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In 2018, cemiplimab-rwlc became the first systemic treatment approved by the US FDA for patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. In 2019, conditional approvals were granted by Health Canada and the European Commission for the same indications. Limited data exist pertaining to the clinical characteristics, disease progression and survivorship of patients with advanced CSCC in real-world clinical practice. CemiplimAb-rwlc Survivorship and Epidemiology (CASE) is a prospective Phase IV, noninterventional, survivorship and epidemiology study that will enroll patients with advanced CSCC who have recently initiated or who plan to receive cemiplimab in a real-world setting. Trial registration number: NCT03836105.

Aim: To estimate the comparative efficacy of cemiplimab, a programmed cell death protein 1 inhibitor, versus EGFR inhibitors, pembrolizumab and platinum-based chemotherapy in terms of overall survival (OS) and progression-free survival. Patients & methods: We performed an indirect treatment comparison of cemiplimab and other available systemic therapies for patients with advanced cutaneous squamous cell carcinoma. Results: Cemiplimab was associated with benefits in OS (hazard ratios range: 0.07–0.52) and progression-free survival (hazard ratios range: 0.30–0.67) versus EGFR inhibitors and pembrolizumab (data from KEYNOTE-629). Cemiplimab was more efficacious versus platinum-based chemotherapy in terms of OS. Conclusion: Cemiplimab may offer improvements in survival for advanced cutaneous squamous cell carcinoma patients compared with existing systemic therapies.

Background Systemic therapies are commonly used for patients with uncontrolled moderate-to-severe atopic dermatitis (AD) and impaired quality of life (QoL). However, real-world treatment patterns and unmet needs of adults with moderate-to-severe AD receiving systemic therapies are poorly quantified. Objective To evaluate unmet needs in patients with moderate-to-severe AD treated with systemic therapies. Methods Adults with AD diagnosis in past 5 years and a prescription for systemic treatment or phototherapy in past 6 months were identified from the Optum Research Database. Patients completed a survey about symptoms, treatment, and QoL. Chi-squared and t tests analyzed bivariable comparisons of demographics and outcomes. Spearman's rank-order correlation analyses examined the relationship between frequency of flares and outcomes. Results Eight hundred and one participants were included (mean age, 45.2 years; 71.8% female). In the 12 months before baseline survey, 38.3% reported no remission from AD. In the month before baseline survey, 63.6% used topical corticosteroids, and 81.3% of patients experienced 1 or more flares. Patients experiencing flares reported worse Patient-Orientated Eczema Measure (POEM), Peak Pruritus Numeric Rating Scale (NRS), and Dermatology Life Quality Index scores (DLQI), lower treatment satisfaction, and greater work productivity loss than patients without flares (all P Conclusion Despite receiving systemic therapies, adults with moderate-to-severe AD reported disease symptoms, recurrent flares, and impaired QoL, suggesting unmet therapeutic needs.

e21034 Background: CSCC is the second most common skin cancer. Most CSCC cases can be cured with surgical excision alone (5-year cure rate > 95%). We sought to evaluate patterns of major surgeries among patients with CSCC, overall and among those requiring systemic therapy. Methods: From Truven MarketScan claims data, we identified patient’s first CSCC diagnosis between 2013 and 2018 and required that they be continuously enrolled in their healthcare plan and have no CSCC diagnosis in the previous 12 months. Major surgeries included facial excisions over 3.1 cm, parotidectomy, removal of ear/eye/nose, amputations, craniectomy, excision of extracranial nerves, sentinel lymph node biopsy, lymphadenectomy, complex repairs of over 7.5 cm, integra, free flaps, and large grafts over 20 sq cm. Risk of a major surgery was assessed using Kaplan-Meier estimators for patients with CSCC overall and for those who received prior or concurrent systemic therapy, stratified by immune status. Results: A total of 240,122 patients with CSCC (mean age [SD]: 67.7 [12.9] years; male: 56.5%; immunocompromised: 12.4%) were identified with a mean (SD) follow-up of 1.34 (1.15) years. Risk of major surgery (95% confidence interval [CI]) at 1 and 2 years was 15.1% (14.9–15.2) and 18.6% (18.4–18.8), respectively. 782 patients received prior or concurrent systemic therapy, of which 22.4% (n = 175) were immunocompromised. Among those who received systemic therapy, 1- and 2-year risks (95% CI) were 8.4% (5.8–11.0) and 14.2% (10.0–18.2) for immunocompetent and 14.1% (7.7–20.0) and 19.3% (10.7–27.0) for immunocompromised patients, respectively. Conclusions: Over 2 years, approximately one in five patients with CSCC will undergo at least one major surgery. Prior or concurrent treatment with systemic therapy did not appreciably diminish the risk of requiring major surgery. For patients who received systemic therapy, the 1-year and 2-year risk of major surgery was higher for immunocompromised patients compared to immunocompetent patients.

e18703Background: Unlike other cancers, information on CSCC is not captured in national cancer registries, and little is known about the management and costs of CSCC. In contrast, more is known abo...

not available. Disclosures: Study sponsored by Regeneron. Copyright 2018 SKIN

The aim of this post hoc analysis of the VELOUR study (ClinicalTrials.gov NCT00561470) was to investigate the treatment effect of adding aflibercept to second-line infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) in patients with metastatic colorectal cancer (mCRC) who had failed any prior oxaliplatin-containing regimen. Adjuvant rapid relapsers (ARR), who were enrolled directly following relapse during or within 6 months of completion of oxaliplatin-containing adjuvant chemotherapy (N = 124, including 17 patients who also received bevacizumab as part of their adjuvant therapy), were excluded from the original VELOUR intention-to-treat (ITT) population (N = 1226). After exclusion of the ARR, overall survival (OS) in the ITT minus ARR (ITT-ARR) population (N = 1102) was longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm [hazard ratio (HR) 0.78, 95 % confidence interval (CI) 0.68–0.90; median survival difference 1.87 months]. In the subgroup of patients assigned to the prior bevacizumab stratum at randomization, OS was numerically longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm (HR 0.81; 95 % CI 0.63–1.04; median survival difference 2.14 months). Comparison of the post hoc analysis results with the primary analysis from VELOUR suggests that the inclusion of the directly enrolled ARR may have understated the aflibercept treatment benefit for both bevacizumab-pretreated and bevacizumab-naive patients in the strictly second-line setting although no definitive conclusion may be inferred. The benefit associated with the addition of aflibercept to second-line FOLFIRI in patients with mCRC was observed whatever the timing of first-line disease progression. There were no unexpected safety concerns.

Purpose: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11). Experimental Design: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m2) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m2, twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies. Results: The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 −118 (dT)9/9 genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response. Conclusions: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)9/9 genotype may be particularly likely to exhibit greater antitumor response with little toxicity.

PurposeTo evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity.Patients and MethodsPatients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m2and capecitabine 1,000 mg/m2bid (n = 15; cohort 1), or irinotecan 100 mg/m2and capecitabine 900 mg/m2bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression.ResultsAn unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response.ConclusionThese data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.

Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11).Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m(2)) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m(2), twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies.The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 -118 (dT)(9/9) genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response.These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)(9/9) genotype may be particularly likely to exhibit greater antitumor response with little toxicity.

e14510 Background: In a phase 1 study investigating ziv-aflibercept (Z, known as aflibercept outside the United States) with FOLFIRI, an analysis was performed to evaluate safety and activity in colorectal cancer (CRC) patients previously treated with irinotecan (I). Methods: The first part of the study was an open-label, dose-escalation stage in which patients with advanced solid tumors received Z at doses of 2, 4, 5, or 6 mg/kg on day 1, followed by FOLFIRI q2wks. The second part of the study was an expansion stage at the recommended dose of Z (4 mg/kg). This analysis is limited to CRC patients previously treated with I and receiving a dose of Z ≥4 mg/kg in either part of the study. Results: Of the 61 patients in the overall study with a planned dose of Z ≥4 mg/kg, 37 CRC patients previously treated with I received an actual dose of Z ≥4 mg/kg (56.8% men; mean age 57.6 years; 94.6% with ECOG performance status 0-1). Table shows response rates for the prior I efficacy population (n=36) and overall study ...

3573 Background: The phase III VELOUR study demonstrated that adding the novel antiangiogenic agent ziv-aflibercept (known as aflibercept outside the United States) to FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin significantly improved overall survival, progression-free survival (PFS), and overall response rate vs placebo/FOLFIRI. We performed an additional analysis of PFS “on-treatment,” censoring events that occurred more than 28 days after last treatment dose. Methods: Patients were randomized to receive ziv-aflibercept 4 mg/kg or placebo every 2 weeks in combination with FOLFIRI. An independent review committee determined progression based on radiologic review. PFS was estimated using Kaplan-Meier analysis, with censoring of events after the last dose plus 28 days. Treatment groups were compared using a log-rank test and were stratified by Eastern Cooperative Oncology Group performance status and prior bevacizumab therapy. Hazard ratio (HR) and confidence interval (CI) were estimated using a Cox proportional hazard model. Results: On-treatment analysis showed significantly increased PFS for patients treated with ziv-aflibercept/FOLFIRI compared with placebo/FOLFIRI (Table). More patients were censored in the ziv-aflibercept arm due to adverse events. Conclusions: The on-treatment PFS analysis demonstrates a significantly improved treatment effect of the addition of ziv-aflibercept to FOLFIRI (HR=0.55) over what was observed in the primary analysis suggesting that continuing treatment with ziv-aflibercept up to disease progression provides additional benefit. Clinical trial information: NCT00561470. [Table: see text]

e14528 Background: Ziv-aflibercept (known outside the US as aflibercept) is a multiple angiogenic factor inhibitor that prevents VEGF-A, VEGF-B, and PlGF from binding their receptors. Ziv-aflibercept in combination with FOLFIRI was FDA approved for metastatic colorectal cancer (mCRC) patients who are resistant to or have progressed following an oxaliplatin-containing regimen. Approval was based on the multinational phase 3 VELOUR trial (N=1226) showing statistically significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with ziv-aflibercept/FOLFIRI. Detailed analyses of the NA subgroup are presented here. Methods: Patients were randomized 1:1 to ziv-aflibercept 4 mg/kg + FOLFIRI or placebo (pbo) + FOLFIRI q2wks. Patients had ECOG PS ≤2 and 1 prior oxaliplatin-based regimen; prior bevacizumab was allowed. Primary endpoint was OS. NA analysis was prespecified but not powered to compare within or between subgroups. Results: NA patients (n=138) were randomized to ziv-aflibercept/FOLFIRI (n=63) or pbo/FOLFIRI (n=75). Baseline characteristics were similar in both arms (ziv-aflibercept: median age 61 y; 60% male; 96% PS 0-1; 56% >1 metastatic organ; 74% prior bevacizumab) and were similar to the worldwide population. Median OS for ziv-aflibercept vs pbo was 17.94 vs 12.88 mos; median PFS was 6.01 vs 4.17 mos; ORR was 12% vs 9%. On average, patients received more cycles (median 8.5 vs 7.0), had longer duration of exposure (median 20 vs 14 wks), and more treatment modifications with ziv-aflibercept vs pbo. Most severe AEs (grade ≥3) with ziv-aflibercept were grade 3, including hypertension, venous thromboembolic events, proteinuria, diarrhea, fatigue/asthenia, infection, stomatitis/ulceration, and neutropenia; there were few grade 4 AEs. Conclusions: Ziv-aflibercept/FOLFIRI in mCRC patients previously treated with an oxaliplatin-based regimen showed improvements in OS, PFS, and ORR with an acceptable safety profile. NA results are consistent with the VELOUR worldwide population. Clinical trial information: NCT00561470.

e14576 Background: An increase in survival seen in recent years in patients with metastatic colorectal cancer (mCRC) has been attributed to improvements in treatments, including introduction of targeted biologic agents. Objectives of this retrospective, observational study are to investigate recent treatment patterns in US mCRC patients and examine real-world survival outcomes. Methods: Data were obtained from a large US database (SDI/IMS Health) of mCRC patients diagnosed between January 1, 2004, and June 30, 2011, ≥18 years of age at diagnosis, who received chemotherapy and/or biologic treatment. Complete follow-up was defined as those who died before June 2011 or had at least 1 claim within 30 days of June 30, 2011. Kaplan-Meier curves were generated to determine overall survival (OS) from the date of diagnosis. Results: 1,066 stage IV mCRC patients with complete follow-up were identified (57.5% male; mean age 61.6 years). Approximately 80% were diagnosed after 2006; 51.7% had liver metastases. The most common 1L, 2L, and 3L regimens were FOLFOX plus bevacizumab (34.52%), FOLFIRI plus bevacizumab (21.83%), and irinotecan plus cetuximab (15.83%), respectively. 445 patients died during the study period, yielding a mortality rate of 41.74%. Mean time from diagnosis to first treatment was 3.31 months (SD=7.13). All patients received 1L therapy; OS from diagnosis was 35.77 months (95% CI, 32.57-38.10); 5-year survival was ~28%. After 1L, 591 patients received 2L therapy. For patients who received 2L, median survival from diagnosis was 37.13 months (95% CI, 34.07-40.43); 5-year survival was ~25%. After 2L, 278 patients received 3L therapy. For patients who received 3L, median survival from diagnosis was 38.10 months (95% CI, 34.83-43.13); 5-year survival was ~25%. Conclusions: In this study, OS (35.77 months) was greater than in other mCRC observational studies (25.1-27.9 months), which reported survival from start of treatment, but is more comparable when the ~3 months from diagnosis to treatment are not included. The addition of targeted agents and novel chemotherapy has prolonged OS in mCRC patients, yet there is still need for additional advanced agents in later lines of therapies.

469 Background: The phase III VELOUR study demonstrated that adding the novel antiangiogenic agent aflibercept (known as ziv-aflibercept in the United States) to FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin significantly improved overall survival, progression-free survival (PFS), and overall response rate versus placebo-FOLFIRI. We performed an additional analysis of PFS “on-treatment,” censoring events that occurred more than 28 days after last treatment dose. Methods: Patients were randomized to receive aflibercept 4 mg/kg or placebo every 2 weeks in combination with FOLFIRI. An independent review committee determined progression based on radiologic review. PFS was estimated using Kaplan-Meier analysis, with censoring of events after the last dose plus 28 days. Treatment groups were compared using a log-rank test stratified by ECOG performance status and prior bevacizumab therapy. Hazard ratio (HR) and confidence interval (CI) were estimated using a Cox proportional hazard model. Results: On-treatment PFS results are shown in the Table. Patients on aflibercept-FOLFIRI showed significantly increased on-treatment PFS compared with patients on placebo-FOLFIRI. More patients were censored in the aflibercept arm due to adverse events, thus decreasing the number of events. Conclusions: On-treatment PFS with aflibercept-FOLFIRI was significantly increased compared with placebo-FOLFIRI, which is consistent with the PFS benefit observed in the primary analysis. Clinical trial information: NCT00561470. [Table: see text]

465 Background: Ziv-aflibercept (trade name ZALTRAP; known outside the US as aflibercept) is a new multiple angiogenic inhibitor that prevents VEGF-A, VEGF-B and PLGF from binding their receptors. Ziv-aflibercept was recently approved by the FDA in combination with FOLFIRI for patients with mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen. Approval was based on the multinational phase III VELOUR trial (N=1226) which showed statistically significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with aflibercept + FOLFIRI. Detailed analyses of the NA subgroup are presented here. Methods: Patients were randomized 1:1 to ziv-aflibercept (4 mg/kg) + FOLFIRI or pbo + FOLFIRI every 2 wk. Patients had ECOG performance status (PS) ≤2, 1 prior oxaliplatin-based regimen, and prior bevacizumab (bev) was allowed. Primary endpoint was OS. The NA analysis was pre-specified, but not powered, to compare within or between subgroups. Results: NA patients (N=138) were randomized to ziv-aflibercept + FOLFIRI (n=63) or pbo + FOLFIRI (n=75). Baseline characteristics were similar in both arms (ziv-aflibercept: median 61 yrs; 60% male; 96% PS 0-1; 56% >1 metastatic organ; 74% prior bev). Ziv-aflibercept vs pbo improved median OS (17.94 vs 12.88 mos; HR=0.691, 95% CI: 0.442-1.079), median PFS (6.01 vs 4.17 mos; HR=0.536, 99.9% CI: 0.222-1.296) and ORR (12% vs 9%). Patients on average received more cycles (median 8.5 vs 7.0) and had longer duration of exposure (median 20 vs 14 wk), but had more treatment modifications with ziv-aflibercept vs pbo. Most of the severe AEs (grade ≥3) with ziv-aflibercept were grade 3 including hypertension, venous thromboembolic events, proteinuria, diarrhea, fatigue/asthenia, infection, stomatitis/ulceration and neutropenia. There were few grade 4 AEs. Conclusions: Ziv-aflibercept + FOLFIRI in NA mCRC patients previously treated with an oxaliplatin-based regimen (with or without prior bev) resulted in improved OS, PFS, and ORR, with an acceptable safety profile. The NA results are consistent with the VELOUR worldwide population. Clinical trial information: NCT00561470.

e14028 Background: Up-to-date information concerning the optimal regimen assignment and sequencing of therapies is lacking for the treatment of mCRC patients. By tracking trends in treatment choice, this retrospective, observational study assesses current treatment patterns in mCRC patients by line of therapy. Methods: Using electronic medical record data from one of the largest US oncology databases (SDI), treatment regimens for 1L, 2L, and 3L were assessed for patients age ≥18 yrs diagnosed with mCRC from 1/1/04-7/31/11 who received anticancer agents. Results: 1,793 stage IV patients were identified in 1L, 1,050 in 2L, and 504 in 3L. Overall mean age was 60.4 yrs, and 54.6% were men. The most common comorbidities were hypertension (18.0%), lipid metabolism disorders (10.6%), and diabetes (8.6%). 47.8% had commercial insurance, 37.2% Medicare, 8.5% Medicaid, and 4.6% self pay. 1,026 patients received bevacizumab (B) in 1L, 583 in 2L, and 204 in 3L. Patients were more likely to receive FOLFOX (FX) + B in 1L and 2L. The top 3 regimens are shown in the table below. For patients who began treatment with B and continued B in a subsequent regimen, mean dose of B increased from 443.7 mg/kg (1L) to 567.0 mg/kg (2L) and 618.1 mg/kg (3L). Conclusions: FX is the regimen of choice in mCRC. In terms of biologics, B is more commonly used in 1L/2L than 3L. Given that approximately half the mCRC patients progressed to 2L/3L treatment, this likely reflects an unmet need for advanced therapies for the effective treatment of the disease. Furthermore, consistent dose escalation with continued B use across 2L/3L was seen despite that use of B in 3L mCRC is inconsistent with NCCN guidelines. Additional research on outcomes implications is needed, including mortality, patient toxicity, and costs. [Table: see text]