Patients with cancer are presumed to be at increased risk from COVID-19 infection–related fatality due to underlying malignancy, treatment-related immunosuppression, or increased comorbidities. A total of 218 COVID-19–positive patients from March 18, 2020, to April 8, 2020, with a malignant diagnosis were identified. A total of 61 (28%) patients with cancer died from COVID-19 with a case fatality rate (CFR) of 37% (20/54) for hematologic malignancies and 25% (41/164) for solid malignancies. Six of 11 (55%) patients with lung cancer died from COVID-19 disease. Increased mortality was significantly associated with older age, multiple comorbidities, need for ICU support, and elevated levels of D-dimer, lactate dehydrogenase, and lactate in multivariate analysis. Age-adjusted CFRs in patients with cancer compared with noncancer patients at our institution and New York City reported a significant increase in case fatality for patients with cancer. These data suggest the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population. Significance: COVID-19 in patients with cancer is associated with a significantly increased risk of case fatality, suggesting the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population. This article is highlighted in the In This Issue feature, p. 890

Purpose: Intratumorally injected Clostridium novyi-NT (non-toxic; lackingthe alpha toxin), an attenuated strain of C.novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. Experimental design: This first-in-humanstudy (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection ofC. novyi-NTacross 6 dose cohorts (1x10⁴to 3x10⁶spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLTs), and the maximum tolerated dose (MTD). Results: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1x10⁶spores) was defined as the MTD; DLTs were grade 4 sepsis (n=2) and grade 4 gas gangrene (n=1), all occurring in 3 patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathological fracture (n=1), limb abscess (n=1), soft tissue infection (n=1), respiratory insufficiency (n=1), and rash (n=1), which occurred across 4 patients. Of 22 evaluable patients, 9 (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. Conclusions: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of anti-tumor activity and the host immune response support additional studies of C. novyi-NT in humans.

PURPOSE: We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by MDM2 and MDMX to induce cell cycle arrest or apoptosis in TP53 wild-type tumors. METHODS: Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and anti-tumor effects in patients with solid tumors or lymphomas: In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B, was twice-weekly for 2 weeks every 21 days. RESULTS: Seventy-one patients were enrolled: 41 in arm A (0.16-4.4 mg/kg), 30 in arm B (0.32-2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLTs) were Grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the maximum tolerated dose in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; three discontinued treatment. In 41 efficacy-evaluable patients with TP53 wild-type disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, two had confirmed partial responses, 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg. CONCLUSION: ALRN-6924 was well tolerated and demonstrated anti-tumor activity.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN^®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC.

Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials.Significance: Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access.This article is highlighted in the In This Issue feature, p. 1426