On-treatment Biopsies Research Articles

Abstract P3-06-07: Phase Ib/II study to evaluate safety and tolerability of cabiralizumab in combination with nivolumab and neoadjuvant chemotherapy in patients with localized triple-negative breast cancer

Abstract Background: Neoadjuvant immune checkpoint inhibition (ICI) in combination with chemotherapy is approved for patients with high-risk, early-stage triple-negative breast cancer (TNBC) based on improved outcomes in the KEYNOTE-522 trial. However, some patients have primary resistant disease and do not achieve a pathological complete response (pCR), while others experience significant toxicity. Tumor-associated macrophages (TAMs) are a potential resistance mechanism for ICIs and are dependent on colony-stimulating factor 1 receptor (CSF1R). Therefore, we examined the addition of cabiralizumab, a CSF1R inhibitor, to neoadjuvant paclitaxel, carboplatin, and nivolumab to assess the safety, tolerability, and changes in the tumor microenvironment (TME) in patients with early-stage TNBC. Methods: This is a phase Ib/II, single-institution, randomized controlled clinical trial (NCT04331067) in patients with newly diagnosed Stage II-III TNBC. The primary endpoints include: (1) to determine the safety of a 12-week neoadjuvant regimen of paclitaxel (80 mg/m2 IV q week) + carboplatin (AUC5 IV q3 weeks) + nivolumab (240 mg IV q2 weeks) with or without cabiralizumab (4 mg/kg IV q2 weeks) and (2) to evaluate the effect of cabiralizumab on TAMs and changes in tumor infiltrating lymphocytes (TILs) in the TME between baseline and an on-treatment biopsy after 4 weeks of therapy. Adjuvant treatment is per investigator’s choice. Secondary objectives include evaluation of pCR rate and recurrence-free survival. Paired tissue and bone marrow biopsies are collected for evaluation of the TME and disseminated tumor cells, respectively. The study was designed to enroll 50 patients, including a 12-patient safety lead-in cohort. Here, we report the planned interim analysis of the safety lead-in cohort. Results: Between December 2020 and May 2022, we enrolled 12 patients to the safety lead-in, including 6 patients in each arm. 5 of 12 patients (41.7%) enrolled are underrepresented minorities, including 4 Black patients and 1 Hispanic patient. 2 of 6 patients in the nivolumab arm experienced grade 3 severe toxicity, including 1 patient who developed sepsis and 1 who developed peripheral neuropathy. 3 of 6 patients in the nivolumab + cabiralizumab arm developed grade 3 severe toxicity including 2 patients who experienced myositis and 1 patient who developed periorbital edema. Of the first 10 patients enrolled, 5 had a pCR (2 pCR in cabiralizumab arm, 3 pCR in non-cabiralizumab arm) and 3 had non-pCR (1 RCB-1 and 1 RCB-3 in cabiralizumab arm, 1 RCB-1 in non-cabiralizumab arm). 2 patients came off study prior to surgery (1 due to toxicity and 1 due to missing study visits). Data from the final 2 patients still on treatment will be available at the time of presentation. Discussion: Full safety, pathologic, and clinical response data in the safety lead-in cohort for patients with early-stage TNBC receiving neoadjuvant chemotherapy + nivolumab with or without cabiralizumab, will be presented. Citation Format: Andrew A. Davis, Leonel Hernandez-Aya, Jingqin Luo, Mateusz Opyrchal, Foluso O. Ademuyiwa, Nusayba A. Bagegni, Katherine K. Clifton, Jill Anderson, Trish Hammerschmidt, Leslie Nehring, David DeNardo, Mark Watson, Rebecca Aft, Cynthia Ma, Katherine Weilbaecher. Phase Ib/II study to evaluate safety and tolerability of cabiralizumab in combination with nivolumab and neoadjuvant chemotherapy in patients with localized triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-07.

Abstract P3-06-03: Trilaciclib induces immune changes within the tumor microenvironment in early-stage triple-negative breast cancer

Abstract Background: In early-stage triple-negative breast cancer (TNBC), there is accumulating evidence of a correlation between tumor-infiltrating lymphocytes in tumor tissue and favorable clinical outcomes, with a high CD8+/regulatory T-cell (Treg) ratio after neoadjuvant chemotherapy being predictive of overall survival and associated with pathologic complete response (Ladoire S, et al. Br J Cancer. 2011; Park YH, et al. Nat Commun. 2020). Trilaciclib is a transient inhibitor of cyclin-dependent kinase 4/6 that is administered intravenously prior to chemotherapy. In preclinical studies, trilaciclib has been shown to have immune-enhancing effects by differentially arresting CD8+ T-cell and Treg subsets, which is followed by the faster recovery of CD8+ T cells than Tregs in the tumor microenvironment. Methods: This phase 2, single-arm, open-label study aims to evaluate neoadjuvant, single-dose trilaciclib followed by trilaciclib plus dose-dense anthracycline/cyclophosphamide and taxane in patients with early-stage TNBC (NCT05112536). Patients with previously untreated, non-metastatic, confirmed TNBC and a primary tumor ≥ 1.5 cm of any nodal status receive a single dose of trilaciclib 240 mg/m2 during the lead-in phase, followed by 4 cycles of doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2, and 12 weekly cycles of paclitaxel 80 mg/m2. Trilaciclib 240 mg/m2 is administered prior to the first chemotherapy dose of each cycle. Pembrolizumab 400 mg every 6 weeks starting on day 1, cycle 1, and/or carboplatin AUC 1.5 every week starting on day 1, cycle 5, is allowed per investigator discretion. Tumor biopsies and peripheral blood samples are collected prior to any treatment, 7 days ± 1 day post administration of trilaciclib, and during surgery, with an additional blood sample collection on day 1, cycle 2. The primary objective is to evaluate the immune-based mechanism of action of trilaciclib after a single dose of trilaciclib, as measured by changes in the CD8+/Treg ratio in tumor tissue. Pathologic complete response, safety and tolerability, and additional exploratory immune biomarker endpoints will also be assessed. Results: As of June 3, 2022, 9 patients with early-stage TNBC had been enrolled and 8 patients had received the trilaciclib lead-in dose and initiated doxorubicin/cyclophosphamide. Patients had a median age of 53.0 years, and all had stage II tumors at diagnosis, with 7 having ductal carcinoma. The median number of chemotherapy cycles received was 3 (range 1–6), and all 8 patients received pembrolizumab. Seven patients continue study treatment; 1 patient discontinued due to disease progression. Five patients had an adverse event (AE) related to any study treatment, including 4 patients with ≥ 1 trilaciclib-related AE. There were no grade ≥ 3 treatment-related AEs or serious AEs. On-treatment, post-trilaciclib monotherapy biopsies were available for 4 patients. Following neoadjuvant trilaciclib treatment, the median density of stromal CD8+ T cells increased from 103.1/mm2 at baseline to 229.8/mm2 at day 7. The median CD8+/Treg ratio increased in 2 patients from 1.85 at baseline to 1.90 at day 7. Conclusions: Preliminary analysis of on-treatment tumor biopsies from 4 patients suggests that a single dose of trilaciclib may modulate the immune cell composition in the tumor microenvironment to support antitumor immune responses. The increase in CD8+ T cells following 7-day neoadjuvant treatment with trilaciclib supports previous data suggesting a role in T-cell infiltration. The complete dataset from all patients (estimated enrollment: N ≈ 24) and additional biomarker analyses will be presented. Citation Format: Michael Danso, Joyce O’Shaughnessy, Lisa S. Wang, Kailash Mosalpuria, Sara Hurvitz, Shom Goel, Sarah Ahn, Subing Cao, John S. Yi, Taofik Oyekunle, Amanda Jacobson, Andrew Beelen, Jeremy Force. Trilaciclib induces immune changes within the tumor microenvironment in early-stage triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-03.

Abstract P4-06-07: Preliminary indications of safety and efficacy of neoadjuvant chemotherapy plus chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib) in triple negative breast cancer

Abstract BACKGROUND: Pathologic complete response (pCR) or microinvasive residual breast cancer (ypTmic) following neoadjuvant chemotherapy (NAC) is critical for good long-term outcomes in triple negative breast cancer (TNBC) patients (pts) but is achieved only in 40-50% of pts. Its combination with pembrolizumab, the new standard of care in TNBC, increases the pCR rate to 65% but is associated with significant immune-related and permanent toxicities. Higher intratumoral levels of CD8+ cytotoxic T-lymphocytes (CTLs) and low levels of regulatory T-cells (Treg) and myeloid derived suppressor cells (MDSC) predict improved relapse-free survival (RFS), overall survival (OS) and higher probability of pCR, a surrogate marker for RFS. Locally produced chemokines CCL5, CXCL9, CXCL10 and CXCL11 are critical for local infiltration with CTLs, while CCL22 is responsible for Treg attraction, with high CXCL9 expression being associated with a 3-fold higher rate of achieving pCR in response to NAC. Our preclinical data show that Chemokine-modulatory (CKM) regimen, combining rintatolimod (TLR3 agonist), interferon (IFN)-α2b and celecoxib (COX-2 inhibitor), selectively induces CTL-attractants but decreases MDSC- and Treg-attractants in the tumor microenvironment (TME). We hypothesized that the combination of CKM with paclitaxel will promote selective CTL infiltration into TNBC, and along with doxorubicin/cyclophosphamide (AC), will result in higher rate of pCR, translating into improved RFS and OS. METHODS: In the phase I study NCT04081389, 9 pts with stage I-III TNBC were enrolled with median age of 47 (37-55) years. All patients were treated with paclitaxel 80 mg/m2 IV weekly for 12 weeks, and for first 3 weeks days 1-3 also received CKM regimen consisting of rintatolimod 200 mg IV and celecoxib 200 mg oral twice daily. IFN-α2b was administered in an accelerated titration design at doses 0 or 5 million units (MU)/m2 [Dose Level (DL) 1,2 respectively] in first 2 pts (no intra-patient dose escalation), then 10 MU/m2 [DL 3] in 4 patients and then 20 MU/m2 [DL 4] in 3 patients. Pre- and 3 week-on treatment biopsies were performed at DL 3 and DL 4 (5 patients). This was followed by standard dose-dense AC and surgery. Dose-limiting toxicity (DLT) was defined as grade 3 or higher toxicity within the first 3 weeks of treatment. The primary endpoint was safety and tolerability, to determine the recommended phase II dose (RP2D) of CKM for extended efficacy study. The secondary endpoints included the efficacy (pCR), along with RFS and OS. Tumor and blood biomarkers were analyzed in exploratory studies. RESULTS: Treatment was well-tolerated with mostly grade 1 or 2 treatment-related adverse events (TRAEs) and no DLTs. Grade 3 TRAE were neutropenia (3/9), attributed to CKM (1/9) or paclitaxel (3/9), pneumonia (1/9) and anemia (1/9) attributed to AC. Two additional severe adverse events (pneumonia and squamous cell carcinoma of skin in situ) were observed, unrelated to study treatment. Paclitaxel- or AC-related toxicities were not higher than expected. There was no evidence of delayed or immune-related toxicities 90 days post-treatment. 5/9 (56%) pts attained pCR, and 1 additional pt had ypTmic at the time of surgery. There were no patients with progressive disease. All patients were able to get planned surgery with no additional delays observed. There was consistent (p=0.07) selective increase in CD8α (CTL marker) in on-treatment tumor biopsies with concomitant decrease in CD8α in the blood (p=0.04). CONCLUSIONS: The treatment was well-tolerated and no DLTs were observed and we determined RP2D for future studies. We observed promising clinical activity with pCR + ypTmic rate of 66%, comparable to pembrolizumab combination with NAC. A larger phase II study is being designed to confirm the observed efficacy and to determine if CKM regimen would be a safer short-term alternative to pembrolizumab or if CKM can overcome the resistance to the standard pembrolizumab/NAC therapy. Citation Format: Shipra Gandhi, Mateusz Opyrchal, Cayla Ford, Ronald Slomba, Kristopher Attwood, Tracey O’Connor, Ellis Levine, Pawel Kalinski. Preliminary indications of safety and efficacy of neoadjuvant chemotherapy plus chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib) in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-06-07.

Abstract OT2-17-01: Phase 1 trial of anthracycline chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer

Abstract Background: Only a subset of patients with metastatic triple-negative breast cancers (TNBC) demonstrate response to FDA approved PD-1 immune checkpoint blockade (ICB), and few have durable responses. Data suggests that breast cancers have defects in antigen presentation and that antigen presenting cells especially the DC1 subtype of dendritic cells (DCs) are required for response to ICB. CD40 agonists activate antigen presenting cells including DCs and B cells and also repolarize macrophages to an anti-tumor phenotype. Flt3 ligand is a growth factor that increases differentiation and expansion of DCs. We recently demonstrated in pre-clinical TNBC models that the combination of liposomal-doxorubicin chemotherapy, a CD40 agonist, and a Flt3 ligand improves outcomes compared to alternate combinations. Methods: This is a single arm phase I pilot study of liposomal-doxorubicin, CDX-1140 (CD40 agonist), and CDX-301 (Flt3 ligand) combination therapy in patients with metastatic or unresectable locally advanced metastatic TNBC. Patients will be randomized to 3 lead-in arms (triplet therapy, doublet immunotherapy only, or liposomal-doxorubicin only) for 1 cycle prior to receiving triplet therapy with fresh tissue biopsies before and after the lead-in treatment. CDX-301 will be discontinued after 2 cycles; liposomal-doxorubicin and CDX-1140 will be continued until disease progression or clinically limiting toxicities. Primary endpoint is determination of a recommended phase 2 dose based on treatment-related adverse events including dose-limiting toxicities. Secondary endpoints include anti-tumor immune response after triplet therapy, after immunotherapy alone, and after liposomal-doxorubicin alone; median progression-free survival, overall response rate, duration of response, and clinical benefit rate. Key eligibility criteria are unresectable stage III or stage IV TNBC (ER ≤10%, PR ≤10%, HER2/neu negative), 1st to 3rd line metastatic treatment setting (1st line patients need to be PD-L1 negative by 22C3 assay), measurable disease by RECIST 1.1 criteria, consent for pre-treatment and on-treatment biopsies of amenable soft tissue tumor lesions, no prior treatment with an anti-CD40 antibody or a Flt3 ligand, no anthracycline treatment in the metastatic setting, no prior progression while on anthracycline-based therapy or within 6 months of completing neoadjuvant chemotherapy, and no history of non-infectious pneumonitis or current pneumonitis. This trial will enroll up to 45 patients across multiple sites (NCT05029999). Citation Format: Sangeetha Reddy, Meredith Carter, Isaac Chan, Nisha Unni, Namrata Peswani, Dawn Klemow, Samira Syed, Shahbano Shakeel, Farjana Fattah, Chul Ahn, Yisheng Fang, Heather McArthur, Nicole Sinclair, Michael Yellin, Denise Yardley, Nan Chen, Joyce O’Shaughnessy, Rita Nanda, Suzanne D. Conzen, Carlos Arteaga. Phase 1 trial of anthracycline chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-17-01.

BMX inhibition and HSD3B1-driven resistance in prostate cancer in the Maverick trial.

144 Background: Kinase inhibitors have been ineffective in prostate cancer and have no known role in androgen biosynthesis. Inheritance of the adrenal-permissive HSD3B1(1245C) allele encodes a 3βHSD1 enzyme missense that up-regulates the rate-limiting step of androgen biosynthesis from non-gonadal precursor steroids and confers poor clinical outcomes in castration-resistant prostate cancer (CRPC). About half of all men with prostate cancer inherit the adrenal-permissive HSD3B1 allele. Multiple clinical studies demonstrate that adrenal-permissive HSD3B1 allele inheritance confers more rapid progression on ADT and others also suggest worse CRPC outcomes even after treatment with abiraterone or enzalutamide. However, there is no known method to clinically block 3βHSD1. Furthermore, 3βHSD1 is not known to be phosphorylated. Methods: Mass spectrometry was used to identify protein phosphorylation sites and steroid metabolites, genetic and pharmacologic methods were used to identify the kinase required for 3βHSD1 phosphorylation and mouse xenograft studies were performed with BMX inhibition. The identified mechanism was used to design and launch a multicenter phase 2 study of the BMX inhibitor abivertinib in combination with abiraterone in men with metastatic CRPC. Results: 3βHSD1 enzyme activity requires tyrosine phosphorylation at Y344 by the BMX kinase. Androgen biosynthesis is blocked by a phosphorylation-defective 3βHSD1 344F, or BMX genetic knockdown, or BMX pharmacologic inhibition. BMX inhibition using zanubrutinib suppresses CRPC growth in the C4-2 and VCaP xenograft models by blocking intratumoral androgen synthesis and tumor androgen receptor (AR) signaling. Discovery of this mechanism provides the rationale for the phase 2 Maverick trial of abivertinib, a BMX inhibitor, combined with abiraterone, in men with CRPC with adrenal-permissive HSD3B1 allele inheritance (NCT05361915). Eligibility includes 1) presence of metastatic CRPC, 2) measurable and/or non-measurable disease, and 3) confirmed positivity of adrenal-permissive HSD3B1(1245C) allele inheritance via central testing (cap heterozygosity at 50%). Patients will be enrolled in 2 arms: 1) abiraterone naïve (n=45) and 2) abiraterone progressing (n=55). All patients will receive treatment with abivertinib 200mg twice daily with abiraterone 1000mg daily and prednisone 5mg by mouth twice daily. The primary outcome is 6-month radiographic progression-free survival. On-treatment biopsies will be used to inform mechanisms of response and resistance in patients. Conclusions: BMX is required for 3βHSD1 phosphorylation, androgen biosynthesis and CRPC progression with the adrenal-permissive HSD3B1(1245C) allele. The Maverick trial will test clinical proof-of-concept of BMX inhibition in men with adrenal-permissive HSD3B1(1245C) inheritance. Clinical trial information: NCT05361915 .

Patient-reported outcomes (PROs) and biomarkers in daNIS-2, a phase III study comparing NIS793 plus nab-paclitaxel/gemcitabine (NG) vs placebo plus NG in first-line (1L) metastatic pancreatic ductal adenocarcinoma (mPDAC).

TPS767 Background: The 5-year survival rate for mPDAC is <5% with current standard-of-care (SOC) chemotherapies, and this period is often associated with a high symptom burden. Currently, targeted treatment options are only available to a minority of patients (pts) with mPDAC. Here, we present the PRO and biomarker objectives of daNIS-2, a randomized, double-blind, Phase III study (NCT04935359) of the anti–TGF-β monoclonal antibody NIS793 in combination with SOC chemotherapy in pts with 1L mPDAC. Methods: Eligible pts are adults (≥18 years) with previously untreated mPDAC who are eligible for treatment in the 1L setting and not amenable to potentially curative surgery. The daNIS-2 study includes safety run-in and randomized parts. In the safety run-in part, pts will receive a combination of NIS793 (2100 mg intravenous [IV] every 2 or 4 weeks) and NG (gemcitabine 1000 mg/m2 IV; nab-paclitaxel 125 mg/m2 IV; each on Days 1, 8, and 15 of a 28-day cycle). Following dose confirmation, ~480 pts will be randomized to one of two treatment arms (~240 pts per arm): an investigational arm (NIS793 + NG) or a control arm (placebo + NG). The primary objective of the randomized part is to compare overall survival between arms. Secondary objectives (randomized part only) include the evaluation of health-related quality of life (using PROMIS-29 v2.1 and EQ-5D-5L). Additional PROs will be assessed as exploratory endpoints (using PRO-CTCAE, PGIC, PGIS, and FACT-GP5). Safety endpoints include the incidence and severity of adverse events, changes in laboratory parameters, vital signs, body weight and cardiac assessments, dose adjustments, and dose intensity. Biomarker assessments will be carried out as exploratory objectives; biomarker assessments in baseline or archival tumor biopsies will explore the relationships of programmed death-ligand 1 expression, CD8, and tumor burden with clinical efficacy endpoints. Recommended, on-treatment biopsies (Cycle 3 and at the end of treatment) will investigate the effect of NIS793 on the tumor microenvironment, immune cell population changes, gene expression, and potential mechanisms of NIS793 resistance. Circulating tumor DNA will be analyzed in serial blood samples (Day 1 of Cycles 1–3, every two cycles for 52 weeks, then every three cycles) to monitor disease and identify/correlate gene-specific oncogenic alterations with clinical efficacy. Additional peripheral assessments will include measurements of cytokine levels relating to clinical/immune responses and nucleic acids to evaluate the effects of TGF-β blockade. This study is ongoing and plans to enroll pts from 145 sites across 28 countries. The first pt was treated on October 20, 2021. Clinical trial information: NCT04935359 .

A window of opportunity trial for metastatic (WOO-M) pancreatic ductal adenocarcinoma (PDAC): A biomarker discovery platform.

TPS781 Background: Even as the number of targeted agents increases, therapeutic options for PDAC patients remain limited by a lack of biomarkers that can predict the potential clinical benefit of single agents or combination therapeutic strategies. To address this challenge, we implemented the WOO-M trial to serve as a highly adaptable, biomarker discovery platform that enables a preliminary assessment of biological activity of one or more targeted agents in patients with metastatic (m) PDAC. By using paired pre- and on-treatment biopsies, we can assess the independent biological impact of targeted agent(s) that perturb key signaling pathways predicted to drive PDAC tumorigenesis and resistance to therapy in order to identify new combination therapy strategies. Methods: WOO-M is a multi-arm early phase I trial platform to obtain longitudinal tumor samples to assess the pharmacodynamic (PD) effects of one or more study agent(s) alone or in combination in patients with mPDAC. The trial uses a Master Protocol to describe overarching design and logistics, and sub-protocols separately describe each study arm with different agent(s) – alone or in combination. Participants are alternatingly assigned to an available study arm (max. 20 participants per arm). There are no limits to the number of prior therapies. Participants undergo a baseline tumor biopsy, then receive their assigned study agent(s) for a specified timeframe (not exceeding 30 days), and then undergo a repeat tumor biopsy before proceeding to receive therapy per standard of care or clinical trials. The paired biopsy material from each patient is analyzed using multiplex assays that provides spatially-resolved, single-cell strategies to assess the effects of targeted therapies on tumor cell state and heterogeneity. The primary study objective is to independently assess the PD feasibility of detecting a measurable change in tumor biology at post-treatment from baseline for participants within a study arm. WOO-M uses a 2-stage Bayesian efficacy monitoring approach with a futility-stopping rule for each study arm. In stage 1, if 6 or more of the first 10 participants of a study arm have a detectable change in tumor biology measurements post-treatment from baseline, then the study arm may enroll up to an additional 10 participants. A study arm stops enrolling if 5 or fewer of the first 10 participants do not have a measurable change in tumor biology. To date, 4 study arms are being evaluated: 1) poly (ADP-ribose) polymerase inhibitor (PARPi), olaparib (300 mg PO BID for 10 days), 2) MEK inhibitor (MEKi), cobimetinib (60 mg PO QD for 10 days), 3) ERK inhibitor, LY3214996 (400 mg PO QD for 10 days), and 4) PLK1 inhibitor, onvansertib (12 mg/m2 PO QD for 10 days). Of 21 participants enrolled and treated to date, 8 received cobimetinib, and 13 received olaparib. Additional arms are in the process of opening at time of submission. Clinical trial information: NCT04005690

A pilot study of gut microbiome modulation to enable efficacy of neoadjuvant checkpoint-based immunotherapy (IO) following chemotherapy in pancreatic ductal adenocarcinoma (PDAC).

TPS759 Background: Neoadjuvant therapy is now a standard strategy for localized PDAC, and this preoperative window provides an excellent opportunity in which to test novel therapeutic approaches. Trials using IO in PDAC have largely been unsuccessful, and immune tolerance is implicated as a major mechanism of IO resistance. The gut and tumor microbiome have emerged as key modulators of response to both IO and chemotherapy. High tumor microbial diversity has been linked to longer survival in PDAC, and gut microbiota may have the ability to colonize pancreatic tumors. There is preclinical evidence that endogenous microbiota promotes the immunosuppressive tumor microenvironment characteristic of PDAC through stimulation of pro-tumor regulatory T cells and myeloid-derived suppressor cells at the expense of anti-tumor activated CD4+ and CD8+ T cells. Further, preclinical data show that ablation of the gut microbiota may induce T cell activation, improve immune surveillance, and increase sensitivity to IO. We hypothesize that ablative antibiotics (abx) will activate tumor infiltrating T cells and enhance IO activity in PDAC. Methods: This is a multi-center, single-arm, open-label pilot study of pre-operative chemotherapy followed by abx and pembrolizumab to evaluate overall immune response to abx + IO. Eligible patients will have histologically confirmed, resectable PDAC, without probiotic consumption or use of immunosuppressive agents. Patients will be enrolled at diagnosis after undergoing a baseline biopsy. They will then receive mFOLFIRINOX every 2 weeks for 5 cycles. After completion of chemotherapy, ciprofloxacin 500 mg PO BID and metronidazole 500 mg PO TID will be administered for 21 days, and pembrolizumab 200 mg IV x1 will be given 7 days after initiation of abx. Patients will then undergo surgical resection and adjuvant therapy at the investigators’ discretion. On-treatment biopsy will be obtained prior to cycle 5 of mFOLFIRINOX. Blood and stool will be collected at baseline, during mFOLFIRINOX therapy, before and after pembrolizumab administration, and postoperatively. The primary endpoint is the overall immune response, which will be measured as activation of one or more of the T cell markers HLA-DR, CD38, CD25, Ki67, and CD69, defined as an increase in expression level of at least 20% from the on-treatment specimen to the surgical specimen, before and after abx + IO. Key secondary endpoints will be the evaluation of adverse events, R0 resection rate, histologic regression score, objective response rate, and overall survival rate. Correlative studies will be carried out to evaluate immune and microbiome changes in the blood and tissue following abx and pembrolizumab. These findings will be correlated with clinical endpoints. The target study accrual is 25 patients. Clinical trial information: NCT05462496 .

Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial

While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAFV600E CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431.

Combining PARP Inhibition and Immunotherapy in BRCA-Associated Cancers.

Poly (ADP-ribose) polymerase (PARP) inhibitors have significantly improved treatment outcomes of homologous recombination (HR) repair-deficient cancers. While the activity of these agents is largely linked to multiple mechanisms underlying the synthetic lethality of PARP inhibition and HR deficiency, emerging data suggest that their efficacy is also tied to their effects on the immune microenvironment and dependent upon cytotoxic T-cell activation. Effects observed in preclinical models are currently being validated in on-treatment biopsy samples procured from patients enrolled in clinical trials. Although this work has stimulated the development of combinations of PARP inhibitors with immunomodulatory agents, results to date have not demonstrated the superiority of combined PARP inhibition and immune checkpoint blockade compared with PARP inhibition alone. These results have stimulated a more comprehensive assessment of the immunosuppressive components of the tumor microenvironment that must be addressed so that the efficacy of PARP inhibitor agents can be maximized.

Landscape of immune-related signatures induced by targeting of different epigenetic regulators in melanoma: implications for immunotherapy

BackgroundImprovement of efficacy of immune checkpoint blockade (ICB) remains a major clinical goal. Association of ICB with immunomodulatory epigenetic drugs is an option. However, epigenetic inhibitors show a heterogeneous landscape of activities. Analysis of transcriptional programs induced in neoplastic cells by distinct classes of epigenetic drugs may foster identification of the most promising agents.MethodsMelanoma cell lines, characterized for mutational and differentiation profile, were treated with inhibitors of DNA methyltransferases (guadecitabine), histone deacetylases (givinostat), BET proteins (JQ1 and OTX-015), and enhancer of zeste homolog 2 (GSK126). Modulatory effects of epigenetic drugs were evaluated at the gene and protein levels. Master molecules explaining changes in gene expression were identified by Upstream Regulator (UR) analysis. Gene set enrichment and IPA were used respectively to test modulation of guadecitabine-specific gene and UR signatures in baseline and on-treatment tumor biopsies from melanoma patients in the Phase Ib NIBIT-M4 Guadecitabine + Ipilimumab Trial. Prognostic significance of drug-specific immune-related genes was tested with Timer 2.0 in TCGA tumor datasets.ResultsEpigenetic drugs induced different profiles of gene expression in melanoma cell lines. Immune-related genes were frequently upregulated by guadecitabine, irrespective of the mutational and differentiation profiles of the melanoma cell lines, to a lesser extent by givinostat, but mostly downregulated by JQ1 and OTX-015. GSK126 was the least active drug. Quantitative western blot analysis confirmed drug-specific modulatory profiles. Most of the guadecitabine-specific signature genes were upregulated in on-treatment NIBIT-M4 tumor biopsies, but not in on-treatment lesions of patients treated only with ipilimumab. A guadecitabine-specific UR signature, containing activated molecules of the TLR, NF-kB, and IFN innate immunity pathways, was induced in drug-treated melanoma, mesothelioma and hepatocarcinoma cell lines and in a human melanoma xenograft model. Activation of guadecitabine-specific UR signature molecules in on-treatment tumor biopsies discriminated responding from non-responding NIBIT-M4 patients. Sixty-five % of the immune-related genes upregulated by guadecitabine were prognostically significant and conferred a reduced risk in the TCGA cutaneous melanoma dataset.ConclusionsThe DNMT inhibitor guadecitabine emerged as the most promising immunomodulatory agent among those tested, supporting the rationale for usage of this class of epigenetic drugs in combinatorial immunotherapy approaches.

CD8 Presence and Dynamics in Glofitamab-Treated Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma Using the CD8-Specific PET Tracer 89Zr-Crefmirlimab Berdoxam

Background: Glofitamab, a CD20xCD3 T-cell-engaging bispecific monoclonal antibody with a novel 2:1 (CD20:CD3) configuration, redirects T cells to eliminate normal and malignant B cells. In ongoing Phase I/II trials, glofitamab has shown high response rates and durable complete responses in patients with relapsed/refractory (R/R) B-cell lymphomas (Hutchings et al. 2021, J Clin Oncol), including diffuse large B-cell lymphoma (DLBCL; Dickinson et al. ASCO 2022). In this imaging study (NCT03533283), the glofitamab-mediated effects on the distribution of CD8-expressing cells, such as cytotoxic T cells, in patients with R/R B-cell non-Hodgkin lymphoma (NHL) were captured with the novel 89Zr-radiolabeled anti-CD8 humanized minibody crefmirlimab berdoxam (CD8 tracer) for positron emission tomography (PET). Methods: Patients received obinutuzumab (1000 mg) once 7 days before the 1st glofitamab dose; glofitamab was then given as step-up doses on Day 1 (2.5 mg) and Day 8 (10 mg). The baseline infusion of the CD8 tracer was administered prior to obinutuzumab and the on-treatment infusion of the CD8 tracer was performed 48 h (±24 h) after the 1st or 2nd glofitamab dose. The tracer was infused at a fixed dose of 37 MBq (1.5 mg protein); PET/CT scans were performed 24 h post infusion. The primary endpoint was quantification of changes of CD8 tracer uptake (SUVmax) in tumor lesions before and after glofitamab treatment. Paired biopsies for CD8 immunohistochemistry (IHC) and serum pharmacokinetic samples were taken at baseline and on-treatment. Results: To date, 9 evaluable patients with a median of 2 prior treatment lines (range: 1-6) with B-cell NHL (follicular lymphoma (FL), n=5; transformed FL, n=1; DLBCL, n=3) were enrolled. CD8 tracer infusions were well tolerated with no reported tracer-related adverse events. No difference in serum clearance of the CD8 tracer was observed between baseline and on-treatment infusions. Tracer uptake was detected in CD8 rich tissues (e.g. spleen, bone marrow, lymph nodes) and clearance organs (liver, kidney, intestine). Three patients with DLBCL received on-treatment CD8-PET/CT scans after the 2nd glofitamab dose. 11 analyzed DLBCL lesions showed variable CD8 tracer uptake at baseline between SUVmax 2.6-38.27. Following treatment with glofitamab, the signal in 64% of the analyzed lesions was increased 1.2-3.3-fold while the signal in 18% of the lesions was stable and 18% showed a decreased signal compared to baseline. The distribution of the CD8 tracer in individual lesions was highly heterogeneous with areas of low and higher uptake (Fig. 1A). The CD8 IHC of paired biopsy samples taken after PET scans in 1 patient with DLBCL showed good correspondence between PET and IHC signal. The on-treatment biopsy contained quantifiable T cell amounts without detection of viable tumor tissue, suggesting a fast onset of glofitamab activity prior to the selected imaging/biopsy timepoint. 6 patients with FL were analyzed. In 87% of the analyzed 39 FL lesions, a high and heterogenous CD8-tracer uptake between SUVmax 5.3-29.2 was observed at baseline. After one dose of 2.5 mg glofitamab, 36% of the analyzed lesions showed a stable or ≤1.3-fold increase of CD8-tracer uptake. In 64% of the analyzed lesions a ≤2.1-fold decrease of CD8-tracer uptake was observed (Fig.1B). After the 2nd glofitamab dose, CD8-PET-scans of patients with FL revealed that in 86% of the analyzed lesions CD8 tracer uptake decreased 1.2-11.9-fold compared with baseline scans, accompanied by shrinkage of lesion size as detected on low dose CT. Conclusions: Changes in the uptake of the CD8 tracer were observed early after treatment with glofitamab. Preliminary results suggest indication-specific differences in T-cell dynamics after two treatment interventions with glofitamab. In DLBCL, the CD8 tracer confirmed recruitment of T cells to the majority of tumor lesions after two glofitamab treatments. In FL, the preliminary CD8-tracer results suggest that the intra tumoral T cells exhibit their antitumoral effects immediately after glofitamab administration and thus faster compared to the glofitamab-mediated effects in DLBCL. In addition these data indicate that the optimal imaging time point is after the 1st glofitamab dose. 89Zr-crefmirlimab berdoxam is a promising innovative tool to assess the presence and dynamic change of CD8 T cells after treatment with novel immunotherapies for hematological malignancies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract A016: Phase 1 study of hypofractionated radiation in combination with tremelimumab and durvalumab in refractory metastatic pancreatic adenocarcinoma

Abstract Immune checkpoint inhibitors have limited clinical activity in pancreatic cancer. Based on preclinical data, we hypothesized that hypofractionated radiation may cooperate with dual checkpoint inhibition in patients (Rech AJ, et al, Cancer Research, 2018). We therefore designed a phase 1 study to evaluate the safety and feasibility of two schedules of hypofractionated radiation with durvalumab (anti-PDL1) and tremelimumab (anti-CTLA-4) in patients with metastatic pancreatic, lung, and breast cancers and melanoma. Here, we present the data for pancreatic adenocarcinoma. Methods: Patients with metastatic pancreatic cancer treated with at least one prior line of therapy with measurable disease by RECIST in addition to an index lesion amenable to hypofractionated radiation were enrolled sequentially to two cohorts – cohort A evaluating 3 fractions of 8 Gy or cohort B evaluating 1 fraction of 17 Gy. Patients received 4 cycles of tremelimumab 1 mg/kg IV and durvalumab 20 mg/kg IV every 4 weeks for 4 doses followed by durvalumab 10 mg/kg IV every 2 weeks until progression. Radiation was given in week 2 of treatment. Patients were replaced if they did not receive week 5 of therapy on trial, but were included in safety/feasibility analysis. Blood and, when feasible, baseline and on-treatment biopsies were obtained for exploratory biomarker evaluation. Results: 10 patients were treated in cohort A and 21 patients in cohort B. All patients were included in the safety and feasibility assessment. Overall, treatment was well tolerated in both cohorts. The most common adverse events were grade 1 or 2 fatigue (A 30%, B 23.8%), diarrhea (A 10%, B 14.3%), pruritis (A 10%, B 14.3%), AST/ALT elevation and constipation (each A 10%, B 9.5%). Grade 3 diarrhea, elevated bilirubin, pneumonitis, and syncope were noted in 1 patient each, all in cohort B. Grade 5 pneumothorax occurred after baseline biopsy in 1 patient. Grade 2 hyperthyroidism (A) and pneumonitis (B) were noted each in 1 patient. 8 patients in cohort A and 13 patients in cohort B were evaluable for response. In cohort A, 50% of patients had stable disease as best response, and median overall survival was 4.9 months. In cohort B, 23.1% had PR and 30.8% had SD as best response and mOS was 5.2 months. Responses occurred more frequently when metastatic lung nodules were radiated – SD in 3/5 (60%) patients in cohort A, PR in 3/10 (30%) and SD in 4/10 (40%) patients in cohort B, compared to SD in 1/3 (33%) patients in cohort A and 0/3 (0%) patients in cohort B who underwent radiation to a liver lesion. Biomarker analysis will be presented. Conclusions: The combination of durvalumab, tremelimumab with hypofractionated radiation is safe and feasible in a refractory pancreatic adenocarcinoma patient population. Encouraging clinical activity warrants further evaluation, especially when hypofractionated radiation is delivered to lung nodules. Citation Format: Mark H. O'Hara, Adham S. Bear, Max M. Wattenberg, Ursina R. Teitelbaum, Kim A. Reiss, Thomas B. Karasic, Charles J. Schneider, Peter J. O'Dwyer, Edgar H. Ben-Josef, Andrzej P. Wojcieszynski, Amit H. Maity, Rosemarie H. Mick, Robert H. Vonderheide. Phase 1 study of hypofractionated radiation in combination with tremelimumab and durvalumab in refractory metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A016.

Pharmacodynamic Biomarkers of Mosunetuzumab Efficacy and Safety in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma: Results from a Phase I/II Study

Background: Mosunetuzumab (Mosun) is a CD20xCD3 bispecific antibody that engages T cells and B cells to induce a synthetic synapse leading to T-cell activation and production of cytokines involved in immune-directed B-cell killing. Mosun is being developed as a fixed-duration, off-the-shelf therapy for the treatment of non-Hodgkin lymphoma (NHL). A Phase I/II study (NCT02500407) is investigating Mosun monotherapy in patients (pts) with relapsed or refractory NHL (aggressive NHL [aNHL; n=278]: DLBCL, MCL, RS, transformed FL, FL3b; indolent NHL [iNHL; n=168]: FL, MZL, SLL) using fixed (Group A; n=33) and step-up (Group B; n=414) dosing schedules. We report exploratory pharmacodynamic (PD) biomarker analyses from this study across dosing cohorts and histologies in relation to mechanism of action, dose, safety, and clinical activity. Methods: In Group A, the target dose (TD) of intravenous Mosun was administered on Cycle (C) 1 Day (D) 1 (0.05-2.8mg). In Group B, step-up doses (SUD) were administered on C1D1 (0.4-1mg), C1D8 (1-2mg) and the TD on C1D15 (2.8mg-60mg). In both groups, TD was given on D1 of subsequent cycles (up to C8 for pts achieving a complete response or C17 for pts achieving partial response or stable disease). The recommended dose was confirmed as C1D1 (1mg), C1D8 (2mg), C1D15 and C2D1 (60mg) and C3D1-C8/C17 (30mg). Cytokines (IL-6, INF-γ, TNF-α, IL-2, IL-10) were measured by ELISA or SIMOA assays and peripheral blood (PB) immune-cell subsets by flow cytometry. Baseline (BL) tumor biopsies and on-treatment (on-Tx) biopsies collected between C1D15 and C3D1 were assessed by CD8 immunofluorescence (IF) and RNAseq. Results: In Group A, cytokine release was observed at Mosun doses of ≥0.4mg. Cytokine release was acute and transient, occurring early after Mosun administration and returning to BL levels by 24 hours. Despite a low to moderate correlation across cytokines at BL, a similar pattern of cytokine secretion was observed following administration of Mosun. High levels of cytokines were detected in pts who experienced cytokine release syndrome (CRS). In Group B, SUD was initiated as a CRS mitigating strategy, using the identified, pharmacodynamically active dose as the initial dose. Although a second cytokine peak was observed at C1D15 during SUD, with a trend towards higher peaks with increasing Mosun doses, significantly higher doses could be administered without corresponding cytokine release. While Mosun exhibited linear pharmacokinetics, dose-dependent PD relationships can be confounded by variables that affect target binding including residual anti-CD20 monoclonal antibodies from prior treatment. Taking CD20 receptor occupancy into account, exposure-response analyses using IL-6 or INF-γ confirmed that SUD ameliorates cytokine release to enable higher Mosun dosing to achieve clinically active exposure (Figure). T-cell margination, activation (CD69), and proliferation (Ki67) were observed in CD4+ and CD8+ T cells in a time-dependent manner that paralleled PD changes observed with cytokines in both aNHL and iNHL. CD4+ and CD8+ T-cell activation was observed after the initial Mosun dose and to a lesser extent with subsequent doses. In contrast, B-cell depletion was observed early after initial Mosun administration and was sustained throughout treatment. At BL, higher levels of PB B cells were associated with improved response in pts with aNHL. However, this may reflect prognostic features and prolonged time since prior therapy. On-Tx increases in activated T-cell subsets (% CD4+DR+GzB+ and % CD4/8 Tn DR+) were also associated with improved response. Changes in biomarker levels were observed predominantly with the first dose of Mosun; associations with response were primarily seen in pts with aNHL vs iNHL, possibly reflective of the distinct immune biology. Importantly, PD changes observed in PB were also observed in tumors. Increases in CD8+ T cells (CD8 IF) in on-Tx tumor biopsies were predominantly, but not exclusively, reported in pts who achieved a response. Consistent with PB observations, changes in RNA levels of CD8, cytokines and markers of T-cell activation (i.e. GZMB and TIM3) were also observed by RNAseq at the tumor site. Conclusions: PD biomarkers of Mosun in PB and tumor biopsies confirm immune-cell activity associated with Mosun treatment and demonstrate the benefit of SUD as a CRS mitigation strategy to enable administration of clinically active doses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Tumour infiltrating B cells discriminate checkpoint blockade-induced responses

BackgroundImmune cell-driven anti-cancer activity is paramount for effective responses to checkpoint inhibitors (ICB). However, the contribution of the different immune cell subsets in the circulation and within the tumour is poorly understood. Materials and methodsTo elucidate the role of the different cell subsets in anti-tumour responses elicited by ICB, we performed single-cell analysis of the transcriptome and surface proteome of paired pre- and early on-treatment metastatic melanoma tumour biopsies and matched peripheral blood mononuclear cell samples. We next compared the survival of metastatic melanoma patients treated with ICB according to the abundance of pre-treatment tumour-infiltrating B cell clonotypes. ResultsWe identified cell clusters associated with disease control or progression, defined differential expression of biological pathways likely involved in the immune awakening against the tumour and examined how cell–cell communication patterns between the tumour cell subsets change during treatment. Furthermore, we discovered that B cells (immunoglobulin expression and abundance of B cell clonotypes) discriminate the clinical response after ICB and propose that B cells likely contribute to anti-tumour immunity by antigen presentation through major histocompatibility complex molecules. Finally, we demonstrated that the abundance of tumour-infiltrating B cell clonotypes at baseline identifies two distinct risk groups, a finding that we confirmed in an independent cohort. ConclusionsOur exploratory translational study provides new insights on the mechanistic role of B cells in anti-melanoma immunity during treatment with ICB. Additionally, we support pre-treatment B cell tumour infiltration as a promising prognostic biomarker to be further validated as a tool for clinical risk stratification.

Immune cells in mesothelioma microenvironment simplistic marker of response to nivolumab plus ipilimumab?

IntroductionMalignant pleural mesothelioma (MPM) is a malignant disease of the pleura which recently can be treated with immune checkpoint inhibitors (ICI). To optimize this treatment, a better understanding of the tumor micro environment is needed. We investigated subgroups of immune cells in subsequent tumor biopsies of patients treated with ICI. MethodsBiopsies from MPM patients included in two clinical ICI trials (nivolumab alone and an ipilimumab/nivolumab combination) were examined. At baseline and after 6 weeks of treatment, pleural biopsies were taken to examine the tumor microenvironment (CD20+, CD4+, CD8+, FoxP3+ and PD-1+ ). Cell density was defined as the number of marker positive cells per mm2. Radiological responses were evaluated as partial response, stable disease or progressive disease according to modified RECIST criteria. ResultsThirty-four and 36 patients were included in the nivolumab and ipiliumumab/nivolumab trial respectively. In the nivolumab trial, no significant differences in cell densities were seen in baseline biopsies of patients with partial response versus progressive disease. In contrast, in the ipilimumab/nivolumab trial, a higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells at baseline was significantly correlated with partial responses. On-treatment biopsies of both trials did not show significant changes when compared to baseline biopsies. ConclusionBiopsies from patients responding to nivolumab plus ipilimumab treatment show a significant higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells, without a change after 6 weeks of treatment. This observation is a first step in exploring the tumor microenvironment as predictor of response in ICI treatment in MPM.

132TiP Biomarker assessments in daNIS-3: A phase II study of NIS793 and other new investigational drug combinations with standard-of-care (SoC) therapy vs SoC alone for the second-line treatment of patients (pts) with metastatic colorectal adenocarcinoma (mCRC)

132TiP Biomarker assessments in daNIS-3: A phase II study of NIS793 and other new investigational drug combinations with standard-of-care (SoC) therapy vs SoC alone for the second-line treatment of patients (pts) with metastatic colorectal adenocarcinoma (mCRC)

820P Nivolumab (NIVO) +/- relatlimab (RELA) or ipilimumab (IPI) for patients (pts) with advanced treatment-naïve or -refractory basal cell carcinoma (BCC)

Standard therapies for pts with locally-advanced or metastatic BCC (aBCC) include hedgehog pathway inhibitors (HHi), limited by tolerability, and 2nd-line (2L) anti-PD-1, limited by suboptimal response rates (∼20-30%). 1L anti-PD-1 efficacy data are limited to case reports, and anti-LAG-3 data have not been reported in BCC. The current study tests NIVO (anti-PD-1) alone in treatment-naïve and HHi-experienced pts, and NIVO+RELA (anti-LAG-3) or NIVO+IPI (anti-CTLA-4) in anti-PD-1-refractory aBCC (NCT03521830). The primary endpoint was overall response rate (ORR) per RECIST v1.1. Treatment-naïve and HHi-experienced pts with aBCC received NIVO 480 mg IV q4 weeks (W) for ≤48W. Pts with stable disease (SD) at ≥36W or progressive disease (PD) on anti-PD-1 received NIVO 480 mg + RELA 480 or 960 mg IV q4W x 12, or NIVO 240 mg + IPI 1 mg/kg IV q3W x 4 then NIVO 480mg q4W x 7. H&E-stained tumor biopsy specimens taken 2-12W after treatment initiation or regimen change were scored for % residual viable tumor (RVT) [Stein, et al. Ann Oncol, 2019]. 24 pts (5 metastatic) were enrolled 12/2018 – 3/2022, 22 of whom were evaluable. Pts received NIVO (n=15; 10 treatment-naïve), NIVO+RELA (n=8), or NIVO+IPI (n=1). Median follow-up was 9.9 mo (range 1.8 - 38.4). Toxicities associated with each regimen were consistent with previous experience. Complete or partial response (CR, PR) to NIVO was observed in 5/10 (50%) and 1/5 (20%) pts in the 1L and 2L settings, respectively. 9 pts had SD (median duration 8 mo). 6 evaluable pts received NIVO+RELA; PD (n=1), SD (n=4), PR (n=1, 0% RVT at 4W; this pt had SD >48W on 1L NIVO). One pt who received NIVO+IPI after HHi and NIVO had PD. No responses were seen in 5 pts with metastatic BCC regardless of cohort. In 14/15 pts who received NIVO or NIVO+RELA and underwent tumor biopsy at ≤12W, ≤35% RVT was associated with PR or CR. 1L NIVO demonstrated an ORR of 50% among 10 pts with aBCC. NIVO+RELA mediated tumor regression in 1/6 anti-PD-1-refractory pts. ≤35% RVT in on-treatment biopsy was associated with response and warrants further exploration as a predictive biomarker. These preliminary findings in this ongoing trial support testing NIVO+RELA in treatment-naïve pts with aBCC.

Intratumoral administration of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells in combination with talimogene laherparepvec in immune checkpoint blockade refractory advanced melanoma patients: a phase I clinical trial

BackgroundIntratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in initiating antitumor immune responses and relicensing of anti-tumor cytotoxic T lymphocytes within the tumor microenvironment. Talimogene laherparepvec (T-VEC) induces...

Safety and immunogenicity of Anti PD-L1 (Atezolizumab) given as an immune primer or concurrently with extended field chemoradiotherapy for node positive locally advanced cervical cancer: an NRG Oncology trial (024)

Safety and immunogenicity of Anti PD-L1 (Atezolizumab) given as an immune primer or concurrently with extended field chemoradiotherapy for node positive locally advanced cervical cancer: an NRG Oncology trial (024)