OBJECTIVES : Immunotherapies targeting Programmed death 1 (PD-1) and Programmed death 1 ligand (PD-L1) hold a significant place in the treatment landscape of NSCLC. However, there are patients who develop resistance to Anti PD-1 and PD-L1 therapies after initial response. We aim to assess ongoing trials for the treatment of this subgroup.

METHODS : A systematic literature review of ongoing trials was performed to identify studies investigating treatment for PD-1/PD-L1 resistant relapsed/refractory NSCLC. The search included ongoing studies from clinicaltrials.gov (accessed in January 2019). A total of 4531 studies were identified in NSCLC. The identified studies were screened according to pre-defined inclusion criteria of the review.

RESULTS : 112 studies currently ongoing in anti PD-1/PD-L1 refractory patient population included 39 trials in Phase I, 64 in Phase II and five in Phase III of development. Most of the trials (approx. 87%) assessed combination therapy. Combinations based on Immuno-oncology therapies (IO) followed by IO plus targeted therapy were being most frequently assessed. Among the Phase III trials, two involved monotherapies (atezolizumab, OSE2101), while two studied combination therapies (sitravatinib + nivolumab and canakinumab + docetaxel). All four studies include OS, PFS, ORR as the key efficacy outcomes. Another phase III study evaluated multiple therapies and was primarily a biomarker based study. None of the ongoing studies reported interim results from Phase III other than ATLANTE-1 investigating OSE2101 (Multi neoepitope vaccine) highlighting OS ≥ 20 mos (n =4).

CONCLUSIONS : The long term efficacy evidence for Anti PD-1/PD-L1 points to the unanticipated outcome of treatment resistance. While there are several early stage molecules, assets is Phase III are currently limited. The underlying mechanisms behind resistance potentially hold the answer. Ongoing studies investigate chemotherapy or targeted therapy plus IO combinations as well as novel monotherapy agents. However, ability to predict resistance could potentially impact overall treatment approach.