Q3 Weeks Research Articles

OTHR-14. PROFILE & OUTCOME OF BRAIN TUMORS IN THE YOUNG CHILDREN < 3YEARS OF AGE: EXPERIENCE FROM A TERTIARY CANCER CENTER IN INDIA

Abstract During the 5 year period from 1st January 2009- 31st December 2013, 33 children< 3 years age presented with brain tumor (7.56 % of all brain tumors among in children aged 0-14 years) . 54.5% were boys. Vomiting(69.7%) ataxia(36%) & head ache(24%) were the most common symptoms. Common histology included Medulloblastoma (36%) , Astrocytoma ( 21%) & Ependymoma ( 18%).Others included ATRT, glioma, ganglioglioma, PNET, Pineoblastoma & choroid plexus carcinoma. 63% were infratentorial & 37% were supratentorial. 58% had gross total resection & 36% had residual disease post surgery .64% of children received chemotherapy with baby brain protocol consisting of Inj VCR 0.06mg/kg IV - D1 &Inj Cyclophosphamide 50mg/kg IV infusion D1 (Cycle A) alternating with Inj CDDP 4m/kg as IV infusion D1&Inj Etoposide 6.5mg/kg IV infusion D1-3( Cycle B) as A – A – B Q3 weeks followed by definitive RT at completion of 3 years or earlier if they relapse on chemotherapy . At a median follow up of 34 months ( ( 2 mo- 106 mo ) 3 year RFS & OS were 20% & 56% respectively. OS was better for Ependymoma ( 100%) & Astrocytoma (80%) compared to (56% )for Medulloblastoma.

Efficacy and safety of nivolumab for patients with pre-treated type B3 thymoma and thymic carcinoma: results from the EORTC-ETOP NIVOTHYM phase II trial

Thymic malignancies are rare intrathoracic tumors, which may be aggressive and difficult to treat. They represent a therapeutic challenge in the advanced/metastatic setting, with limited treatment options after the failure of first-line platinum-based chemotherapy. They are frequently associated with autoimmune disorders that also impact oncological management. NIVOTHYM is an international, multicenter, phase II, two-cohort, single-arm trial evaluating the activity and safety of nivolumab [240 mg intravenously (i.v.) q2 weeks] alone or with ipilimumab (1 mg /kg i.v. q6 weeks) in patients with advanced/relapsed type B3 thymoma or thymic carcinoma, after exposure to platinum-based chemotherapy. The primary endpoint is progression-free survival rate at 6 months (PFSR-6) based on RECIST 1.1 as per independent radiological review. From April 2018 to February 2020, 55 patients were enrolled in 15 centers from 5 countries. Ten patients (18%) had type B3 thymoma and 43 (78%) had thymic carcinoma. The majority were male (64%), and the median age was 58 years. Among the 49 eligible patients who started treatment, PFSR-6 by central review was 35% [95% confidence interval (CI) 22% to 50%]. The overall response rate and disease control rate were 12% (95% CI 5% to 25%) and 63% (95% CI 48% to 77%), respectively. Using the Kaplan-Meier method, median progression-free survival and overall survival by local assessment were 6.0 (95% CI 3.1-10.4) months and 21.3 (95% CI 11.6-not estimable) months, respectively. In the safety population of 54 patients, adverse events (AEs) of grade 1/2 were observed in 22 (41%) patients and grade 3/4 in 31 (57%) patients. Treatment-related AEs of grade 4 included one case of neutropenia, one case of immune-mediated transaminitis, and two cases of myocarditis. Nivolumab monotherapy demonstrated an acceptable safety profile and objective activity, although it has been insufficient to meet its primary objective. The second cohort of NIVOTHYM is currently ongoing to assess the combination of nivolumab plus ipilimumab.

IMRT followed by pembrolizumab in the adjuvant setting in anaplastic cancer of the thyroid (IMPAACT): Phase II trial adjuvant pembrolizumab after IMRT in ATC.

TPS6117 Background: Anaplastic thyroid carcinoma (ATC) has historically been an almost uniformly rapidly fatal disease. In patients with loco-regional disease with no distant metastasis (stage IVB), and without a targetable mutation, a combination of external beam radiation delivered via intensity modulated techniques (IMRT) +/- concurrent cytotoxic chemotherapy is the current standard of care. However, the relapse rate is very high within the first year of diagnosis. Our data show that 90% of ATCs express PD-L1, with 43% having expression levels greater than 50%. A clinical trial with an anti-PD1 drug in ATC patients with active disease showed that patients with ATC had a response rate of 19%. Additionally, as tumor PD-L1 expression has been linked to radioresistance and there is a need to target micrometastatic disease, using adjuvant checkpoint inhibitor is a rational strategy in these patients. Methods: This is an open label, single center, phase 2 trial of adjuvant pembrolizumab after external beam radiation to the primary tumor in patients with stage IVB ATC. The primary cohorts will include those with gross, locoregional disease who have completed treatment with IMRT +/- concurrent radiosensitizing chemotherapy. Patients will be treated with adjuvant pembrolizumab (400mg IV Q6 weeks for up to 9 cycles), 2-6 weeks after completion of radiation. Patients will be enrolled based on dose of radiation in cohort 1 (high dose group, > 51 Gy), cohort 2 (palliative dose group, < 50 Gy). Cohort 3, consisting of those who underwent surgery followed by IMRT plus concurrent chemotherapy will be an exploratory cohort. Restaging scans will be performed every 12 weeks after enrollment. MRI brain will be repeated every 6 months in the absence of evidence of progression. The primary endpoint is median PFS (from the start of adjuvant pembrolizumab) in cohorts 1 and 2. Secondary endpoint is median overall survival in cohorts 1 and 2. Cohort 3 (5 patients) will have an exploratory endpoint, to estimate the median disease-free survival (DFS). Statistics: Survival analyses will be performed using the Kaplan-Meier method. Based on historical data, the median PFS for unresected patients is 6.8 months. For an expected improvement of median PFS by 3.7 months, with a combined total of 30 evaluable patients in cohorts 1 and 2, we anticipate having 80.0% power using 1-sided 10% alpha for a one-sample log rank test. The trial began enrollment in July 2022. This trial is sponsored by philanthropic funds and Merck. ClinicalTrials.gov ID NCT05059470. Clinical trial information: NCT05059470 .

Dual PD1 and CTLA4 immune checkpoint blockade and hypofractionated radiation in patients with salivary gland cancers.

6011 Background: No systemic therapy standard of care exists for recurrent/metastatic malignancies of the salivary glands (SGC) and immune checkpoint inhibitors (ICIs) have low response rates. Preclinical data in solid tumors suggest syngergistic antitumor effects of ICIs with hypofractionated radiation (XRT). This study explored the safety and activity of nivolumab (N) and ipilimumab (I)with palliative XRT. Methods: This phase I/II open label single arm trial enrolled patients (pts) with incurable SGCs (WHO 2017) with evidence of progression, ECOG 0-1, no prior antiPD1 or CTLA4 directed therapy, RECIST 1.1 measurable disease excluding the XRT site. Pts received N 3mg/kg IV Q 2 weeks x 12 doses followed by 480 mg IV Q4 weeks x 8 doses and I 1 mg/kg IV Q6 weeks x 4 doses. XRT was given to a total dose of 24Gy in 3 fractions every other day over 1 week (wk) and initiated 2 wks after the first dose of N and I. Research blood collection was obtained prior to wks 1, 8 and 16. The primary endpoint was safety and tolerability using CTCAE v. 4, secondary endpoints were objective response rates (ORR) by RECIST 1.1 criteria in non-radiated sites of measurable disease, overall survival (OS) and progression free survival (PFS). The study was approved by the FHCC IRB and registered on clinicaltrials.gov (NCT03749460). Results: Between 4/2019 and 5/2022, 20 pts were enrolled, the median age was 58 (range 27-77) years, 10 (50%) were male, 12 (60%) had ECOG 0, and 7 (35%) were Asian. Most common histologies were adenoid cystic 9 (45%) and salivary duct 4 (20%), 15 (75%) had no prior systemic therapy. Ten (50%) had both local and distant disease, 14 (70%) had commercial NGS testing, all had TMB < 10mut/Mb, MSI-stable tumors. All patients completed XRT with the most common XRT site being the lung 13(65%) and bone 7(35%). The median number of N doses received was 12 (range 3-20) and I doses 4 (range 1-4). Enrollment was halted until first 6 pts were assessed for dose limiting toxicities during initial 12 wks of treatment, none were observed. Among all pts enrolled, 5 (20%) Grade 3 AEs were observed: adrenal insufficiency, hypokalemia , lung infection, hypotension, and mania. No grade 4/5 toxicities were observed. One pt was not evaluable for RECIST 1.1 due to rapid disease progression: partial responses were observed in 4 (20%: 2 pts with salivary duct, 1 acinic cell and 1 adenoid cystic) with a median duration of 15.5 months (mos) (range 6-16 mos), stable disease in 6 (30%) all lasting 6 mos or greater, and progressive disease in 9 (45%). With a median follow-up of 16 mos, median OS was 25 mos (95% CI: [1.56, 2.59]) and median PFS was 7.2 mos (95% CI: [0.21, 1.56]). Exploratory correlative peripheral blood analysis is ongoing and will be reported. Conclusions: Nivolumab/ipilimumab and palliative XRT results in low rates of severe toxicities, modest ORR but durable ORR/SD. Further work is necessary to explore predictors for response. Clinical trial information: NCT03749460 .

Interim results of a phase 2 study using talimogene laherparepvec, nivolumab, and trabectedin for advanced leiomyosarcoma.

11556 Background: Intratumoral injection of Talimogene Laherparepvec (TVEC) has a local oncolytic effect and evokes a cytotoxic immune response. The combination of Trabectedin (T) and Nivolumab (N) is a safe and effective therapy in soft tissue sarcoma (STS). This study aims to determine the safety and efficacy of adding TVEC to the combination of T and N in advanced leiomyosarcoma (LMS). Methods: Objectives: Primary: To assess progression-free survival (PFS). Secondary: (1) To evaluate the best overall response, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 9, and 12 months, (4) Incidence of conversion from unresectable to the resectable tumor, and (5) Incidence of treatment-related adverse events (TRAEs). Patients and Methods: Eligible patients included patients ≥ 18 years of age with locally advanced unresectable or metastatic LMS, measurable disease by RECIST v1.1, and at least one accessible tumor for TVEC intratumoral injection. N (3 mg/kg q2 weeks), T (1.2 mg/m2 q3 weeks), and TVEC (1x10e8 PFU/ml q 2 weeks depending on tumor size) were administered. A starting dose of TVEC (1x10e6 PFU/ml) was initially given, followed by a total dose of 1x10e8 PFU/ml q 2 weeks depending on tumor size) three weeks later. Results: Efficacy: Per protocol, there were 11 evaluable subjects (Modified Intention to Treat [mITT] patients who had completed at least one treatment cycle and had a follow-up CT scan). The median number of prior lines of therapy was 4 (range 1-8). Confirmed Best Overall Response (BOR)by RECIST v1.1 = 2 PR, 9 SD (BOR Rate 18.2%). The disease control rate (PR+SD) at week 6 was 100%. The median PFS was 7 months (range: 3- 18); 6-month PFS rate, 55%; median OS 18.2 months (range: 4- 32); 6-month OS rate, 91%. There was no conversion from unresectable to resectable tumor. Response was not related to PD-L1 positivity but both patients with PR were ER+/PR+ and had uterine LMS. There were 15 evaluable subjects for OS analysis under the Intention-to-Treat (ITT) population who received at least one dose of study drug. The median OS was 12 (range 0-32) months; 6-month OS rate, 60%. Safety: Eight of 15 (53.3%) patients experienced at least one > Grade 3 treatment-related adverse event (TRAE). Grade 3 TRAEs include anemia (n=3), thrombocytopenia (n=2), neutropenia (n=1), increased ALT (n=1), increased GGT (n=1), decreased LVEF (n=1), myalgia (n=1) . Grade 4 TRAE include thrombocytopenia (n=1). The TRAEs were related to Trabectedin use. No new safety signals noted in this study. Conclusions: These results suggest that (1) By indirect comparison, the combination regimen using Talimogene laherparepvec, Nivolumab & Trabectedin may be more effective as second/third-line/fourth therapy for advanced leiomyosarcoma with manageable toxicity (Trabectedin alone for LMS= 4.3 mos; Dacarbazine alone = 1.6 mos; Demetri 2015), and (2) The best responders are patients with HR+ uterine LMS. Clinical trial information: NCT03886311 .

Phase II trial of combination pembrolizumab, olaparib, and temozolomide for patients with recurrent glioma.

TPS2087 Background: Diffuse gliomas are primary brain tumors characterized by substantial morbidity and mortality. Standard treatment includes maximal safe surgical resection followed by combination radiation and chemotherapy. Despite aggressive treatment, diffuse gliomas inevitably recur. Alkylating agents, and in particular temozolomide, play an important role in the treatment of gliomas, resulting in single-strand DNA breakages which require PARP activity for detection and repair. Gliomas with mutations in isocitrate dehydrogenase ( IDH) 1 or 2 have an accumulation of 2-hydroxyglutarate (2HG) which results in a BRCA-like state of homologous recombination deficiency (HRD). When PARP is inhibited in the setting of HRD, single-strand DNA damage progresses to double-strand breaks resulting in synthetic lethality. PARP inhibition has also been shown to increase mutational burden and neoantigen expression (“immune-priming”) and increases tumor-infiltrating lymphocytes and expression of PD-L1. Here, we present an ongoing clinical trial combining the checkpoint inhibitor pembrolizumab, the PARP inhibitor olaparib, and temozolomide for treatment of recurrent gliomas with HRD. Methods: This is an open-label, non-randomized phase II trial of combination pembrolizumab, olaparib, and temozolomide for patients with recurrent glioma. The main study cohort (A) will consist of 52 patients with recurrent enhancing grade 2 or 3 IDH-mutant gliomas. An exploratory cohort (B) will consist of 5 patients with recurrent IDH-wildtype gliomas and mutations associated HRD. Study intervention is administered in 21-day cycles and includes pembrolizumab (200mg IV q3 weeks day 1), olaparib (200mg bid orally days 8-14) and temozolomide (50mg/m2 orally days 8-14). The primary outcome is overall response rate (ORR) in cohort A. Secondary objectives include safety and toxicity of triplet therapy, overall and progression-free survival, and best radiographic response. Exploratory objectives will describe outcomes in the IDH-wildtype cohort and associate response to tumor markers obtained through archival tissue and cell free DNA of cerebrospinal fluid. The trial includes a 6-patient safety lead-in to assess tolerability of triplet therapy. Cohort A patients must have grade 2 or 3 IDH-mutant glioma without known CDKN2A/B loss. Patients in Cohort B must have IDH-wildtype glioma with an alternate deleterious mutation involved in homologous recombination. Additional inclusion criteria include age ≥ 18, ECOG 0-1, and glioma recurrent after prior therapy with measurable disease by RANO. Patients must be on a stable dose of corticosteroids not to exceed 2mg/day. There are no restrictions regarding number of recurrences or prior therapies if an appropriate washout has been completed. To date, seven of 57 patients have enrolled. The safety-lead in was completed without dose-limiting toxicities. Clinical trial information: NCT05188508 .

A phase 1 study of TPST-1495 as a single agent and in combination with pembrolizumab in patients with advanced solid tumors.

3107 Background: TPST-1495 is a novel oral therapy designed to be a selective dual antagonist of the prostanoid receptors, EP2 and EP4. Through these receptors, PGE2 stimulates tumor growth, suppresses immunity, and supports adaptive resistance to checkpoint inhibitors. In preclinical models, dual EP2/EP4 inhibition with TPST-1495 increased anti-tumor efficacy, reduced immune suppression, and activated immune effector response significantly better than single EP2 or EP4 antagonists and the COX-2 inhibitor celecoxib. Methods: In this Phase 1 study, subjects with advanced solid tumors received TPST-1495 in a modified 3+3 design optimizing dose and schedule as monotherapy and in combination with standard dose pembrolizumab. Study objectives included safety, PK/PD, recommended phase 2 dose (RP2D), anti-tumor activity and exploratory biomarkers. AEs were assessed per CTCAE v5 and efficacy per RECIST v1.1. Results: TPST-1495 monotherapy was dosed BID (n=11), QD (n=22) or QD days 1-5 every 7 days (n=17) and in combination was dosed QD only with pembrolizumab 200 mg IV q3 weeks (n=24). TPST-1495 doses ranged from 15 mg QD to 100 mg BID. Most subjects had CRC (61%) followed by endometrial (5.4%) and pancreatic (5.4%) cancer. Median prior lines of systemic therapy were 4 (2-10) in monotherapy; 3 (1-8) in combination The most common treatment related AEs (TRAEs) were diarrhea (22%), abdominal pain (20%), fatigue, and nausea (18% each) for monotherapy and nausea (29%), fatigue (21%) and diarrhea (17%) for combination therapy. The most common Gr 3 TRAEs were anemia (6.0%) in monotherapy, and ALT/ AST increased and fatigue (4.2% each) in combination. No Gr 4/5 TRAEs were reported. For mono vs combo cohorts, the median time on study was 1.9 mo (0.2 – 10.2) vs 2.7 mo (0.5 – 10.4) and the disease control rate was 43% (19/44) vs 43% (9/21) with 1 PR in a combination subject with MSS CRC. Pharmacodynamic activities included on-treatment increases in urine PGE2 metabolites and drug-dependent TNF-α rescue in an ex-vivo whole blood PGE2 challenge assay. The RP2D is 50 mg QD for mono and in evaluation for combo therapy. In a subject with endometrial cancer with 22% tumor shrinkage and 222+ days on combination therapy paired biopsies showed high COX-2 expression in the TME at baseline and increased CD8+ and CD8+GrB T cell infiltration on treatment. Conclusions: PGE2 is an important target for cancer and immunotherapy but remains ineffectively drugged. TPST-1495 is a novel oral therapy that inhibits signaling only at the tumor promoting EP2/EP4 receptors. In patients with heavily treated solid tumors, primarily MSS CRC, TPST-1495 had pharmacodynamic activity, a manageable safety profile, and a potential signal of activity consistent with the preclinical data and IO combination mechanism. A combination therapy cohort in endometrial cancer is underway. Updated results and biomarker work will be presented. Clinical trial information: NCT04344795 .

Improved survival on morning pembrolizumab with or without chemotherapy during initial treatment for stage IV non-small cell lung cancer.

e21055 Background: Seven retrospective studies have shown that a greater proportion of infusions of immune checkpoint inhibitors (ICIs) in the morning or at early daytime improved survival in patients (pts) with stage IV cancers. Pembrolizumab (Pembro) binds to PD-1 receptors and targets T(CD8) and other immune cells, whose functions and trafficking are regulated by the circadian timing system. Since 4 courses are needed to reach Pembro steady-state plasma levels, we questioned whether Pembro timing would predict survival outcomes. Methods: Non-small-cell lung cancer (NSCLC) pts received Pembro alone or with chemotherapy (CT) according to PD-L1 status q3 weeks. Infusion timeslots were allocated by the day-hospital coordinators and recorded. The study population was split into two groups according to the median timing of the initial four Pembro infusions. The ‘morning’ group received 2 to 4 infusions starting before this median timing, whilst the ‘afternoon’ group received 0 or 1 infusion before it. Progression-free survival (PFS), and overall survival (OS) were analyzed according to timing group. Results: 97 consecutive pts with stage IV NSCLC (M/F, 68/29; PS 0-1, 97%; 37-87 y.o.) received Pembro as 1st line for 86% of the pts or 2nd-3rd line for 14%. Pembro was administered as a single agent to 41 pts (42%) or with CT to 56 pts (58%). Tumor PD-L1 expression was not assessed for 5 pts, < 1% for 18 pts, 1-49% for 20 pts, and ≥ 50% for 54 pts. Main metastatic sites were bone (43% of the pts), pleura (26%), brain (29%), liver (20%), and adrenal gland (14%). The median infusion time of the initial 4 courses was at 11:45. Pts were retrospectively allocated to the ‘morning’ group (48 pts) or the ‘afternoon’ group (49 pts). Pembro+CT was given to 77 % of the ‘morning’ group pts and to 39% of the ‘afternoon’ group pts (p < 0.001), as expected from the longer infusional Pembro+CT duration. All other pt characteristics were similar between both groups. Pts receiving single-agent Pembro or Pembro+CT displayed non-significant differences in PFS (HR = 0.58, p = 0.08) or OS (HR = 0.81, p = 0.57). PFS did not differ significantly between timing groups (HR = 0.64, p = 0.145). In contrast, OS was significantly longer in the ‘morning’ as compared to the ‘afternoon’ group (HR = 0.41 [95%CI, 0.20-0.82], P = 0.012), with respective 2-year survival rates of 65% and 38% (p = 0.010). Multivariable analysis confirmed that morning dosing of 2-4 of the initial 4 Pembro courses predicted longer OS (HR = 0.28 [0.13-0.64], p = 0.003) irrespective of combination with CT, PD-L1 status, and other clinical features. Conclusions: Pembro was largely more effective on OS in those NSCLC pts receiving 2 to 4 infusions before 11:45 over the initial 3 treatment months. Randomized trials and translational studies are now needed to recommend morning timing for Pembro and possibly other ICIs in NSCLC in order to optimize survival benefits from immunotherapy.

Phase II study of cabozantinib (Cabo) with nivolumab (Nivo) and ipilimumab (Ipi) in advanced renal cell carcinoma with variant histologies (RCCvh).

4520 Background: New therapeutic approaches in RCCvh are needed. Herein, we report on treatment intensification with the combination of Cabo/Nivo/Ipi in patients with metastatic RCCvh in a multi-institutional prospective single arm phase II trial. (NCT04413123). Methods: Eligible patients (pts) had metastatic RCCvh with ECOG performance status of 0-1 and may have received one line of prior therapy excluding immunotherapy or Cabo. Pts underwent a baseline biopsy and received treatment with Nivo 3 mg/kg and Ipi 1 mg/kg intravenously Q3 weeks (W) for 4 cycles followed by Nivo 480 mg IV Q4W. Cabo was given continuously at dose of 40 mg daily; reductions to 20 mg daily and 20 mg every other day were allowed. The primary endpoint was objective response rate (ORR) by RECIST 1.1. Safety was a secondary endpoint. Results: 40 pts have been enrolled. At the time of data cut-off (Dec 9, 2022), 38 pts received at least 1 study drug. 11% (n=4) pts received prior systemic therapy. 45% (n=17) received all 4 doses of Nivo and Ipi; 18% (n=7) received 3 and 37% (n=14) received ≤ 2 doses. 61% (n=23) (15 of whom received 4 cycles Nivo/Ipi) received Nivo maintenance (median number of cycles, 5 (range, 1-21)). 71% (n=27) and 13% (n=5) required Cabo dose reduction to 20 mg and 20 mg every other day, respectively. Median follow-up was 8.4 (range, 2.1-23) months. Objective response was achieved in 8 pts (ORR 21%, two-sided 80% CI, 13%-32%). Median duration of response was not reached with 5 pts maintaining response > 6 months. Median progression-free survival was 8.9 (95% CI, 4.2-12.7) months. 74% (n=28) developed treatment-related grade 3 or higher toxicities; 37% (n=14) developed ≥ grade 3 elevation in AST or ALT. 29% (n=11) required high dose steroids (prednisone ≥ 40 mg daily or equivalent). 13% (n=5) discontinued all study drugs due to toxicity. No grade 5 toxicity has been reported. Conclusions: The study suggests activity for this combination in patients with RCCvh particularly among those without chromophobe histology. An additional cohort of 20 pts is enrolling with Cabo starting dose of 20 mg daily. Clinical trial information: NCT04413123 . [Table: see text]

XMT-1660: A phase 1b trial of a B7-H4 targeted antibody drug conjugate (ADC) in breast, endometrial, and ovarian cancers.

TPS3154 Background: Breast cancer (BC) is the most commonly diagnosed cancer and one of the leading causes of cancer death in women. Despite significant therapeutic advances, the majority of patients with unresectable or recurrent/metastatic disease eventually develop resistance to available standard of care (SOC) therapies. High B7-H4 expression has been observed in several cancers including breast, endometrial, and ovarian, with limited expression in normal tissue. As a member of the CD28/B7 family of cell surface proteins, it promotes tumorigenesis by suppressing anti-tumor immunity. XMT-1660 is a B7-H4-directed Dolasynthen antibody drug conjugate designed with a precise, optimized drug-to-antibody ratio and a DolaLock microtubule inhibitor payload with controlled bystander effect. In the preclinical setting, XMT-1660 has demonstrated anti-tumor activity in TNBC and ER+/HER2- patient-derived xenograft mouse models, which included tumors from heavily pre-treated patients (Collins et al, AACR 2022). Increased anti-tumor activity tended to be more frequent in preclinical models with higher B7-H4 expression, providing rationale for a Ph1 clinical trial. Methods: The Ph1 trial includes a first-in-human open-label dose escalation (DES) portion followed by dose expansion (EXP) evaluating XMT-1660 in patients with BC, EC, and OC following progression on SOC as applicable (i.e., CDK4/6i + ET; platinum-based chemotherapy). In the DES, Bayesian Optimal Interval (BOIN) design will be used to determine the MTD. Patients will receive XMT-1660 IV Q3 weeks. Primary endpoints in DES are to assess safety and determine a recommended phase 2 dose (RP2D) and assessment of preliminary efficacy as a secondary endpoint. In parallel with DES, optional backfill cohorts will enroll patients into tumor-type specific cohorts (TNBC, HR+/HER2- BC, EC, or OC) at a selected dose level from DES and can be initiated at multiple dose levels simultaneously. In the EXP portion, cohorts enrolling TNBC, ER+/HER2- BC, EC/OC are planned and additional patients may be enrolled based on emerging data. The primary endpoint of EXP is to assess safety and tolerability, overall response rate, disease control rate, and duration of response. Secondary endpoints include pharmacokinetic analysis and assessment of antidrug antibodies. Patients are not selected by B7-H4 status, but baseline tumors samples are collected for retrospective tumor tissue evaluation. The trial is currently enrolling patients. NCT05377996. Clinical trial information: NCT05377996 .

A randomized phase 2 trial of encorafenib + binimetinib + nivolumab vs ipilimumab + nivolumab in BRAFV600-mutant melanoma brain metastases: SWOG S2000.

TPS9603 Background: While anti-PD-1 and anti-CTLA4 immunotherapies are widely used in the treatment of metastatic melanoma, including melanoma brain metastases (MBM), their efficacy in patients with symptomatic MBM is very limited. In the Checkmate-204 trial of ipilimumab with nivolumab in MBM, the 6-month progression free survival (PFS) rate was 19% with a median PFS of only 1.2 months in symptomatic participants (those with neurological symptoms including steroids up to 4 mg/day of dexamethasone, n=18). (Tawbi, Lancet et al., 2021) In the COMBI-MB study of BRAF/MEK-inhibitors in BRAF-V600 mutant MBM, median PFS was 5.5 months in those with symptomatic metastases (n=17). (Davies et al., Lancet Oncol, 2017) The combination of anti-PD-1/PD-L1 therapy with BRAF/MEK inhibitors has been tested in various trials. The single-arm phase 2 TRICOTEL study explored the triplet regimen of vemurafenib + cobimetinib + atezolizumab in MBM; in the symptomatic brain met cohort, 6-month PFS was 57% (n=24). (Dummer et al., Lancet Oncol 2022). Methods: SWOG S2000 is a randomized phase 2 trial exploring the efficacy of a triplet regimen of BRAF/MEK inhibitors with PD-1 therapy (encorafenib 450 mg qday + binimetinib 30 mg BID + nivolumab 480 mg IV q4 weeks) versus ipilimumab 3 mg/kg + nivolumab 1 mg/kg q3 weeks in patients with symptomatic BRAF-mutant MBM. (The study was amended to exclude patients with asymptomatic MBM.) Eligible patients are ≥18 years old, ECOG 0-2, and prior neoadjuvant or adjuvant anti-PD-1, CTLA-4, or BRAF/MEK-inhibitors is permitted. Steroids up to 8 mg of dexamethasone/day (or equivalent), leptomeningeal spread, and prior local therapy (radiation or surgery) for brain mets are permitted, if a patient has at least one measurable, progressing brain met ≥0.5 cm in size. Primary objective is to compare PFS per (RECIST 1.1) between the two study arms. Secondary objectives include overall survival, toxicity profile, objective tumor response, intracranial response and duration per modified RECIST 1.1, modified RANO-BM, and iRANO criteria, and evaluation of radiographic response criteria by centralized review of banked images. This study is powered to detect an increase in estimated 6-month PFS from 20% to 52% with 80% power and type I error rate of 10%, with 24 eligible patients required. Total sample size is 28 to account for ineligible patients. Available blood, tissue, CSF and stool samples are banked for future correlative studies. The study is currently enrolling patients through SWOG, ECOG and NRG centers. Funding: NIH/NCI grants U10CA180888, U10CA180819, U10CA180820 U10CA180868; and in part by Pfizer, Inc. Clinical trial information: NCT04511013 .

Neoadjuvant nivolumab alone or in combination with relatlimab or ipilimumab in resectable head and neck squamous cell carcinoma (HNSCC).

6018 Background: PD-1 inhibition using nivolumab (nivo) monotherapy is modestly effective in metastatic HNSCC. Neoadjuvant trials using nivo may permit development of more effective combinations in surgically resectable HNSCC. We evaluated combinations with nivo plus additional immune checkpoints, CTLA-4 (ipilimumab, ipi) and LAG-3 (relatlimab, rela). Methods: Phase II randomized trial of neoadjuvant nivo alone (240 mg q2 weeks), or with ipi (1 mg/kg q3 weeks) or rela (160 mg q4 weeks) for 4 weeks prior to surgery. Response was scored using RECIST and standard pathologic response criteria. Patients were stratified by p16, PD-L1, and LAG-3, with staining assessed by immunohistochemistry. Freshly digested tumors were subjected to single cell RNA sequencing (scRNAseq) for T cell receptors and gene pathways to identify biomarkers of response or progression. The Cochran-Armitage trend test was used to explore associations with increasing pathological response efficacy. Results: 41 patients (pts) have been enrolled, with 33 evaluable for this analysis. Of these 33, median age is 63 (32-81), primary site oral cavity (n=25), oropharynx (n=5, 3 HPV), larynx (n=3), clinical T2 (n = 5), T3 (n = 12), T4 (n = 13), and cN0/1 (n = 22), cN2 (n = 9), and PD-L1 CPS > 1 (n=25). There were no serious study drug-related AEs or unexpected surgical delays/complications. Pathologic response (Table) was more frequent with nivo/rela (11/13) vs. nivo/ipi (6/10) or nivo (4/10). Partial (>50%) or major (>90%) pathologic responses were more frequent and deeper in the combination arms. Minor (<50%) pathologic responses were more frequent with nivo/rela, and similar between nivo/ipi and nivo. There was no association between RECIST response, PD-L1, or LAG3 and pathologic response. Combined PD-L1 and LAG3 expression was not associated with pathologic response in the nivo/rela arm, however more patients with combined positivity had a >50% response (4 vs. 0). Expansion of CD8+ T cells, as well as expanded proportion of CD8+ CXCL13+ T cells in responder tumors were identified in post-treatment specimens using scRNAseq. Conclusions: Neoadjuvant nivo/ipi or nivo/rela combinations were safe and associated with promising pathologic responses compared to nivo monotherapy. Anti-tumor CD8+ T cell populations and targetable pathways are emerging in responder patients. The trial continues to enroll and further evaluation of this strategy is warranted. Clinical trial information: NCT04080804 . [Table: see text]

Phase IIa study of αDC1 vaccines targeting HER2/HER3 combined with pembrolizumab in patients with asymptomatic brain metastasis from triple negative breast cancer or HER2+ breast cancer.

TPS1112 Background: Brain metastases develop in up to 50% patients (pts) with metastatic triple negative breast cancer (TNBC) and HER2+ BC, constituting an increasing source of morbidity and mortality. HER3, overexpressed in triple negative and HER2+ brain metastatic breast cancer (BMBC), is a resistance factor to HER2-targeted therapies and a driver of CNS metastasis. Disease progression is associated with loss of anti-HER2 and anti-HER3 immunity. Previously, we have demonstrated that glioma-specific peptide-loaded αDC1 which produce CXCL9, CXCL10, CXCL11, CCL5, the chemokines which attract CXCR3- and CCR5- expressing cytotoxic T-lymphocytes (CTLs) and T-helper 1 (Th1) cells, induce clinical responses and long-term disease stabilization in pts with aggressive recurrent primary brain tumors (Okada et al. JCO 2011. PMID: 21149657). We hypothesized that anti-HER2/3-loaded αDC1 in combination with PD1 blockade will result in strong Th1/CTL response against HER2/3 epitopes (Basu A et al. Cancer Immunol Res. 2022 PMID: 34785506), being effective against brain lesions and systemic disease. Methods: This is a phase II single-arm, non-randomized multicenter study (NCT04348747). Eligibility includes pts with triple negative and HER2+ BMBC ≥18 years, ECOG PS ≤1, normal marrow and organ function with asymptomatic untreated brain metastases ≥ 5 mm who will receive αDC1 q3 weeks x 3 along with pembrolizumab every 3 weeks. Thereafter, αDC1 booster doses (if available) would be administered every 3 months until disease progression, intolerable side effects or withdrawal from study, up to 24 months. Baseline and 9-week post-αDC1 peripheral biopsies (non-CNS) are required for six pts. 1 of the planned 21 pts have been enrolled and is undergoing treatment. Primary endpoint is CNS response rate (RR) by RANO-BM criteria. If no CNS response is observed after 12 pts, study will be terminated. If ≥ 1 response observed, then 9 more pts will be enrolled, for a total of 21 pts. If ≥ 3 CR are observed, the proposed therapy will be considered as promising for further evaluation. Secondary endpoints include non-CNS RR per RECIST v1.1, median CNS, non-CNS and overall progression-free survival, overall survival and safety. Exploratory endpoints include changes in intratumoral biomarkers (CTLs, PDL1, chemokines) in pre- and post-treatment peripheral tumor biopsies and immune changes in the blood. Clinical trial information: NCT04348747 .

Intratumoral INT230-6 (cisplatin, vinblastine, shao) alone or with ipilimumab prolonged survival with favorable safety in adults with refractory sarcomas.

11568 Background: Sarcomas are a rare and diverse group of solid tumors from mesenchymal cells; chemotherapy provides limited benefit for metastatic disease. INT230-6 is a novel formulation of cisplatin (CIS), vinblastine (VIN) and a tissue dispersion enhancer (SHAO) designed for intratumoral (IT) delivery. The drug diffuses into cancer cells, causes apoptosis and recruits dendritic and T-cells to the tumor. Adding ipilimumab (IPI) appears to improve INT230-6 responses in models and clinically. The study evaluated INT230-6 for safety and efficacy alone and with intravenous (IV) IPI. Previously reported results showed INT230-6 alone induced tumor regression, T-cell influx and abscopal effects in uninjected lesions1,2. Methods: IT-01 is an open-label phase1/2 study in adults with locally advanced, unresectable or metastatic solid tumors, including sarcoma. INT230-6 dose was set by tumor diameter or volume. INT230-6 was dosed IT Q2W for up to 5 doses alone or with IPI at 3mg/kg Q3 weeks for 4 doses. Maintenance INT230-6 dosing was Q9W. Results: The study enrolled 29 sarcoma patients with 11 subtypes (mainly leiomyosarcoma, liposarcoma, pleomorphic, chondrosarcoma and chordoma). The maximum INT230-6 dose at a single visit was 175 mL (87.5 mg of CIS, 17.5 mg VIN) in 1 or more tumors, an amount that exceeds an IV dose of VIN or CIS. PK analysis shows that >95% of VIN stays in the tumor. The >20% treatment-related adverse events (TRAEs) in evaluable monotherapy patients (n=15) were localized pain (80%), nausea (40%), fatigue (33%), decreased appetite (27%), and vomiting (20%). The >20% TRAEs in evaluable IPI/INT230-6 patients (n=14) were fatigue (39%), localized pain (39%), nausea (31%), pruritus (23%), rash (23%) and vomiting. G3 TRAEs occurred in 20% and 7% of patients in the INT230-6 and combination arms respectively with no grade 4 or 5 events in either arm. RECIST metrics are confounded by IT injections due to the large volume of highly retained INT230-6 and the influx of immune infiltrates. Analysis of median overall survival (mOS) for INT230-6 alone (n=15) was 649 days. For INT230-6 dosed at a volume/total tumor burden (TTB) ratio of ≥40%, the mOS was 715 days. The mOS of the combination has not been reached with over 1 year of median follow-up. OS data compare favorably to a synthetic control (mOS of 205 days) based on historical data3. The hazard ratios of INT230-6 alone or with IPI for OS to the synthetic control were 0.446 and 0.270, p-values <0.01. Conclusions: INT230-6 dosed IT alone or with IPI was well-tolerated in diverse sarcomas. INT230-6 use was associated with immune infiltration and favorable mOS as compared to a synthetic control, particularly when ≥40% of the TTB was injected. A randomized phase 3 trial vs. SOC in selected sarcoma subtypes with an OS endpoint is planned.

A phase I/II study of durvalumab and stereotactic ablative body radiotherapy (SABR) in locally advanced (LA) and borderline resectable (BR) pancreatic cancer.

4164 Background: Pancreatic cancer (PC) is largely refractory to immune checkpoint blockade (ICB) in genomically unselected patients (pts). Synergistic effects of combined ICB and radiotherapy have been suggested in varied solid tumors. Few studies have evaluated this approach in pts with PC. We sought to evaluate the safety and efficacy of PD-L1 inhibitor durvalumab (D) and SABR after induction chemotherapy, in LA and BR PC. Herein, we present phase II data from two cohorts. Methods: A multi-institutional, non-randomized phase 1/2 trial of SABR and D was conducted at Cedars-Sinai Medical Center (CS) and Memorial Sloan Kettering (MSK). Key eligibility: ECOG 0-1; unresectable PC, with stable/responding disease following 2-3 cycles gemcitabine and nab-paclitaxel (GnP) or 4-6 months (m) FOLFIRINOX (FFX). CS enrolled pts with BR and LA PC; MSK enrolled pts with LA PC only. All pts received SABR between dose 1 and 2 of D, with slight variation in ablative radiation techniques (CS: 33Gy/5#; MSK: MRI adaptive ablative radiation, 50Gy/5#). D dosed on day 1: 750mg x 4 doses Q14 days, and subsequently Q2 or Q4 weeks x 1 year total, or until resection, progression of disease (POD), or limiting toxicity. Primary endpoint: 6-month progression free survival (6 m PFS). Secondary endpoints: rate of downstaging to resectability, objective response by RECIST v1.1, duration of response, PFS, Overall Survival (OS). PFS and OS estimated from consent date using Kaplan-Meier method. Association between surgery and outcomes was analyzed as a time dependent covariate in univariate Cox regression models for OS and PFS. To assess immunogenomic biomarkers of response, pre- and on-treatment tissue, blood and microbiome samples were gathered. Results: Between 08/2017 and 05/2022, N= 36 enrolled. Median age 67.5 years (range 48-79), 39% (14/36) female. Performance Status: N=12 (33%) ECOG 0; N= 24 (67%) ECOG 1. Median duration chemotherapy: 3.5 m (range 1.4, 5.8). Staging: N=31 (86%) LA; N=5 (14%) BR. N = 9 (25%) underwent resection; all R0. Conversion to resection was not associated with PFS (HR 0.45; 95% CI 0.17, 1.17, p=0.1) or OS (HR 0.69; 95% CI 0.26, 1.84, p=0.5). Survival and response data summarized in table. Toxicities of special interest: Grade 3 treatment-related: in N= 7; diarrhea N= 2; elevated AST/ALT N= 2; lipase/amylase elevation, N=1; nausea N=1. Grade 4: amylase elevation N=1. Conclusions: D and SABR after induction chemotherapy in LA and BR PC is safe, had an encouraging 6-m PFS of 69% and favorable R0 resection rate, warranting further evaluation. Immuno-genomic biospecimen analyses underway. Clinical trial information: NCT03245541 . [Table: see text]

CABIOS trial: A phase Ib study of cabozantinib and nivolumab in combination with abiraterone in patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC).

5084 Background: Androgen deprivation therapy (ADT) combined with novel hormonal agents +/- docetaxel is a standard of care treatment for mHSPC. The combination of tyrosine kinase inhibitors (TKI) and immune checkpoint blockade (ICB) is FDA approved in renal cell carcinoma, and shows promising efficacy in preclinical models of prostate cancer by favorably altering the tumor immune microenvironment. There are currently ongoing trials of TKI + ICB in metastatic castration resistant prostate cancer. Here we present interim safety results from an ongoing phase Ib single-arm trial of cabozantinib + nivolumab + abiraterone/prednisone (cabo, nivo, abi/pred) in pts with newly diagnosed mHSPC (NCT04477512). Methods: Eligible pts had de-novo or recurrent mHSPC with up to 12 weeks ADT prior to enrollment, ECOG 0-1, and adequate organ function. Prior abi and docetaxel were excluded. Pts received cabo 20 mg or 40 mg daily (3+3 dose escalation in 2 cohorts) combined with nivo 480mg IV q4 weeks, and abi/pred 1,000mg/5mg daily until progression or unacceptable toxicity. The primary endpoint is safety and tolerability. Secondary endpoints include overall response rate (ORR) by RECIST 1.1, overall survival (OS), progression free survival (PFS), and PSA response. Exploratory analyses include CyTOF of peripheral blood and serum cytokine ELISA. Results: As of 19DEC2022, 17 pts were enrolled, 3 at 20mg and 14 at 40mg cabo with no dose-limiting toxicity (DLTs) observed. Median age was 65 yrs, 4/17 pts are Black, 11 had de-novo and 6 recurrent disease, with median baseline PSA 78ng/mL. Most had bone (n=16), lymph node (6), or lung (1) mets, and 11 (64.7%) had high-volume disease. With median follow-up 12.8 months, 9 pts (53%) remain on study. 1 withdrew, 3 discontinued due to disease progression (with 1 death), and 4 stopped due to toxicity. Grade ≥ 3 adverse events (AEs) include encephalitis (n=1, grade 4 likely nivo-related after 1yr on therapy), diarrhea (n=2), elevated AST/ALT (n=4), wound infection/dehiscence, adrenal insufficiency, hypertension, elevated lipase, and proteinuria (grade 3, n=1 each). No other AEs were reported outside the current safety labels for the study agents. Of 15 response evaluable pts, 7 had RECIST-measurable lesions; 4 had partial response and 3 had stable disease as best response at data cutoff. 9/14 (64.3%) evaluable had PSA <0.2ng/mL at 7 months. Immune correlative studies are ongoing. Conclusions: Here we present the initial safety and preliminary efficacy results of the first trial of cabo + nivo in mHSPC patients receiving SOC ADT + abi. To date, the combination has a safety profile consistent with known AEs for these agents, no DLTs, and evidence of clinical benefit. Further follow up will be required to fully assess clinical safety, efficacy and immune responses. Future, larger studies could compare this combination to SOC ADT + abi. Clinical trial information: NCT04477512 .

De-correlating immune checkpoint inhibitor toxicity and response in melanoma via the microbiome.

9569 Background: Immune-checkpoint inhibitor (ICI) immunotherapy increases survival in patients with melanoma. Yet only half of the patients respond, and 10-40% of patients experience immune-related adverse events (irAEs). Previous studies have found a correlation between the development of an irAE and treatment response. Modifying the gut microbiome could positively affect response to ICIs and reduce toxicities. We sought to determine if the microbiome at the onset of treatment, during an irAE, and at 12 weeks, can predict the response or toxicity during ICI treatment for metastatic melanoma. Methods: Melanoma patients (pts) > 18 yo treated with ICI enrolled in a prospective observational cohort study at The Ohio State University Comprehensive Cancer Center Skin Cancer Clinic. Excluded were patients on corticosteroids at the start of ICI cycle 1, except for adrenal physiologic replacement. Stools were collected at baseline, within 2 days of an adverse event assessed by physician chart review using CTCAE (Common Terminology Criteria for Adverse Events) v5.0, and at 12 weeks. Response (ORR) to ICIs was assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) q12 weeks and progression-free survival recorded. Metagenomic whole-genome shotgun sequencing was performed on an Illumina NovaSeq 6000 and classified using HUMAnN3. The effect of microbe relative abundances on irAEs was modeled by logistic regression with the R package glmm. Results: Of the 88 patients enrolled, 48 had metastatic disease with 32 assessable for response. ORR at 12 weeks was 28% (1 CR, 8 PR, 17 SD, and 6 PD) and 24 patients showed PFS at 12 months. Grade > 2 irAEs were observed in 11/48 pts. Abundance of Bacteroides dorei (False Discovery Rate Corrected p-value = 9.5E-07) and Blautia species CAG:257 (padj = 0.001) were enriched in responders, Prevotella Stercorea (padj = 1.1E-07) and a phage with a predicted target of Salmonella (padj = 8.3E-09) in non-responders. Responders with an irAE had enrichment of Bacteroides plebeius (padj = 4.2E-13) and Bacteroides coprophilus (padj = 0.0002) whereas responders without irAE had enrichment of Eubacterium siraeum (padj = 7.2E-05). Conclusions: Longitudinal and event-driven biospecimen collection in patients treated with ICIs showed several bacteria and viruses but no fungi associated with response, with and without the development of an irAE. The abundance of the two high-taxonomic rank microbe groups is significantly associated with irAEs. The association with the Bacteroides Genus is consistent with previous studies and is associated with response to ICIs. A microbiome abundant in Bacteroides and lacking Prevotella is associated with response to ICI. An abundance of Bacteroides could be a biomarker for irAEs, and an abundance of Eubacterium, a biomarker for response without irAEs. Future analyses are necessary to assign causal roles for microbe biomarkers with specific irAEs. Clinical trial information: NCT05102773 .

A single-arm phase 2 study of peri-operative immune checkpoint inhibition and cryoablation in women with hormone receptor-negative, HER2-negative, early-stage/resectable breast cancer.

TPS635 Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with immune checkpoint inhibition (ICI) augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ICI [ipilimumab (ipi) +/- nivolumab (nivo)] was safe in patients (pts) with operable, early stage breast cancer (ESBC) and generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ICI in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible women are ≥18y, with ER <10%, PR <10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. As of 2/14/21, 16/80 pts have been enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and received ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts received 3 additional doses of nivo at 240mg IV Q2 weeks. To reflect the US FDA approval of curative-intent pembrolizumab (pembro) in 2021, the protocol was recently amended to allow standard-of-care pembro as an alternative ICI option. Adjuvant capecitabine or olaparib is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Clinical trial information: NCT03546686 .

Phase 2 multicenter trial of rucaparib and nivolumab as maintenance therapy following first-line platinum-based chemotherapy in patients with advanced biliary tract cancer (BTC): BilT-02.

4113 Background: Gemcitabine, cisplatin and durvalumab followed by maintenance durvalumab is standard of care first-line (1L) therapy for patients (pts) with advanced BTC. In this trial, we investigated the combination of a PARP inhibitor with anti-PD1 antibody in absence of progression after at least 4 months of standard 1L platinum-based chemotherapy. Methods: Pts with advanced BTC, ECOG PS 0-1 and absence of progression on 1L platinum-based therapy were enrolled on a phase 2 trial to receive rucaparib 600 mg PO BID in combination with nivolumab 240 mg IV Q2 weeks every 28 days for up to 2 years. The primary endpoint was 4-month progression-free survival (PFS) rate from the date of first study treatment with an alternative hypothesis of 85%. Secondary endpoints included median PFS and overall survival (OS) from first study treatment (PFS1, OS1) as well as from start date of first-line chemotherapy (PFS2, OS2), best overall response, and safety. Results: 31 pts were enrolled of which 14 (45%) were women, 25 (80.6%) Caucasian and 24 (77.64%) with ECOG 1. Primary disease site was intrahepatic, extrahepatic hilar and distal, and gallbladder cancer in 21 (67.7%), 4 (12.9%), 1 (3.2%) and 4 (12.9%), respectively. 1L platinum-based treatment included gemcitabine/cisplatin based in 26 (83.9%), FOLFOX in 3 (9.7%) and carboplatin/paclitaxel in 1 (3.2%) pts. Mean (range) cycles of rucaparib and nivolumab were 6.75 (1-24) and 5.9 (1-24). The median follow-up time is 28.7 months using reverse censoring methodology. PFS rate at 4 months was 54.8% (95% CI, 36-70.3), comparable to the 63% null estimate based on ABC-02 trial. Median PFS1 and OS1 are estimated to be 4.6 months (95% CI, 3.7-6.2) and 15.9 months (95% CI, 9.8-24.1). Median PFS2 and OS2 calculated from date of 1L chemotherapy are estimated as 9.9 months (95% CI, 8.3-11.3) and 21.4 months (95% CI, 14.8-26.7). Two (6.4%) pts had partial response (with IDH R132G and KRAS G12D) as best response with stable disease in an additional 22 (71%) pts. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 15 (48.4%) pts, including 1 patient who died on therapy due to possibly-related immune-related myocarditis. The most common grade 2 or greater TRAEs included fatigue (9, 29.0%), anemia (7, 22.6%), neutropenia (6, 19.3%), elevated AST (5, 16.1%) and elevated ALT (4, 12.9%). Reasons for treatment discontinuation included death (2), progression (27), adverse event (1) while 1 patient completed 2 years of study treatment. Conclusions: The primary endpoint of PFS rate at 4 months was not met but the preliminary measures of PFS1 and OS1 are much longer than expected, and hypothesis generating for rational combination of PARP inhibitor with maintenance immunotherapy in this rare cancer. Exploratory endpoint of association of genomic analysis with efficacy is ongoing and will be discussed. Clinical trial information: NCT03639935 .

The Ave-Rec trial: Phase II trial of PD-L1/PD-1 blockade with avelumab plus chemoradiotherapy for locally advanced resectable T3B-4/N1-2 rectal cancer—Toxicity and interim efficacy data.

3616 Background: Neoadjuvant long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological response rate in 10-30% of patients (pts), but with 20-40% non-responders and 10-15% have local recurrence. Radiotherapy (RT) is immuno-stimulatory by enhancing local/distant tumour cell death, but also immunosuppressive as it stimulates PDL1 production and myeloid-derived suppressor cell activity. Hence PDL1 inhibition may be required to enhance the immuno-stimulatory effects of RT. Hypothesis: In pts with resectable LARC, the anti-PDL1 antibody Avelumab given post LCCRT may enhance the pathological/imaging response rates whilst reducing local/distant relapse rates. Methods: Phase II single arm trial. All pts had standard LCCRT (50.4Gy RT plus 5FU [225mg/m2/day/CI] or Capecitabine [825mg/m2 BID on days of RT] over 5.5 weeks). Post LCCRT (prior to surgery), pts received 4 cycles Avelumab (AV) (10mg/kg, q2 weeks), then surgical resection at 10-12 weeks post LCCRT. Fresh tumour biopsy and ctDNA sampling taken pre LCCRT, pre Cycle 1 AV and at surgery. Response by FDG PET/CT and pelvic MRI at 8 weeks post LCCRT, pre surgery. Inclusion Criteria: pts with LARC (MRI stage T3b-4/N1-2/M0), planned for LCCRT followed by curative resection, tumoural lower border within 12cm from anal verge, measurable disease (RECIST1.1), ECOG 0-1, adequate organ function and no contraindications to AV therapy. Endpoints: (a) Primary; Complete pathological response rate post-LCCRT (Target ≥ 35%), documented by central pathologist, (b) Secondary; MRI and FDG PET/CT imaging responses by RECIST1.1 and PERCIST, respectively. Toxicity. (c) Exploratory; Tumoural immune cell subsets/checkpoint expression (by multiplex immunohistochemistry and in-vitro functional assays) and ctDNA analysis. Distant relapse-free survival and the sites of relapse. ANZCTR : NCT03299660. Results: 37 pts across 6 sites, with 33 patients (89%) received allocated interventions: LCCRT, AV and surgery (where possible). Age median 55 years (31-76). M:F 23:10. Baseline tumoural stage: T3b-d 75%, T4a-b 25%. No pts with dMMR/MSI-H tumour. Overall 33 pts completed LCCRT, 31 pts (83%) completed all 4 cycles of AV and 32 pts (86%) had planned surgery (22, ULAR, 2 APR, 2 AR, 6 Other). ORR Pelvic MRI presurgery (N = 33): 2 CR, 14 PR, and 31 DCR. FDG PET/CT (N = 31): 10 CMR, 18 PMR and 3 SMD. Overall 10 pts Grade 3/4 AEs, with 15 G3/4 events. Only 3 pts with treatment-related G3 and no G4 AEs. No specific immune-related G3 AEs observed. Post-operative complications were not unexpected. Conclusions: Consolidation Avelumab post LCCRT for pts with LARC, was well tolerated with promising activity. Pathological response, biological substudies (immunological and ctDNA) and survival endpoints to be reported. Clinical trial information: NCT03299660 .