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89 Background: Combination treatment with regorafenib (80–120 mg/day, PO, 3 wks on/1 wk off) plus nivolumab (480 mg IV Q4W) showed manageable safety but modest efficacy in a phase 2 study of 70 pts from North America with pMMR/MSS chemotherapy-resistant metastatic CRC (mCRC). Five pts had a partial response (PR; objective response rate [ORR]: 7%); all did not have liver metastases at baseline (n = 5/23; ORR: 22%). One pt had a confirmed complete response (CR) after the primary completion analysis of the study (ASCO 2021). This retrospective exploratory analysis investigated the potential association between specific biomarkers and anti-tumor activity, and how those biomarkers are modulated by treatment with regorafenib plus nivolumab. Methods: In formalin-fixed paraffin-embedded tumor samples obtained at baseline and Cycle (C) 2 Day (D) 8, immune-related biomarkers were assessed via immunohistochemistry (IHC), and RNA sequencing was used for gene expression profiling/gene signatures. Pre-/on-treatment blood samples were collected to measure circulating tumor DNA (ctDNA) and soluble biomarkers. Results: A total of 40 and 27 baseline tumor samples and 14 and 5 paired tumor samples at baseline/C2D8 were available for IHC and RNA sequencing, respectively. Higher baseline protein and mRNA expression of biomarkers for pre-existing immune sensitivity (eg, effector T cells) trended with anti-tumor activity. These biomarkers were expressed at lower levels in pts with liver metastases vs those without liver metastases at baseline. Cytotoxic T cell density was elevated on C2D8 but did not correlate with anti-tumor activity. Increased mean variant allelic frequency in ctDNA at C2D1 predominated in pts with progressive disease (PD), while clearance of ctDNA at C2D1 was only noted for the one pt with a CR. High clonal tumor mutational burden in ctDNA showed a numerical trend with anti-tumor activity (PD vs. SD/PR; P=0.058) and PFS (P = 0.072). Baseline serum levels of select markers related to angiogenesis (eg, vascular endothelial growth factor [VEGF] D) were associated with inferior anti-tumor activity (P = 0.002). Serum levels of immune-related soluble biomarkers (eg, tumor necrosis factor alpha) increased on treatment (P < 0.005), while levels of soluble VEGF receptor 2 decreased (P < 0.001). Conclusions: This study of pts with MSS mCRC treated with regorafenib plus nivolumab suggests that baseline tumor biomarkers for pre-existing immune sensitivity trended with anti-tumor activity, whereas select baseline peripheral biomarkers related to angiogenesis trended with inferior anti-tumor activity. Pharmacodynamics effects were observed, yet no significant correlation with anti-tumor activity was found. Due to the small sample size and retrospective nature, these analyses are hypothesis-generating. Clinical trial information: NCT04126733.

3560 Background: The role of immunotherapy in the treatment of pMMR/MSS metastatic CRC is not established. A Japanese phase 1b trial in this setting showed the combination of regorafenib (multikinase inhibitor with immunomodulatory activity) plus nivolumab (anti PD-1) had encouraging activity and manageable safety (Fukuoka, 2020). This study further assessed the safety and efficacy of this combination. Methods: Patients (pts) from the US aged ≥18 years who progressed on/were intolerant to standard chemotherapy were enrolled. Regorafenib was given orally, once daily in 28-day (D) cycles (21D on/7D off) plus IV nivolumab 480 mg on D1. Regorafenib starting dose was 80 mg; if well tolerated, it could be escalated to 120 mg in Cycle 2. Primary endpoint was overall response rate (ORR; RECIST 1.1); secondary aims included disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety (NCI-CTCAE v5.0 grade). Biomarker analysis was exploratory. Results: 70 pts (59% male) started treatment. At baseline, median age was 57 years (range 34–85), ECOG PS 0/1 was 51%/49%, 67% had liver metastases (mets), and the primary tumor site was right-sided colon in 36% and rectum in 17%. Median number of cycles was 3.0 (range 1–13); 41% of pts escalated regorafenib to 120 mg. Five pts (7.1%) had a partial response (PR) lasting ≥16 weeks (wks) and 22 (31.4%) had stable disease (SD); pts without liver mets had a higher ORR (21.7%). In pts with tumor samples (n = 40), higher baseline expression (IHC) of cytotoxic T cells (CD3+/CD8+/GranzymeB+), Tregs (FoxP3+), and macrophages (CD68+) trended with clinical benefit (PR/SD ≥16 wks/PFS); pts with liver mets had lower expression. Lower plasma levels of biomarkers of vascular biology (e.g. VEGF-D, Ang-2, VWF) trended with longer PFS. Grade (Gr) 3 treatment-emergent adverse events (TEAEs) occurred in 53% of pts and Gr 4 in 10%. Three pts had a Gr 5 TEAE: n = 1 related to the combination (sepsis); n = 1 related to nivolumab only by investigator (sepsis); n = 1 unrelated to treatment (respiratory failure). Most common Gr 3/4 TEAEs: maculopapular rash (14%), fatigue (7%), pneumonia (6%), increased bilirubin (6%). Conclusions: Combination treatment with regorafenib (up to 120 mg/day) and nivolumab (480 mg every 28D) has manageable safety. Efficacy of this combination in the North American population did not emulate results in the Japanese population. Absence of liver mets and expression of specific biomarkers indicate a better response and may warrant further analysis. Clinical trial information: NCT04126733. [Table: see text]

Context: For patients with metastatic papillary thyroid carcinoma (PTC) refractory to radioactive iodine (RAI) treatment, systemic chemotherapy has limited efficacy. Such tumors frequently harbor BRAF V600E, and this alteration may predict responsiveness to vemura-fenib treatment. Objective: We report a metastatic PTC patient refractory to RAI treatment that underwent genomic profiling by next-generation sequencing. The sole genomic alteration identified was BRAF V600E on a near diploid genome with trisomy 1q. With vemurafenib treatment, the patient experienced a dramatic radiographic and clinical improvement, with the duration of an ongoing antitumor response exceeding 23 months. Design: Hybridization capture of 3,769 exons of 236 cancer-related genes and the introns of 19 genes frequently rearranged in cancer was applied to >50 ng of DNA extracted from a formalin-fixed, paraffin-embedded biopsy of a lymph node containing metastatic PTC and was sequenced to a high, uniform coverage of ×616. Results: A BRAF V600E alteration was identified with no other somatic genomic alterations present within a near diploid tumor genome. The patient initially received vemurafenib at 960 mg twice daily that was reduced to 480 mg twice daily due to rash and diarrhea and has experienced an ongoing antitumor response exceeding 23 months by both PET-CT and dedicated CT imaging. Conclusions: Genomic profiling in metastatic, RAI-refractory PTC can reveal a targetable BRAF V600E alteration without compounding somatic alterations, and such patients may derive a more prolonged benefit from vemurafenib treatment. Prospective clinical trials are ongoing to confirm our preliminary observation.

Conjugation of radionuclides to monoclonal antibodies provides a strategy to target radiation therapy directly to cells expressing the antigen of interest, also known as radio-immunotherapy (RIT). This modality has emerged as an effective targeted anti-neoplastic strategy in patients with B cell lymphoma. Certain hematologic malignancies express abnormally high levels of interleukin (IL)-2Rα (CD25, Tac) including cutaneous T cell lymphoma, peripheral T cell lymphoma, anaplastic large cell lymphoma, Hodgkin’s lymphoma (HL) and chronic lymphocytic leukemia. In this study 90Y-labeled daclizumab in CD25 positive malignancies, other than adult T cell leukemia, was investigated. We determined that 15 millicuries (mCi) was the maximum tolerated dose (MTD) in patients without a history of stem cell transplantation. As objective responses were only seen in HL, the phase II component of the study has focused on patients (pts) with relapsed and refractory HL. Eligibility criteria include: Karnofsky performance status (KPS) >50%, AGC >1,500/mm3, platelet >100,000/mm3, adequate hepatic/renal function and informed consent. As an added safety measure pts with a prior history of peripheral stem cell transplantation received an initial dose of 10mCi; in the absence of hematologic toxicity subsequent cycles were administered at 15mCi. All other pts received 15 mi 90Y-daclizumab every 6 weeks until disease progression, DLT or completion of 7 cycles. Ca-DTPA was used to reduce bone marrow exposure to free 90Y. 111In-labeled daclizumab was used for tumor imaging. Thirty pts with Hodgkin’s lymphoma have been treated, median age of 35 years (range, 20 to 67 years). The majority are heavily pre-treated, median of 4 prior chemotherapy regimens, range 1–8. Twenty pts had received a prior autologous transplantation; while 4 patients had received both autologous and allogeneic transplantation. One hundred cycles have been administered, median cycles per patient is 3 (range 1–7 cycles). Of 30 pts treated with 90Y-daclizumab, 12 achieved a complete response (CR), 7 had a partial response (PR), 5 had stable disease and 6 progressed. The response rate in pts who had undergone a transplant was 80%. Interestingly, many of the responses were seen in pts with CD25 negative malignant cells but with surrounding CD25 positive T cells within the tumor microenvironment. The median response duration was 129 days (range 28 to 720 days). The freedom from progression for the pts with a CR ranged from 28 to 788 days with a median of 222 days. There were no infusional reactions, however 5 pts developed non-symptomatic human anti-human antibody (HAHA) titers to daclizumab after one or more treatments. Seven pts failed to recover platelet count to the protocol mandated limit of 75,000, resulting in halting therapy, and 3 pts developed myelodysplastic syndrome (MDS) after 90Y-daclizumab, however one of those patients in retrospect had evidence of the same cytogenetic abnormalities predating therapy. 90Y-daclizumab produces objective responses in relapsed and refractory HL but as with other RIT strategies is not a curative approach. The role for 90Y-daclizumab in patients with relapsed HL with stem cell transplantation will be investigated.