There’s been no improvement in outcome for patients with unresectable locally advanced (stage III) nonCsmall cell lung cancer (NSCLC) for more than 10 years. tumor cells or antigen-presenting cells to PD-1 on T cells. The PACIFIC study recently evaluated consolidation immunotherapy with durvalumab versus placebo administered after concurrent chemoradiotherapy (CCRT) in patients with unresectable stage III NSCLC. It revealed a significant improvement in both progression-free and overall survival with durvalumab, and this improvement was associated with a favorable safety profile. This achievement has made durvalumab a standard of care for consolidation after CCRT in patients with unresectable stage III NSCLC, and it has now been approved in this setting by regulatory agencies in the United States, Canada, Japan, Australia, Switzerland, Malaysia, Singapore, India, and the United Arab Emirates. In this review, we briefly summarize the results of the PACIFIC trial, including those of post hoc analysis, and we address possible molecular mechanisms, perspectives, and remaining questions related to combined treatment with CCRT and ICIs in this patient population. Keywords: durvalumab, PD-L1, immunogenic cell death, lung cancer Introduction NonCsmall cell lung cancer (NSCLC) is the leading reason behind cancer-related mortality world-wide, being one of the most common neoplasms in created countries and having an unhealthy prognosis.1 First stages (We and II) take into account ~20% of lung cancer diagnoses, with individuals creating a 5-yr survival price of 40% to 70% after regular medical procedures (lobectomy with systemic lymph node resection). Around 20% to 25% of NSCLC instances are diagnosed following the disease offers progressed to medical stage III. Although locally advanced (stage III) NSCLC can be heterogeneous, it really is thought as having pass on locoregionally through major 7-Methylguanosine tumor expansion into extrapulmonary 7-Methylguanosine 7-Methylguanosine constructions (T3 or T4) and concerning hilar or mediastinal lymph nodes (N1CN3), but without faraway metastases (M0). At this time, if the tumor is known as unresectable actually, the treatment technique ought to be to attain a remedy. At the proper period of preliminary analysis, it is essential for medical oncologists to intentionally pick the best treatment technique for each individual through assembly of the multidisciplinary treatment group including thoracic cosmetic surgeons and rays oncologists, even though the indication for medical procedures of clinical N2 stage III NSCLC might vary across institutions. For greater than a 10 years, concomitant chemoradiotherapy (CCRT) offers remained the typical treatment for unresectable stage III NSCLC, regardless of tumor histology or molecular characteristics. The expected survival at 5 years for such patients is only 15% to 30%, however,2C4 highlighting the fact 7-Methylguanosine that most are not cured by CCRT5,6 and undergo relapse, with nearly 40% manifesting locoregional recurrence and ~50% developing distant metastases.7,8 This situation clearly calls for the development of novel anticancer treatments to augment the rate of cure or to improve clinical outcome. Given the high risk of metastasis and short progression-free survival (PFS) after CCRT, consolidation therapy defined as treatment administered after a defined number of chemotherapy cycles with or without radiotherapy9 has been considered a possible strategy to improve clinical outcome. Whereas the development of molecularly targeted therapy has improved clinical outcome in advanced NSCLC, it has not affected the management of stage III NSCLC patients. Indeed, there have been no substantial advances in the treatment of unresectable stage III NSCLC for more than a decade despite the performance of numerous randomized Phase III trials including those of induction or consolidation therapy with chemotherapeutic agents, biologics, or a cancer vaccine.8,10?12 In contrast to the failure to develop new therapies for unresectable stage III NSCLC, much Rabbit Polyclonal to PERM (Cleaved-Val165) progress has been made in our understanding of the underlying mechanisms 7-Methylguanosine of tumor immunology in particular, with regard to the role of immune checkpoints, which contribute to suppression of the tumor-associated antigen (TAA)Cspecific antitumor immune response, also referred to as T cell exhaustion.13 The extent of T.