Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas.

BACKGROUND: To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. METHODS: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. PRIMARY ENDPOINT: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. RESULTS: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. DISCUSSION: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03136055.

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.

BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial.

BACKGROUND: Sotorasib, a specific, irreversible KRASG12C protein inhibitor, has shown monotherapy clinical activity in KRASG12C-mutated solid tumours, including colorectal cancer, in the CodeBreaK100 phase 1 trial. We aimed to investigate the activity and safety of sotorasib in phase 2 of the trial. METHODS: In this single-arm, phase 2 trial, adult patients with KRASG12C-mutated advanced solid tumours were enrolled, from 59 medical centres in 11 countries, if they were aged 18 years or older, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Only data for patients with colorectal cancer, enrolled at 33 medical centres in nine countries, are presented from this basket trial. To be enrolled, the patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg sotorasib orally once per day until disease progression, development of unacceptable side-effects, withdrawal of consent, or death. The primary endpoint was objective response (complete or partial response) as assessed by blinded independent central review. Response was evaluated in patients who received at least one dose of sotorasib and had at least one measurable lesion at baseline; safety was evaluated in patients who received at least one dose of sotorasib. This analysis is a prespecified analysis triggered by the phase 2 colorectal cancer cohort. This study is registered with ClinicalTrials.gov, NCT03600883, and is active but no longer recruiting. FINDINGS: On March 1, 2021, at data cutoff, 62 patients with KRASG12C-mutant colorectal cancer had been enrolled between Aug 14, 2019, and May 21, 2020, and had received at least one dose of sotorasib monotherapy. Objective response was observed in six (9·7%, 95% CI 3·6-19·9) of 62 patients, all with partial response. Treatment-related adverse events at grade 3 occurred in six (10%) patients, the most common of which was diarrhoea (two [3%] of 62 patients), and at grade 4 occurred in one (2%) patient (blood creatine phosphokinase increase); no fatal events were recorded. Serious treatment-related adverse events occurred in two (3%) patients (back pain and acute kidney injury). INTERPRETATION: Although the 9·7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms. FUNDING: Amgen.

Late-onset Proteus syndrome with cerebriform connective tissue nevus and subsequent development of intraductal papilloma.

Proteus syndrome (PS) is a rare segmental overgrowth disorder caused by a mosaic activating variant in AKT1. The features of PS are often not present at birth but develop during the first few years of life. We describe a 55-year-old female, whose first symptom of overgrowth, a cerebriform connective tissue nevus, occurred at 19 years of age. We report the identification of the AKT1 c.49G > A p.(Glu17Lys) variant in this progressive lesion, the bony overgrowth, and recurrence after surgical intervention. In the sixth decade of life, this individual developed intraductal papillomas within her right breast which were confirmed to contain the same activating AKT1 variant as the connective tissue nevus. While similar neoplasms have been described in an individual with Proteus syndrome, none has been evaluated for the presence of the AKT1 variant. The tumor also contained two likely pathogenic variants in PIK3R1, c.1392_1403dupTAGATTATATGA p.(Asp464_Tyr467dup) and c.1728_1730delGAG p.(Arg577del). The finding of additional genetic variation putatively affecting the PI3K/AKT pathway in the neoplastic tissue may provide preliminary evidence of a molecular mechanism for tumorigenesis in PS. The late onset of symptoms and molecular characterization of the breast tumor expand the clinical spectrum of this rare disorder.

Specialized computational methods for denoising, B1 correction, and kinetic modeling in hyperpolarized 13 C MR EPSI studies of liver tumors.

PURPOSE: To develop a novel post-processing pipeline for hyperpolarized (HP) 13 C MRSI that integrates tensor denoising and B1+ correction to measure pyruvate-to-lactate conversion rates (kPL ) in patients with liver tumors. METHODS: Seven HP 13 C MR scans of progressing liver tumors were acquired using a custom 13 C surface transmit/receive coil and the echo-planar spectroscopic imaging (EPSI) data analysis included B0 correction, tensor rank truncation, and zero- and first-order phase corrections to recover metabolite signals that would otherwise be obscured by spectral noise as well as a correction for inhomogeneous transmit ( B1+ ) using a B1+ map aligned to the coil position for each patient scan. Processed HP data and corrected flip angles were analyzed with an inputless two-site exchange model to calculate kPL . RESULTS: Denoising averages SNR increases of pyruvate, lactate, and alanine were 37.4-, 34.0-, and 20.1-fold, respectively, with lactate and alanine dynamics most noticeably recovered and better defined. In agreement with Monte Carlo simulations, over-flipped regions underestimated kPL and under-flipped regions overestimated kPL . B1+ correction addressed this issue. CONCLUSION: The new HP 13 C EPSI post-processing pipeline integrated tensor denoising and B1+ correction to measure kPL in patients with liver tumors. These technical developments not only recovered metabolite signals in voxels that did not receive the prescribed flip angle, but also increased the extent and accuracy of kPL estimations throughout the tumor and adjacent regions including normal-appearing tissue and additional lesions.

Technique development of 3D dynamic CS-EPSI for hyperpolarized 13 C pyruvate MR molecular imaging of human prostate cancer.

PURPOSE: The purpose of this study was to develop a new 3D dynamic carbon-13 compressed sensing echoplanar spectroscopic imaging (EPSI) MR sequence and test it in phantoms, animal models, and then in prostate cancer patients to image the metabolic conversion of hyperpolarized [1-13 C]pyruvate to [1-13 C]lactate with whole gland coverage at high spatial and temporal resolution. METHODS: A 3D dynamic compressed sensing (CS)-EPSI sequence with spectral-spatial excitation was designed to meet the required spatial coverage, time and spatial resolution, and RF limitations of the 3T MR scanner for its clinical translation for prostate cancer patient imaging. After phantom testing, animal studies were performed in rats and transgenic mice with prostate cancers. For patient studies, a GE SPINlab polarizer (GE Healthcare, Waukesha, WI) was used to produce hyperpolarized sterile GMP [1-13 C]pyruvate. 3D dynamic 13 C CS-EPSI data were acquired starting 5 s after injection throughout the gland with a spatial resolution of 0.5 cm3 , 18 time frames, 2-s temporal resolution, and 36 s total acquisition time. RESULTS: Through preclinical testing, the 3D CS-EPSI sequence developed in this project was shown to provide the desired spectral, temporal, and spatial 5D HP 13 C MR data. In human studies, the 3D dynamic HP CS-EPSI approach provided first-ever simultaneously volumetric and dynamic images of the LDH-catalyzed conversion of [1-13 C]pyruvate to [1-13 C]lactate in a biopsy-proven prostate cancer patient with full gland coverage. CONCLUSION: The results demonstrate the feasibility to characterize prostate cancer metabolism in animals, and now patients using this new 3D dynamic HP MR technique to measure kPL , the kinetic rate constant of [1-13 C]pyruvate to [1-13 C]lactate conversion.

Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors.

BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. METHODS: MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography-mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma-mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson's correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs). RESULTS: Veliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26-44%), 74% (40-97%) and 46% (9-37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi-platinum interaction was observed in patients' PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60-1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21-0.66%, P < 0.0001). CONCLUSIONS: PARPi/platinum tumor penetration can be measured by MALDI-MSI and ICP-MS in PBMCs and fresh frozen, OCT embedded core needle biopsies. Large variability in platinum adduct formation and spatial heterogeneity in veliparib distribution may lead to insufficient drug exposure in select cell populations.

A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies.

PURPOSE: Akt plays a key role in the aggressive pathogenesis of HER2+ malignancies, suggesting that Akt-inhibitors may be of therapeutic value in the treatment of HER2+ tumors. Preclinical studies demonstrate synergy between MK-2206, a selective allosteric Akt-inhibitor, with paclitaxel and trastuzumab. We aimed to evaluate the safety of this combination in patients with HER2+ malignancies. METHODS: We conducted a phase 1b study of weekly MK-2206 in combination with weekly paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg in patients with HER2+ malignancies. Dose escalation was performed using a modified toxicity probability interval method. Molecular profiling of archived tissue samples and limited PK analyses were performed. RESULTS: 16 patients with HER2+ tumors were enrolled (12 breast, 3 gastric, 1 esophageal). 81 and 75 % had received prior trastuzumab and taxane chemotherapy, respectively. MK-2206 135 mg/week was determined to be tolerable. Three dose-limiting toxicities were observed including two grade 3 rashes and 1 grade 3 neutropenia resulting in a > 7 day delay in treatment. Grade 3/4 adverse events include neutropenia (44 %), rash (13 %), peripheral neuropathy (6 %), and depression (6 %). 10 patients (63 %) demonstrated tumor response (3 complete, 7 partial). Median duration of response was 6 months. Exploratory analyses identified STARD3, TM7SF2, and G3BP1 as potential biomarkers of response. CONCLUSIONS: MK-2206 at a dose of 135 mg/week in combination with weekly paclitaxel and trastuzumab is safe and well tolerated, and is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in patients with HER2+ tumors despite prior HER2-directed therapy.

Combined histone deacetylase inhibition and tamoxifen induces apoptosis in tamoxifen-resistant breast cancer models, by reversing Bcl-2 overexpression.

INTRODUCTION: The emergence of hormone therapy resistance, despite continued expression of the estrogen receptor (ER), is a major challenge to curing breast cancer. Recent clinical studies suggest that epigenetic modulation by histone deacetylase (HDAC) inhibitors reverses hormone therapy resistance. However, little is known about epigenetic modulation of the ER during acquired hormone resistance. Our recent phase II study demonstrated that HDAC inhibitors re-sensitize hormone therapy-resistant tumors to the anti-estrogen tamoxifen. In this study, we sought to understand the mechanism behind the efficacy of this combination. METHODS: We generated cell lines resistant to tamoxifen, named TAMRM and TAMRT, by continuous exposure of ER-positive MCF7 and T47D cells, respectively to 4-hydroxy tamoxifen for over 12 months. HDAC inhibition, along with pharmacological and genetic manipulation of key survival pathways, including ER and Bcl-2, were used to characterize these resistant models. RESULTS: The TAMRM cells displayed decreased sensitivity to tamoxifen, fulvestrant and estrogen deprivation. Consistent with previous models, ER expression was retained and the gene harbored no mutations. Compared to parental MCF7 cells, ER expression in TAMRM was elevated, while progesterone receptor (PGR) was lost. Sensitivity of ER to ligands was greatly reduced and classic ER response genes were suppressed. This model conveyed tamoxifen resistance through transcriptional upregulation of Bcl-2 and c-Myc, and downregulation of the cell cycle checkpoint protein p21, manifesting in accelerated growth and reduced cell death. Similar to TAMRM cells, the TAMRT cell line exhibited substantially decreased tamoxifen sensitivity, increased ER and Bcl-2 expression and significantly reduced PGR expression. Treatment with HDAC inhibitors reversed the altered transcriptional events and reestablished the sensitivity of the ER to tamoxifen resulting in substantial Bcl-2 downregulation, growth arrest and apoptosis. Selective inhibition of Bcl-2 mirrored these effects in presence of an HDAC inhibitor. CONCLUSIONS: Our model implicates elevated ER and Bcl-2 as key drivers of anti-estrogen resistance, which can be reversed by epigenetic modulation through HDAC inhibition.

A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma.

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is essential for tumor development, yet mTOR inhibitors have yielded modest results. This phase 1 study investigated the mTORC1/mTORC2 inhibitor CC-223 in patients with advanced cancer. METHODS: Patients with advanced solid tumors or multiple myeloma received an initial dose of 7.5-60 mg of CC-223, followed by oral daily dosing in 28-day cycles until disease progression. The primary objective was to determine the safety, tolerability, nontolerated dosage, maximum tolerated dosage (MTD), and preliminary pharmacokinetic profile. Secondary objectives were to evaluate pharmacodynamic effects and to describe preliminary efficacy. RESULTS: Twenty-eight patients were enrolled and received ≥1 dose of CC-223. The most common treatment-related grade 3 adverse events were hyperglycemia, fatigue, and rash. Four patients had dose-limiting toxicities, including hyperglycemia, rash, fatigue, and mucositis. Therefore, 45 mg/d was determined to be the MTD. The pharmacokinetics of CC-223 demonstrated a mean terminal half-life ranging from 4.86 to 5.64 hours and maximum observed plasma concentration ranging from 269 to 480 ng/mL in patients who received CC-223 ≥45 mg/d. Phosphorylation of mTORC1/mTORC2 pathway biomarkers in blood cells was inhibited by CC-223 ≥30 mg/d with an exposure-response relationship. Best responses included 1 partial response (breast cancer; response duration 220 days; 30-mg/d cohort), stable disease (8 patients across ≥15 mg/d cohorts; response duration range, 36-168 days), and progressive disease (12 patients). The disease control rate was 32%. CONCLUSIONS: CC-223 was tolerable, with manageable toxicities. Preliminary antitumor activity, including tumor regression, and evidence of mTORC1/mTORC2 pathway inhibition were observed.

Association of tamoxifen use and ovarian function in patients with invasive or pre-invasive breast cancer.

The impact of long-term tamoxifen therapy on ovarian function is not known. Understanding these effects will help reproductive-aged patients who desire future pregnancy make more informed decisions regarding their treatment. This is a retrospective cohort study in patients identified through the UCSF Cancer Registry and SPORE database. We enrolled women with a history of ductal carcinoma in situ (DCIS) or early stage invasive breast cancer who were premenopausal at diagnosis and did not receive chemotherapy. Menstrual histories were obtained through electronic and paper surveys. We compared the age of menopause onset and menstrual pattern changes between women who received tamoxifen (TAM) and those who did not receive tamoxifen (control). Neither group received chemotherapy. 250 subjects were included in this study (125 TAM, 125 control). Mean age of menopause onset was 51.0 for both the groups and was not associated with duration of tamoxifen use or the age at tamoxifen initiation. Menstrual pattern changes, including amenorrhea, were more frequent in the TAM group than control group (any change: 48% TAM vs. 15 % control, p < 0.001; amenorrhea: 22% TAM vs. 3% control, p < 0.001). Older age was associated with an increased risk of developing amenorrhea within 6 months of starting tamoxifen (HR 1.32, p < 0.001). Menstrual pattern changes are common in premenopausal women taking tamoxifen. Tamoxifen use in the absence of chemotherapy is not associated with an earlier age onset of menopause in patients with DCIS or invasive breast cancer and is unlikely to significantly accelerate ovarian aging.

A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170).

We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response. SIGNIFICANCE: WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.

First-in-human Phase I Trial of TPST-1120, an Inhibitor of PPARα, as Monotherapy or in Combination with Nivolumab, in Patients with Advanced Solid Tumors.

PURPOSE: TPST-1120 is a first-in-class oral inhibitor of peroxisome proliferator-activated receptor α (PPARα), a fatty acid ligand-activated transcription factor that regulates genes involved in fatty acid oxidation, angiogenesis, and inflammation, and is a novel target for cancer therapy. TPST-1120 displayed antitumor activity in xenograft models and synergistic tumor reduction in syngeneic tumor models when combined with anti-PD-1 agents. EXPERIMENTAL DESIGN: This phase I, open-label, dose-escalation study (NCT03829436) evaluated TPST-1120 as monotherapy in patients with advanced solid tumors and in combination with nivolumab in patients with renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma. Objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity (RECIST v1.1). RESULTS: A total of 39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAE) were grade 1-2 nausea, fatigue, and diarrhea. No grade 4-5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 patients with RCC, both of whom had previously progressed on anti-PD-1 therapy, and 1 patient with late-line CCA. CONCLUSIONS: TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers. SIGNIFICANCE: TPST-1120 is a first-in-class oral inhibitor of PPARα, whose roles in metabolic and immune regulation are implicated in tumor proliferation/survival and inhibition of anticancer immunity. This first-in-human study of TPST-1120 alone and in combination with nivolumab supports proof-of-concept of PPARα inhibition as a target of therapeutic intervention in solid tumors.

ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Nab-Paclitaxel in Patients with Advanced Solid Tumors.

PURPOSE: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of antiapoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 clinical trial. PATIENTS AND METHODS: The ability of ORIC-101 to reverse taxane resistance was assessed in cell lines and xenograft models, and a phase 1 study (NCT03928314) was conducted in patients with advanced solid tumors to determine the dose, safety, and antitumor activity of ORIC-101 with nab-paclitaxel. RESULTS: ORIC-101 reversed chemoprotection induced by glucocorticoids in vitro and achieved tumor regressions when combined with paclitaxel in both taxane-naïve and -resistant xenograft models. In the phase 1 study, 21 patients were treated in dose escalation and 62 patients were treated in dose expansion. All patients in dose expansion had previously progressed on a taxane-based regimen. In dose escalation, five objective responses were observed. A preplanned futility analysis in dose expansion showed a 3.2% (95% confidence interval, 0.4-11.2) objective response rate with a median progression-free survival of 2 months (95% confidence interval, 1.8-2.8) across all four cohorts, leading to study termination. Pharmacodynamic analysis of tissue and plasma showed GR pathway downregulation in most patients in cycle 1. CONCLUSIONS: ORIC-101 with nab-paclitaxel showed limited clinical activity in taxane-resistant solid tumors. Despite clear inhibition of GR pathway signaling, the insufficient clinical signal underscores the challenges of targeting a single resistance pathway when multiple mechanisms of resistance may be in play. SIGNIFICANCE: Glucocorticoid receptor (GR) upregulation is a mechanism of resistance to taxane chemotherapy in preclinical cancer models. ORIC-101 is a small molecule GR inhibitor. In this phase 1 study, ORIC-101 plus nab-paclitaxel did not show meaningful clinical benefit in patients who previously progressed on taxanes despite successful GR pathway downregulation.

Fertility preservation and breast cancer: A complex problem.

A considerable number of women with breast cancer are diagnosed during their reproductive years. In the short period of time in which newly diagnosed women will need to make decisions about surgical options and adjuvant therapy, younger women with breast cancer also face the potential impairment or complete loss of their fertility. The preservation of fertility should therefore be an integral consideration in the choice of breast cancer therapy. Preserving ovarian function is particularly challenging for women with estrogen receptor-positive tumors, as the suppression of ovarian function has been shown to be beneficial therapy with regard to breast cancer outcomes. The current emerging recommendations of hormonal therapy extending to a 10-year period will likely further impact the timing of any subsequent pregnancy or require an interruption in hormonal therapy. To optimally counsel patients on how to best weigh the risks and benefits of each intervention, both the care provider and the patient must understand the options and the likelihood of their success. Here we summarize the current challenges and options for women diagnosed with breast cancer who wish to preserve their fertility.

ATM-SPARK: A GFP phase separation-based activity reporter of ATM.

The kinase ataxia telangiectasia mutated (ATM) plays a key role in the DNA damage response (DDR). It is thus essential to visualize spatiotemporal dynamics of ATM activity during DDR. Here, we designed a robust ATM activity reporter based on phosphorylation-inducible green fluorescent protein phase separation, dubbed ATM-SPARK (separation of phases-based activity reporter of kinase). Upon ATM activation, it undergoes phase separation via multivalent interactions, forming intensely bright droplets. The reporter visualizes spatiotemporal dynamics of endogenous ATM activity in living cells, and its signal is proportional to the amount of DNA damage. ATM-SPARK also enables high-throughput screening of biological and small-molecule regulators. We identified the protein phosphatase 4 that blocks ATM activity. We also identified BGT226 as a potent ATM inhibitor with a median inhibitory concentration of ~3.8 nanomolars. Furthermore, BGT226 sensitizes cancer cells to the radiomimetic drug neocarzinostatin, suggesting that BGT226 might be combined with radiotherapeutic treatment. ATM-SPARK achieves large dynamic range, bright fluorescence, and simple signal pattern.

A long-term fulvestrant eluting implant is safe, non-toxic, and reduces the risk of breast cancer in in vivo models.

For individuals at high risk of developing breast cancer, interventions to mitigate this risk include surgical removal of their breasts and ovaries or five years treatment with the anti-estrogen tamoxifen or aromatase inhibitors. We hypothesized that a silicone based anti-estrogen-eluting implant placed within the breast would provide the risk reduction benefit of hormonal therapy, but without the adverse effects that limit compliance. To this end, we demonstrate that when placed adjacent to mammary tissue in the DMBA-induced rat breast cancer model a fulvestrant-eluting implant delays breast cancer with minimal systemic exposure. Using adult female sheep, fulvestrant-eluting implants were found to be safe and non-toxic when placed at the base of the udder for directed elution into the mammary tissue. At 30 days of elution, fulvestrant was found to penetrate mammary tissue forming a concentration gradient beyond 15 mm from the implant. Consistent with the small animal rat study, minimal systemic fulvestrant biodistribution was found. Together, these studies provide the proof of principle that a breast indwelling fulvestrant-eluting implant can reduce the risk of breast cancer and limit systemic exposure, while penetrating and distributing through breast tissue.

Targeting RAD51-Mediated Homologous Recombination as a Treatment for Advanced Solid and Hematologic Malignancies: Opportunities and Challenges Ahead.

RAD51 is integral in homologous recombination DNA damage repair and has garnered much interest as both a biomarker and potential therapeutic target in oncology. Multiple in vitro and in vivo studies have demonstrated its role as a predictive marker, particularly in the context of platinum-based therapies and poly ADP-ribose polymerase (PARP) inhibitors. In this review, we highlight the development of RAD51 inhibitors, with a focus on novel molecules and ongoing clinical trials. Despite many efforts to develop effective and tolerable direct RAD51 inhibitors, identification of these agents remains challenging. Clinically, however, there may be a role of pharmacological indirect RAD51 inhibition.

A Phase IB Trial of the PI3K Inhibitor Alpelisib and Weekly Cisplatin in Patients with Solid Tumor Malignancies.

The PI3K pathway may be a potential mechanism to overcome cisplatin resistance. We conducted a phase Ib trial of alpelisib and cisplatin for patients with solid tumor malignancies with planned dose expansion in HPV-associated tumors. The primary objective was to determine the MTD and recommended phase II dose. Two different weekly doses of cisplatin (30 and 35 mg/m2) were evaluated with escalating doses of alpelisib, administered daily during a 21-day treatment cycle. Twenty-three patients were enrolled: 91% received >3 prior regimens with median of 4 (range 1-10), and 78% progressed on prior platinum. The MTD was alpelisib 250 mg daily with weekly cisplatin 30 mg/m2. There were 3 DLTs: all grade 4 hyperglycemia. Frequent treatment-related adverse events of any grade included fatigue (52%), diarrhea (39%), nausea (38%), hyperglycemia (30%), anemia (22%), and nephropathy (17%). Hyperglycemia was linked to baseline hemoglobin A1C, but not body mass index. Twelve patients discontinued treatment for toxicity (n = 9 during cycle 1) and 11 discontinued for progression. Of 14 evaluable patients who received at least one treatment cycle, 4 (29%) patients demonstrated partial response, and 7 had stable disease for a disease control rate of 79%. The median PFS measured 4.3 months (95% CI, 1.6-4.5). No difference in PFS was observed between PIK3CA-mutated and wild-type tumors. While the combination of alpelisib and cisplatin demonstrated preliminary evidence of activity despite platinum resistance, toxicities hindered prolonged treatment. Prospective studies are planned using carboplatin and alpelisib to improve toxicity and tolerability. Significance: The PI3K inhibitor alpelisib has limited activity alone, but there is interest in combinations in platinum-resistant tumors. In this phase Ib study of alpelisib with cisplatin, the objective response rate measured 29% but adverse events limited dose intensity. These promising results provide rationale for studying combinations with better tolerated platinum agents.

Malignant glioma subset from actuate 1801: Phase I/II study of 9-ING-41, GSK-3ß inhibitor, monotherapy or combined with chemotherapy for refractory malignancies.

Background: GSK3ß serine/threonine kinase regulates metabolism and glycogen biosynthesis. GSK3ß overexpression promotes progression and resistance through NF-κB and p53 apoptotic pathways. GSK3ß inhibits immunomodulation by downregulating PD-L1 and LAG-3 checkpoints and increasing NK and T-cell tumor killing. 9-ING-41, a small-molecule, selective GSK3ß inhibitor, showed preclinical activity in chemo-resistant PDX glioblastoma models, including enhanced lomustine antitumor effect. Methods: Refractory malignancies (n = 162) were treated with 9-ING-41 monotherapy (n = 65) or combined with 8 cytotoxic regimens after prior exposure (NCT03678883). Recurrent gliomas (n = 18) were treated with 9-ING-41 IV TIW q21day cycles at 3.3, 5, 9.3, 15 mg/kg, as monotherapy or combined with lomustine 30 mg/m² PO weekly q84day cycles. Primary objective was safety. Results: RP2D of 15 mg/kg IV TIW was confirmed across all 9 regimens, no accentuated chemotherapy toxicity noted. Glioma subtypes included: 13 glioblastoma, 2 anaplastic astrocytomas, 1 anaplastic oligodendroglioma, 1 astrocytoma. Median age 52 (30-69) years; 6 female, 12 male; median ECOG 1 (0-2); median recurrences 3 (1-6). All received upfront radiation/temozolomide (18/18), plus salvage nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), or immunotherapy (4/18). IDH/mutation(3/18); 1p19q/codeletion(1/18); MGMT/methylated(1/18). Four received 9-ING-41 monotherapy, 14 concurrent with lomustine. No severe toxicities were attributed to 9-ING-41, only mild vision changes (9/18, 50%), or infusion reactions (4/18, 22%). Lomustine-related toxicities: G3/4 thrombocytopenia (3/14, 21%), G1/2 fatigue (4/14, 28%). Median days on therapy was 55 (4-305); 1 partial response (>50%) was noted. Median OS was 5.5 (95% CI: 2.8-11.4) months and PFS-6 was 16.7%. Conclusion: 9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.