Abstract B176: Sequential immunotherapy and association with clinical outcomes in advanced-stage cancer patients
Authors: Bilen Mehmet , Martini Dylan , Liu Yuan , Lewis Colleen , Collins Hannah , Shabto Julie , Akce Mehmet , Kissick Haydn , Carthon Bradley , Shaib Walid , Alese Olatunji , Pillai Rathi , Steuer Conor , Wu Christina , Lawson David , Kudchadkar Ragini , El-Rayes Bassel , Master Viraj , Ramalingam Suresh , Owonikoko Taofeek , Harvey R. Donald 
Published: February 2019

Abstract
Background: There are now six approved immune checkpoint inhibitors for several different malignancies including melanoma, head and neck cancer, lung cancer, and renal cell carcinoma. Given the increased number of available immunotherapeutic agents, more patients are presenting in clinic as candidates for sequential immunotherapy. However, the efficacy of sequential immunotherapy in a trial setting is unknown. We investigated the association between prior treatment with immune checkpoint inhibitors and clinical outcomes in patients treated with subsequent immunotherapy in a phase 1 clinical trial. Methods: We conducted a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute between 2009 and 2017. We included 49 patients with an immune checkpoint-indicated histology (melanoma, lung cancer, head and neck cancer, and bladder cancer). Patients were then analyzed based on whether they had received at least one immune checkpoint inhibitor prior to enrollment. Overall survival (OS) and progression-free survival (PFS) were calculated in months from immunotherapy initiation on trial to date of death and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard or logistic regression model. Covariates included age, presence of liver metastases, number of prior lines of systemic therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results: The median age was 67 years and most patients (78%) were men. The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). The majority (81%) of patients were RMH good risk. More than half of patients (n=27, 55%) had received at least one immune checkpoint inhibitor prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination therapy, and ten received multiple immune checkpoint inhibitors. In MVA, patients who had not received a prior immune checkpoint inhibitor had significantly longer OS (HR: 0.22, CI: 0.07-0.70, p=0.010). These patients also trended towards longer PFS (HR: 0.86, CI: 0.39-1.87, p=0.699) and higher chance of CB (HR: 2.52, CI: 0.49-12.97, p=0.268). Immunotherapy-naïve patients had substantially longer OS (24.3 vs 10.9 months) and PFS (5.1 vs. 2.8 months) than patients who had prior immunotherapy per Kaplan-Meier estimation. Conclusion: Optimal treatment options for oncology patients who progress on immune checkpoint inhibitors are lacking. In this study, patients who received at least one prior immune checkpoint inhibitor had worse clinical outcomes on immunotherapy-based phase 1 clinical trials than immune checkpoint-naïve patients. This suggests that further development of immunotherapy combination therapies is needed to improve clinical outcomes of these patients. The results from this study should be validated in a larger, prospective study.
Citation Format: Mehmet Bilen, Dylan Martini, Yuan Liu, Colleen Lewis, Hannah Collins, Julie Shabto, Mehmet Akce, Haydn Kissick, Bradley Carthon, Walid Shaib, Olatunji Alese, Rathi Pillai, Conor Steuer, Christina Wu, David Lawson, Ragini Kudchadkar, Bassel El-Rayes, Viraj Master, Suresh Ramalingam, Taofeek Owonikoko, R. Donald Harvey. Sequential immunotherapy and association with clinical outcomes in advanced-stage cancer patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B176.