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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.

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.

Background Primary analysis from the pivotal ERIVANCE BCC study resulted in approval of vismodegib, a Hedgehog pathway inhibitor indicated for treatment of adults with metastatic or locally advanced basal cell carcinoma (BCC) that has recurred after surgery or for patients who are not candidates for surgery or radiation. Objective An efficacy and safety analysis was conducted 12 months after primary analysis. Methods This was a multinational, multicenter, nonrandomized, 2-cohort study in patients with measurable and histologically confirmed locally advanced or metastatic BCC taking oral vismodegib (150 mg/d). Primary outcome measure was objective response rate (complete and partial responses) assessed by independent review facility. Results After 12 months of additional follow-up, median duration of exposure to vismodegib was 12.9 months. Objective response rate increased from 30.3% to 33.3% in patients with metastatic disease, and from 42.9% to 47.6% in patients with the locally advanced form. Median duration of response in patients with locally advanced BCC increased from 7.6 to 9.5 months. No new safety signals emerged with extended treatment duration. Limitations Limitations include low prevalence of advanced BCC and challenges of designing a study with heterogenous manifestations. Conclusion The 12-month update of the study confirms the efficacy and safety of vismodegib in management of advanced BCC.

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.

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...

Purpose Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor kinase activity. The activity of vandetanib plus docetaxel was assessed in patients with previously treated non–small-cell lung cancer (NSCLC). Patients and Methods This two-part study comprised an open-label run-in phase and a double-blind randomized phase. Eligible patients had locally advanced or metastatic (stage IIIB/IV) NSCLC after failure of first-line platinum-based chemotherapy. The primary objective of the randomized phase was to prolong progression-free survival (PFS) in patients receiving vandetanib (100 or 300 mg/d) plus docetaxel (75 mg/m2 intravenous infusion every 21 days) versus placebo plus docetaxel. The study was designed to have more than 75% power to detect 50% prolongation at a one-sided significance level of P < .20. Secondary objectives included objective response rate, overall survival, safety and tolerability. Results In the randomized phase (n = 127), median PFS was 18.7 weeks for vandetanib 100 mg plus docetaxel (n = 42; hazard ratio v docetaxel = 0.64; one-sided P = .037); 17.0 weeks for vandetanib 300 mg plus docetaxel (n = 44; hazard ratio v docetaxel = 0.83; one-sided P = .231); and 12 weeks for docetaxel (n = 41). There was no statistically significant difference in overall survival among the three treatment arms. Common adverse events included diarrhea, rash, and asymptomatic prolongation of corrected QT (QTC) interval. Conclusion The primary objective was achieved, with vandetanib 100 mg plus docetaxel demonstrating a significant prolongation of PFS compared with docetaxel in relation to the prespecified significance level. On the basis of these encouraging data, phase III evaluation of vandetanib 100 mg plus docetaxel in second-line NSCLC has been initiated.

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.

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.

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...

9081 Background: Vismodegib (VISMO) (Erivedge) is a first-in-class Hedgehog pathway inhibitor (HPI) approved for advanced basal cell carcinoma (aBCC). In the ERIVANCE trial, VISMO-treated patients ...

We sought to determine whether illness severity and anticipated level of function, as evaluated at the time of admission, were associated with outcomes and costs of care for patients admitted to the medical service.All 1,759 patients admitted to the medical service at a large urban academic medical center between July 1, 1997, and September 30, 1997 (excluding those admitted directly to the intensive care units or for protocol chemotherapy), were evaluated and categorized by the admitting intern by illness severity (not ill, mildly ill, moderately ill, severely ill, or moribund) and anticipated level of function at discharge (excellent, good, fair, or poor) as part of their routine sign-out process. Interns' ratings were always available within 24 to 28 hours of admission. In-hospital mortality, length of stay, cost of hospitalization, and anticipated billing revenue were evaluated.Patients who were more severely ill had significantly greater in-hospital mortality. For example, mortality was 1.1% (11 of 972) among those who were not ill or mildly ill, 3.6% (26 of 724) among those who were moderately ill, and 15% (9 of 60) among those who were severely ill. Illness severity (P = 0.003) and anticipated functional status (P0.01) were significant predictors of in-hospital mortality. Illness severity and function were also significant predictors of greater length of stay and greater costs of hospitalization (all P0.0001). The 389 patients who were moderately ill with fair or poor anticipated function were associated with the largest cumulative losses (about $330,000 during the 3-month period), whereas the 798 mildly ill patients with good or excellent function were associated with the largest cumulative profits ($550,000).Physicians' estimates of patients' illness severity and anticipated function at the time of discharge, as made by interns using a system designed to help them sign out to their colleagues, predict outcomes and costs of hospitalization. Such a system may be useful in developing new approaches to management strategies based on prognosis.

9037 Background: Therapies for aBCC, which includes metastatic (m) and locally advanced (la) BCC, are limited. Abnormal Hedgehog pathway signaling is a key driver in BCC pathogenesis. Primary analysis of the pivotal ERIVANCE BCC trial of vismodegib, an oral hedgehog pathway inhibitor (HPI), demonstrated an objective response rate (ORR) of 30% and 43%, in mBCC and laBCC patients, respectively, with a median duration of response (DOR) of 7.6 months. We present safety and investigator (INV) assessed efficacy results 18 months (29 May 2012) after primary analysis (26 Nov 2010). Methods: Multicenter, international, nonrandomized study in patients (N=104) with radiographically measurable mBCC or laBCC (surgery inappropriate due to multiple recurrence, or substantial morbidity or deformity anticipated) receiving 150 mg oral vismodegib daily until disease progression or intolerable toxicity. Key secondary endpoints included INV-assessed ORR, progression-free survival (PFS), DOR, overall survival (OS), and safety. Results: At data cutoff, 21 patients continued to undergo protocol-specified assessments and 56 patients were in survival follow-up. The median dose intensity was comparable with primary analysis. ORR was 48.5%, mBCC; 60.3%, laBCC, comparable with primary analysis. However, median DOR improved (mBCC=14.7; laBCC=20.3 months). The median OS for mBCC was 30.9 months but not estimable in laBCC. Adverse events remained consistent, with muscle spasm, alopecia, dysgeusia, weight decrease, and fatigue most frequently reported. Eleven more deaths were reported in the update period after primary analysis; these occurred in survival follow-up and were not drug-related. Conclusions: Vismodegib is the first FDA-approved HPI; thus, long-term efficacy and safety data are particularly relevant. 18-month update data confirmed prolonged responses and consistent safety in vismodegib-treated aBCC patients. Clinical trial information: NCT00833417.

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.

8585 Background: Basal cell carcinoma (BCC), the most common skin cancer, rarely metastasizes. Consequently, the epidemiology of metastatic BCC (mBCC) is poorly characterized. The largest published mBCC review includes 170 cases reported from 1894–1980 (von Domarus H, Stevens P. J Am Acad Dermatol 1984;10:1043-60). Targeted therapies with hedgehog signaling pathway inhibitors, such as vismodegib, are currently being developed to treat this rare disease. The objective of the current analysis was to provide an updated description of the epidemiology and survival outcomes for mBCC. Methods: A PubMed literature search was conducted for mBCC case reports published in English during 1981–2011. mBCC cases that met the following criteria were evaluated: primary BCC located on skin; primary tumor and metastasis confirmed by pathology, and metastasis was not the result of direct tumor spread. Only cases with survival data giving dates (month and year) or durations were included in the analysis. Differences between groups were assessed with t tests and χ2 tests as appropriate. Survival was assessed with Kaplan–Meier (K-M) methods. Results: We identified 101 mBCC cases that met the selection criteria; 38 patients (38%) had lymph node-only disease (LD) and 63 (62%) had distant metastases (DM). In both groups, males predominated. DM patients were younger at mBCC diagnosis (mean 59 vs 66 y for LD). Among 96 cases with treatment data for metastatic disease, more DM patients received chemotherapy (25% vs 9% for LD), but more LD patients underwent surgery (85% vs 52% for DM). Survival duration ranged from 0 to 120+ months in all patients. The overall 1-y probability of survival after mBCC diagnosis was 75.7% (95% CI 67.2–84.2%), with lower survival in DM patients (69.1%; 95% CI 57.5–80.7%) vs LD patients (86.5%; 95% CI 75.5–97.5%). Conclusions: Patients with LD and DM mBCC may have different clinical courses and outcomes. Based on published case reports, DM patients were younger at mBCC diagnosis and had a lower 1-y survival probability vs LD patients. To our knowledge, these are the first K-M survival estimates reported for an mBCC case series of this size. These data help to provide a historical context for novel mBCC therapies under development, such as vismodegib.

8579 Background: The ERIVANCE BCC study is the pivotal trial of vismodegib (GDC-0449), a first-in-class small-molecule inhibitor of Hedgehog signaling, for treatment of locally advanced (laBCC) and metastatic BCC (mBCC), for whom there are no other effective therapy options. The study met the primary endpoint of overall response rate by independent review (Sekulic, Melanoma Res 2011). Here we report a 6-mo update of investigator-assessed (I-A) efficacy and safety endpoints as of May 26, 2011. Methods: This multicenter, international, nonrandomized 2-cohort study enrolled patients (pts) with laBCC (deemed inoperable or for whom surgery would be significantly disfiguring), and mBCC pts with RECIST-measurable disease. Pts received 150 mg oral vismodegib daily. Results: 104 pts (71 laBCC/33 mBCC) enrolled at 31 sites in the US, Europe, and Australia. I-A efficacy endpoints are shown in the table. One-year survival rate was 77.3% (95% CI 62.48–92.09%) for mBCC and 93.1% (95% CI 86.49–99.63%) for laBCC. Adverse events (AEs) in >30% of pts were muscle spasms, alopecia, dysgeusia, weight decrease, fatigue, nausea, and amenorrhea (33.3%; 2/6 pts). Serious AEs were reported in 32 pts (31%). No additional fatal AEs were reported since the prior data cut (n=7, 7%; none considered related to vismodegib). Conclusions: This 6-mo update of I-A efficacy and safety endpoints from the ERIVANCE BCC study supports the significant clinical benefit of vismodegib in both laBCC and mBCC reported at the primary analysis. Median DOR and PFS increased numerically with follow-up. The AE profile was consistent with the prior data cut. These results further support the efficacy of vismodegib for treatment of advanced BCC. [Table: see text]

LBA4 Background: About 50% of melanomas have an activating V600EBRAF mutation which led to the hypothesis that inhibition of the mutated BRAF kinase may be of clinical benefit. Phase I and II trials with vemurafenib (previously PLX4032/RO5185426), an orally available inhibitor of oncogenic BRAF kinase, showed response rates (RR; CR+PR) >50% in V600EBRAF- mutated melanoma patients (pts). We conducted a phase III trial to determine if vemurafenib improved overall survival (OS) and progression-free survival (PFS) in melanoma pts with V600EBRAF mutation. Methods: Pts with previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for V600EBRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) to vemurafenib (960 mg po bid) or DTIC (1,000 mg/m2, IV, q3w). Randomization was stratified by PS, stage, LDH, and geographic region. Pts were assessed for tumor responses after weeks 6, 12, and then q9 weeks. Co-primary endpoints were OS and PFS on the intent-to-treat population; secondary endpoints included RR, response duration, and safety. Final analysis was planned at 196 deaths. Results: 675 pts were enrolled at 103 centers worldwide between Jan and Dec 2010. Treatment cohorts were well-balanced. At the pre-planned interim analysis (50% of deaths needed for final analysis), the hazard ratios for OS and PFS were 0.37 (95% CI 0.26 to 0.55; pV600EBRAF-mutated metastatic melanoma.

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.

LBA4 The full, final text of this abstract will be available in Part II of the 2011 Annual Meeting Proceedings, distributed onsite at the Meeting on June 4, 2011, and as a supplement to the June 20...