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Advanced, unresectable hepatocellular carcinoma (HCC) has a poor prognosis with median life expectancy of approximately 1 year. Overexpression of PD-L1 in tumor cells and PD-1 on tumor-infiltrating T cells has been associated with poorer prognosis, more advanced disease and higher recurrence rates in HCC. Monoclonal antibodies against PD-1 have demonstrated antitumor activity in patients with solid tumors, including HCC. Tislelizumab, an investigational, humanized IgG4 monoclonal antibody with high affinity and binding specificity for PD-1, has demonstrated preliminary antitumor activity in HCC. Here we describe a head-to-head Phase III study comparing the efficacy, safety and tolerability of tislelizumab with sorafenib as first-line treatment in unresectable HCC.

DAY101 (formerly TAK-580) is an oral, CNS-penetrant, selective small molecule pan-RAF kinase inhibitor that is equipotent against BRAF V600E, wildtype BRAF, and CRAF and can inhibit both RAF monomers and dimers, including BRAF fusions. KIAA1549:BRAF fusions have been identified as a key oncogenic driver for pilocytic astrocytoma (Jones et al. 2008). DAY101 has demonstrated significant activity against this fusion preclinically (Sun et al. 2017). Clinical data for DAY101 has shown a durable 63% response rate with good tolerability in children with low-grade glioma (LGG) harboring RAF fusions (Wright et al. 2020). To explore the potential impact of DAY101 in adult solid tumors harboring specific genomic alterations beyond BRAF V600E, a panel of tumor cell lines and PDX models harboring BRAF fusions, non V600 BRAF mutations or RAS mutations were assessed for anti-proliferative activity in response to DAY101. Furthermore, hypothesis-driven MAPK pathway node inhibitor combinations were explored for potential synergy. While performing favourably in preclinical in vivo studies, DAY101 does exhibit some technical challenges in long-term in vitro assays, particularly in those that extend for more than three days. Accordingly, the tool compound TAK-632, which exhibits comparable biochemical and cellular potency to DAY101, was used alternatively as needed for in vitro assays. Single-agent anti-proliferative activity was observed in a melanoma BRAF fusion PDX model treated with TAK-632 ex vivo, with less sensitivity observed in models beyond melanoma harboring other BRAF fusions. Ongoing combination studies with MEK inhibitors demonstrated strong synergy in PDX models harboring BRAF fusions ex vivo, as assessed by Bliss independence or other relevant scoring systems. In cell lines or PDX models harboring non V600 BRAF mutations, in vitro combination studies demonstrated strong synergy when DAY101 was combined with MEK inhibitors, as assessed by Bliss independence score. DAY101 exhibited modest single agent anti-proliferative activity in a panel of KRAS mutant cell lines in vitro and ongoing combination studies will assess potential synergy when combined with MAPK pathway node inhibitors. DAY101 is currently in clinical development for the treatment of patients under 25 years old with LGG harboring RAF alterations, including BRAF fusions and BRAF mutations. Inhibition of both RAF monomers and dimers by DAY101 enables a broader indication selection strategy, beyond LGG and BRAF alterations. Ongoing translational work will highlight the potential utility of DAY101 in adult tumors harboring RAS or RAF alterations, both as a single agent and in hypothesis-driven combinations. Citation Format: Eleni Venetsanakos, Mike Preigh, Jeannie Hou, Michael C. Cox, Jeremy Bender, Sam C. Blackman. DAY101, a potent pan-RAF inhibitor with activity in preclinical models harboring MAPK pathway alterations beyond BRAF V600E mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1481.

Background Tislelizumab (BGB-A317), an investigational monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. Previous reports from early phase studies suggest tislelizumab was generally well tolerated and had antitumor activity in patients (pts) with advanced solid tumors. Clinical effects of tislelizumab LTE (>12 mo) in pts enrolled in the first-in-human study (NCT02407990) are presented here. Methods Patients with advanced solid tumors received IV tislelizumab 0.5, 2, 5, or 10 mg/kg Q2W, 2 or 5 mg/kg administered Q2W or Q3W, or 200 mg IV Q3W. Antitumor activity was assessed by RECIST v1.1 criteria; PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Results As of 31 Aug 2018, 63 of the 451 pts received tislelizumab for >12 mo. In these 63 pts, median age was 64 yr and 70% had received ≥1 prior systemic therapy. Tislelizumab LTE was most common in NSCLC (n=9), HCC (n=7), and bladder and ovarian (n=5 each) cancers. Four of the 5 pts who achieved CR during this study had LTE to tislelizumab (Table); all 4 pts were PD-L1+ (≥1% expression on tumor cells). Across the LTE cohort, ORR was 66.7%; PR and SD were observed in both PD-L1+ and PD-L1- tumors. The median time to CR/PR (3.7 mo) and duration of CR/PR (21.1 mo) were longer in pts with LTE than pts who responded but did not remain on treatment for >12 mo (2.1 and 6.3 mo, respectively). Rash was the only treatment-related AE (TRAE) reported in ≥15% of pts. Most TRAEs were of mild or moderate severity; arthritis, diarrhea, fatigue, granuloma, hyperglycemia, and lichenoid keratosis (n=1 each) were the only grade ≥3 TRAEs reported with tislelizumab LTE. Conclusion Tislelizumab remained well tolerated for >12 mo and elicited durable responses in pts with a variety of tumor types regardless of PD-L1 status. PD-L1+ (n=35)PD-L1- (n=22)Missing (n=6)Total (N=63)CR4004 (6.3%)PR2113438 (60.3%)SD99220 (31.7%)PD1001 (1.6%)Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD stable disease. Citation Format: Jayesh Desai, Benjamin Markman, Michael Friedlander, Hui Gan, Lisa Horvath, Amanda Townsend, Michael Millward, Michael Jameson, Chia-Jui Yen, Ming-Mo Hou, Jeannie Hou, John Wu, Liang Liang, Sanjeev Deva. Long-term exposure (LTE) to Tislelizumab, an investigational anti-PD-1 antibody, in a first-in-human Phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT084.

Background Vismodegib is approved for treatment of advanced basal cell carcinoma. Objective We sought to characterize vismodegib efficacy and safety in operable basal cell carcinoma. Methods Patients with new, operable, nodular basal cell carcinoma received vismodegib (150 mg/d) followed by excision and Mohs micrographic surgery to ensure clear margins. Cohort 1 received vismodegib for 12 weeks; cohort 2 received vismodegib for 12 weeks, then 24 weeks of observation before excision; and cohort 3 received vismodegib for 8 weeks on/4 weeks off/8 weeks on. Results In all, 24 patients enrolled in cohort 1, and 25 in cohorts 2 and 3. Complete histologic clearance was achieved by 42%, 16%, and 44% of patients in cohorts 1, 2, and 3, respectively. Muscle spasms (76%), alopecia (58%), and dysgeusia (50%) were the most frequent adverse events (AEs). Five (7%) patients discontinued treatment because of an AE. AE reversibility was evaluated in cohort 2 with 24 weeks of observation after treatment discontinuation. Limitations Nonrandomized, small cohort sizes, and short observation durations for some patients are limitations. Conclusion Primary efficacy end points were not met (predefined complete histologic clearance rate: >50% in cohorts 1 and 3; >30% in cohort 2). Safety was comparable when dosed continuously versus intermittently. Posttreatment reversibility of vismodegib-related AEs was demonstrated.

PurposeThis review provides a description of the epidemiology and survival outcomes for cases with metastatic basal cell carcinoma (mBCC) based on published reports (1981–2011).MethodsA literature search (MEDLINE via PubMed) was conducted for mBCC case reports published in English: 1981–2011. There were 172 cases that met the following criteria: primary BCC located on skin, metastasis confirmed by pathology and metastasis not resulting from direct tumour spread. From these, 100 mBCC cases with explicit information on follow-up time were selected for analysis. Survival analysis was conducted using Kaplan–Meier methods.ResultsAmong 100 mBCC cases selected for analysis, including one case with Gorlin syndrome, 50% had regional metastases (RM) and 50% had distant metastases (DM). Cases with DM were younger at mBCC diagnosis (mean age, 58.0 versus 66.3years for RM; P=0.0013). Among 93 (of 100) cases with treatment information for metastatic disease, more DM cases received chemotherapy (36.2% versus 6.5% for RM), but more RM cases underwent surgery (87.0% versus 40.4% for DM). Among all 100 cases, median survival after mBCC diagnosis was 54months (95% confidence interval (CI), 24–72), with shorter survival in DM (24months; 95% CI, 12–35) versus RM cases (87months; 95% CI, 63–not evaluable).ConclusionCases with RM and DM mBCC may have different clinical courses and outcomes. Based on published reports, DM cases were younger at mBCC diagnosis, with shorter median survival than RM cases. This study provides a historical context for emerging mBCC treatments.

Humanized anti-CD25 antibodies (eg, daclizumab) have been successfully used to treat several autoimmune diseases. Paradoxically, IL-2 blockade in mice can induce autoimmunity. An interspecies difference in the relative contribution of IL-2 to CD25+ T regulatory cell (CD25+Treg) versus CD25+ effector cell function might explain this conundrum. Consistent with this are reports that daclizumab inhibits human CD25+ effector cell cytokine production by blocking the expression of CD40L. However, in mice, IL-4 and IL-12 regulate CD40L expression. As human Th1/Th2 cytokine production is also dependent on IL-2, daclizumab's inhibition of CD40L expression could be due to an indirect, rather than a direct, effect of IL-2. Here, we clarify the mechanisms underlying CD40L expression. In contrast to the mouse, human CD40L is regulated by CD28 signaling and IL-2, not the principal Th1/Th2-polarizing cytokines. We find that CD40L is expressed on naive and memory cells and inhibited by daclizumab independently of cell division. Collectively, our results indicate that daclizumab could inhibit CD25+ effector T-cell function in vivo by directly blocking CD40L expression. This difference between mice and human may help explain the paradoxical effects of IL-2R blockade in the 2 species.

9013 Background: BCC pathogenesis involves abnormal Hedgehog pathway (HP) signaling. In the ERIVANCE BCC trial, vismodegib (VISMO), the first FDA-approved HP inhibitor (HPI), showed objective respo...

Background Vismodegib (Erivedge™, GDC-0449) is a first-in-class small-molecule inhibitor of the Hedgehog signaling pathway, which is implicated in the pathogenesis of BCC. ERIVANCE BCC is the pivotal trial of vismodegib for treatment of locally advanced (laBCC) and metastatic BCC (mBCC) patients (pts) for whom there are no other effective therapies. The study met its primary endpoint of overall response rate by independent review (Dirix, ESMO 2011 LBA#1). On behalf of the ERIVANCE BCC investigators, we present the previously unreported updated investigator-assessed (I-A) efficacy and safety endpoints as of Nov 28, 2011 (additional 12 months of follow-up). Methods In this multicenter, nonrandomized 2-cohort study, pts with histologically confirmed laBCC (deemed inoperable or for whom surgery would be significantly disfiguring) or mBCC with RECIST-measurable disease, received 150 mg oral vismodegib daily. Results 104 pts (71 laBCC/33 mBCC) enrolled at 31 global sites. I-A efficacy endpoints were: Nov 26, 2010 Data Cut Nov 28, 2011 Data Cut Parameter mBCC (n = 33) laBCC (n = 63) mBCC (n = 33) laBCC (n = 63) Overall Response Rate (ORR), n (%) [95% CI] 15 (45.5) [28.1–62.2] 38 (60.3) [47.2–71.7] 16 (48.5) [30.8–66.2] 38 (60.3) [47.2–71.7] Median Duration of Response (DOR), months [95% CI] (n = 15) 12.9 [5.6–12.9] (n = 38) 7.6 [7.4–NE] (n = 16) 14.7 [5.6–NE] (n = 38) NE [9.0–NE] Median Progression-free Survival (PFS), months [95% CI] 9.2 [7.4–NE] 11.3 [9.5–16.8] 9.3 [7.4–16.6] 12.9 [10.2–NE] Median Overall Survival (OS), months [95% CI] NA NA 24.1 [14.3–NE] NE [NE–NE] With a median follow-up of 22.3 months, 1- and 2-year survival rates were 78% (95% CI 63.6–92.4%) and 60% (95% CI 42.6–78.1%), for mBCC and 93.1% (95% CI 86.6–99.6%) and 85% (95% CI 75.6–94.7%), for laBCC. Adverse events (AEs) in >30% of pts were muscle spasms, alopecia, dysgeusia, weight decrease, fatigue, nausea, and amenorrhea (in 2/6 female nonmenopausal pts). Serious AEs were reported in 33 pts (32%), compared with 26 (25%) in Nov 2010. Conclusions This 12-month update of I-A efficacy and safety data from the ERIVANCE BCC study confirms the significant clinical benefit of vismodegib in laBCC and mBCC reported at primary analysis. Median DOR and PFS increased numerically with further follow-up. The AE profile was consistent with the prior data cut. Following approval of vismodegib by the FDA, these data further support vismodegib as an effective treatment option for pts with advanced BCC. Disclosure A. Sekulic: Speaker bureau: Genentech/Roche. M.R. Migden: Advisory board: Genentech. A. Oro: Grant: Genentech, Novartis, Infinity. K. Lewis: Grant: Genentech Consulting fee/honoria: Genentech. J. Hou: Employee: Genentech Shareholder: Genentech. H. Yue: Employee: Genentech Shareholder: Genentech. A. Hauschild: Consult/honoraria:Roche, AZ, Biovex, BMS, Boehringer-Ingelheim, Celgene, Eisai, GSK, IGEA, Merck/MSD, Novartis,SOBI Reviews:Roche Spker bureau:Roche, AZ, Biovex, BMS, Boehringer-Ingelheim, Celgene, Eisai, GSK, IGEA, Merck/MSD, Novartis,SOBI. All other authors have declared no conflicts of interest.

The primary objective of this clinical trial was to evaluate the safety, feasibility, and biologic effects of administering costimulated, interleukin (IL)-4 polarized donor CD4(+) T cells in the setting of HLA-matched sibling, T cell-replete allogeneic hematopoietic cell transplantation (HCT). Forty-seven subjects with hematologic malignancy received granulocyte colony-stimulating factor-mobilized allogeneic hematopoietic cell transplants and cyclosporine graft-versus-host disease (GVHD) prophylaxis after reduced intensity conditioning. Initial subjects received no additional cells (n = 19); subsequent subjects received additional donor CD4(+) T cells generated ex vivo by CD3/CD28 costimulation in medium containing IL-4 and IL-2 (administered day 1 after HCT at 5, 25, or 125 x 10(6) cells/kg). Studies after HCT included measurement of monocyte IL-1alpha and tumor necrosis factor alpha, detection of T cells with antitumor specificity, and characterization of T cell cytokine phenotype. The culture method generated donor CD4(+) T cells that secreted increased T helper 2 (Th2) cytokines and decreased T helper 1 (Th1) cytokines. Such Th2-like cells were administered without infusional or dose-limiting toxicity. The Th2 cohort had accelerated lymphocyte reconstitution; both cohorts had rapid hematopoietic recovery and alloengraftment. Acute GVHD and overall survival were similar in the Th2 and non-Th2 cohorts. Th2 cell recipients tended to have increased monocyte IL-1alpha and had increased tumor necrosis factor alpha secretion. CD8(+) T cells with antitumor specificity were observed in Th2 and non-Th2 cohorts. Post-transplantation T cells from Th2 cell recipients secreted IL-4 and IL-10 (Th2 cytokines) and IL-2 and interferon gamma (Th1 cytokines). Allograft augmentation with costimulated, IL-4-polarized donor CD4(+) T cells resulted in activated Th1, Th2, and inflammatory cytokine pathways without an apparent increase in GVHD.