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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.

TPS3110Background: Advanced hepatocellular carcinoma (HCC) accounts for 70% of diagnosed HCC. Tislelizumab (also known as BGB-A317) is a humanized, IgG4 monoclonal antibody with high affinity and b...

TPS3113Background: Programmed cell death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), play critical roles in the immune modulation of tumor progression. Tislelizumab is a humanized I...

Few data exist on the occurrence of metastatic basal cell carcinoma (mBCC). To identify all cases of mBCC in Denmark over a 14-year period. We searched the Danish National Patient Registry covering all Danish hospitals, the Danish Cancer Registry, the National Pathology Registry and the Causes of Death Registry during the period 1997 to 2010 for potential cases of mBCC registered according to the International classification of diseases ICD-10 and the International Systemized Nomenclature of Medicine (SNOMED). We identified 126,627 patients with a history of primary basal cell carcinoma (BCC) in the registries during the 14-year study period. Using case identifications from the four registries, a total of 170 potential mBCC cases were identified. However, after a pathology review, only five cases could be confirmed, of which three were basosquamous carcinomas. The 14-year cumulative incidence proportion of mBCC was 0.0039% (95% CI 0.0016-0.0083) among individuals with a history of previous BCC (n = 126,627) and 0.0001% (95% CI 0.0000-0.0002) in the general population. MBCC is a rare disease and only a small proportion of potential cases identified in automated clinical databases or registries can be confirmed by pathology and medical record review.

9562Background: A Hh pathway inhibitor, vismodegib (VISMO) is approved for the treatment of locally advanced (la BCC) and metastatic BCC (mBCC). While most patients respond to drug treatment, in th...

Introduction Une activation anormale de la voie de signalisation Hedgehog (HP) est impliquee dans la physiopathologie du carcinome basocellulaire (CBC). Dans l’essai ERIVANCE BCC, le vismodegib, premier inhibiteur de la voie Hedgehog (HPI) autorise par la FDA, montrait des taux de reponses objective (ORR) de 30 % dans le CBC metastatique et de 43 % dans le CBC localement avance (comite independant), avec une duree mediane de reponse (DOR) de 7,6 mois dans les deux cas. Selon les investigateurs (INV), les ORR etaient de 45 % et 60 % respectivement, et les DOR de 12,9 et 7,6 mois respectivement. Dans cette meme etude, certains patients ont poursuivi le traitement pendant plus de 3 ans. Nous presentons une reactualisation a 30 mois (30 mai 2013) apres l’analyse principale (26 novembre 2010) de la tolerance et l’efficacite evaluees par les investigateurs. Materiel et methodes ERIVANCE BCC est une etude multicentrique, internationale, non randomisee chez 104 patients avec CBC metastatique mesurable radiologiquement ou CBC localement avance (pour lequel la chirurgie etait inappropriee en raison d’une recidive multiple ou de l’anticipation d’une morbidite ou difformite substantielle). Un traitement par vismodegib (150 mg/j po) etait administre jusqu’a progression ou tolerance inacceptable. Les criteres secondaires d’evaluation etaient l’ORR (INV), la survie sans progression (SSP), la DOR, la survie globale, et la tolerance. Observations A la date d’analyse, 9 patients (9 %) poursuivaient l’evaluation selon le protocole et 69 patients (66 %) etaient en suivi pour la survie. Le ORR (INV) etait de 48,5 % (CBCm) et 60,3 % (CBCla), semblables a l’analyse principale. La DOR mediane (INV) etait modifiee de 7,6 a 26,2 mois pour les CBCla et de 12,9 a 14,8 mois pour les CBCm. La mediane de survie globale etait de 33,4 mois (18,1 - non mesurable) pour le CBCm et non atteinte pour le CBCla. Les effets indesirables etaient en accord avec l’analyse principale : > 30 % des patients rapportaient des crampes musculaires, alopecie, dysgueusie, amaigrissement, fatigue et nausees. Les arrets de traitement pour effets indesirables etaient notes chez 23 patients (22,1 %). Dix-sept deces (10 CBCm et 7 CBCla) ont ete rapportes depuis l’analyse principale, tous consideres comme non relies au medicament. Seize deces sont intervenus dans le suivi. Un patient decedait d’alteration de l’etat general. Discussion L’analyse de l’etude ERIVANCE, actualisee a 30 mois de suivi, confirme l’efficacite du vismodegib dans le traitement du CBC avance et montre une tolerance a long terme semblable a celle notee dans l’analyse principale. Conclusion Cette etude a permis l’enregistrement du vismodegib dans le traitement du carcinome basocellulaire localement avance ou metastatique symptomatique pour lequel la chirurgie ou la radiotherapie sont inappropriees.