Patel, Manish R.

Abstract Purpose: VV1 is designed to induce selective oncolysis of tumor cells and amplify cellular antitumor immune responses. This open-label, phase I, multicenter clinical trial assessed the safety and tolerability of VV1 monotherapy administered intratumorally or intravenously or administered intravenously in combination with avelumab. Patients and Methods: Patients with advanced solid tumors received intratumoral (n = 27) or intravenous VV1 monotherapy (n = 33) or intravenous VV1 plus avelumab (n = 16). Infusion durations (15–180 minutes) and viral dose (1.7 × 1010 or 1 × 1011 TCID50) were also evaluated. Study objectives included VV1 safety and tolerability, pharmacokinetics, pharmacodynamics, preliminary efficacy, and immune responses. Results: Intratumoral and intravenous VV1 were well tolerated, and injection reactions were infrequent. The most common adverse events of any grade related to VV1 were cytokine release syndrome (58%), fatigue (33%), and decreased lymphocyte count (32%). Virus infection of tumors was confirmed by NIS imaging and increases in serum levels of virally encoded interferon-β (IFNβ). Histologic tumor analysis at 28 days after intratumoral VV1 administration indicated increases in tumor-infiltrating immune cells. Two durable partial responses were recorded: a patient with pheochromocytoma after one intravenous dose of VV1 and a patient with thymic cancer in the combination arm. Stable disease was observed in 17 of 49 patients (34.7%) who received intravenous VV1. Conclusions: This first-in-human study demonstrates that intratumoral or intravenous VV1 administration had an acceptable safety profile as monotherapy and intravenously in combination with avelumab. There is preliminary antitumor activity. Intratumoral VV1 plus cemiplimab is now showing promise in the neoadjuvant setting. Significance: VV1 is a tumor-selective oncolytic vesicular stomatitis virus engineered to express IFNβ and the thyroidal NIS reporter gene. In this phase I study, we have demonstrated that a single administration of VV1, as a monotherapy or with an immune checkpoint inhibitor is safe, infects tumor lesions resulting in intratumoral infiltration of immune cells, and exhibits early signs of antitumor activity in patients with advanced unresectable and metastatic solid tumors.

TPS9595 Background: There is a need for novel immunotherapies to address the patient population that never or no longer responds to immune checkpoint inhibitors (CPI). VV1 is an oncolytic vesicular stomatitis virus engineered to express human interferon beta (IFNβ) to enhance cellular anti-tumor immune responses and tumor selectivity. Phase 1 studies demonstrated VV1 anti-tumor activity in several malignancies with or without a CPI. We are exploring ways to optimize VV1 efficacy in combination with cemiplimab, an anti-PD1 antibody approved for lung, basal and squamous cell skin cancers. Recent clinical data support a 5-fold higher dose of VV1 than was previously explored, and pre-clinical data show synergy between the oncolytic and an anti-CTLA4 antibody, in addition to cemiplimab, supporting exploration of a triplet. What was originally a five-arm study of intravenous (IV) VV1 in combination with IV cemiplimab has been amended to focus on 2 means of optimizing efficacy: use of a higher dose of VV1 and triplet combination in proof-of-concept populations. Methods: We are now enrolling pts with advanced melanoma (after progression on anti-PD1) and plan to include 1 st -line NSCLC pts with PD-L1 expression ≥50%. The study is first exploring the preliminary anti-tumor activity, safety, and immunogenic activity of the combination of IV VV1 at a dose of 1.0 x 10 11 TCID 50 once on D1 followed by IV cemiplimab Q3W starting on D8, or the same regimen with an additional intratumoral injection of VV1 1.0 x 10 9 TCID 50 once on D1 for pts with accessible lesions. Pts receive IV cemiplimab Q3W until confirmed disease progression or intolerable toxicity. Once at least 6 pts have been treated with acceptable safety across the 2 melanoma doublet cohorts using this higher dose of VV1, a 3 rd melanoma cohort will open to add a single dose of ipilimumab 50 mg on D1 (all IV triplet). Once 6 melanoma pts have received the triplet safely, the 1 st -line NSCLC cohort will open. All cohort decisions are guided by a Data Review Committee. Cohorts will be expanded based on a Simon 2-stage design using a type I error rate of 0.05 and power of 85%. Null ORR is 10% with a target of 35% for 2 nd line melanoma and null ORR is 40% in 1 st line NSCLC with a target of 70%. Each melanoma cohort will require a response in ≥2 of 10 pts in the 1 st stage to add 11 more in the 2 nd stage, while NSCLC will first need 5/9 evaluable pts to respond, then an additional 13 to complete the design. Response is assessed at week 7 then Q9W per RECIST v1.1. The study includes serial biopsies in ≥3/10 pts in Stage 1 of each of the IV melanoma cohorts (doublet and triplet therapy), all pts in Stage 2 of these IV melanoma cohorts, and all pts in both Stage 1 and Stage 2 of the IV/IT melanoma cohort, to permit a thorough investigation of the impact of the 3 immunotherapies under investigation. The study is currently ongoing in the USA. Clinical trial information: NCT04291105.

Abstract Background It is unclear how acute coronavirus disease 2019 (COVID-19)-directed therapies are used in children with life-threatening COVID-19 in US hospitals. We described characteristics of children hospitalized in the intensive care unit or step-down unit (ICU/SDU) who received COVID-19-directed therapies and the specific therapies administered. Methods Between March 15, 2020 and December 27, 2020, children <18 years of age in the ICU/SDU with acute COVID-19 at 48 pediatric hospitals in the United States were identified. Demographics, laboratory values, and clinical course were compared in children who did and did not receive COVID-19-directed therapies. Trends in COVID-19-directed therapies over time were evaluated. Results Of 424 children in the ICU/SDU, 235 (55%) received COVID-19-directed therapies. Children who received COVID-19-directed therapies were older than those who did not receive COVID-19-directed therapies (13.3 [5.6-16.2] vs 9.8 [0.65-15.9] years), more had underlying medical conditions (188 [80%] vs 104 [55%]; difference = 25% [95% CI: 16% to 34%]), more received respiratory support (206 [88%] vs 71 [38%]; difference = 50% [95% CI: 34% to 56%]), and more died (8 [3.4%] vs 0). Of the 235 children receiving COVID-19-directed therapies, 172 (73%) received systemic steroids and 150 (64%) received remdesivir, with rising remdesivir use over the study period (14% in March/April to 57% November/December). Conclusion Despite the lack of pediatric data evaluating treatments for COVID-19 in critically ill children, more than half of children requiring intensive or high acuity care received COVID-19-directed therapies.

e18634 Background: Informed patients have better health outcomes. In a study of 1,057 patient encounters with 3,552 clinical decisions, only 9% resulted in informed medical decisions.The complexity of treatments and patients' limitations in health literacy (especially common in underserved communities) make it difficult for patients to engage in SDM. In 2017, A Breath of Hope Lung Foundation introduced An Animated Patient’s Guide to Lung Cancer (APG), an online resource aimed at improving patient knowledge. Methods: APG consists of animations, expert FAQ videos, slide shows, infographics, patient-experience videos, knowledge-assessment tools, and learner feedback. Video views, duration of use, and learner responses to multiple-choice questions on the APG website were collected for 33 months – through August 2020. Total APG views, most frequently viewed animations and expert videos were monitored on the website and on YouTube, to measure learner responses to outcome-based questions, and learner intent-to-implement changes. Results: 212,336 total views: 142,998 unique visitors: 59% from U.S. and 41% from 50 other countries. Unique U.S. visitors: 43,872 patients, 16,030 caregivers, and 7,593 health providers. 94% reported they will ‘use new information to better self-manage their lung cancer’ (n = 277); 98% ‘will discuss information learned with their doctor’ (n = 455), and 93% ‘plan to discuss treatment options with their doctor’ (n = 272). Conclusions: Multimedia ‘animated’ formats of learning tailored to the needs and learning styles of lung cancer patients provides effective learning, informed patients, increased management skills, and improved engagement in shared decision making.

TPS3161 Background: VV1 is an oncolytic vesicular stomatitis virus engineered to express human IFNβ to enhance cellular anti-tumor immune responses and tumor selectivity, and the human sodium iodide symporter (NIS) for virus tracking by SPECT imaging. Cancer cells are often hyporesponsive to IFNβ, enabling the efficient spread of VV1 and resulting in increased oncolysis. Differently from other oncolytic viruses, VV1 is suitable for both intra-tumoral (IT) and/or intra-venous (IV) administration. Despite considerable anti-tumor activity with checkpoint inhibitors (CPI) among some malignancies, long term survival and overall cures remain elusive. Prior Ph 1 studies have shown significant anti-tumor activity among several malignancies when VV1 was administered either as monotherapy or in combination with a CPI, despite progression on prior CPI monotherapy. Furthermore, pre- and post-treatment biopsy evaluations after VV1 treatment have demonstrated T cell infiltration and inflammation in both IT injected and non-injected lesions. Among IV treated patients (pts), IFNβ was detectable in the serum correlating with viral replication, making it an effective biomarker. C is a high-affinity potent human IgG4 anti-PD-1 monoclonal antibody. Though approved for use in cutaneous squamous cell carcinoma, C has shown anti-tumor activity, similar to other CPI, in several other indications. Therefore, VV1 and C could be an attractive combination for the immunotherapy for several solid tumors. This study represents the first clinical evaluation of VV1 in combination with C in pts with advanced solid tumors. Methods: The Ph 2 Simon 2 stage five-arm study of IV administration VV1 in combination with IV C will enroll pts with advanced NSCLC, HCC, melanoma & endometrial cancer. Enrolled pts with NSCLC & melanoma will be recent CPI-progressors, whereas enrolled HCC & endometrial cancer will be CPI-naïve. The study’s objectives include assessment of preliminary anti-tumor activity, safety, & immuno-regulatory activity of the combination. Pts will receive IV VV1 once on D1 and IV C once every 3 weeks until confirmed disease progression or intolerable toxicity. Pts enrolled in one melanoma cohort will also receive IT VV1 administered to palpable lesions. Response will be assessed every 9 weeks per RECIST v1.1. The null hypothesis of each cohort’s ORR will be tested versus a one-sided alternative yielding a Type I error rate of 5% and power of 80%. Cohorts will be expanded based on signal of activity. Clinical trial information: NCT .

3090 Background: VV1 (Voyager V1) is derived from VSV, an RNA virus with low human seroprevalence, engineered to replicate selectively in and kill human cancer cells. In Part 1 of this study, we demonstrated the safety of intratumoral VV1 and dose-response, using serum IFNβ as a biomarker; we observed viral replication in tumor and concomitant lymphocyte/neutrophil trafficking (SITC 2018). 2 other studies suggested greater efficacy and higher IFNβ levels with IV administration. Longer infusion durations were reported to mitigate infusion reactions (IRRs) for another oncolytic. Methods: We studied 3 different infusion durations of VV1 monotherapy at the recommended phase 2 IV dose (1.7 x 1010 TCID50) in patients with advanced solid tumors. Endpoints included safety, preliminary anti-tumor activity, viral titers, IFNβ PD and shedding. Patients received IV VV1 once on D1 and were monitored for DLT over 21 days with efficacy assessments every 6 weeks. IRRs were classified using Lee 2014 criteria for CRS as either constitutional symptoms only (G1) or involving hypotension (G2). Results: 18 patients were treated at 30, 60 and 180-minute durations (n = 7, 5 and 6, respectively). No DLTs, deaths or G3-4 related IRR AEs were observed. Most pts were female (67%), white (100%), with ECOG PS 0 (61%) and median 4 lines of prior systemic therapy (range 1-14) for colorectal (CRC; 56%), squamous cell carcinoma (11%), pheochromocytoma (11%), sarcoma (11%) or other (11%) cancers. The table shows results (number of patients) by infusion duration. Conclusions: There was no difference in safety between the 3 infusion durations, while efficacy and PD markers suggested better anti-tumor effect with 30-minute infusion. VV1 is safe for caregivers, with no viral shedding. Part 3 of this study will now treat CRC patients with VV1 in combination with a checkpoint inhibitor (avelumab). A 5-arm phase 2 basket study in combination with cemiplimab is proceeding with 30-minute infusions. Clinical trial information: NCT02923466 . [Table: see text]

e20600 Background: Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm of advanced NSCLC and SCLC. The populations in clinical trials generally were composed of patients (pts) with excellent performance status (PS), a minimal number of prior lines of therapy, and no history of (h/o) autoimmune disease (AD). The aim of this retrospective study was to investigate the predictors of survival in less fit and more heavily pretreated lung cancer pts at our institution. Methods: Medical records of lung cancer pts who started single-agent ICI from 2015 to 2018 were reviewed for data collection. Progression-free survival (PFS) and overall survival (OS) were compared by age, PS, smoking, PD-L1 expression, brain metastasis, prior lines of systemic therapy, h/o AD, and immune-related adverse events (irAE). Results: We included 150 pts who received at least 1 dose of nivolumab, pembrolizumab, or atezolizumab (median age 66, range 36-92, 56% female, 89% NSCLC, 97% stage 4, 13% never smoker, 34% ECOG ≥ 2, 37% ≥ 2 prior lines of therapy, 29% developed irAE). The overall response rate was 30% and clinical benefit rate 51% (3% CR, 27% PR, 21% SD). The median PFS was 3.7 months (m) overall and 12.3 m for those with ≥ 4 cycles of therapy. The median OS was 12.4 m overall and 26.0 m for those with ≥ 4 cycles. The median PFS and OS were not significantly different by age, PS, smoking, PD-L1, brain metastasis, prior lines of therapy, or h/o AD. The median OS was longer for pts with ECOG 0-1 than those ≥ 2 (14.6 vs 7.5 m, p < .001). The median PFS and OS for pts with irAE were longer compared to those without irAE (12.3 vs 2.6 m, p < .001 for PFS and 28.9 vs 9.1 m, p = .001 for OS). Multiple Cox regression analysis identified ECOG 0-1 (HR 0.54, p = .007) and irAE (HR 0.48, p = .003) to be independently associated with improved OS. 27 pts (18%) required steroids for irAE. There were no treatment-related deaths. Of 11 pts with h/o AD, only 1 experienced disease flare. Conclusions: The clinical benefit of ICIs persists in older or heavily pretreated pts. ECOG 0-1 and incident irAE predicted for improved survival. Survival for pts with ECOG ≥ 2 is very limited, suggesting ICIs should be used judiciously in this group. Therapy was well tolerated, with a low risk for flare of previous autoimmune disease.

Abstract Introduction Voyager-V1TM is derived from VSV, a bullet-shaped negative sense RNA virus with very low human seroprevalence; it is engineered to selectively replicate in and kill human cancer cells. Voyager-V1 encodes the human IFNβ gene to boost antitumoral immune responses and the thyroidal sodium iodide symporter NIS gene to permit noninvasive imaging of virus spread. FIH studies are underway via both IV and IT routes. Here we report safety and preliminary correlative data from the FIH IT study. Methods and objectives This is a classical 3+3 phase 1 design, using escalating single IT viral doses from 3 x 106 to 3 x 109 TCID50 into one target lesion. The primary objective is safety and tolerability, monitored by committee. Other objectives include PK by RT-PCR for viral genomes, serum IFNβ levels, Tc-99m SPECT/CT imaging to monitor virus infection in injected lesions, peripheral blood immunophenotyping with 11-color flow cytometry for activation markers on T cells, T-regs, NK cells, and MDSCs, and serial biopsies to assess the tumor microenvironment (TME). IHC was performed on tumor biopsies for CD3, CD8, CD4, FoxP3, CD68, PD-1 and PDL-1 pre and post treatment in non-injected and injected lesions. CD45 staining is ongoing. Results Dose level 3 is ongoing (n=8+). No DLTs have been observed to date. Most patients were male (75%), white (100%), with ECOG PS1 (75%) and a median of &gt;6 lines of prior systemic therapy. AEs (in 63% patients) reported as related to study drug were mild-moderate, short-lived, and consisted of G1 fever, chills, hot flashes, nausea, vomiting, hyperhidrosis and G2 fatigue. Most patients had some mild AEs (pain, bruising, subclinical pneumothorax) related to biopsy and IT injection procedures and one had an SAE related to biopsy (G2 pneumothorax). There was no difference in incidence, intensity or duration of related AEs between dose levels so far. In patients analyzed to date, at the first three dose levels of 3 x 106, 1 x 107 and 3 x 107 TCID50 (n=7), viremia and serum IFNβ were below levels of detection after IT injection. There is evidence in all patients of an increase in PD-1 expression on CD4 and CD8 T cells, suggesting T cell activation post- single virus injection. One patient at dose level 2 had increased CD4 and CD8 T cells in the peripheral blood. TME analysis revealed increased infiltration of CD3 and CD8 cells in tumors of some patients. In addition, there are changes in numbers of FoxP3 and CD68 positive cells in the injected lesions compared to the pre-treatment and non-injected lesion. Two patients at dose level 3, one with an injected adrenal metastasis of colorectal cancer and another with a chest wall lesion from a head of pancreas primary, have positive SPECT/CTs on days 3-15 showing viral replication in tumor plus concomitant lymphocyte/neutrophil trafficking in the periphery. Conclusions IT injection of a single dose of the novel oncolytic virotherapy Voyager-V1 has proven safe at doses up to 3 x 107 TCID50. There was evidence of T cell activation with increased PD-1 expression in peripheral blood lymphocytes after a single IT injection. Tumor biopsies indicate increased lymphocyte infiltration. Two patients at the highest dose tested show signs of viral replication in the injected lesion plus evidence of systemic impact on leukocyte populations. Citation Format: Steven Powell, Manish R. Patel, Jaime R. Merchan, Timothy P. Cripe, James Strauss, Rosa M. Diaz, Nandakumar Packiriswamy, Bethany A. Brunton, Deepak Upreti, Rehan Khan, Lukkana Suksanpaisan, Rianna Vandergaast, Stephen J. Russell, Alice S. Bexon, Kah Whye Peng. Preliminary correlative and clinical data from a first-in-human (FIH) study of the intratumoral (IT) oncolytic virotherapy, Voyager-V1, in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT051.