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.

Orgasmic epilepsy is another mode of presentation of paraneoplastic limbic encephalitis leading to the diagnosis of an occult SCLC. EEG and MRI findings suggest that in this case the seizures originated from the left hemisphere. It is possible that early recognition and treatment of the SCLC will improve the prognosis of this neurologic entity.

Background: Pembrolizumab is a programmed death receptor-1 masking antibody approved for advanced NSCLC in program death receptor ligand-1 high tumors, and in chemotherapy combinations. This trial studies the effect of neoadjuvant pembrolizumab on surgical tolerability (primary endpoint), tumor response, side effects, and immune biomarkers in blood and tumor. Method: Baseline PET/CT, brain imaging, histologic diagnosis NSCLC, and surgical consultation were required for eligibility. Patients with stage T >3 cm and N0, N1, or resectable N2 NSCLC received neoadjuvant pembrolizumab 200 mg every 21 days 2 cycles prior to pre-operative chest CT scan followed by standard surgery. Adjuvant chemotherapy was strongly encouraged but not required. After completion of standard chemotherapy, 4 cycles of adjuvant pembrolizumab 200 mg every 21 days was offered. Blood for immune profiling of circulating immune cells was collected at baseline, after cycle 2 pembrolizumab, after surgery, and after adjuvant pembrolizumab. Excess tumor was disaggregated for tumor infiltrating lymphocytes, regulatory immune cells, and tumor cells, and viably stored for later analysis. We report clinical outcomes of tumor response and surgical outcomes.

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The manuscript presents: a) a number of promising agents which appear applicable to further Phase II prevention trials; b) approaches to defining potential preventive agents as well; c) approaches which might mitigate the side effects associated with potential agents most specifically the use of aerosols. Finally, we discuss biomarker studies both preclinical and clinical which might help support potential Phase II trials. The particular appeal to the preclinical studies is that they can be followed to a tumor endpoint. We hope that this will give the reader further background and allow one to appreciate the potential and some of the hurdles associated with lung cancer chemoprevention.