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9553 Background: RP1 is an enhanced potency oncolytic version of HSV1 that expresses human GM-CSF and the fusogenic protein GALV-GP R-. IGNYTE is a multicohort phase 1/2 study that evaluates the safety and efficacy of RP1 in combination with nivo (NCT03767348) in a range of tumor types. Preliminary data demonstrated a durable anti-tumor activity and tolerability for RP1+nivo. Here, we present updated results from the initial and melanoma (mel) and anti-PD1 naïve non-melanoma skin cancer (NMSC) cohorts with RP1+nivo. Methods: RP1 is administered via intratumoral injection Q2W, up to 10 mL/visit, first alone at a dose of 106 PFU/mL and then starting with the 2nd dose at 107 PFU/mL in combination with nivo (240 mg IV Q2W for 4 months (mos) then 480 mg IV Q4W up to 2 yrs) for up to 8 doses, with the option to re-initiate RP-1. Eligible patients (pts) must have at least one measurable & injectable tumor of ≥ 1 cm, ECOG 0-1, and no prior oncolytic therapy. For mel, both anti-PD1 naïve and failed pts were eligible, for NMSC pts who were anti-PD1 naïve. Results: As of data extraction on January 31, 2022, 13/36 pts with mel (36.1%) and 19/31 pts with NMSC (61.3%) had a best response of PR or CR. For mel this was 5/8 (62.5%), 6/16 (37.5%), 0/6 and 2/6 (33.3%) for pts with anti-PD1 naïve cutaneous, anti-PD1/anti-PD1+anti-CTLA-4 failed cutaneous, uveal and mucosal mel respectively. For the anti-PD1 naïve NMSC this included 11/17 (64.7%), 1/4 (25%), 3/4 (75%) and 4/6 (66.6%) patients with CSCC, BCC, MCC and angiosarcoma respectively, including 8/17 (47.1%) being CR for CSCC. Current immature median DOR was 13.27 mos (current range 3.67-16.93 mos) for mel, and 7.32 mos (current range 1.88-23.11mos) for anti-PD1 naïve NMSC. Any grade TEAE ( > 25%) in all cohorts combined were fatigue, nausea, pyrexia, chills, diarrhoea, pruritus, and influenza-like illness. TEAE ≥grade 3 ( > 5%) were disease progression and fatigue. No deaths related to RP1 was observed, with one death related to nivo (myocarditis). Biomarker data from paired biopsies indicated robust T cell infiltration and an increase in tumor inflammation gene signature post-treatment. Clinical responses observed were independent of baseline tumor PD-L1 expression status. Conclusions: RP1 in combination with nivo provides a durable anti-tumor activity in pts with skin cancers, including anti-PD1 failed and anti-PD1/anti-CTLA-4 failed mel. The combination continued to be generally well tolerated with no new safety signals identified. Based on this data, enrollment into both a registration-directed cohort of pts who have anti-PD1 failed cutaneous mel (n = 125) and a cohort of pts with anti-PD1 failed NMSC (n = 30) is ongoing. Up-to-date data from this ongoing trial will be reported at the conference. A randomized Ph2 trial of RP1+cemiplimab vs. cemiplimab alone in anti-PD1 naïve NMSC is also underway (NCT04050436). Clinical trial information: NCT03767348.

6087 Background: Few effective drug therapies exist for patients with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). Mutations in genes encoding chromatin remodelling proteins are described in almost 50% of ACC patients (pts). Novel drug therapies are being developed to target these pathways, and may have clinical utility in this sub-group. We sought to classify mutations in chromatin remodelling genes in ACC based on predicted pathogenicity and to determine the impact of chromatin remodelling dysregulation (CRD) on clinical outcomes. Methods: Matched clinical-genomic data from 269 pts with non-resectable or R/M ACC were included in this study. 130 pts were prospectively recruited to an ethically approved study. For these pts, DNA extracted from FFPE tissue was sequenced on a commercially available platform to detect point mutations, indels and copy number variation in 324 genes. In addition, clinical-genomic data from 139 ACC pts were collected from cBioPortal (MetTropism, Cell 2021) for analysis. Mutations were classified as pathogenic using COSMIC, ClinVar and OncoKB. Univariate survival analysis was performed to determine the impact of one or more mutations in chromatin remodelling genes on survival from first recurrence or metastasis. p values determined using Kaplan-Meier and log-rank. Results: In 269 pts with non-resectable or R/M ACC, mutations promoting CRD were identified in ARID1A (11%), CREBBP (5%), EP300 (5%), KMT2C (1%), KMT2D (5%), KDM6A (13%), and SETD2 (3%). CRD mutations were identified in 94/269 (35%) pts, with 27/269 (10%) having 2 or more CRD mutations. For patients in whom CRD mutations were present survival from recurrence was decreased (median OS 4.6 v 8.2 years, HR 1.65 (95% confidence interval (CI) 1.13-2.40), p = 0.01). Analysis of each individual CRD gene identified that association with decreased survival from recurrence was significant for mutations in KDM6A (n = 35; median OS 4.2 vs 6.5 years; HR 2.01 (95% CI 1.25-3.22); p = 0.004), CREBBP (n = 11; median OS 4.2 vs 5.9 years; HR 2.97 (95% CI 1.20-7.38); p = 0.019) and SETD2 (n = 7; median OS 3.7 vs 5.9; HR 2.47 (95% CI 1.002-6.09); p = 0.042). Previous studies have identified NOTCH pathway activation and TP53 loss-of-function as prognostic. In a secondary analysis of pts without NOTCH activation and/or TP53 mutations (n = 202), OS from recurrence was decreased in those with CRD mutations (n = 58 median OS 5.7 vs 9.2 years, HR 1.5 (CI 95% 0.95-2.55), p = 0.07). Conclusions: We have identified a novel prognostic group of ACC pts characterised by mutations promoting CRD, which may have potential therapeutic options. Alterations in EP300/CREBBP/ARID1A may provide a rationale for treatment with CREBBP/EP300 inhibitors currently in clinical development. Significant co-occurrence with NOTCH gain of function may provide a rationale for future combination studies.

TPS2705 Background: RP3 is a genetically modified herpes simplex virus 1 (HSV-1) that contains insertions for the gibbon ape leukemia virus surface glycoprotein (GALV-GP) with the R- sequence deleted (R-), an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule, CD40 ligand, and 4-1BB ligand. Together, these insertions are expected to increase oncolytic potency, cell-to-cell spread, immunogenic cell death, and systemic immune activation. RP3 has demonstrated antitumor activity in preclinical models using viruses similar to RP3 expressing murine versions of anti-CTLA-4, CD40L, and 4-1BBL both alone and in combination with PD1-1 blockade. Methods: This is an open-label, multicenter, Phase 1 study evaluating RP3 as monotherapy or in combination with nivolumab (nivo) in patients (pts) with solid tumors (NCT04735978). Part 1 evaluated escalating doses of RP3. Pts in Part 1 received IT injections of up to 10 mL RP3 into superficial, nodal, or visceral lesions Q2W x 5 across two dose levels (DL1: 105 plaque-forming units (PFU)/mL once, then 106 PFU/mL x 4; DL2: 106 PFU/mL once, then 107 PFU/mL x4). The RP2D is 106 PFU/mL once, followed by 107 PFU/mL IT Q2W. In Part 2, pts are being enrolled into expansion cohorts of 45 patients with GI (including HCC), lung, breast, and squamous cell carcinoma of the head and neck treated with RP1 combined with nivo. Additional cohorts will enroll patients treated with RP3 followed by nivo, RP3 monotherapy to further explore biomarkers in injected and uninjected tumors, and with the potential to also open a cohort in melanoma. Pts in both Part 1 and Part 2 may receive up to 8 additional doses of RP3 if protocol-specified criteria are met. Key inclusion criteria: confirmed advanced or metastatic non-neurological solid tumors, at least one measurable tumor ≥ 1 cm and injectable tumors ≥ 1 cm in aggregate, ECOG ≤1, and adequate hematologic, hepatic, and renal function. In Cohorts 1, 2, and 4, approximately 50% of the pts with lung, breast, and GI cancer must have liver lesions intended for injection. Exclusion criteria include prior oncolytic virus treatment, need for immunosuppressive therapy, an autoimmune disease requiring systemic therapy, active significant herpetic infections or prior complications of HSV-1 infection, active or chronic HBV or HCV infection, known HIV infection, or prior active malignancy within 3 years. Clinical trial information: NCT04735978.

TPS2704 Background: RP2 is a selective replication-competent herpes simplex virus 1 (HSV-1) that contains a codon-optimized sequence for human granulocyte-macrophage colony-stimulating factor (GM-CSF), the gibbon ape leukemia virus surface glycoprotein (GALV-GP) with the R- sequence deleted (R-), GM-CSF, and an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule. These modifications are intended to increase oncolytic potency, cell-to-cell spread, tumor antigen release, and systemic anti-tumor immune activation. RP2 has demonstrated antitumor activity in preclinical models using viruses similar to RP2 expressing murine versions of anti-CTLA-4 and GM-CSF, both alone and in combination with PD1-1 blockade. Methods: This is a Phase 1 multicenter, open-label, study evaluating RP2 ± nivolumab (NCT04336241). Part 1 evaluated escalating doses of monotherapy RP2 with a modified 3 + 3 design. Patients (pts) received intratumoral (IT) injections of up to 10 mL of RP2 into superficial or visceral tumors Q2W x5 across two dose levels (DL1: 105 plaque-forming units (PFU)/mL once, then followed by 106 PFU/mL x4; DL 2: 106 PFU/mL once, then followed by 107 PFU/mL x4). The recommended Phase 2 dose of RP2 was identified as 106 PFU/mL once, followed by subsequent doses of 1 × 107 PFU/mL. In Part 2, up to 60 evaluable pts will be enrolled, including 30 pts in Cohort 2a and 30 in Cohort 2b. Cohort 2a was designed to evaluate the safety and antitumor activity of the combination in pts with solid tumors, and is fully enrolled. Cohort 2b is open for enrollment of pts with advanced or metastatic uveal melanoma, NSCLC, breast cancer, head and neck cancer or GI cancers (NSCLC, breast or GI cancers must have at least one liver tumor suitable for injection). Pts in Part 2 receive intra-tumoral RP2 at the RP2D Q2W for up to 8 doses in combination with 240 mg nivolumab IV Q2W or 480 mg nivolumab IV Q4W for up to two years from the first RP2 dose. In Part 3 (not yet open for enrollment), up to 15 evaluable pts are able to be enrolled to evaluate RP2 monotherapy including at least 10 pts with NSCLC, breast or GI cancers with at least one liver tumor suitable for injection. Reinitiation of up to 8 additional RP2 doses is permitted if prespecified criteria are met. Pts are dosed with RP2 by direct visualization or ultrasound-guided injection into superficial, subcutaneous, or nodal tumors and by image-guided injection into deeper lesions, including visceral lesions. Key inclusion criteria include histologically confirmed advanced or metastatic non-neurological solid tumors, at least one measurable and injectable tumor of diameter ≥1 cm, ECOG ≤1, and adequate hematologic, hepatic, and renal function. Exclusion criteria include prior treatment with oncolytic viruses, acute or chronic hepatitis B or C infection, and HIV infections. Clinical trial information: NCT04336241.