PURPOSE External control (EC) arms derived from electronic health records (EHRs) can provide appropriate comparison groups when randomized control arms are not feasible, but have not been explored for metastatic colorectal cancer (mCRC) trials. We constructed EC arms from two patient-level EHR-derived databases and evaluated them against the control arm from a phase III, randomized controlled mCRC trial. METHODS IMblaze370 evaluated atezolizumab with or without cobimetinib versus regorafenib in patients with mCRC. EC arms were constructed from the Flatiron Health (FH) EHR-derived de-identified database and the combined FH/Foundation Medicine Clinico-Genomic Database (CGDB). IMblaze370 eligibility criteria were applied to the EC cohorts. Propensity scores and standardized mortality ratio weighting were used to balance baseline characteristics between the IMblaze370 and EC arms; balance was assessed using standardized mean differences. Kaplan-Meier method estimated median overall survival (OS). Cox proportional hazards models estimated hazard ratios with bootstrapped 95% CIs to compare differences in OS between study arms. RESULTS The FH EC included 184 patients; the CGDB EC included 108 patients. Most characteristics were well-balanced (standardized mean difference < 0.1) between each EC arm and the IMblaze370 population. Median OS was similar between the IMblaze370 control arm (8.5 months [95% CI, 6.41 to 10.71]) and both EC arms: FH (8.5 months [6.93 to 9.92]) and CGDB (8.8 months [7.85 to 9.92]). OS comparisons between the IMblaze370 experimental arm and the FH EC (hazard ratio, 0.85 [0.64 to 1.14]) and CGDB EC (0.86 [0.65 to 1.18]) yielded similar results as the comparison with the IMblaze370 control arm (1.01 [0.75 to 1.37]). CONCLUSION EC arms constructed from the FH database and the CGDB closely replicated the control arm from IMblaze370. EHR-derived EC arms can provide meaningful comparators in mCRC trials when recruiting a randomized control arm is not feasible.

High-dose chemotherapy and autologous marrow or peripheral stem cell support offers the best chance of cure in some subgroups of patients with non-Hodgkin's lymphoma (NHL). Less is known about the role of a second course of myeloablative chemotherapy in patients who relapse after a first autologous transplant. The aim of this retrospective study was to evaluate the disease outcome, morbidity and mortality associated with second autologous transplantation in patients with NHL. Between 1985 and 2001, 225 patients who had received autologous transplantation for NHL in two institutions in Lyon relapsed. Of these 225 patients 18 underwent a second autologous transplantation. The median age at second transplant was 41 years. There were six indolent lymphomas and 12 aggressive lymphomas. The median follow-up from the second transplant was 42 months. The OS rate at 2 and 5 years were 58 and 27%, respectively. The PFS rate at 2 and 5 years was 36%. Five patients are alive without disease 20 to 100 months after the second transplant. Seven patients died of disease recurrence. Four (22%) toxic deaths occurred: one of pulmonary fibrosis, one of fungal infection and cardiac failure and two of acute leukaemia. A minority of patients with NHL recurrence after a first transplant can be cured by a second course of myeloablative chemotherapy at the cost however of high-risk toxic death.

Background Treatment for metastatic colorectal cancer patients beyond the second line remains challenging, highlighting the need for early phase trials of combination therapies for patients who had disease progression during or following two prior lines of therapy. Leveraging hybrid control design in these trials may preserve the benefits of randomization while strengthening evidence by integrating historical trial data. Few examples have been established to assess the applicability of such design in supporting early phase metastatic colorectal cancer trials. Methods MORPHEUS-CRC is an umbrella, multicenter, open-label, phase Ib/II, randomized, controlled trial (NCT03555149), with active experimental arms ongoing. Patients enrolled were assigned to a control arm (regorafenib, 15 patients randomized and 13 analysed) or multiple experimental arms for immunotherapy-based treatment combinations. One experimental arm (atezolizumab + isatuximab, 15 patients randomized and analysed) was completed and included in the hybrid-control study, where the hybrid-control arm was constructed by integrating data from the IMblaze370 phase 3 trial (NCT02788279). To estimate treatment efficacy, Cox and logistic regression models were used in a frequentist framework with standardized mortality ratio weighting or in a Bayesian framework with commensurate priors. The primary endpoint is objective response rate, while disease control rate, progression-free survival, and overall survival were the outcomes assessed in the hybrid-control study. Results The experimental arm showed no efficacy signal, yet a well-tolerated safety profile in the MORPHEUS-CRC trial. Treatment effects estimated in hybrid control design were comparable to those in the MORPHEUS-CRC trial using either frequentist or Bayesian models. Conclusions Hybrid control provides comparable treatment-effect estimates with generally improved precision, and thus can be of value to inform early-phase clinical development in metastatic colorectal cancer.

BackgroundThe MORPHEUS platform comprises multiple randomized Phase Ib/II trials to identify early safety and efficacy signals for treatment combinations across cancers. Seli interacts with CD40 on antigen presenting cells, resulting in activation and priming of CD8 T-cells. Atezo (anti-PD-L1)+seli (CD40 agonist) was evaluated with gem+nabP for pancreatic ductal adenocarcinoma (PDAC), or with bev for triple-negative breast cancer (TNBC) and colorectal cancer (CRC).MethodsMORPHEUS-PDAC, MORPHEUS-TNBC and MORPHEUS-CRC enrolled 1L metastatic (m) PDAC, 2L locally advanced or mTNBC or 3L mCRC patients, respectively. Experimental arm patients received atezo (840 mg IV q2w) and seli (16 mg SC on D1 every 28-day cycle for C1-4 and every third cycle thereafter). Patients also received gem (1000 mg/m2) and nabP (1000 mg/m2, 125 mg/m2 respectively, IV on D1, 8, 15 every 28-day cycle) in PDAC or bev (10 mg/kg IV q2w) in TNBC and CRC. Control treatments were gem+nabP in PDAC, capecitabine in TNBC, and regorafenib in CRC. Primary endpoints were safety and objective response rate (ORR; investigator-assessed RECIST 1.1). PD-L1 and CD8/panCK IHC were tested in all biopsies.ResultsAll treated patients were safety evaluable. MORPHEUS-PDAC (20-week interim analysis): 9 patients received atezo+seli+gem+nabP and 4 received control. Treatment-related adverse events (TRAEs) were seen in all. Treatment-related serious AEs (SAEs) occurred in 6 patients (67%) receiving atezo+seli+gem+nabP and 1 (25%) receiving control. Confirmed ORRs: 44% (95%CI:14–79) and 25% (95%CI:6–81), respectively. MORPHEUS-TNBC (27-week interim analysis): 6 patients received atezo+seli+bev and 24 received control. TRAEs were seen in 5 patients (83%) receiving atezo+seli+bev and 18 (75%) receiving control. Treatment-related SAEs occurred in 1 patient in each arm (17% and 4%, respectively). Confirmed ORRs: 17% (95%CI:0.4–64) and 21% (95%CI:7–42), respectively. All 6 patients receiving atezo+seli+bev were PD-L1 negative (SP142 IHC assay) at baseline; the only patient with partial response (PR) showed upregulation of PD-L1 expression at week 3. MORPHEUS-CRC (18-week interim analysis): 6 patients received atezo+seli+bev and 13 received control. TRAEs were seen in all patients receiving atezo+seli+bev and 12 (92%) receiving control. Treatment-related SAEs occurred in 3 patients (50%) receiving atezo+seli+bev and 1 (8%) receiving control. No responses occurred in either study arm. Paired biopsies for 3 patients (60%) receiving atezo+seli+bev suggest on-treatment increases in CD8 T-cell infiltration into tumors.ConclusionsToxicities related to the atezo+seli combinations were consistent with individual study treatments. Preliminary efficacy was observed for atezo+seli+gem+nabP in PDAC. Together with preliminary evidence of on-treatment pharmacodynamic effects in CRC and TNBC tumor samples, CD40 agonist strategies warrant further investigation.Trial RegistrationMORPHEUS-PDAC: NCT03193190; MORPHEUS-TNBC: NCT03424005; MORPHEUS-CRC: NCT03555149.Ethics ApprovalThe trial was conducted according to the principles of the Declaration of Helsinki. All patients provided written informed consent. Protocol approval was obtained from independent review boards or ethics committees at each site.

3559 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy and safety signals of treatment (tx) combinations across cancers. Here, atezo (anti-PD-L1) was tested with Imprime and bev (anti-VEGF) for MSS mCRC, a poorly immunogenic cancer generally resistant to checkpoint inhibitors. Imprime acts as a pathogen-associated molecular pattern that, when bound to anti-β glucan antibodies (ABA), activates the innate immune system with the potential to 1) promote priming and expansion of tumor-specific T cells, 2) promote M2-M1 macrophage polarization and 3) enhance the immunomodulatory effects of atezo and bev. Therefore, we hypothesized that atezo + Imprime + bev would induce an antitumor response beyond that of rego, a standard-of-care multikinase inhibitor, in patients (pts) with MSS mCRC. Methods: Pts with MSS mCRC unselected for the Imprime-specific biomarker (ABA) and refractory to 1-2 prior lines of standard therapy received atezo (1200 mg IV every 3 weeks [q3w]) + Imprime (4 mg/kg IV on Days 1, 8, 15) + bev (7.5 mg/kg IV q3w) or control tx with rego (160 mg orally days 1-21; dose escalation to 160 mg during Cycle 1 allowed per institutional guidelines). The primary endpoint was objective response rate (ORR; investigator-assessed RECIST 1.1); secondary endpoints included disease control rate (DCR; response or stable disease ≥ 12 weeks), progression-free survival (PFS), overall survival (OS) and safety. Results: Pts were followed-up for ≥18 wk. 15 pts received atezo + Imprime + bev and 13 received rego. Grade (Gr) 3/4 tx-related adverse events (TRAEs) were seen in 13% of atezo + Imprime + bev and 62% of rego pts. No Gr 5 AEs occurred in atezo + Imprime + bev pts and 1 (8%) was reported in a rego pt. One pt in each arm (7% vs 8%, respectively) withdrew from tx due to a TRAE. No radiological responses were seen in either arm. Five pts (33%) receiving atezo + Imprime + bev and 8 (62%) receiving rego had stable disease as best response. DCR was 13% with atezo + Imprime + bev and 23% with rego. Median PFS was 1.5 mo (95% CI: 1.4, 2.8) and 2.8 mo (95% CI: 1.6, 3.1), and median OS was 5.7 mo (95% CI: 4.4, 10.5) and 10.2 mo (95% CI: 4.8, NE) with atezo + Imprime + bev and rego, respectively. There was no apparent correlation between baseline PD-L1 expression or CD8+ lymphocyte tumor infiltration and clinical benefit. Further, the systemic exposure of atezo, Imprime and bev and immunogenicity of atezo and bev are in line with previous clinical experience. Additional biomarker, pharmacokinetics and anti-drug antibody data will be shown. Conclusions: Atezo + Imprime + bev was well tolerated; toxicities were consistent with the safety profiles of the individual agents. No efficacy signal was identified with atezo + Imprime + bev in pts with MSS refractory mCRC. Clinical trial information: NCT03555149.