BackgroundChemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.Patients and methodsThis was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.ResultsA total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).ConclusionTrilaciclib demonstrated an improvement in the patient’s tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib’s myelopreservation benefits.Clinical Trail numberNCT02499770.

SummaryDickkopf-1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti-DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose-limiting toxicity (DLT) of escalating doses in combination with anti-myeloma therapy and zoledronic acid. Twenty-eight patients were enrolled and received BHQ880 at doses of 3-40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal-related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.

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Background Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab. Methods This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS). Results Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91–1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3–5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction. Conclusions In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results. Clinical trials registration NCT02511405

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Background: Abemaciclib is an orally administered, selective small molecule cyclin-dependent kinase (CDK) 4 and 6 inhibitor, approved to treat HR+, HER2- mBC pts on a continuous twice daily dosing schedule as monotherapy or in combination with endocrine therapy (ET), an aromatase inhibitor as initial endocrine based therapy, or in combination with fulvestrant. In preclinical models, abemaciclib monotherapy induced intra-tumoral immune inflammation and had a synergistically enhanced anti-tumor efficacy when administered in combination with programmed cell death protein 1 blockade. Here we report the safety and preliminary anti-tumor activity of abemaciclib plus pembrolizumab plus anastrozole in HR+, HER2- locally advanced or mBC pts. Methods: This multicenter, nonrandomized, open-label, multi-cohort phase 1b study of abemaciclib plus pembrolizumab plus anastrozole enrolled a cohort of post-menopausal HR+, HER2- pts with locally advanced or mBC. No prior CDK4/6 inhibitor, chemotherapy, or ET for locoregional advanced or mBC were allowed. Patients received 150-mg abemaciclib orally every 12 hours plus pembrolizumab 200 mg intravenously on day 1 every 21 days plus anastrozole 1 mg orally every 24 hours. The primary objective was to characterize the safety of abemaciclib plus pembrolizumab plus anastrozole. Key secondary objectives included objective response rate (ORR), progression-free survival, and overall survival. Results: Out of 26 pts enrolled, 13 (50%) had received prior systemic anti-cancer therapy, including 12 (46%) who had received ET in the adjuvant setting. The majority of pts had visceral disease (65%); 54% had 3 or more metastatic sites. The nature of adverse events (AEs) observed for the triplet therapy was overall consistent with the known side effects of abemaciclib, pembrolizumab and anastrozole. Grade 3/4 AEs in > 2 pts included increased alanine aminotransferase and neutropenia (8 pts each, 31%) and increased aspartate aminotransferase (6 pts, 23%). In general, Grade 3/4 AEs were reversible following drug holds and corticosteroid treatment. There were 2 fatal events as a result of pneumonitis. Fifteen pts (58%) discontinued treatment including 9 pts (35%) due to an AE (7 transaminase elevations). Preliminary response assessment showed 5 pts had a confirmed partial response (19% ORR), and disease control rate (CR+PR+SD) was 77%. Clinical benefit rate (CR+PR+SD persisting for ≥6 months) was 27%. Conclusions: Abemaciclib plus pembrolizumab plus anastrozole demonstrated a numerically higher rate of transaminase elevations and pneumonitis than reported for the individual treatments and 2 experienced a fatal AE. At this time, evaluation of anti-cancer activity is premature. Citation Format: Hope S. Rugo, J. Thad Beck, Guy Jerusalem, Hans Wildiers, Peter Kabos, Michael Chisamore, Rhian McNaughton, Yanyun Chen, Anwar Hossain, Sara M. Tolaney. A phase 1b study of abemaciclib in combination with pembrolizumab for patients (pts) with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC) (NCT02779751): Preliminary results [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT108.

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