MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer.

Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selecti-vity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study. SIGNIFICANCE: PRMT5 was identified as a synthetic lethal target for MTAP del cancers; however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ∼10% of patients with cancer with this biomarker. See related commentary by Mulvaney, p. 2310. This article is featured in Selected Articles from This Issue, p. 2293.

MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Nonsquamous NSCLC Progressing On or After Checkpoint Inhibitor Therapy or Chemotherapy.

INTRODUCTION: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TYRO3, AXL, MERTK receptors, and vascular epithelial growth factor receptor 2, can shift the tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPIs) may augment antitumor activity. METHODS: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2 or 4 wk) in patients with advanced nonsquamous NSCLC who progressed on or after previous CPI (CPI-experienced) or chemotherapy (CPI-naive). CPI-experienced patients had a previous clinical benefit (PCB) (complete response, partial response, or stable disease for at least 12 weeks then disease progression) or no PCB (NPCB) from CPI. The primary end point was objective response rate (ORR); secondary objectives included safety and secondary efficacy end points. RESULTS: Overall, 124 CPI-experienced (NPCB, n = 35; PCB, n = 89) and 32 CPI-naive patients were treated. Investigator-assessed ORR was 11.4% in patients with NPCB, 16.9% with PCB, and 25.0% in CPI-naive. The median progression-free survival was 3.7, 5.6, and 7.1 months with NPCB, PCB, and CPI-naive, respectively; the median overall survival was 7.9 and 13.6 months with NPCB and PCB, respectively (not reached in CPI-naive patients; median follow-up 20.4 mo). Overall, (N = 156), any grade treatment-related adverse events (TRAEs) occurred in 93.6%; grade 3/4 in 58.3%. One grade 5 TRAE occurred in a CPI-naive patient. TRAEs led to treatment discontinuation in 14.1% and dose reduction or interruption in 42.9%. Biomarker analyses supported an immunostimulatory mechanism of action. CONCLUSIONS: Sitravatinib with nivolumab had a manageable safety profile. Although ORR was not met, this combination exhibited antitumor activity and encouraged survival in CPI-experienced patients with nonsquamous NSCLC.

A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy.

The accumulation of immune-suppressive myeloid cells is a critical determinant of resistance to anti-programmed death-1 (PD-1) therapy in advanced clear cell renal cell carcinoma (ccRCC). In preclinical models, the tyrosine kinase inhibitor sitravatinib enhanced responses to anti-PD-1 therapy by modulating immune-suppressive myeloid cells. We conducted a phase 1-2 trial to choose an optimal sitravatinib dose combined with a fixed dose of nivolumab in 42 immunotherapy-naïve patients with ccRCC refractory to prior antiangiogenic therapies. The combination demonstrated no unexpected toxicities and achieved an objective response rate of 35.7% and a median progression-free survival of 11.7 months, with 80.1% of patients alive after a median follow-up of 18.7 months. Baseline peripheral blood neutrophil-to-lymphocyte ratio correlated with response to sitravatinib and nivolumab. Patients with liver metastases showed durable responses comparable to patients without liver metastases. In addition, correlative studies demonstrated reduction of immune-suppressive myeloid cells in the periphery and tumor microenvironment following sitravatinib treatment. This study provides a rationally designed combinatorial strategy to improve outcomes of anti-PD-1 therapy in advanced ccRCC.

Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study.

BACKGROUND: Sitravatinib, a tyrosine kinase inhibitor that targets TYRO3, AXL, MERTK and the VEGF receptor family, is predicted to increase the M1 to M2-polarized tumor-associated macrophages ratio in the tumor microenvironment and have synergistic antitumor activity in combination with anti-programmed death-1/ligand-1 agents. SNOW is a window-of-opportunity study designed to evaluate the immune and molecular effects of preoperative sitravatinib and nivolumab in patients with oral cavity squamous cell carcinoma. METHODS: Patients with newly-diagnosed untreated T2-4a, N0-2 or T1 >1 cm-N2 oral cavity carcinomas were eligible. All patients received sitravatinib 120 mg daily from day 1 up to 48 hours pre-surgery and one dose of nivolumab 240 mg on day 15. Surgery was planned between day 23 and 30. Standard of care adjuvant radiotherapy was given based on clinical stage. Tumor photographs, fresh tumor biopsies and blood samples were collected at baseline, at day 15 after sitravatinib alone, and at surgery after sitravatinib-nivolumab combination. Tumor flow cytometry, multiplex immunofluorescence staining and single-cell RNA sequencing (scRNAseq) were performed on tumor biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing and circulating tumor DNA and cell-free DNA were evaluated at each time point. RESULTS: Ten patients were included. Grade 3 toxicity occurred in one patient (hypertension); one patient required sitravatinib dose reduction, and one patient required discontinuation and surgery delay due to G2 thrombocytopenia. Nine patients had clinical-to-pathological downstaging, with one complete response. Independent pathological treatment response (PTR) assessment confirmed a complete PTR and two major PTRs. With a median follow-up of 21 months, all patients are alive with no recurrence. Circulating tumor DNA and cell-free DNA dynamics correlated with clinical and pathological response and distinguished two patient groups with different tumor biological behavior after sitravatinib alone (1A) versus sitravatinib-nivolumab (1B). Tumor immunophenotyping and scRNAseq analyses revealed differential changes in the expression of immune cell populations and sitravatinib-targeted and hypoxia-related genes in group 1A vs 1B patients. CONCLUSIONS: The SNOW study shows sitravatinib plus nivolumab is safe and leads to deep clinical and pathological responses in oral cavity carcinomas. Multi-omic biomarker analyses dissect the differential molecular effects of sitravatinib versus the sitravatinib-nivolumab and revealed patients with distinct tumor biology behavior. TRIAL REGISTRATION NUMBER: NCT03575598.

Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads.

Background Antibody drug conjugates (ADCs) utilize a monoclonal antibody to deliver a cytotoxic payload specifically to tumor cells, limiting exposure to healthy tissues. Major clinical toxicities of ADCs include hematologic, hepatic, neurologic, and ophthalmic events, which are often dose-limiting. These events may be off-target effects caused by premature release of payload in circulation. A meta-analysis was performed to summarize key clinical safety data for ADCs by payload, and data permitting, establish a dose-response model for toxicity incidence as a function of payload, dose/regimen, and cancer type. Methods A literature search was performed to identify and extract data from clinical ADC studies. Toxicity incidence and severity were collected by treatment arm for anemia, neutropenia, thrombocytopenia, leukopenia, hepatic toxicity, peripheral neuropathy, and ocular toxicity. Exploratory plots, descriptive summaries, and logistic regression modelling were used to explore Grade ≥ 3 (G3/4) toxicities and assess the impact of covariates, including cancer type and dose/regimen. Results The dataset contained 70 publications; quantitative analysis included 43 studies with G3/4 toxicity information reported for the endpoints above. G3/4 anemia, neutropenia and peripheral neuropathy were consistently reported for MMAE ADCs, thrombocytopenia and hepatic toxicity for DM1, and ocular toxicity for MMAF. Safety profiles of MMAE, DM1, and DM4 ADCs differed between solid and hematologic cancers. Conclusions Published ADC clinical data is limited by non-uniform reporting for toxicity and lack of dosing information, limiting the ability to develop quantitative models relating toxicity to exposure. However, the current analysis suggests that key G3/4 toxicities of ADCs in the clinic are likely off-target and related to payload.

First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors.

Background The antibody-drug conjugate PF-06263507 targets the cell-surface, tumor-associated antigen 5T4 and consists of a humanized IgG1 conjugated to the microtubule-disrupting agent monomethylauristatin-F by a non-cleavable maleimidocaproyl linker. In this first-in-human, dose-finding trial (NCT01891669), we evaluated safety, pharmacokinetics, and preliminary antitumor activity of PF-06263507 in pretreated patients with advanced solid tumors, unselected for 5T4 expression. starting at 0.05 mg/kg, with 25, 56, and 95% dose increments, depending on observed dose-limiting toxicities (DLTs), applying a modified continual reassessment method. Results Twenty-six patients received PF-06263507 at 0.05 to 6.5 mg/kg. The first DLT, grade 3 photophobia, occurred at 4.34 mg/kg and two additional DLTs, grade 2 keratitis and grade 1 limbal stem cell deficiency (> 2-week dosing delay), at 6.5 mg/kg. The most common adverse events (AEs) were fatigue (38.5%), photophobia (26.9%), and decreased appetite, dry eye, nausea, and thrombocytopenia (23.1% each). No treatment-related grade 4-5 AEs were reported. Systemic exposure of PF-06263507 increased in a dose-related manner. At the maximum tolerated dose (MTD, 4.34 mg/kg), mean terminal half-life for PF-06263507 and unconjugated payload were ~6 and 3 days, respectively. Payload serum concentrations were substantially lower compared with PF-06263507. No objective responses were observed. Conclusions The MTD and recommended phase II dose were determined to be 4.34 mg/kg. Ocular toxicities accounted for the DLTs observed, as previously reported with monomethylauristatin-F payloads. Further studies are warranted to investigate clinical activity of this agent in patients with 5T4-expressing tumors.Trial registration ID: NCT01891669.

Successful treatment of metastatic androgen-independent prostate carcinoma in a transsexual patient.

The occurrence of prostate carcinoma in transsexual patients has rarely been reported. These cases present a unique challenge in that such patients are effectively receiving androgen deprivation therapy. By definition, their disease is androgen-independent prostate cancer, and the role of local therapy is undefined. We report on a male-to-female transsexual patient with metastatic prostate cancer treated successfully with combination chemotherapy after previous standard therapy failed.

Raloxifene, an oestrogen-receptor-beta-targeted therapy, inhibits androgen-independent prostate cancer growth: results from preclinical studies and a pilot phase II clinical trial.

OBJECTIVES: To determine, in preclinical in vivo animal and in clinical studies, whether raloxifene (a selective oestrogen-receptor (ER) modulator that targets ER-beta and induces apoptosis in vitro in androgen-independent prostate cancer, AIPC cells) affects prostate cell differentiation, proliferation and carcinogenesis, and in the pilot phase II clinical trial, the response rate and duration of patients with AIPC treated with a daily oral dose of raloxifene. PATIENTS, MATERIALS AND METHODS: Tumour proliferation rate in response to raloxifene treatment, and molecular markers of cell cycle and apoptosis, were evaluated in established ER-beta-positive androgen-dependent (AD) CWR22 and AI CWRSA9 human xenograft prostate cancer models. Twenty-one patients with AIPC and evidence of disease progression were enrolled into the clinical trial and given daily oral raloxifene. RESULTS: There was significant growth inhibition by raloxifene in the ADPC and AIPC xenograft models (CWR22 68%, P < 0.010; CWRSA9 64%, P < 0.001), with no tumour regression. There was evidence of G1 arrest by increased p27kip1 expression in the raloxifene-treated group. Eighteen patients comprised the efficacy analysis, as three withdrew before the first evaluation. At the first evaluation, five men had stable disease and continued on the study for a median of five cycles. The longest response was 17 cycles. Drug related toxicity was minimal. CONCLUSION: Raloxifene has activity in xenograft models, slowing disease progression. This translated to possible disease stabilization in patients with AIPC. Further studies are warranted.

Targeting the HER-kinase axis in cancer.

The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases controls critical pathways involved in the differentiation, growth, division, and motility of normal epithelial cells. Most human solid tumors are of epithelial origin. The process of malignant transformation and progression in many cancers may depend on activation of ligands and receptors that function as part of the HER-kinase pathway. This signaling axis has earned increased attention because of the development of antibodies and small-molecule tyrosine kinase inhibitors that specifically target components of the HER-kinase axis for cancer therapy. This review focuses on the basic biology underlying HER-kinase pathway activation and the current state of development for agents that target this axis. In particular, the importance of pan-HER inhibitors is discussed.