ES06.02 What Is the Best Strategy in Progressive Disease After Consolidation with Durvalumanb, or Rapid Progressors to First Line?

Abstract

Immune Check Points Inhibitors (ICIs) have dramatically changed the management of locally advanced and advanced NSCLC patients. While the survival improvement compared to previous standard of care is undoubtable, several patients still progress on or relapse after ICIs. How should these patients be managed? To better understand how to manage these patients, we should probably try to better understand the underlying mechanism(s) of resistance to ICIs. Schematically, we can propose three main categories, with primary resistances, occurring early after ICIs initiation, secondary resistances, occurring after a previous response or disease stabilization on ICIs, and follow-up resistances, occurring after stopping ICIs, either per protocol or severe adverse event(s). Management of primary resistances to ICIs. Although no validated definition is available, primary resistances might include hyperprogressors and progressors within the first 12- (to 18) weeks of treatment with ICIs. It represents approximately 20 to 30% of stage III NSCLC patients receiving durvalumab after concomitant chemo-radiation, 30% of stage IV patients PD-L1 50% or more NSCLC patients treated with pembrolizumab and 20 to 30% of stage IV patients NSCLC patients treated with a combination of chemotherapy and ICIs. Few data are available on the underlying biological mechanisms to explain these primary resistances. Considering clinical data of the PACIFIC trial, 41% of patients in the durvalumab arm (without precise characterization of the time or progression) received a subsequent therapy. For the patients who already received durvalumab as a consolidation treatment, 20 patients received a subsequent ICI. The response rate in this case was 0%. With a longer follow, different patients’ profiles will certainly be reported in this setting, with possibly responses to ICIs alone or in combination for patients relapsing a long time after stopping Durvalumab. Considering clinical data for stage IV NSCLC patients treated in the first line setting in monotherapy, a recent long term analysis of the Keynote 024 trial. The management of patients with an early progression on Pembrolizumab was not specifically detailed. Globally, 56 out of 154 patients received a subsequent oncologic treatment, mainly chemotherapy. Considering clinical data for stage IV NSCLC patients treated in the first line setting with combination of chemotherapy and ICIs, few results are available to date on the management of early progressors. Finally, all trials assessing the efficacy of new IO agents or new ICI-based combinations as a rescue treatment after failure of a previous line of ICIs are globally disappointing. A summary of ongoing trials will be presented at the meeting. In summary, the best strategy to date for early progressors on ICIs, alone or in combination, unfortunately remains a standard chemotherapy; a participation in a clinical trials should be also discussed giving the efficacy of rescue treatments in this situation. Rescue immunotherapy, Early progressors, durvalumab