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.

A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours.

BACKGROUND & AIMS: Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours. METHODS: Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure. RESULTS: In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p <0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p = 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96). CONCLUSIONS: Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes. IMPACT AND IMPLICATIONS: Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival.

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial.

KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.

The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial.

Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3+ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2+ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .

First-in-human Study of AZD5153, A Small-molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma.

AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase I study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. Adults with relapsed tumors intolerant of, or refractory to, prior therapies received escalating doses of oral AZD5153 once daily or twice daily continuously (21-day cycles), or AZD5153 once daily/twice daily continuously or intermittently plus olaparib 300 mg twice daily, until disease progression or unacceptable toxicity. Between June 30, 2017 and April 19, 2021, 34 patients received monotherapy and 15 received combination therapy. Dose-limiting toxicities were thrombocytopenia/platelet count decreased (n = 4/n = 2) and diarrhea (n = 1). The recommended phase II doses (RP2D) were AZD5153 30 mg once daily or 15 mg twice daily (monotherapy) and 10 mg once daily (intermittent schedule) with olaparib. With AZD5153 monotherapy, common treatment-emergent adverse events (TEAE) included fatigue (38.2%), thrombocytopenia, and diarrhea (each 32.4%); common grade ≥ 3 TEAEs were thrombocytopenia (14.7%) and anemia (8.8%). With the combination, common TEAEs included nausea (66.7%) and fatigue (53.3%); the most common grade ≥ 3 TEAE was thrombocytopenia (26.7%). AZD5153 had dose-dependent pharmacokinetics, with minimal accumulation, and demonstrated dose-dependent modulation of peripheral biomarkers, including upregulation of HEXIM1. One patient with metastatic pancreatic cancer receiving combination treatment had a partial response lasting 4.2 months. These results show AZD5153 was tolerable as monotherapy and in combination at the RP2Ds; common toxicities were fatigue, hematologic AEs, and gastrointestinal AEs. Strong evidence of peripheral target engagement was observed.

Cannabis use among adults undergoing cancer treatment.

BACKGROUND: Little is known about the risks and benefits of cannabis use in the context of cancer care. This study characterized the prevalence, reasons for use, and perceived benefits of cannabis and compared symptoms and perceived risks between those who reported past 30-day cannabis use and those who did not. METHODS: Adults undergoing cancer treatment at a National Cancer Institute-designated cancer center completed measures of sociodemographic characteristics, cannabis use, use modalities, reasons for use, perceived harms/benefits of use, physical and psychological symptoms, and other substance/medication use. Analyses compared patients who used or did not use cannabis in the past 30 days. RESULTS: Participants (N = 267) were 58 years old on average, primarily female (70%), and predominantly White (88%). Over a quarter of respondents (26%) reported past 30-day cannabis use, and among those, 4.5% screened positive for cannabis use disorder. Participants who used cannabis most often used edibles (65%) or smoked cannabis (51%), and they were younger and more likely to be male, Black, and disabled, and to have lower income and Medicaid insurance than participants who did not use cannabis. Those who used cannabis reported more severe symptoms and perceived cannabis as less harmful than those who did not use cannabis. The most common medical reasons for cannabis use were pain, cancer, sleep problems, anxiety, nausea/vomiting, and poor appetite. Participants reported the greatest cannabis-related symptom relief from sleep problems, nausea/vomiting, headaches, pain, muscle spasms, and anxiety. CONCLUSIONS: Patients with cancer who used cannabis perceived benefits for many symptoms, although they showed worse overall symptomatology. PLAIN LANGUAGE SUMMARY: Among adults undergoing cancer treatment, 26% reported cannabis use in the past 30 days. Those who used cannabis were more likely to be male and disabled and to have lower income and Medicaid insurance than those who did not use cannabis. Participants most commonly reported using cannabis for pain, cancer, sleep, anxiety, and nausea/vomiting and reported the greatest perceived benefits for sleep, nausea/vomiting, headaches, pain, muscle spasms, and anxiety, yet participants who used cannabis also reported feeling worse physically and psychologically compared to those who did not use cannabis. Participants who used cannabis were more likely to report that cannabis was less risky to their health than alcohol, smoking, and opioids than those who did not use cannabis.

Phase 1b study of pan-AKT inhibitor vevorisertib alone or with paclitaxel or fulvestrant in PIK3CA/AKT/PTEN-mutated advanced solid tumors.

BACKGROUND: In this first-in-human phase 1b study (ClinicalTrials.gov identifier NCT02761694) of advanced solid tumors with PIK3CA/AKT/PTEN mutations, the authors investigated the safety and efficacy of the pan-AKT inhibitor vevorisertib (MK-4440; ARQ 751) as monotherapy or with paclitaxel or fulvestrant. METHODS: Patients with histologically confirmed, advanced or recurrent, PIK3CA/AKT/PTEN-mutated solid tumors, measurable disease according to Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status ≤1 received vevorisertib (dose range, 5-100 mg) alone or with paclitaxel 80 mg/m2 or fulvestrant 500 mg. The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Of 78 patients enrolled, 58 received vevorisertib monotherapy, 10 received vevorisertib plus paclitaxel, and nine received vevorisertib plus fulvestrant. Dose-limiting toxicity occurred in three patients (vevorisertib monotherapy, n = 2 [grade 3 pruritic and maculopapular rashes]; vevorisertib plus paclitaxel, n = 1 [grade 1 asthenia]). Across doses, treatment-related AEs occurred in 46 patients (79%) with vevorisertib monotherapy, in 10 patients (100%) with vevorisertib plus paclitaxel, and in nine patients (100%) with vevorisertib plus fulvestrant; and grade 3 treatment-related AEs occurred in 13 (22%), 7 (70%), and 3 (33%) patients, respectively. No grade 4/5 treatment-related AEs occurred. Maximum vevorisertib concentrations were reached 1-4 hours after dosing; the elimination half-life ranged from 8.8 to 19.3 hours. The objective response rate was 5% with vevorisertib monotherapy (three partial responses), 20% with vevorisertib plus paclitaxel (two partial responses), and 0% with vevorisertib plus fulvestrant. CONCLUSIONS: Vevorisertib alone or with paclitaxel or fulvestrant had a manageable safety profile, and vevorisertib alone or with paclitaxel had minimal to modest antitumor activity in this patient population with PIK3CA/AKT/PTEN-mutated advanced solid tumors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02761694.

Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors: Results From JAVELIN BRCA/ATM, an Open-Label, Multicenter, Phase 2b, Tumor-Agnostic Trial.

Importance: Nonclinical studies suggest that the combination of poly(ADP-ribose) polymerase and programmed cell death 1/programmed cell death-ligand 1 inhibitors has enhanced antitumor activity; however, the patient populations that may benefit from this combination have not been identified. Objective: To evaluate whether the combination of avelumab and talazoparib is effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type. Design, Setting, and Participants: In this pan-cancer tumor-agnostic phase 2b nonrandomized controlled trial, patients with advanced BRCA1/2-altered or ATM-altered solid tumors were enrolled into 2 respective parallel cohorts. The study was conducted from July 2, 2018, to April 12, 2020, at 42 institutions in 9 countries. Interventions: Patients received 800 mg of avelumab every 2 weeks and 1 mg of talazoparib once daily. Main Outcomes and Measures: The primary end point was confirmed objective response (OR) per RECIST 1.1 by blinded independent central review. Results: A total of 200 patients (median [range] age, 59.0 [26.0-89.0] years; 132 [66.0%] women; 15 [7.5%] Asian, 11 [5.5%] African American, and 154 [77.0%] White participants) were enrolled: 159 (79.5%) in the BRCA1/2 cohort and 41 (20.5%) in the ATM cohort. The confirmed OR rate was 26.4% (42 patients, including 9 complete responses [5.7%]) in the BRCA1/2 cohort and 4.9% (2 patients) in the ATM cohort. In the BRCA1/2 cohort, responses were more frequent (OR rate, 30.3%; 95% CI, 22.2%-39.3%, including 8 complete responses [6.7%]) and more durable (median duration of response: 10.9 months [95% CI, 6.2 months to not estimable]) in tumor types associated with increased heritable cancer risk (ie, BRCA1/2-associated cancer types, such as ovarian, breast, prostate, and pancreatic cancers) and in uterine leiomyosarcoma (objective response in 3 of 3 patients and with ongoing responses greater than 24 months) compared with non-BRCA-associated cancer types. Responses in the BRCA1/2 cohort were numerically higher for patients with tumor mutational burden of 10 or more mutations per megabase (mut/Mb) vs less than 10 mut/Mb. The combination was well tolerated, with no new safety signals identified. Conclusions and Relevance: In this phase 2b nonrandomized controlled trial, neither the BRCA1/2 nor ATM cohort met the prespecified OR rate of 40%. Antitumor activity for the combination of avelumab and talazoparib in patients with BRCA1/2 alterations was observed in some patients with BRCA1/2-associated tumor types and uterine leiomyosarcoma; benefit was minimal in non-BRCA-associated cancer types. Trial Registration: ClinicalTrials.gov Identifier: NCT03565991.

Phase Ia/b, Open-Label, Multicenter Study of AZD4635 (an Adenosine A2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors.

PURPOSE: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor-naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non-small cell lung cancer with prior anti-PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti-PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75-200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC. RESULTS: As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks. CONCLUSIONS: AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC.

Targeting Doublecortin-Like Kinase 1 (DCLK1)-Regulated SARS-CoV-2 Pathogenesis in COVID-19.

Host factors play critical roles in SARS-CoV-2 infection-associated pathology and the severity of COVID-19. In this study, we systematically analyzed the roles of SARS-CoV-2-induced host factors, doublecortin-like kinase 1 (DCLK1), and S100A9 in viral pathogenesis. In autopsied subjects with COVID-19 and pre-existing chronic liver disease, we observed high levels of DCLK1 and S100A9 expression and immunosuppressive (DCLK1+S100A9+CD206+) M2-like macrophages and N2-like neutrophils in lungs and livers. DCLK1 and S100A9 expression were rarely observed in normal controls, COVID-19-negative subjects with chronic lung disease, or COVID-19 subjects without chronic liver disease. In hospitalized patients with COVID-19, we detected 2 to 3-fold increased levels of circulating DCLK1+S100A9+ mononuclear cells that correlated with disease severity. We validated the SARS-CoV-2-dependent generation of these double-positive immune cells in coculture. SARS-CoV-2-induced DCLK1 expression correlated with the activation of ß-catenin, a known regulator of the DCLK1 promoter. Gain and loss of function studies showed that DCLK1 kinase amplified live virus production and promoted cytokine, chemokine, and growth factor secretion by peripheral blood mononuclear cells. Inhibition of DCLK1 kinase blocked pro-inflammatory caspase-1/interleukin-1ß signaling in infected cells. Treatment of SARS-CoV-2-infected cells with inhibitors of DCLK1 kinase and S100A9 normalized cytokine/chemokine profiles and attenuated DCLK1 expression and ß-catenin activation. In conclusion, we report previously unidentified roles of DCLK1 in augmenting SARS-CoV-2 viremia, inflammatory cytokine expression, and dysregulation of immune cells involved in innate immunity. DCLK1 could be a potential therapeutic target for COVID-19, especially in patients with underlying comorbid diseases associated with DCLK1 expression. IMPORTANCE High mortality in COVID-19 is associated with underlying comorbidities such as chronic liver diseases. Successful treatment of severe/critical COVID-19 remains challenging. Herein, we report a targetable host factor, DCLK1, that amplifies SARS-CoV-2 production, cytokine secretion, and inflammatory pathways via activation of ß-catenin(p65)/DCLK1/S100A9/NF-κB signaling. Furthermore, we observed in the lung, liver, and blood an increased prevalence of immune cells coexpressing DCLK1 and S100A9, a myeloid-derived proinflammatory protein. These cells were associated with increased disease severity in COVID-19 patients. Finally, we used a novel small-molecule inhibitor of DCLK1 kinase (DCLK1-IN-1) and S100A9 inhibitor (tasquinimod) to decrease virus production in vitro and normalize hyperinflammatory responses known to contribute to disease severity in COVID-19.

Reversible HER2 antibody-drug conjugate-induced ocular toxicity.

PURPOSE: To report 3 cases of reversible epitheliopathy induced by A166-a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate (ADC) therapy for resistant HER2 tumours. METHODS: Advanced HER2 tumour patients were enrolled in A166 phase I/II clinical trial using Bayesian logistic regression model dose escalation. Key exclusion criteria were ≥grade 2 (G2) corneal pathology, severe organ disease, and other cancer therapy within 4 weeks. Eye exams were performed at baseline, regularly scheduled intervals, and additionally upon A166-induced ocular symptoms. Topical therapy with autologous serum tears (ASTs) was implemented based on visual acuity, symptoms, and slit lamp exam. A166 was withheld if ≥G2 ocular toxicity developed; if status improved to ≤G1, A166 therapy was resumed. Visual acuity, corneal exam, and subjective comfort were recorded. RESULTS: After ≥2 cycles of A166, 6 eyes of 3/23 enrolled patients developed whorl pattern epitheliopathy suggestive of limbal stem cell (LSC) dysfunction requiring cessation of A166 despite positive tumour response. Patients 1 and 3 received 3.6 mg/kg A166 dose, and patient 2 received 3.0 mg/kg. Topical steroids (2/4 eyes) failed to improve epitheliopathy. Adding ASTs improved vision, ocular comfort, and whorl pattern epitheliopathy in 6/6 eyes within 3 weeks. Patient 1 continues to improve on ASTs; patient 2 withdrew from the study; and patient 3 resumed A166 therapy. CONCLUSION: A166 precipitates LSC dysfunction-like epitheliopathy. Combination therapy including aggressive lubrication, withholding drug, and ASTs help reverse toxicity. Recognizing that ADC-induced epitheliopathy can respond to ocular management may enable cancer patients to continue lifesaving therapy.

A Phase 1a/b Open-Label, Dose-Escalation Study of Etigilimab Alone or in Combination with Nivolumab in Patients with Locally Advanced or Metastatic Solid Tumors.

PURPOSE: TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) is a co-inhibitory receptor of T-cell and natural killer cell activity. Targeting TIGIT with or without PD-1/PD-L1 checkpoint inhibition may enhance antitumor immunity. PATIENTS AND METHODS: This Phase 1a/b trial was a first-in-human, open-label, multicenter, dose-escalation and -expansion study in patients with locally advanced or metastatic solid tumors. Using 3 + 3 design, patients underwent 14-day treatment cycles with anti-TIGIT antibody etigilimab alone (Phase 1a; 0.3, 1.0, 3.0, 10.0, 20.0 mg/kg intravenously) or in combination with anti-PD-1 antibody nivolumab (Phase 1b; 3.0, 10.0, 20.0 mg/kg etigilimab and 240 mg nivolumab). Primary objective was safety and tolerability. RESULTS: Thirty-three patients were enrolled (Phase 1a, n = 23; Phase 1b, n = 10). There were no dose-limiting toxicities (DLT). MTD for single and combination therapy was not determined; maximum administered dose was 20 mg/kg. The most commonly reported adverse events (AE) were rash (43.5%), nausea (34.8%), and fatigue (30.4%) in Phase 1a and decreased appetite (50.0%), nausea (50.0%), and rash (40%) in Phase 1b. Six patients experienced Grade ≥3 treatment-related AEs. In Phase 1a, 7 patients (30.0%) had stable disease. In Phase 1b, 1 patient had a partial response; 1 patient had prolonged stable disease of nearly 8 months. Median progression-free survival was 56.0 days (Phase 1a) and 57.5 days (Phase 1b). Biomarker correlative analyses demonstrated evidence of clear dose-dependent target engagement by etigilimab. CONCLUSIONS: Etigilimab had an acceptable safety profile with preliminary evidence of clinical benefit alone and in combination with nivolumab and warrants further investigation in clinical trials.

A Phase 1b Trial of Prexasertib in Combination with Standard-of-Care Agents in Advanced or Metastatic Cancer.

BACKGROUND: The checkpoint kinase 1 (CHK1) inhibitor prexasertib exhibited modest monotherapy antitumor activity in prior trials, suggesting that combination with chemotherapy or other targeted agents may be needed to maximize efficacy. OBJECTIVES: The aim of this study was to determine the recommended phase II dose and schedule of prexasertib in combination with either cisplatin, cetuximab, pemetrexed, or 5-fluorouracil in patients with advanced and/or metastatic cancer, and to summarize preliminary antitumor activity of these combinations. PATIENTS AND METHODS: This phase Ib, nonrandomized, open-label study comprised dose-escalation phase(s) with multiple sub-arms evaluating different prexasertib-drug combinations: Part A, prexasertib + cisplatin (n = 63); Part B, prexasertib + cetuximab (n = 41); Part C, prexasertib + pemetrexed (n = 3); Part D, prexasertib + 5-fluorouracil (n =8). Alternate dose schedules/regimens intended to mitigate toxicity and maximize dose exposure and efficacy were also explored in sub-parts. RESULTS: In Part A, the maximum tolerated dose (MTD) of prexasertib in combination with cisplatin (75 mg/m2) was declared at 80 mg/m2, with cisplatin administered on Day 1 and prexasertib on Day 2 of a 21-day cycle. The overall objective response rate (ORR) in Part A was 12.7%, and 28 of 55 evaluable patients (50.9%) had a decrease in target lesions from baseline. The most frequent treatment-related adverse events (AEs) in Part A were hematologic, with the most common being white blood cell count decreased/neutrophil count decreased, experienced by 73.0% (any grade) and 66.7% (grade 3 or higher) of patients. In Part B, an MTD of 70 mg/m2 was established for prexasertib administered in combination with cetuximab (500 mg /m2), both administered on Day 1 of a 14-day cycle. The overall ORR in Part B was 4.9%, and 7 of 31 evaluable patients (22.6%) had decreased target lesions compared with baseline. White blood cell count decreased/neutrophil count decreased was also the most common treatment-related AE (56.1% any grade; 53.7% grade 3 or higher). In Parts A and B, hematologic toxicities, even with the addition of prophylactic granulocyte colony-stimulating factor, resulted in frequent dose adjustments (> 60% of patients). In Part C, evaluation of prexasertib + pemetrexed was halted due to dose-limiting toxicities in two of the first three patients; MTD was not established. In Part D, the MTD of prexasertib in combination with 5-fluorouracil (label dose) was declared at 40 mg /m2, both administered on Day 1 of a 14-day cycle. In Part D, overall ORR was 12.5%. CONCLUSIONS: This study demonstrated the proof-of-concept that prexasertib can be combined with cisplatin, cetuximab, and 5-fluorouracil. Schedule was a key determinant of the tolerability and feasibility of combining prexasertib with these standard-of-care agents. Reversible hematologic toxicity was the most frequent AE and was dose-limiting. Insights gleaned from this study will inform future combination strategies for the development of prexasertib and next-generation CHK1 inhibitors. CLINICALTRIALS. GOV IDENTIFIER: NCT02124148 (date of registration 28 April 2014).

Preclinical Evaluation and Phase Ib Study of Prexasertib, a CHK1 Inhibitor, and Samotolisib (LY3023414), a Dual PI3K/mTOR Inhibitor.

PURPOSE: Prexasertib, a checkpoint kinase 1 inhibitor (CHK1), exhibited modest monotherapy antitumor activity in previous studies. Preclinical data were generated to support the clinical combination of prexasertib + samotolisib, a PI3K/mTOR inhibitor. PATIENTS AND METHODS: Prexasertib + samotolisib was first evaluated in triple-negative breast cancer (TNBC) cells, MDA-MB-231 orthotopic xenograft tumors, and TNBC patient-derived xenograft (PDX) mouse models. In the phase Ib trial, following dose escalation, the initial expansion arm (E1, solid tumors) explored prexasertib 105 mg/m2 intravenously every 14 days + samotolisib 200 mg orally twice daily. Subsequent expansion arms evaluated samotolisib 150 mg twice daily in patients carrying PIK3CA mutations (E2, solid tumors) or with TNBC (E3). Safety and antitumor activity were assessed. RESULTS: Prexasertib + samotolisib inhibited cell proliferation in TNBC lines and primary tumor growth in the MDA-MB-231 model. Prexasertib + samotolisib exhibited synergistic or additive effects in 30 of 38 PDX single-mouse ("n = 1") models, and provided rationale for clinical evaluation. In the phase Ib study, 53 patients were enrolled (escalation, n = 13; E1, n = 9; E2, n = 15; and E3, n = 16). No dose-limiting toxicities (DLT) were observed during escalation; however, DLT-equivalent toxicities were observed in E1, leading to samotolisib dose reduction (150 mg twice daily) in E2/E3. Common treatment-related adverse events were leukopenia/neutropenia (94.3%), thrombocytopenia (62.3%), and nausea (52.8%). During escalation, 2 patients achieved partial response for an overall response rate (ORR) of 15.4%, and ORRs were 13.3% for E2 (PIK3CA) and 25% for E3 (TNBC). CONCLUSIONS: Prexasertib + samotolisib showed antitumor activity in preclinical models and preliminary efficacy in heavily pretreated patients. The clinical combination was associated with toxicity, suggesting supportive measures may be required. However, these data may inform future trials using other CHK1 and PI3K pathway inhibitors.

Phase I and Preliminary Phase II Study of TRC105 in Combination with Sorafenib in Hepatocellular Carcinoma.

Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium.Experimental Design: Patients with HCC (Child-Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum.Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18-76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1-42.2], and 25% (95% CI, 8.7-49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2-5.6 months); median overall survival was 15.5 months (95% CI, 8.5-26.3 months).Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633-41. ©2017 AACR.

Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation. METHODS: Thirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36-76). Patients were given tremelimumab at two dose levels (3.5 and 10mg/kg i.v.) every 4weeks for 6 doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8weeks. RESULTS: No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1-51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8+ T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4months (95% CI 4.7 to 19.4months). Median overall survival was 12.3months (95% CI 9.3 to 15.4months). CONCLUSIONS: Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8+ T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load. LAY SUMMARY: Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation. CLINICAL TRIAL NUMBER: ClinicalTrials.gov: NCT01853618.

Pancreatic Squamous Cell Carcinoma: A Population-Based Study of Epidemiology, Clinicopathologic Characteristics and Outcomes.

OBJECTIVES: Squamous metaplasia is commonly detected in pancreatic parenchyma; however, primary pancreatic squamous cell carcinoma (SCC) is a rare malignancy with unknown incidence and unclear prognosis. METHODS: Surveillance, Epidemiology, and End Results (SEER) registries were examined identifying pancreatic SCC and adenocarcinoma cases from 2000 to 2012. Age-adjusted incidence rates were calculated. Patients with SCC versus adenocarcinoma were compared by clinical features and relative survival outcomes. RESULTS: We identified 214 patients with SCC and 72,860 with adenocarcinoma. For SCC, incidence rates tripled between 2000 and 2012. Significantly higher SCC incidence rates were observed in older age groups, blacks, and males. Greater proportion of patients with SCC than those with adenocarcinoma had poorly differentiated histology (73.0% vs 43.7%, P < 0.001). In both subtypes, majority of patients had stage IV disease, 59.0% for adenocarcinoma versus 62.6% for SCC. The 1- and 2-year relative survival rate was significantly lower in patients with SCC versus adenocarcinoma. The 1-year relative survival was 14.0% (95% confidence interval, 9.5%-19.4%) for SCC, compared with 24.5% (95% confidence interval, 24.2%-24.8%) for adenocarcinoma. CONCLUSIONS: Although primary pancreatic SCC is a rare neoplasm, incidence rates for this subtype are increasing. Relative to adenocarcinoma, pancreatic SCC is characterized by poorly differentiated histology and worse survival.

Population attributable fractions of risk factors for hepatocellular carcinoma in the United States.

BACKGROUND: Hepatocellular carcinoma (HCC) incidence has been increasing in the United States for several decades; and, as the incidence of hepatitis C virus (HCV) infection declines and the prevalence of metabolic disorders rises, the proportion of HCC attributable to various risk factors may be changing. METHODS: Data from the Surveillance, Epidemiology, and End Results-Medicare linkage were used to calculate population attributable fractions (PAFs) for each risk factor over time. Patients with HCC (n = 10,708) who were diagnosed during the years 2000 through 2011 were compared with a 5% random sample of cancer-free controls (n = 332,107) residing in the Surveillance, Epidemiology, and End Results areas. Adjusted odds ratios (ORs) and PAFs were calculated for HCV, hepatitis B virus (HBV), metabolic disorders, alcohol-related disorders, smoking, and genetic disorders. RESULTS: Overall, the PAF was greatest for metabolic disorders (32%), followed by HCV (20.5%), alcohol (13.4%), smoking (9%), HBV (4.3%), and genetic disorders (1.5%). The PAF for all factors combined was 59.5%. PAFs differed by race/ethnicity and sex. Metabolic disorders had the largest PAF among Hispanics (PAF, 39.3%; 95% confidence interval [CI], 31.9%-46.7%) and whites (PAF, 34.8%; 95% CI, 33.1%-36.5%), whereas HCV had the largest PAF among blacks (PAF, 36.1%; 95% CI, 31.8%-40.4%) and Asians (PAF, 29.7%; 95% CI, 25.9%-33.4%). Between 2000 and 2011, the PAF of metabolic disorders increased from 25.8% (95% CI, 22.8%-28.9%) to 36% (95% CI, 33.6%-38.5%). In contrast, the PAFs of alcohol-related disorders and HCV remained stable. CONCLUSIONS: Among US Medicare recipients, metabolic disorders contribute more to the burden of HCC than any other risk factor, and the fraction of HCC caused by metabolic disorders has increased in the last decade. Cancer 2016;122:1757-65. Published 2016. This article is a U.S. Government work and is in the public domain in the USA..