 and ypN1 patients, there was no significant benefit to either adjuvant CT or RT in this patient cohort. Similarly, in patients with a LNR < 15%, there was no benefit of adjuvant CT or RT. However, in patients with ypN2 disease and a LNR > 15%, there appeared to be an approximately 20% relative benefit in OS on MVA with both CT and RT. Both ypN2 status and higher LNR following neoadjuvant chemotherapy are suggestive of more aggressive disease. While the NCDB does not record patterns of failure, one may speculate the survival benefit observed with adjuvant therapy for patients with persistent nodal disease or higher nodal ratio is due to RT and CT reducing risk of local and distant recurrence respectively, which contribute to overall survival as appreciated in smaller retrospective series .