Drabick, Joseph J.

Background The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma. Methods Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label. Results Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P). The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P). Conclusion In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Abstract Background We hypothesized that the addition of receptor tyrosine kinase inhibitors (RTKis, e.g., lapatinib, erlotinib, cetuximab, bevacizumab, panitumumab) to radiotherapy-based treatment for solid tumors does not increase overall survival but may increase toxicity. Methods Population, Intervention, Control, Outcome, Study Design; Preferred Reporting Items for Systematic Reviews and Meta-Analyses; and Meta-analysis of Observational Studies in Epidemiology methods were used to identify prospective randomized studies including patients with solid tumor cancers treated with radiotherapy with or without RTKis. Extracted variables included use of radiotherapy vs chemoradiotherapy, RTKi type (antibody vs small molecule), outcomes, and toxicities. The primary endpoint was overall survival; the secondary endpoint was grade 3+ toxicity. Random-effects meta-analyses were performed for each outcome measure. All statistical tests were 2-sided. Results A total of 405 studies met the initial search criteria, of which 13 prospective randomized trials of radiotherapy with or without RTKi met the inclusion criteria, encompassing 5678 patients. The trials included cancers of the head and neck (6 trials, 3295 patients), esophagus (3 trials, 762 patients), lung (2 trials, 550 patients), and brain (2 trials, 1542 patients). Three studies evaluated a small molecule and radiotherapy in 949 patients, and 10 studies evaluated antibodies and radiotherapy in 4729 patients. The addition of RTKis to radiotherapy-based treatment did not improve overall survival (hazard ratio = 1.02, 95% confidence interval = 0.90 to 1.15, P = .76) but increased grade 3+ toxicity (relative risk = 1.18, 95% confidence interval = 1.06 to 1.33, P = .009). Conclusions The addition of RTKis to radiotherapy does not improve survival and worsens toxicity.

Purpose: We aim to systematically review and analyze the available literature on “exceptional responders” in oncology. We hypothesize that survival or patients with an exceptional response may be predicted based on clinical factors. Materials and Methods: A PICOS/PRISMA/MOOSE selection protocol was used to find studies that reported oncology patients with an exceptional response. A total of 333 initial articles were screened, and 76 articles were included, accounting for 85 patients. The primary outcome was survival after exceptional response therapy (ERT). The secondary outcome was survival since diagnosis. Univariate and multivariate analyses were conducted for both outcomes with 17 covariates. Results: The median age was 52 years (interquartile range, 35-66 y), 51.8% were male individuals, 18 (21.2%) had lung cancer, and 1 patient (1%) met all National Cancer Institute criteria for exceptional response. The most common treatment resulting in exceptional response was a form of chemotherapy (49.2%) followed by targeted therapy (26.8%) and radiation therapy (7.7%). The median time from diagnosis to initiation of ERT was 7.92 months (interquartile range, 0-24.72 mo). On multivariate analysis of survival after initiation of ERT, there were no predictors of exceptional response. On multivariate analysis of survival since diagnosis, predictors of prolonged survival included time between diagnosis and ERT initiation (hazard ratio, 0.52; 95% confidence interval, 0.32-0.87; P=0.0124) and single prior surgery versus none (0.08; 95% confidence interval, 0.01-0.98; P=0.04853). Conclusions: There were no clinically apparent patient or treatment factors that predicted favorable survival following ERT; instead, reporting of exceptional response appears to be biased.

Abstract Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that normally inhibits immune responses when appropriate. In the setting of cancer, IDO pathway-mediated immune suppression is exploited by tumors in order to prevent and defeat anti-tumor immunity. Small-molecule inhibitors of the IDO pathway, such as indoximod, are an increasingly validated class of potential cancer therapeutics. Additionally, pre-clinical tumor models have shown complementary effects with indoximod / anti-PD1 checkpoint inhibitor treatment combinations. A clinical trial was developed based upon these data. Methods: Upon successful completion of a Phase 1b dose escalation cohort, metastatic melanoma patients were enrolled in a single arm Phase 2 trial evaluating the addition of indoximod to standard of care checkpoint inhibitors approved for melanoma. Treating physicians were allowed to administer their choice of approved checkpoint inhibitor. The large majority of patients received indoximod with pembrolizumab and this interim report is limited to those patients. Indoximod was administered continuously in 21 days cycles (1200mg po twice daily) concurrently with pembrolizumab (3mg/kg q21 days). Study endpoint is best overall response (objective response rate (ORR) = complete response rate (CR) + partial response rate (PR)) per site reported RECIST criteria. Results: At time of data cut-off, 60 patients had received indoximod /pembrolizumab and were evaluable for response, defined as having at least one follow-up imaging study performed. The ORR was 52% (31/60) with a CRR of 8% (5/60). The combination was well tolerated. The most frequently reported adverse events (regardless of attribution), occurring in ≥ 20% of subjects, were fatigue, diarrhea, nausea, arthralgia, headache, cough, rash, pruritus, and hypertension. The most frequently reported laboratory abnormalities (regardless of attribution), were anemia (17%) and hyperglycemia (17%). Conclusions: The interim analysis of the combination of indoximod and pembrolizumab demonstrates an ORR of 52% which compares favorably with the established ORR for pembrolizumab alone. Updated data to be presented. NCT02073123. Citation Format: Yousef Zakharia, Robert McWilliams, Monaster Shaheen, Kenneth Grossman, Joseph Drabick, Mohammed Milhem, Olivier Rixie, Samir Khleif, Ryan Lott, Eugene Kennedy, David Munn, Nicholas Vahanian, Charles Link. Interim analysis of the Phase 2 clinical trial of the IDO pathway inhibitor indoximod in combination with pembrolizumab for patients with advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT117. doi:10.1158/1538-7445.AM2017-CT117