During the last 12 months, progress has been reported in non-small cell lung cancer (NSCLC). The main fields of investigations are related to the management of metastatic disease with further development of immunotherapies with anti PD-1/PD-L1 and management of oncogene-driven NSCLC providing improved outcomes. Also, locally advanced non-resectable NSCLC is now better controlled with immunotherapies in addition to conventional chemoradiation combination. In early stages, several recent publications reported interesting data with the use of targeted agents or immunotherapies in the neoadjuvant or adjuvant setting.
Among the numerous trials published, I would like to focus on the management of early stages, a curable situation for some patients but still a disease where much improvement is needed.
Early diagnosis is of paramount importance to possibly offer a chance of cure. Recently published data1,2 showed that between 2010 and 2017, the incidence of NSCLC in the US decreased from 46.4 to 40.9 per 100,000, interestingly incidence of stages II, IIIA, and IIIB were stable while stage IV slightly decreased (21.7 to 19.6) and stage I increased from 10.8 to 13.2/100 000. One of the hypotheses for the increase of stage I is the possible role of screening.
Regarding therapeutic management in resectable disease, the concept of neoadjuvant approach should be revisited as extensively discussed recently by Saw and the group of Singapore.3
A dozen of clinical trials at least, have reported encouraging results with the use of nivolumab, atezolizumab, durvalumab, sintilimab, and ipilimumab, as single agent or in combination with chemotherapy, in the neoadjuvant setting. In most of them, a high major pathological response rate (MPR) was reported. Follow-up is too short, however, to evaluate the impact on DFS or OS, but earlier studies in lung cancer and other tumor types have suggested a good correlation between MPR and DFS or OS. There is some limited evidence as well that Immunotherapy combined with stereotactic body radiotherapy (SBRT) increases MPR and pCR and does not impair surgery.4 Further trials incorporating radiotherapy in the neoadjuvant setting are ongoing and results eagerly awaited. Oncogene-driven (EGFR), resectable NSCLC also has been treated with neoadjuvant EGFR TKI (erlotinib, gefitinib). Fewer clinical trials have been reported and most of them are not randomized. Globally, if expected ORR were observed, the MPR rates were rather low. The present results are scarce and do not allow any conclusion. Several trials are ongoing.
For locally advanced unresectable NSCLC, standard of care has changed in the past years with the addition of durvalumab as consolidation after conventional RTCT. The initial improved PFS and OS were recently confirmed after 4 years of follow-up with a 29% reduction of the risk of death.5 Fewer studies have used neoadjuvant immunotherapy and data are lacking for locally advanced unresectable NSCLC but considering the high MPR rates reported in earlier stages, would be worth exploring. Similarly, in locally advanced unresectable EGFR-mutant NSCLC, data are scarce on the use of EFGR TKI with concurrent radiotherapy. Initial results on a limited number of patients are encouraging but need to be confirmed in larger series with randomized trials.
There is no doubt that the introduction of immunotherapy with PD-1/PD-L1 or targeted agents in oncogene-driven NSCLC has been practice changing in recent years. The applicability in the neoadjuvant setting of early-stage disease has not been studied as much as in the adjuvant setting, but encouraging results have been reported and further clinical trials are ongoing. Regarding the old debate of neoadjuvant vs adjuvant (or the combination of both) that was inconclusive with chemotherapy is now re-open. The same questions remain, however, on patient selection, definition of endpoints, and prognostic and predictive factors of efficacy. In terms of patient management, dynamic monitoring of circulating tumor DNA (ctDNA) seems to be informative in terms of recurrence prediction and OS, and with the progress in technology, could soon be easily incorporated into patient follow-up.6