Sekulić, Aleksandar

9566 Background: Cemiplimab-rwlc is the first immunotherapy to receive approval in the US, fully for pts with laBCC and accelerated for metastatic BCC, post hedgehog inhibitors or for whom hedgehog inhibitors are not appropriate. Cemiplimab resulted in clinically meaningful anti-tumor activity in pts with laBCC who progressed on or were intolerant to hedgehog inhibitor therapy (NCT03132636). This analysis evaluated HRQoL in these pts. Methods: Adults with laBCC and ECOG performance status ≤1 (n=84) received IV cemiplimab 350 mg Q3W for up to 9 treatment cycles. At baseline (BL) and day 1 of each cycle (C), pts completed EORTC QLQ-C30 and SKINDEX-16 questionnaires that assess Global Health Status (GHS)/QoL, functioning, and BCC-related symptoms. Mixed-effects repeated measures (MMRM) models were used to estimate least squares (LS) mean (standard error [SE]) change from BL during treatment (i.e., across C2 to C9); changes ≥|10| points were considered clinically meaningful. Responder analyses were conducted in pts with non-missing data from BL to determine the proportions with clinically meaningful improvement or deterioration, or stability on QLQ-C30 and SKINDEX-16 at C2 and C9; a 10-point threshold was considered meaningful for both instruments. Results: BL scores showed moderate to high levels of functioning and low symptom burden. In MMRM models, overall changes from BL on QLQ-C30 indicated stability for GHS/QoL and all scales except for clinically meaningful worsening of fatigue (LS mean [SE] change 12.5 [3.9]; P<.05). In responder analysis, the majority of pts reported clinically meaningful improvement or stability at C2 and C9 on all QLQ-C30 functioning scales and the key symptom of pain but not fatigue (Table). On SKINDEX-16, MMRM models showed clinically meaningful improvement on the emotional subscale (LS mean [SE] change –13.2 [3.9]; P<.05) and stability on the symptom and functional subscales. Responder analysis showed clinically meaningful improvements or stability across the SKINDEX-16 subscales in approximately 80% of pts at C2, and 70–80% of pts at C9. Conclusions: In laBCC pts treated with cemiplimab, the majority reported clinically meaningful improvement or stability in GHS/QoL and functional status while maintaining a low symptom burden except for fatigue. Clinical trial information: NCT03132636. [Table: see text]

9082 Background: Human tumors, including melanoma, are complex mixtures of individual, molecularly distinct subpopulations, or clones of cancer cells. Effective cancer therapy will likely require targeting of all tumor subsets within a given cancer. Understanding the tumor complexity and the ability to identify points of therapeutic vulnerability within the individual tumor subsets will be essential for development of effective personalized cancer therapies. Methods: We have developed an approach that combines identification of individual tumor subsets using a multiparameter nuclear flow cytometry coupled with a high-resolution genomic analysis using the array-based comparative genomic hybridization (aCGH). Melanoma nuclei were isolated from tumor tissues and subjected to flow cytomery using melanocyte-specific antibodies (to separate melanoma cells from stroma) and DNA content, to separate individual tumor subpopulations. DNA extracted from isolated nuclear subpopulations was extracted and analyzed by aCGH. This approach was adopted for both fresh-frozen and paraffin-embedded clinical specimens. Results: We initially demonstrate the feasibility of the outlined approach by successful separation of melanoma from stromal nuclei and separation of individual melanoma nuclear subpopulations by DNA content. aCGH analysis of the DNA derived from isolated tumor subpopulations allowed successful identification of potentially targetable molecular aberrations in individual subsets of tumor cells. Notably, such aberrations were often not detected in unsorted, bulk tumors analyzed by the same high-resolution aCGH approach. Conclusions: We demonstrate a feasible approach to in-depth molecular analysis of tumor subpopulations within a clinical cancer tissue. This approach allows identification of potentially targetable molecular aberrations within individual tumor subsets, thus opening a possibility for a broad tumor targeting through design of individually-tailored therapeutic approaches. No significant financial relationships to disclose.

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.

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]

Abstract Motivation Functions of cancer driver genes vary substantially across tissues and organs. Distinguishing passenger genes, oncogenes (OGs) and tumor-suppressor genes (TSGs) for each cancer type is critical for understanding tumor biology and identifying clinically actionable targets. Although many computational tools are available to predict putative cancer driver genes, resources for context-aware classifications of OGs and TSGs are limited. Results We show that the direction and magnitude of somatic selection of protein-coding mutations are significantly different for passenger genes, OGs and TSGs. Based on these patterns, we develop a new method (genes under selection in tumors) to discover OGs and TSGs in a cancer-type specific manner. Genes under selection in tumors shows a high accuracy (92%) when evaluated via strict cross-validations. Its application to 10 172 tumor exomes found known and novel cancer drivers with high tissue-specificities. In 11 out of 13 OGs shared among multiple cancer types, we found functional domains selectively engaged in different cancers, suggesting differences in disease mechanisms. Availability and implementation An R implementation of the GUST algorithm is available at https://github.com/liliulab/gust. A database with pre-computed results is available at https://liliulab.shinyapps.io/gust. Supplementary information Supplementary data are available at Bioinformatics online.