The clinical profiles and outcomes of patients with neurotrophic tropomyosin receptor kinase fusion-positive (NTRK+) solid tumors receiving standard of care other than tropomyosin receptor kinase inhibitor (TRKi) targeted therapy have not been well documented. Here, we describe the clinical characteristics of patients with NTRK+ tumors treated in clinical practice using information from a United States electronic health record-derived clinicogenomic database. We also compared survival outcomes in NTRK+ patients and matched NTRK fusion-negative (NTRK–) patients and investigated the clinical prognostic value of NTRK fusions. NTRK positivity was defined by the presence of a fusion or rearrangement involving NTRK1/2/3, determined using NGS (Foundation Medicine, Inc.). NTRK+ patients (n = 28) were diagnosed with locally advanced/metastatic solid tumors between January 1, 2011 and December 31, 2019 and had received no TRKis (e.g., entrectinib or larotrectinib) during their patient journey. The unselected NTRK−population comprised 24,903 patients, and the matched NTRK−cohort included 280 patients. NTRK+ patients tended to be younger, were more commonly not smokers, and had a shorter time from advanced diagnosis to first NGS report, compared with unselected NTRK−patients; however, these differences were not significant. Median overall survival (OS) from advanced/metastatic diagnosis was 10.2 months (95% CI, 7.2–14.1) for the NTRK+ cohort versus 10.4 months (95% CI, 6.7–14.3) for the matched NTRK−cohort; hazard ratio for death in NTRK+ versus matched NTRK−patients was 1.6 (95% CI, 1.0–2.5; P = 0.05). Genomic co-alterations were rare in the NTRK+ cohort (only two of 28 patients had a co-alteration). Overall, while hazard ratios suggest NTRK fusions may be a negative prognostic factor of survival, there are no significant indications of any favorable impact of NTRK fusions on patient outcomes. TRKis, with their high response rate and good tolerability, are likely to improve outcomes for patients compared with existing standard-of-care treatments.

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Background: Emerging evidence suggests that p53 participates in the regulation of tumor immunity. TP53 activation in the myeloid linage suppresses alternative (M2) macrophage polarization and attenuates tumor development and invasion. Retrospective clinical analyses suggested that MDM2 amplification is associated with hyper-progression. Targeting MDM2-p53 pathway may represent a novel strategy for reversing immunosuppression and enhancing antitumor immunity of PD-1/PD-L1 blockade. APG-115 is a potent and orally active small-molecule MDM2 protein inhibitor. Binding to MDM2 protein, APG-115 restores p53 expression, activates p53 -mediated apoptosis in tumor cells retaining wild-type p53. Preclinical studies demonstrated that APG-115 promoted the production of proinflammatory cytokines in T cells, enhanced CD4 þ T cell activation, and increased PD-L1 expression on tumor cells. Enhanced antitumor activity was demonstrated in syngeneic tumor models after APG-115 combined with PD-1 blockade. Methods: APG-115 has been evaluated as a single agent in a Phase I study in US (NCT02935907). In this study, total six dose levels (10 mg, 20 mg, 50 mg, 100 mg, 200 mg and 300 mg) have been tested. The preliminary results suggested a favorable safety and tolerability profile. APG-115 exhibited an approximately dose proportional increase in exposure in PK analyses. A Phase Ib/II study of APG-115 in combination with pembrolizumab for treatment of patients with metastatic solid tumor is ongoing. Pembrolizumab is administrated as a fixed dose of 200mg IV on d1 of a 21-d cycle. Safety, tolerability, and determination of the MTD and RP2D are primary objectives of phase Ib. Results: The second cohort (APG 115 at 100 mg) has enrolled, no DLT was observed, and evidence of antitumor activity has been observed. Biomarker studies are ongoing to identify potential selection criteria. Updated clinical data will be presented. Conclusions: This represents one of the first clinical trials to evaluate MDM2mediated resistance to immunotherapy. Clinical trial identification: NCT03611868. Legal entity responsible for the study: Ascentage Pharma Group Corp Limited.

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Aim: Generating direct comparative evidence in prospective randomized trials is difficult for rare diseases. Real-world cohorts may supplement control populations. Methods: Entrectinib-treated adults with advanced ROS1 fusion-positive NSCLC (n = 94) from Phase I/II trials (ALKA-372-001 [EudraCT2012-00148-88], STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]) were compared with a real-world crizotinib-treated cohort (n = 65). Primary end point, time-to-treatment discontinuation (TTD); secondary end points, PFS and OS. Results: Median (95% CI) weighted TTD: 12.9 (9.9–17.4) months for entrectinib; 8.8 (6.2–9.9) months for crizotinib (weighted hazard ratio, 0.72 [0.51–1.02]). Median OS with entrectinib was not reached, weighted median OS with crizotinib was 18.5 (15.1–19.9) months. Conclusion: Entrectinib administered in clinical trials may be associated with longer TTD than a real-world crizotinib population.