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Five patients who were RAS mutant at baseline reverted to wild-type at SFU

Purpose: The accumulation of emergent RAS mutations during anti-EGFR therapy is of interest as a mechanism for acquired resistance to anti-EGFR treatment. Plasma analysis of circulating tumor (ct) DNA is a minimally invasive and highly sensitive method to determine RAS mutational status.Experimental Design: This biomarker analysis of the global phase III ASPECCT study used next-generation sequencing to detect expanded RAS ctDNA mutations in panitumumab-treated patients. Plasma samples collected at baseline and posttreatment were analyzed categorically for the presence of RAS mutations by the PlasmaSelect-R 64-gene panel at 0.1% sensitivity.Results: Among panitumumab-treated patients with evaluable plasma samples at baseline (n = 238), 188 (79%) were wild-type (WT) RAS, and 50 (21%) were mutant RAS. Of the 188 patients with baseline ctDNA WT RAS status, 164 had evaluable posttreatment results with a 32% rate of emergent RAS mutations. The median overall survival for WT and RAS mutant status by ctDNA at baseline was 13.7 (95% confidence interval, 11.5–15.4) and 7.9 months (6.4–9.6), respectively (P < 0.0001). Clinical outcomes were not significantly different between patients with and without emergent ctDNA RAS mutations.Conclusions: Although patients with baseline ctDNA RAS mutations had worse outcomes than patients who were WT RAS before initiating treatment, emergent ctDNA RAS mutations were not associated with less favorable patient outcomes in panitumumab-treated patients. Further research is needed to determine a clinically relevant threshold for baseline and emergent ctDNA RAS mutations. Clin Cancer Res; 24(22); 5602–9. ©2018 AACR.

Purpose:This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC).Patients and Methods:Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4–6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control.Results:Overall (N = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50–0.88; P = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36–0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09–1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic.Conclusions:Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.

BACKGROUND: In the BROCADE3 trial, addition of the poly(ADP-ribose) polymerase inhibitor, veliparib, to carboplatin/paclitaxel improved progression-free survival (PFS) (hazard ratio 0.71, 95% confidence interval 0.57-0.88; P = 0.002) in patients with advanced human epidermal growth factor receptor 2-negative, germline BRCA1/2-mutated breast cancer. A subset of patients discontinued both carboplatin and paclitaxel before progression and continued on veliparib/placebo maintenance monotherapy until progression. Analyses in this patient subgroup are reported. PATIENTS AND METHODS: Patients were randomized 2 : 1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Veliparib (120 mg twice daily) or placebo was given on days -2 to 5, carboplatin (area under the curve 6 mg/ml) on day 1, and paclitaxel (80 mg/m2) on days 1, 8, and 15 of 21-day cycles. Patients who discontinued both carboplatin and paclitaxel before progression received blinded study drug monotherapy at an increased dose of 300-400 mg twice daily continuously. PFS was the primary endpoint. Exploratory analyses were carried out in the subgroup of patients who received blinded study drug as monotherapy. A time-varying Cox model including data from all patients was also used to evaluate treatment effect in the combination and monotherapy phases. RESULTS: A total of 136 of 337 patients randomized to veliparib plus carboplatin/paclitaxel and 58/172 patients randomized to placebo plus carboplatin/paclitaxel discontinued both carboplatin and paclitaxel before progression and continued on blinded veliparib or placebo monotherapy. In this blinded monotherapy subgroup, investigator-assessed median PFS from randomization was 25.7 months with veliparib versus 14.6 months with placebo. Hazard ratios from a time-varying Cox model favored veliparib during both combination therapy and monotherapy. Any-grade adverse events occurring in the monotherapy phase were primarily gastrointestinal. The most common grade ≥3 adverse events were neutropenia and anemia (4% each with veliparib; 5% and 2%, respectively, with placebo). CONCLUSIONS: Veliparib maintenance monotherapy had a tolerable safety profile and may extend PFS following combination chemotherapy. ispartof: ANNALS OF ONCOLOGY vol:33 issue:3 pages:299-309 ispartof: location:England status: published

Objectives Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/metastatic NSCLC. Materials and Methods Patients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and paclitaxel 200 mg/m2 (C/PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and pemetrexed 500 mg/m2 (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed. Results Twenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80–240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range 80–240 mg BID combined with nivolumab and C/PEM, with no effects on pemetrexed pharmacokinetics. Overall, the confirmed objective response rate was 40%, and best overall response was 64%. Conclusion Veliparib combined with nivolumab and platinum doublet CT was tolerated in patients with advanced/metastatic NSCLC, and no evidence of drug–drug interaction was observed. Although preliminary, this quadruple therapy may have promising antitumor activity.

BACKGROUND: Addition of veliparib to carboplatin-paclitaxel, with continuation of veliparib monotherapy if carboplatin-paclitaxel was discontinued, improved progression-free survival (PFS) in patients with germline BRCA-associated locally advanced/metastatic HER2- breast cancer and ≤2 lines of previous cytotoxic therapy for metastatic disease in BROCADE3. A pre-planned subgroup analysis evaluated efficacy and safety in patients without previous cytotoxic therapy for metastatic disease. METHODS: Patients were randomised 2:1 to receive veliparib (120 mg orally BID) or placebo on days -2 to 5. Carboplatin (AUC 6) was administered on day 1, and paclitaxel (80 mg/m2) on days 1, 8 and 15 (21-day cycles). Patients discontinuing carboplatin-paclitaxel for reasons besides progression could continue veliparib/placebo monotherapy (300 mg BID, increasing to 400 mg BID if tolerated) until progression. The primary end-point was PFS assessed by investigator. RESULTS: Of 509 patients in the intention-to-treat population (98.6% female; mean age 47, standard deviation 11), 413 (81%) had no previous cytotoxic therapy for metastatic disease (274, veliparib; 139, placebo). In the first-line subgroup, median PFS was 16.6 months (95% confidence interval [CI] 13.4-18.7) versus 13.1 months (95% CI 11.4-14.5) for the veliparib versus control groups (hazard ratio 0.70, 95% CI 0.54-0.89, P = .004). More patients were alive and progression-free at 2 years (36% versus 23.2%) and 3 years (27.9% versus 13.3%) in the veliparib versus control group. Adverse events unrelated to progression leading to study drug discontinuation occurred in 25 (9.1%) and 8 (5.8%) patients. CONCLUSIONS: Veliparib with carboplatin-paclitaxel led to durable disease control among first-line patients, suggesting a benefit of this treatment approach in early lines. CLINICAL TRIAL REGISTRATION: NCT02163694. ispartof: European Journal Of Cancer vol:154 pages:35-45 ispartof: location:England status: accepted

Purpose: This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC). Patients and Methods: Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4–6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control. Results: Overall (N = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50–0.88; P = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36–0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09–1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic. Conclusions: Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.

Veliparib (ABT‐888) is a poly(ADP‐ribose) polymerase inhibitor in development for the treatment of high‐grade ovarian cancer or BRCA‐mutated breast cancer in combination with carboplatin and paclitaxel. The population pharmacokinetics of veliparib were characterized using combined data from 1470 adult subjects with ovarian cancer, breast cancer, or other solid tumors enrolled in 6 phase 1 studies, 1 phase 2 study, and 2 phase 3 studies of veliparib oral doses of 10 to 400 mg twice daily as monotherapy or in combination with chemotherapy. A 1‐compartment model with linear clearance and first‐order absorption best characterized veliparib pharmacokinetics. The predicted apparent oral clearance (CL/F) and volume of distribution (Vc/F) were 479 L/day and 152 L, respectively. The significant covariates in the final model included albumin, creatinine clearance, strong inhibitors of cytochrome P450 (CYP) 2D6, and sex on CL/F and albumin, body weight, and sex on Vc/F. Mild and moderate renal impairment increased veliparib median (95%CI) steady‐state AUC (AUCss) by 27.3% (23.7%‐30.9%) and 65.4% (56.0%‐75.5%), respectively, compared with normal renal function. Male subjects had 16.5% (7.53%‐23.9%) lower AUCss compared with female subjects and coadministration with strong CYP2D6 inhibitors increased AUCss by 13.0% (6.11%‐20.8%). Race, age, region, cancer type, or enzyme (CYP3A4, CYP2C19) or transporter (P‐glycoprotein, multidrug and toxin extrusion protein 1/2, organic cation transporter 2) inhibiting/inducing comedications were not found to significantly impact veliparib pharmacokinetics. Other than baseline creatinine clearance and hence renal impairment effect on veliparib clearance, no other covariates had a clinically meaningful effect on veliparib exposure warranting dose adjustment.

Background The choice of chemotherapy for women diagnosed with metastatic breast cancer (BC) has been evolving as new agents and clinical trial results become available. Current NCCN guidelines recommend sequential single chemotherapeutic agents and combination therapy including platinum-based regimens for patients with high risk disease. Platinum-based chemotherapies are recommended for triple-negative breast cancer (TNBC) and, in particular, for a more defined population of TNBC with a BRCA mutation that may have particular sensitivity to platinum agents due to the impaired ability to repair DNA damage inherent in these patients.1 Here, we aim to leverage real world data to ascertain the use of platinum-based treatments in BRCA-mutation positive (BRCA+) metastatic BC patients, characterized by their hormonal receptor status. Methods Optum’s electronic health records (EHR) database was used to identify a cohort of women with 1) confirmed BC ICD-9/ICD-10 diagnosis between 2008 and 2018, 2) at least 12 months of history in the EHR, 3) at least one distant metastasis diagnosis (per ICD-9/ICD-10, or from physician notes), and 4) no previous diagnosis of other primary cancers in previous 12 months. BRCA-mutation status, ER, PR and HER2 test results were used to create relevant biomarker subgroups. Distinct lines of therapy (LOT) in the post-metastatic period were established using business rules, and the extent of use of platinum-based treatments, overall and of specific platinum regimens, were analyzed in various LOTs. Results Among 33,878 metastatic BC patients receiving a systemic chemotherapy, 8.7% were treated with a platinum-based regimen, while among the subgroup who were BRCA+, the proportion receiving platinum-based regimens was higher at 12.3%. In LOT2 and LOT3, the proportion receiving platinum regimens was 3.9% and 2.5% for the overall cohort, compared with 5.2% and 3.0% for the BRCA+ cohort. Within the BRCA+ cohort, the use of platinum-based regimens in TNBC patients was substantially higher than in other patients, accounting for 21.6%, 15.3% and 14.2% of patients in LOT1, LOT2 and LOT3 respectively, compared with 8.7%, 3.1% and 1.7% in ER+/PR+ patients (Table 1). The choice of specific platinum-containing combination regimens differed by biomarker cohorts; the combination of carboplatin and paclitaxel was most common in TNBC patients, while a quadruplet regimen was most used in the ER+/PR+ cohort. Conclusions Real-world evidence on use of platinum-based regimens in metastatic BC patients revealed differences across BRCA and hormonal status phenotypes. Women with TNBC had higher use of platinum agents than other subgroups across all lines of treatment. The observation that the use of platinum-based chemotherapy, including combination regimens, was highest in TNBC across lines of treatment highlights the persistent unmet need around alternative therapies for women affected with TNBC and BRCA+ disease. Table 1. Use of platinum-based regimens in women with metastatic BC in LOTs 1-3All metastatic BCBRCA+All BRCA+ER+/PR+TNBCN (treated with LOT1)33,8785,6494,228782Age at LOT1 start (in years): Median (IQR)63 (53-73)54 (46-64)54 (46-64)54 (45-62)Total proportion (%) of platinum-based regimens in LOT18.7%12.3%8.7%21.6%REGIMENCarboplatin+paclitaxel1.8%2.8%1.4%8.3%Carboplatin+docetaxel+pertuzumab+trastuzumab1.7%2.8%2.6%0.4%Carboplatin+docetaxel+trastuzumab1.2%1.9%1.8%0.3%Carboplatin+gemcitabine0.9%1.4%0.7%5.5%Carboplatin0.7%0.8%0.5%1.9%Carboplatin+docetaxel0.3%0.4%0.2%1.3%Cisplatin0.3%0.4%0.2%1.0%Other platinum-based regimens1.9%2.0%1.4%2.9%N (treated with LOT2)21,1484,1973,317495Total proportion (%) of platinum-based regimens in LOT23.9%5.2%3.1%15.3%N (treated with LOT3)13,9372,9592,523226Total proportion (%) of platinum-based regimens in LOT32.5%3.0%1.7%14.2%Footnotes1 Isakoff, SJ. Triple-Negative Breast Cancer: Role of Specific Chemotherapy Agents. Cancer J 2010;16: 53-61 Citation Format: Wendy Sebby, Alexander Liede, Debasish Mazumder, Anirban Ghosh, Eros Papademetriou, Ravi Potluri, Bruce Bach, Jerzy Tyczynski. Real-world evidence of platinum-based chemotherapy for the treatment of BRCA-positive metastatic breast cancer in a cohort of 33,878 women in the United States [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-41.

BACKGROUND: This open-label Phase III trial (NCT02264990) evaluated the PARP inhibitor, veliparib, combined with carboplatin/paclitaxel versus chemotherapy alone for first-line treatment of patients with advanced non-squamous non-small cell lung cancers (NSCLC). A 52-gene expression classifier (LP52) previously shown to identify patients more likely to respond to veliparib was evaluated as a planned correlative analysis.; MATERIALS AND METHODS: Adult current or former smokers with advanced non-squamous NSCLC were randomized 1:1 to veliparib (120 mg daily for 7 days/cycle) with carboplatin and paclitaxel or to investigators' choice of platinum doublet chemotherapy (up to 6, 21-day cycles), with optional pemetrexed maintenance. Prospective analysis of the LP52 signature was conducted using a clinical Qiagen/HTG assay. The primary endpoint was overall survival (OS) in LP52+ patients.; RESULTS: Overall, 595 patients received veliparib+carboplatin/paclitaxel (n=298) or chemotherapy alone (n=297); 13% (n=40) in each arm were LP52+. The primary endpoint was not met; median OS was 11.2 months with veliparib+carboplatin/paclitaxel versus 9.2 months with chemotherapy alone in the LP52+ subgroup (hazard ratio [HR] 0.644, 95% confidence interval [CI]: 0.396-1.048; P=.113). In the overall population, median OS was 12.1 months in both arms (HR 0.986, 95% CI: 0.827-1.176; P=.846). No new safety signals were observed.; CONCLUSION: In patients with non-squamous NSCLC, there was no significant improvement in OS with veliparib+carboplatin/paclitaxel versus chemotherapy alone, although a trend toward improved OS in the LP52+ population suggests this subgroup may benefit from veliparib. Statistical power was limited due to the small sample size. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P

Background: Veliparib (Vel) is a potent PARP1/2 inhibitor with demonstrated antitumor activity when administered alone or combined with carboplatin and paclitaxel (C/P). The phase 3 randomized, double-blind, multicenter BROCADE3 study (NCT02163694) evaluated the efficacy and safety of Vel + C/P treatment compared with placebo (Pbo) + C/P treatment in patients (pts) with germline BRCA1/2 mutations and HER2-negative metastatic or locally advanced breast cancer (BC). Vel + C/P significantly prolonged progression-free survival (PFS) compared with Pbo + C/P treatment (14.5 months [mo] vs 12.6 mo, hazard ratio [HR]=0.71 [95% CI: 0.57, 0.88]; P=0.002). Previous studies have identified increased acute hematologic toxicity in response to chemotherapy in pts with BC carrying BRCA1 mutations compared with BRCA2 mutations or wildtype BRCA1/2. Herein we report a subgroup analysis of the efficacy and safety of Vel + C/P treatment in pts with BRCA1- or BRCA2-positive BC. Methods: Pts ≥18 years of age who received ≤2 prior lines of cytotoxic chemotherapy for metastatic disease were randomized 2:1 to receive Vel + C/P or Pbo + C/P: Vel (120 mg PO BID) or Pbo on days -2 to 5, C (AUC 6 IV) on day 1, and P (80 mg/m2 IV) on days 1, 8, and 15 in 21-day cycles. Pts who discontinued C/P in the absence of disease progression could continue receiving Vel or Pbo monotherapy (300-400 mg BID continuous). Subgroup analysis of PFS stratified by BRCA1/2 status was preplanned. The primary endpoint was investigator-assessed PFS. Adverse events (AEs) were graded according to NCI CTCAE version 4.0. Ten pts with both BRCA1 and BRCA2 mutations were excluded from the analyses presented here. Results: In the intent-to-treat population, 256 pts had BRCA1 mutations and 243 pts had BRCA2 mutations. The proportion of as-treated pts with BRCA1 or BRCA2 mutations was comparable between the Vel + C/P (51.4% BRCA1, 48.6% BRCA2) and Pbo + C/P (50.9% BRCA1, 49.1% BRCA2) study arms. Investigator-assessed PFS for the Vel + C/P and Pbo + C/P arms was 14.2 mo vs 12.6 mo, respectively, in the BRCA1 subgroup (HR=0.75 [95% CI: 0.55, 1.03]; P=0.073) and 14.6 mo vs 12.6 mo, respectively, in the BRCA2 subgroup (HR=0.69 [95% CI: 0.50, 0.95]; P=0.021). Safety data in the as-treated population are presented in the Table. Regarding any grade AEs, thrombocytopenia and anemia were slightly more frequent in pts in the BRCA1 subgroup compared with the BRCA2 subgroup, whereas pts in the BRCA2 subgroup experienced slightly more frequent nausea, fatigue, and neuropathy. Conclusions: Globally, there was no clinically relevant difference in toxicity between BRCA1 and BRCA2 subgroups. Comparisons between treatment arms were generally consistent with findings in the overall study population, with more frequent thrombocytopenia and anemia of any grade reported in the Vel + C/P arm within both the BRCA1 and BRCA2 subgroups. Vel + C/P treatment improved PFS similarly in both BRCA1 and BRCA2 subgroups over C/P alone. BRCA1-Positive Subgroup (n=253)BRCA2-Positive Subgroup (n=241)Vel + C/P (n=168)Pbo + C/P (n=85)Vel + C/P (n=159)Pbo + C/P (n=82)Any grade AE [≥50% of pts], n (%)Any event167 (99.4)85 (100)158 (99.4)82 (100)Neutropenia151 (89.9)78 (91.8)140 (88.1)74 (90.2)Thrombocytopenia140 (83.3)66 (77.6)124 (78.0)54 (65.9)Anemia139 (82.7)64 (75.3)122 (76.7)52 (63.4)Nausea118 (70.2)49 (57.6)119 (74.8)58 (70.7)Alopecia89 (53.0)43 (50.6)89 (56.0)41 (50.0)Fatigue79 (47.0)37 (43.5)87 (54.7)48 (58.5)Peripheral sensory neuropathy69 (41.1)37 (43.5)82 (51.6)49 (59.8)Any grade ≥3 AE [≥30% of pts], n (%)Any event164 (97.6)82 (96.5)152 (95.6)77 (93.9)Anemia73 (43.5)31 (36.5)67 (42.1)35 (42.7)Leukopenia54 (32.1)20 (23.5)44 (27.7)25 (30.5)Neutropenia136 (81.0)72 (84.7)131 (82.4)67 (81.7)Thrombocytopenia72 (42.9)30 (35.3)59 (37.1)18 (22.0)Serious AEs, n (%)58 (34.5)26 (30.6)56 (35.2)22 (26.8)AEs of special interest, n (%)Infections within 14 days of neutropenia64 (38.1)34 (40.0)59 (37.1)25 (30.5)Hemorrhages within 14 days of thrombocytopenia14 (8.3)5 (5.9)17 (10.7)7 (8.5)Any AE leading to study drug discontinuation not due to disease progression, n (%)16 (9.5)5 (5.9)15 (9.4)4 (4.9)Any AE leading to study drug interruption, n (%)153 (91.1)77 (90.6)139 (87.4)67 (81.7)Any AE leading to study drug reduction, n (%)28 (16.7)6 (7.1)27 (17.0)7 (8.5)Any AE leading to death with reasonable possibility related to study drug, n (%)0 (0)0 (0)0 (0)0 (0)AE, adverse event; BRCA, breast cancer susceptibility gene; C/P, carboplatin plus paclitaxel; Pbo, placebo; pts, patients; Vel, veliparib. Citation Format: Hans Wildiers, Jean-Pierre Ayoub, Michael Friedlander, Bella Kaufman, Banu K. Arun, Hyo S. Han, Shannon L. Puhalla, David Maag, Dai Feng, Christine K. Ratajczak, Bruce A. Bach, Véronique Diéras. Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: A subgroup analysis of germline BRCA1 or BRCA2 mutations from the phase 3 BROCADE3 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-03.

PURPOSE Squamous non–small-cell lung cancer (sqNSCLC) is genetically complex with evidence of DNA damage. This phase III study investigated the efficacy and safety of poly (ADP-ribose) polymerase inhibitor veliparib in combination with conventional chemotherapy for advanced sqNSCLC ( NCT02106546 ). PATIENTS AND METHODS Patients age ≥ 18 years with untreated, advanced sqNSCLC were randomly assigned 1:1 to carboplatin and paclitaxel with veliparib 120 mg twice daily (twice a day) or placebo twice a day for up to six cycles. The primary end point was overall survival (OS) in the veliparib arm versus the control arm in current smokers, based on phase II findings. Archival tumor samples were provided for biomarker analysis using a 52-gene expression histology classifier (LP52). RESULTS Overall, 970 patients were randomly assigned to carboplatin and paclitaxel plus either veliparib (n = 486) or placebo (n = 484); 57% were current smokers. There was no significant OS benefit with veliparib in current smokers, with median OS 11.9 versus 11.1 months (hazard ratio [HR], 0.905; 95% CI, 0.744 to 1.101; P = .266). In the overall population, OS favored veliparib; median OS was 12.2 versus 11.2 months (HR, 0.853; 95% CI, 0.747 to 0.974), with no difference in progression-free survival (median 5.6 months per arm). In patients with biomarker-evaluable tumor samples (n = 360), OS favored veliparib in the LP52-positive population (median 14.0 v 9.6 months; HR, 0.66; 95% CI, 0.49 to 0.89), but favored placebo in the LP52-negative population (median 11.0 v 14.4 months; HR, 1.33; 95% CI, 0.95 to 1.86). No new safety signals were observed in the experimental arm. CONCLUSION In current smokers with advanced sqNSCLC, there was no therapeutic benefit of adding veliparib to first-line chemotherapy. The LP52 signature may identify a subgroup of patients likely to derive benefit from veliparib with chemotherapy.

Objectives: Previous phase 3 trials of front-line maintenance with the PARP inhibitors (PARPi) olaparib and niraparib only included patients (pts) with complete (CR) or partial (PR) response following front-line chemotherapy (CT); both agents were adopted as standard of care (SOC) in these pts. This prevented the systematic study of all pts who are eligible for PARPi maintenance therapy after front-line CT or to predict their responses. The phase 3 VELIA study (NCT02470585) added veliparib (VEL) to front-line CT at diagnosis, followed by VEL maintenance in the absence of progressive disease (PD), permitting treatment of a broader cohort of pts. This exploratory analysis evaluated baseline characteristics associated with first-line CT response, to understand if predictive variables exist that could identify those who would be eligible vs ineligible for SOC PARPi maintenance. Methods: Pts with untreated Stage III/IV ovarian cancer were randomized to carboplatin/paclitaxel (CP) + placebo (PBO) followed by PBO maintenance (control arm), CP + VEL followed by PBO maintenance (VEL combination only), or CP + VEL followed by VEL maintenance (VEL throughout). Pts without progression after combination treatment transitioned to assigned maintenance therapy. In this exploratory analysis, pts with germline or somatic BRCA mutations (BRCAm) were grouped as maintenance eligible (ME; with CR/PR or non-PD with surgical complete resection) or maintenance not eligible (MNE; with stable disease/progression/non-CR/non-PD). Progression-free survival (PFS) in pts starting maintenance was measured from initiation of maintenance treatment. Results: Of 1,140 randomized pts, 298 had germline or somatic BRCAm; of these, 278 could be classified according to maintenance eligibility. MNE pts (n=56) were distributed equally among the control, VEL combination only, and VEL throughout arms (21%, 19%, and 21% of evaluable pts, respectively). MNE subgroups were enriched for advanced disease (18-39% of MNE subgroups vs 13-19% of ME subgroups had Stage IV disease) and less favorable performance status (41-67% MNE vs 20-40% of ME pts had ECOG performance status ≥1). For ME pts (n=222), median PFS from initiation of maintenance was not reached in the VEL throughout arm vs 19.7 months in the control arm (HR 0.29, 95% CI 0.16-0.52, Figure). For MNE pts, median PFS was 16.4 months in the VEL throughout arm and 18.9 months in the control arm (HR 1.331, 95% CI 0.52-3.44); however, sample sizes (n=18 and n=16, respectively) limit a meaningful analysis of PFS in these pts. Download : Download high-res image (79KB) Download : Download full-size image Conclusions: The results of this exploratory analysis suggest that VEL has robust efficacy in pts with BRCA-mutated tumors eligible for SOC PARPi maintenance. Baseline characteristics of advanced disease and less favorable performance status were more common in MNE pts than ME pts. Molecular characterization is ongoing to identify mechanisms of sensitivity that predict eligibility for, and response to, PARPi therapy.

Purpose: Telisotuzumab vedotin (Teliso-V) is an anti–c-Met–directed antibody–drug conjugate. Here, we present safety and efficacy data from a phase I/Ib study of Teliso-V monotherapy evaluated in once every 2 weeks/once every 3 weeks schedules in patients with non–small cell lung cancer (NSCLC). Patients and Methods: During dose escalation, patients received Teliso-V monotherapy intravenously once every 3 weeks (0.15–3.3 mg/kg) or once every 2 weeks (1.6–2.2 mg/kg). The dose-expansion phase enrolled patients with NSCLC and c-Met H-score ≥150 (c-Met+) or MET amplification/exon 14 skipping mutations. Safety, pharmacokinetics, and efficacy were assessed. Herein, the analysis of patients receiving ≥1.6 mg/kg once every 2 weeks or ≥2.4 mg/kg once every 3 weeks Teliso-V is reported. Results: Fifty-two patients with NSCLC were enrolled and received ≥1.6 mg/kg Teliso-V once every 2 weeks (n = 28) or ≥2.4 mg/kg Teliso-V once every 3 weeks (n = 24). The most common adverse events were fatigue (54%), peripheral neuropathy (42%), and nausea (38%). No dose-limiting toxicities were observed for Teliso-V once every 2 weeks and once every 3 weeks up to 2.2 and 2.7 mg/kg, respectively. The recommended phase II dose was established at 1.9 mg/kg once every 2 weeks and 2.7 mg/kg once every 3 weeks on the basis of overall safety and pharmacokinetics. Forty of 52 patients were c-Met+ (33 nonsquamous, 6 squamous, 1 mixed histology) and were included in the efficacy-evaluable population. Of those, 9 (23%) had objective responses with median duration of response of 8.7 months; median progression-free survival was 5.2 months. Conclusions: Teliso-V monotherapy was tolerated and showed antitumor activity in c-Met+ NSCLC. On the basis of overall safety, pharmacokinetics, and efficacy outcomes, 1.9 mg/kg Teliso-V once every 2 weeks and 2.7 mg/kg once every 3 weeks schedules were selected for further clinical development.

Objectives Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). Materials and methods Patients received veliparib orally twice daily (BID) in escalating doses (60–240 mg, Day –3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m2), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120–240 mg BID, Days –2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m2, Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. Results Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7–32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0–not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0–not reached). Conclusions When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.

Introduction Giant-cell tumor of bone (GCTB) is a locally aggressive histologically benign neoplasm with a less common malignant counterpart. Longitudinal data sources on GCTB are sparse, limited to single institution case series or surgical outcomes studies. The Swedish Cancer Registry is one of the few national population-based databases recording GCTB, representing a unique source to study GCTB epidemiology. We estimated incidence rate (IR) and overall mortality rates based on registry data. Materials and methods We identified patients with a GCTB diagnosis in the Swedish Cancer Registry from 1983 to 2011: benign (ICD-7 196.0–196.9; PAD 741) and malignant (PAD 746). Results were stratified by age at diagnosis, gender, and anatomical lesion location. Results The cohort included 337 GCTB cases (IR of 1.3 per million persons per year). The majority (n = 310) had primary benign GCTB (IR of 1.2 per million per year). Median age at diagnosis was 34 years (range 10–88) with 54% (n = 183) females. Malignant to benign ratio for women was 0.095 (16/167) and for men 0.077 (11/143). Incidence was highest in the 20–39 years age group (IR of 2.1 per million per year). The most common lesion sites were distal femur and proximal tibia. Mortality at 20 years from diagnosis was 14% (n = 48) and was slightly higher for axial (17%; n = 6) and pelvic (17%; n = 4) lesions. Recurrence occurred in 39% of primary benign cases and 75% of primary malignant cases. Conclusions In our modern population-based series primary malignant cases were uncommon (8%), peak incidence 20–39 years with slight predominance in women. Recurrence rates remain significant with overall 39% occurring in benign GCTB, and 75% in malignant form. The linkage between databases allowed the first population based estimates of the proportion of patients who received surgery at initial GCTB diagnosis, and those who also received subsequent surgeries.

1091 Background: In BROCADE3 (NCT02163694), addition of PARP inhibitor V to CP resulted in improved progression-free survival (PFS) (HR 0.71 [95% CI 0.57−0.88], p=0.002) in patients (pts) with advanced HER2-negative breast cancer and g BRCA1/2 mutation. A subset of pts transitioned to V/placebo (PL) monoTx at an intensified dose/schedule after CP discontinuation prior to progression (investigator discretion). Here, we evaluate the impact of this transition on efficacy and safety. Methods: Pts were randomized 2:1 to CP with V (n=337) or PL (n=172). V (120 mg po BID) or PL was given on Days (D) −2 to 5, C (AUC 6) on D1, and P (80 mg/m2) on D1, 8, and 15 (21-day cycles). Pts who transitioned to monoTx received V/PL 300-400mg BID daily until progression. A Cox model with a time varying covariate indicating transition from V/PL with CP to V/PL monoTx was fit to estimate treatment effect during combination and monoTx phases. PFS by cycles of CP prior to monoTx and AEs during monoTx are summarized. Results: A subgroup of 136 (40%) and 58 (34%) pts on the V and PL arms, respectively, received monoTx. When a Cox model with a time-varying covariate was fit for PFS (per investigator), the nominal P-value for treatment by covariate interaction was 0.038. The HRs (95% CI) for V vs PL during combination therapy and monoTx were 0.81 (0.62–1.06) and 0.49 (0.33–0.73). The Table summarizes PFS by cycles of C and/or P prior to monoTx. Common AEs (>20% of pts) during V or PL monoTx were nausea (52%/10%), fatigue (23%/12%), headache (21%/17%), and diarrhea (21%/9%). Seizures (2.2%/0%) were reported during monoTx. Rates of cytopenias for V or PL monoTx were: anemia 12%/14%; neutropenia 13%/12%; and thrombocytopenia 10%/5%. Conclusions: These analyses suggest that pts treated with V + CP derive benefit from both combination therapy as well as V monoTx after CP discontinuation. Pts receiving V monoTx after ≤ 6 cycles of VCP experienced a similar benefit to those who transitioned to monoTx after 7–12 cycles of VCP, suggesting that V maintenance therapy may be suitable following a limited duration of combination therapy. Clinical trial information: NCT02163694 . [Table: see text]

e13046 Background: BRCA1/2 mutations account for 5-10% of breast cancer (BC) patients. BRCA1 mutations are associated with aggressive tumors, often triple negative (TNBC) (HER2, estrogen-receptor [ER], progesterone-receptor [PR] negative) and are mainly treated with combination chemotherapy or platinum agents. This study aimed to compare real world treatment patterns in breast cancer patients who were BRCA-mutation positive (BRCA+) and those who were BRCA-mutation negative (BRCA-), focusing on hormone-receptor positive (HR+) and TNBC subgroups. Methods: Optum’s Humedica electronic health records (EHR) database was used to identify a cohort of women with 1) confirmed BC ICD-9/ICD-10 diagnosis between 2008 and 2018, 2) at least 12 months of history in EHR, 3) at least one distant metastasis diagnosis (per ICD-9/ICD-10 or physician notes), and 4) no previous diagnosis of other primary cancers in previous 12 months. HR and HER2 test results were used to create relevant subgroups. Distinct lines of therapy (LOT) in the post-metastatic period were established using business rules. Treatment patterns and duration of treatment were analyzed. Results: Among 65,934 metastatic BC patients identified, 7941 were BRCA+, of whom 5366 (68%) were HR+ and 1323 (17%) had TNBC phenotype, while 4027 were BRCA-, of whom 2859 (71%) were HR+ and 561 (14%) had TNBC phenotype. Seventy-one percent of BRCA+ women underwent drug treatment, compared to 65% of BRCA- women. Drug treatments included hormonal treatment (+/-other agents), targeted therapy, and chemotherapy only, and varied across the different cohorts (Table). Mean (median) duration of treatment in LOT1 in the BRCA+ and BRCA- cohorts was 117 (73) and 117 (72) days, respectively. Conclusions: Real-world evidence on treatment patterns in BC patients revealed substantial differences across important biomarker and hormonal status BC phenotypes. As a preponderance of women with TNBC are still being treated exclusively with chemotherapy, these data highlight how the need for development of effective treatment options for TNBC remains high. [Table: see text]

Background: BROCADE3 (NCT02163694) evaluated the PARP inhibitor veliparib in combination with carboplatin/paclitaxel (C/P) vs placebo + C/P in patients with HER2-negative locally advanced/metastatic breast cancer and a germline BRCA1/2 mutation. In the intent-to-treat (ITT) population, investigator-assessed median progression-free survival (PFS) was 14.5 months for veliparib vs 12.6 months for placebo (hazard ratio=0.71 [95% CI 0.57-0.88], p=0.002); 75th percentile PFS was 39.9 months for veliparib vs 20.7 months for placebo. In this preplanned analysis, we evaluated efficacy and safety of veliparib plus C/P in patients with no previous cytotoxic chemotherapy for metastatic disease. Methods: Patients with ≤2 prior lines of cytotoxic chemotherapy for metastatic breast cancer were randomized 2:1 to C/P with veliparib or C/P with placebo. Veliparib (120 mg p.o. BID) or placebo was given on Days −2 to 5, C (AUC 6 mg/mL/min IV) on Day 1, and P (80 mg/m2 IV) on Days 1, 8, and 15 (21-day cycles). Patients who discontinued both C and P for toxicity or reasons other than disease progression could continue veliparib/placebo monotherapy until progression. Monotherapy dose was 300 mg BID, increasing to 400 mg BID if tolerated. Although randomization was not stratified by lines of prior cytotoxic chemotherapy, the treatment arms were well-balanced with respect to this baseline characteristic. The primary endpoint was PFS as assessed by investigator. Secondary endpoints included overall survival (OS), clinical benefit rate (CBR), and objective response rate (ORR). Adverse events were monitored throughout the study. Analysis of PFS in patients with no prior cytotoxic therapy for metastatic disease was pre-planned. Results: In the ITT population, 337 patients (81% of the entire cohort) received treatment as first line and were randomized to veliparib plus C/P and 172 patients to placebo plus C/P. Most patients received prior cytotoxic chemotherapy in the neo-adjuvant/adjuvant setting (66%, placebo plus C/P; 70%, veliparib plus C/P). Among the 81% of patients in each arm who had no prior cytotoxic chemotherapy in the metastatic setting, median PFS was longer in patients receiving veliparib plus C/P compared to placebo plus C/P (16.6 mo vs 13.1 mo), and median PFS for both arms was over 1 year (Table). Proportion of patients with a serious AE was 30.9% for placebo plus C/P and 33.1% for veliparib plus C/P; proportion with an AE leading to study drug discontinuation was 10.8% for placebo plus C/P and 15.6% for veliparib plus C/P. Additional safety data will be presented. Conclusions: In patients with HER2-negative advanced/metastatic breast cancer and a germline BRCA1/2 mutation who had no prior cytotoxic chemotherapy for metastatic disease, veliparib with C/P demonstrated an improvement in median PFS over C/P alone. This benefit was durable with 25% of patients alive and progression free at nearly 4 years. Table. Efficacy in patients with no prior cytotoxic chemotherapy for metastatic disease.Veliparib + C/P, n=274Placebo + C/P, n=139mPFS per INV (mo, 95% CI)16.6 (13.4, 18.7)13.1 (11.4, 14.5)PFS HR (95% CI)0.69 (0.54, 0.88)PFS 75th percentile (mo, 95% CI)46.3 (29.3, NR)22.6 (16.5, 27.2)mPFS per ICR (mo, 95% CI)21.5 (18.7, 29.2)14.0 (12.5, 16.5)PFS HR (95% CI)0.63 (0.47, 0.84)PFS 75th percentile (mo, 95% CI)NR33.3 (19.7, NR)mOS (mo, 95% CI) [interim]36.0 (32.0, 43.1)29.9 (26.0, 39.3)OS HR (95% CI)0.92 (0.68, 1.2)CBR at 24 weeks (% [95% CI])92.8 (90.0, 94.9)93.4 (89.1, 96.0)ORR (% [95% CI])79.7 (74.0, 84.7)76.3 (67.4, 83.8) C/P, carboplatin and paclitaxel; CBR, clinical benefit rate; HR, hazard ratio; m, median; mo, months; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; INV, investigator; ICR, independent central review. Citation Format: Banu K. Arun, Hyo S. Han, Bella Kaufman, Hans Wildiers, Michael Friedlander, Jean-Pierre Ayoub, Shannon L. Puhalla, Bruce A. Bach, Matthew Dudley, Christine K. Ratajczak, David Maag, Véronique Diéras. First-line veliparib plus carboplatin/paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: Planned subgroup analysis from the phase 3 BROCADE3 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-01.

Denosumab has been shown to reduce tumor size and progression, reform mineralized bone, and increase intralesional bone density in patients with giant cell tumor of bone (GCTB); however, radiologic assessment of tumors in bone is challenging. The study objective was to assess tumor response to denosumab using three different imaging parameters in a prespecified analysis in patients with GCTB from two phase 2 studies. The studies enrolled adults and adolescents (skeletally mature and at least 12 years of age) with radiographically measurable GCTB that were given denosumab 120 mg every 4 weeks, with additional doses on days 8 and 15 of cycle 1. The proportion of patients with an objective tumor response was assessed using either Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), European Organisation for Research and Treatment of Cancer response criteria (positron emission tomography [PET] scan criteria), or inverse Choi density/size (ICDS) criteria. Target lesions were measured by computed tomography or magnetic resonance imaging (both studies), PET (study 2 only), or plain film radiograph (study 2 only). Most patients (71.6%) had an objective tumor response by at least one response criteria. Per RECIST, 25.1% of patients had a response; per PET scan criteria, 96.2% had a response; per ICDS, 76.1% had a response. 68.5% had an objective tumor response ≥ 24 weeks. Using any criteria, crude incidence of response ranged from 56% (vertebrae/skull) to 91% (lung/soft tissue), and 98.2% had tumor control ≥ 24 weeks. Reduced PET avidity appeared to be an early sign of response to denosumab treatment. Modified PET scan criteria and ICDS criteria indicate that most patients show responses and higher benefit rates than modified RECIST, and therefore may be useful for early assessment of response to denosumab. ClinicalTrials.gov Clinical Trials Registry NCT00396279 (retrospectively registered November 6, 2006) and NCT00680992 (retrospectively registered May 20, 2008).

Purpose To validate a next-generation sequencing (NGS)-based companion diagnostic using the MiSeqDx® sequencing instrument to simultaneously detect 56 RAS mutations in DNA extracted from formalin-fixed paraffin-embedded metastatic colorectal cancer (mCRC) tumor samples from the PRIME study. The test’s ability to identify patients with mCRC likely to benefit from panitumumab treatment was assessed. Methods Samples from PRIME, which compared first-line panitumumab + FOLFOX4 with FOLFOX4, were processed according to predefined criteria using a multiplex assay that included input DNA qualification, library preparation, sequencing, and the bioinformatics reporting pipeline. NGS mutational analysis of KRAS and NRAS exons 2, 3, and 4 was performed and compared with Sanger sequencing. Results In 441 samples, positive percent agreement of the Extended RAS Panel with Sanger sequencing was 98.7% and negative percent agreement was 97.6%. For clinical validation (n = 528), progression-free survival (PFS) and overall survival (OS) were compared between patients with RAS mutations (RAS Positive) and those without (RAS Negative). Panitumumab + FOLFOX4 improved PFS in RAS Negative patients (P = 0.02). Quantitative interaction testing indicated the treatment effect (measured by the hazard ratio of panitumumab + FOLFOX4 versus FOLFOX4) differed for RAS Negative versus RAS Positive for PFS (P = 0.0038) and OS (P = 0.0323). Conclusions NGS allows for broad, rapid, highly specific analyses of genomic regions. These results support use of the Extended RAS Panel as a companion diagnostic for selecting patients for panitumumab, and utilization is consistent with recent clinical guidelines regarding mCRC RAS testing. Overall, approximately 13% more patients were detected with the Extended RAS Panel versus KRAS exon 2 alone. Clinical trial registry identifier NCT00364013 (ClinicalTrials.gov). Electronic supplementary material The online version of this article (10.1007/s00432-018-2688-3) contains supplementary material, which is available to authorized users.

Background ctDNA allows monitoring of response to therapy and serves as a liquid biopsy for pt selection for targeted therapies. We used samples from pts with NSCLC enrolled in an ongoing phase I/Ib trial (NCT02099058) treated with telisotuzumab vedotin (ABBV-399; teliso-v) alone and in combination with erlotinib or nivolumab to assess the frequency of mutant alleles in ctDNA and the association between ctDNA levels and OR to teliso-v. Methods Plasma was collected pre- (C1D1) and post-treatment (≥C2D1) and analyzed using 64-gene PlasmaSELECT™ assay (PGDx). Correlations between ctDNA detection probability and best OR were assessed by Fisher’s exact test; if C2D1 samples were not available, C3D1 (if CR/PR/SD) or FV samples (if PD) were used. The sum of variant allele fraction for all somatic mutations (SumVAF) at C1D1 and C2D1 was compared between response groups and between matched C1D1 and C2D1 samples. Results 109 pts were analyzed (C1D1 [n = 108]). Among 56 pts without variant alleles detected at C1D1, ctDNA detection probability at ≥C2D1 was similar regardless of response (P = 0.51). For 52 pts with ctDNA detectable at C1D1, ctDNA detection probability at ≥C2D1 was higher for SD/PD (85%) vs CR/PR (55%), but not significant (P = 0.15). For all response groups SumVAF decreased from C1D1 to C2D1, suggesting a pharmacodynamic effect of teliso-v. SumVAF was significantly lower in pts with CR/PR vs SD/PD at C1D1 (P = 0.015) and marginally lower at C2D1 (P = 0.097). Table . 1469P Pre- and post-treatment mean (stdev) sum of variant allele fraction by response category CR/PR n = 24 SD n = 58 PD n = 27 P § (FC) of SumVAF: SD/PD vs CR/PR Pre-treatment (C1D1) n = 108 * 3% (6%) 8% (15%) 6% (15%) 0.015 (2.88) Post-treatment (C2D1) n = 83 † 1% (5%) 4% (7%) 3% (9%) 0.097 (2.87) P ‡ , C1D1 vs C2D1 Mean decrease of SumVAF from C1D1 to C2D1 0.01 2% 0.04 3% 0.02 4% C, cycle; CR, complete response; D, day; FC, fold change; PD, progressive disease; PR, partial response; SD, stable disease; stdev, standard deviation; SumVAF, sum of variant allele fraction for all somatic mutations. * C1D1 data, missing for 1 patient with SD. † C2D1 data, missing for 26 patients (4 CR/PR, 11 SD, and 11 PD). ‡ By pair-wise t-test on 82 patients with both C1D1 and C2D1 data available. § By 2-group t-test. Conclusions Baseline SumVAF levels and ctDNA detection probability at ≥C2D1 were lower with CR/PR vs SD/PD in pts with detectable ctDNA at C1D1. SumVAF decreased by C2D1 regardless of response, with more consistent reduction in pts with CR/PR. These data may suggest that discrete patterns of change in SumVAF over time correlate with OR outcome. Further investigation is warranted to assess ctDNA’s predictive value. Clinical trial identification NCT02099058. Editorial acknowledgement Iratxe Abarrategui, PhD, CMPP, from Aptitude Health, The Hague, Netherlands; funded by AbbVie. Legal entity responsible for the study AbbVie Inc. Funding AbbVie Inc. Disclosure R.S. Heist: Advisory / Consultancy: Apollomics; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Tarveda Therapeutics; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Peregrine Pharmaceuticals; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Debiopharm Group; Research grant / Funding (institution): Corvus Pharmeceuticals; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Pfizer. M. Motwani: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. L. Naumovski: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. J. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. B.A. Bach: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. X. Lu: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. K. Kelly: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Regeneron; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AbbVie; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Honoraria (self), Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer; Licensing / Royalties, web information resource : UpToDate; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Transgene; Research grant / Funding (institution): Lycera.

Aims Trebananib, a peptide-Fc fusion protein, inhibits angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. This randomised, double-blind, placebo-controlled phase 3 study evaluated whether trebananib plus pegylated liposomal doxorubicin (PLD) improved progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer. Methods Women with recurrent ovarian cancer (platinum-free interval ≤12 months) were randomised to intravenous PLD 50 mg/m2 once every 4 weeks plus weekly intravenous trebananib 15 mg/kg or placebo. PFS was the primary end-point; key secondary end-points were objective response rate (ORR) and duration of response (DOR). Owing to PLD shortages, enrolment was paused for 13 months; the study was subsequently truncated. Results Two hundred twenty-three patients were enrolled. Median PFS was 7.6 months (95% CI, 7.2–9.0) in the trebananib arm and 7.2 months (95% CI, 4.8–8.2) in the placebo arm, with a hazard ratio of 0.92 (95% CI, 0.68–1.24). However, because the proportional hazards assumption was not fulfilled, the standard Cox model did not provide a reliable estimate of the hazard ratio. ORR in the trebananib arm was 46% versus 21% in the placebo arm (odds ratio, 3.43; 95% CI, 1.78–6.64). Median DOR was improved (trebananib, 7.4 months [95% CI, 5.7–7.6]; placebo, 3.9 months [95% CI, 2.3–6.5]). Adverse events with a greater incidence in the trebananib arm included localised oedema (61% versus 32%), ascites (29% versus 9%) and vomiting (45% versus 33%). Conclusions Trebananib demonstrated anticancer activity in this phase 3 study, indicated by improved ORR and DOR. Median PFS was not improved. No new safety signals were identified. Trial registration: ClinicalTrials.gov , NCT01281254

Background Mutations in rat sarcoma (RAS) genes may be a mechanism of secondary resistance in epidermal growth factor receptor inhibitor-treated patients. Tumor-tissue biopsy testing has been the standard for evaluating mutational status; however, plasma testing of cell-free DNA has been shown to be a more sensitive method for detecting clonal evolution. Materials and methods Archival pre- and post-treatment tumor biopsy samples from a phase II study of panitumumab in combination with irinotecan in patients with metastatic colorectal cancer (mCRC) that also collected plasma samples before, during, and after treatment were analyzed for emergence of mutations during/post-treatment by next-generation sequencing and BEAMing. Results The rate of emergence of tumor tissue RAS mutations was 9.5% by next-generation sequencing (n= 21) and 6.3% by BEAMing (n = 16). Plasma testing of cell-free DNA by BEAMing revealed a mutant RAS emergence rate of 36.7% (n = 39). Exploratory outcomes analysis of plasma samples indicated that patients who had emergent RAS mutations at progression had similar median progression-free survival to those patients who remained wild-type at progression. Serial analysis of plasma samples showed that the first detected emergence of RAS mutations preceded progression by a median of 3.6 months (range, -0.3 to 7.5 months) and that there did not appear to be a mutant RAS allele frequency threshold that could predict near-term outcomes. Conclusions This first prospective analysis in mCRC showed that serial plasma biopsies are more inclusive than tissue biopsies for evaluating global tumor heterogeneity; however, the clinical utility of plasma testing in mCRC remains to be further explored. ClinicalTrials.gov Identifier NCT00891930

e20552 Background: Peripheral neuropathy (PN) occurs in NSCLC patients and may be due to various factors. One of the major factors is chemotherapy treatment. This study assessed the frequency and risk of PN among chemotherapy exposed NSCLC patients. Methods: This retrospective cohort study used the Optum claims in 2015-2017. The main inclusion criteria included: at least 2 diagnosis (Dx) claims for lung cancer; no other systemic cancer Dx within 6 months prior to the NSCLC Dx; at least one line of systemic anti-cancer treatment after the NSCLC Dx; presence of secondary metastatic disease. NSCLC was identified using a published algorithm. PN was identified by at least one claim with ICD-9/ICD-10 PN diagnosis code. Patients were followed from the earliest chemotherapy treatment date until a censoring event (PN Dx, end of enrollment, death, or end of study interval). Descriptive statistics were used to describe demographics; the Cox model and logistic regression were used to analyze risk associated with PN. Results: A total of 5082 patients were identified with an average age of 70.9 years (SD = 8.7) and 52% of male. Most common first line of treatment (LoT) was carboplatin + paclitaxel (31.9%); 32.7% of patients received a 2nd line, 7.6% received a 3rd line, and 1.7% received a 4th or higher line. 857 patients had PN during the follow-up period (16.9%). Median Charlson comorbidity index (CCI) was 1, and mean 1.7 (SD = 1.8). Patients with CCI of 4+ (716 patients) had nearly 60% elevated risk of PN as compared with CCI = 0. Patients with diabetes presented the OR (odds ratio) of 1.58; patients with a history of PN had a higher risk of PN after the initiation of chemotherapy (OR = 3.90). Compared with the PN risk during 1st LoT (reference), the OR of developing PN during 2nd and 3rd+ LoTs was elevated to 1.78 (95%CI 1.49-2.11; p < 0.0001) and 2.61 (95%CI 2.03-3.34; p < 0.0001), respectively. The most common type of PN was sensory neuropathy (33%), then polyneuritis (21%) and diabetic polyneuropathy (18%). Conclusions: PN is common in NSCLC patients. This analysis shows that the risk of PN in NSCLC patients increases significantly along increasing number of LoT. A history of PN and presence of diabetes play an important role as risk factors of PN during anti-cancer systemic treatment.

9023 Background: c-Met overexpression (OE) and MET amplification (amp) are prognostic of poor outcome for non-small cell lung cancer (NSCLC). Telisotuzumab vedotin (ABBV-399; teliso-v [T]), an anti–c-Met Ab and monomethyl auristatin E drug conjugate, showed efficacy as monotherapy (mono) and combined with erlotinib (T+Er) in a phase 1/1b trial (NCT02099058) in NSCLC patients (pts) with c-Met OE. Here, c-Met OE (by immunohistochemistry [IHC]) and its association with T efficacy were explored. IHC, mRNA, and amp platforms for MET were also compared. Methods: Archival tissue from pts with NSCLC in the phase 1/1b trial was examined. c-Met was assessed centrally by IHC with SP44 Ab (Ventana Medical Systems) and pts with c-Met OE (membrane H-score [H-S] of ≥150) were enrolled. MET mRNA expression was analyzed from total RNA and sequenced on HiSeq 3000 (Illumina). MET amp was analyzed by FISH ( MET/ CEP7 ratio of ≥2) or whole-exome sequencing (copy number ≥2). Efficacy in the T mono every 2 (TQ2W) or 3 (TQ3W) weeks and the T+Er EGFR mutant cohorts was assessed for IHC H-S ≥150 and ≥225. Results: As of Dec 2018, 238 pts with NSCLC were screened centrally for c-Met OE. Of these, 118 pts were enrolled. For screened pts, 76%/37% of nonsquamous (NSQ, n = 201) and 58%/16% of squamous (SQ, n = 32) pts had H-S ≥150/≥225; 75%/41% of NSQ and 55%/16% of SQ NSCLC pts had ≥50% cells with 2+/3+ staining intensity. MET amp was reported for 5 pts, all with high H-S (≥270); there was an association between MET amp and MET RNA levels (n = 4) (t-test p value: 0.0002). See Table for ORR and median PFS by H-S and T treatment. Conclusions: c-Met expression prevalence in NSCLC showed a similar trend as in previous reports. In T+Er-treated pts, ORR was higher for those with c-Met H-S ≥225 than ≥150– < 225, suggesting that biomarker expression may act as an effect size multiplier. Optimization of the c-Met IHC cutoff warrants further investigation. Clinical trial information: NCT02099058. [Table: see text]

PurposeTrebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolonged progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer in the phase 3 TRINOVA-1 study. We report overall survival (OS) in the intent-to-treat population and clinically relevant subgroups and time to second disease progression (PFS-2).Patients and methodsWomen with recurrent disease (platinum-free interval

BACKGROUND To evaluate the influence of treatment on health-related quality of life (HRQoL) in 919 women with recurrent ovarian cancer enrolled in the TRINOVA-1 study, a randomized, placebo-controlled phase III study that demonstrated that trebananib 15 mg/kg QW plus weekly paclitaxel significantly improved progression-free survival (PFS) compared with placebo plus weekly paclitaxel (7.2 versus 5.4 months; hazard ratio, 0.66; 95% confidence interval 0.57-0.77; P < 0.001). PATIENTS AND METHODS HRQoL was assessed with the Functional Assessment of Cancer Therapy-Ovary [FACT-O; comprising FACT-G and the ovarian cancer-specific subscale (OCS)] and EuroQOL EQ-5D instruments before treatment on day 1 of weeks 1, 5, 9, 13, 17, and every 8 weeks thereafter and at the safety follow-up visit. A pattern-mixture model was used to evaluate the influence of patient dropout on FACT-O and OCS scores over time. RESULTS Of 919 randomized patients, 834 (91%) had a baseline and ≥1 post-baseline HRQoL assessment. At baseline, scores for all instruments were similar for both arms. At 25 weeks, mean ± SD changes from baseline were negligible, with mean ± SD changes typically

The Swedish Cancer Registry (founded in 1958) constitutes a unique resource for epidemiological studies of giant cell tumor of bone with potential for use for population-based studies of incidence over time. The aim of this study was to provide what we believe is the first modern population-based assessment of the incidence trends of giant cell tumor, a unique osteoclastogenic lytic stromal tumor with both benign and malignant histological forms, and to compare the findings with data from the same registry on osteosarcoma, a tumor that may display similar histological characteristics.Cases were identified with use of codes for pathological bone tumor (International Classification of Diseases [ICD]-7 196). Specific morphological coding distinguishes benign (PAD 741) from malignant giant cell tumor (PAD 746) and osteosarcoma (PAD 766).During the period of 1958 to 2011, 4625 bone tumors were reported, including 505 giant cell tumors (383 benign and 122 malignant) and 1152 osteosarcomas. From 1958 to 1982 the ratio of malignant to benign giant cell tumors was 1.3, whereas from 1983 to 2011 the ratio inverted to 0.09, suggesting a change in the reporting or diagnosis of malignant or benign cases. Cases of giant cell tumor diagnosed from 1983 to 2011 displayed an age and sex distribution (median age at diagnosis, 34.0 years; 54% female) that were consistent with those in large published case series but differed from those in 1958 to 1982 (median age at diagnosis, 31.5 years; 48% female). The most current data (1983 to 2011) showed the giant cell tumor incidence in Sweden to be 1.3 per million per year, while the osteosarcoma incidence was 2.3 per million per year.Early Swedish Cancer Registry data (1958 to 1982) revealed a higher proportion of malignant giant cell tumors than seen in large sequential case series and a distinct age and sex profile compared with more recent data (1983 to 2011). This likely represents changes in the diagnostic workup and introduction of multidisciplinary review of giant-cell-containing tumors around 1982. Recent data may reflect the impact of expert centralized biopsy and multidisciplinary case review and more comprehensive reporting of benign giant cell tumors.

Background: Estimating the incidence of giant cell tumor of bone is challenging because few population-based cancer registries record benign bone tumors. We compared two approaches, the indirect (relative index) estimation approach used in The Burden of Musculoskeletal Diseases in the United States (BMUS) and a direct incidence rate approach (from registries that record giant cell tumor), to estimate giant cell tumor incidence in France, Germany, Italy, Spain, the U.K., Sweden, Australia, Canada, Japan, and the U.S. Methods: Giant cell tumor of bone incidence was calculated with use of the BMUS relative index of giant cell tumor to osteosarcoma in three scenarios (low, base case, and high) from case series. We compared the BMUS approach with the latest data from tumor registries in Australia (1972 to 1996), Japan (2006 to 2008), and Sweden (1993 to 2011) that record giant cell tumors. United Nations population estimates were used to project results to 2013. Results: The low scenario in the BMUS approach reflects data from Unni and Inwards; the incidence of giant cell tumor of bone is 0.34 relative to osteosarcoma. As the incidence of osteosarcoma is 31.4% of the total incidence of bone and joint cancers, the incidence of giant cell tumor is 0.11 times that of all bone and joint cancers. The base scenario reflects the series by Mirra et al., with a giant cell tumor incidence of 0.47 relative to osteosarcoma (0.15 to all bone and joint cancers). The high scenario reflects the series by Ward, with an incidence of 0.84 relative to osteosarcoma (0.26 to all bone and joint cancers). Differences among the three series reflect referral to a national center of excellence compared with referral to a local oncology practice. Registry data indicated a giant cell tumor incidence rate per million per year of 1.33 in Australia, 1.03 in Japan, and 1.11 in Sweden in 2013. The estimated incidence rate per million in the ten countries in 2013 ranged from 1.03 (Japan) to 1.17 (Canada) with use of the registry-based approach and from 0.73 (Japan) for the low scenario) to 2.20 (Germany) for the base case with use of the BMUS approach. Conclusions: Giant cell tumor of bone affects approximately one person per million per year in the ten countries studied. Estimates derived with use of age-specific incidences from tumor registries were typically within the range of the low and base case BMUS scenarios. We recommend the registry-derived method for estimating the incidence of giant cell tumor.

e15170 Background: Skin toxicity can be a limiting factor for the use of anti-EGFR therapies, such as panitumumab, and there are currently no standard practice guidelines for rash management in the United States (U.S.). This study aimed to evaluate if there were regional or practice setting differences in strategies used among oncologists to manage EGFR rash, including utilization of dermatologic and nursing support. Methods: 250 practicing oncologists who had treated at least three mCRC patients with panitumumab in the last year completed an online survey to report their opinions and perceptions regarding skin toxicity management strategies. Participants reported if they were affiliated with an academic/university or a community-based practice. Participants were stratified into years of practice post-fellowship ( < 10 and > 10 years) and geographic region of primary practice (West, Midwest, Northeast, Southern U.S.). Results: Oncologists surveyed did not consistently utilize dermatology support. 40% (n = 99) of practicing oncologists surveyed reported consulting a dermatologist “occasionally.” Less than 5% reported “always” consulting dermatology and 6% reported “never” utilizing dermatology support. Utilization of dermatology support varied significantly by region. In the Southern US more oncologists reported “never” consulting dermatology while in the Midwest more oncologists reported “always” utilizing dermatology support (p = 0.05). While dermatology was inconsistently utilized, oncologists frequently utilized nursing support to minimize and manage anti-EGFR skin toxicity. 73% (n = 182) of oncologists engaged nursing support to “monitor skin toxicity during treatment” and 70% (n = 175) of oncologists had nursing support to “educate on skin toxicity prior to starting treatment.” Conclusions: While nursing support is consistently utilized by oncologists in the management of EGFR rash in mCRC patients treated with panitumumab, use of dermatology support was inconsistent and varied significantly by region. This lack of consistency in toxicity management strategies highlights the need for increased physician education.

3523 Background: ASPECCT was a clinical trial performed in the chemotherapy-refractory third-line mCRC setting (N = 1010). This biomarker analysis explores the mutational landscape in panitumumab monotherapy subjects. Analysis of plasma ctDNA at baseline and post-treatment (PT) by next-generation sequencing provides a snapshot of the main changes in key genes before and after therapy. Methods: CtDNA collected at baseline and PT was analyzed for mutations using the Plasma Select-R™ 63-gene panel (0.1% limit of detection). Gain or loss of mutation was defined at the amino acid level. Net change is the sum of mutations gained minus the sum of mutations lost. A single individual could have both net gain and/or net loss of mutations within a single gene. Results: Significant tumor clonal diversification was observed during therapy. In 238 subjects with paired plasma samples,29% of subjects had multiple mutations in the same gene at baseline and 41% of subjects had multiple mutations in the same gene PT. At least 10% of subjects demonstrated an on-therapy acquired mutation in at least one of the following genes: APC, EGFR, ALK, HER4, TP53, AR, KRAS, BRAF, PDGFRA, STK11, ESR1, FBXWT, and KIT (ordered by frequency). New mutations were noted both inside and outside the EGFR pathway. Unexpectedly, patients with a large decrease in mutant DNA burden after anti-EGFR treatment were also seen. EGFR pathway genes with significant net gain were: KRAS, EGFR, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1. Non-EGFR pathway mutations gained included: APC, CDK6, SMARCB1, FBXW7, TERT, RB1, CTNNB1, and IDH1. Conclusions: This 63-gene plasma analysis suggests that there are significant dynamic changes in clonal mutational fraction under anti-EGFR selection. Our analysis reveals that increasing global tumor heterogeneity is associated with poorer overall survival. A subset of patients demonstrated an overall decrease in tumor heterogeneity on panitumumab therapy (28%), indicating that under anti-EGFR selective pressure mutational heterogeneity can also decrease. Clinical trial information: NCT01001377.

3584 Background: ASPECCT was a phase III clinical trial performed in the chemotherapy-refractory third-line mCRC setting (N = 1010). This analysis explores the relationship between circulating levels of mutations and clinical outcomes for panitumumab-treated subjects using univariate and multivariate models that treat total mutational load as a continuous measure. Methods: 238 subjects treated with panitumumab had paired plasma samples at baseline and post-treatment (PT). Samples were analyzed for mutations using the Plasma Select-R™ 63-gene panel (0.1% limit of detection). The fraction of mutant RAS reads was evaluated for association with tumor response (by RECIST) and overall survival using univariate and multivariate Cox proportional hazards models. Results: 52% of the subjects who were RAS wild-type by plasma at baseline never developed a RAS mutation. For those with mutant RAS ctDNA ( KRAS+ NRAS) detected at baseline or PT, there was an overall increase in RAS mutant DNA fraction at PT compared to baseline. By non-parametric analysis, there was no difference in the distribution of baseline mutant RAS fraction between those who achieved stable disease (SD) or those with progression ( P = 0.09). There was also no difference in the increase in mutant RAS fraction on therapy between subjects with SD or progressive disease (PD). In addition, RAS mutation was not required for progression: 48% of subjects with PD had no RAS mutant DNA detected. Conclusions: In this exploratory analysis, baseline plasma mutant RAS fraction is an unreliable predictor of subsequent tumor response. Subjects with objective response or SD may have stable or rising levels of mutant RAS DNA. Subjects without any detectable RAS mutation still experience PD. These findings suggest that detectable plasma ctDNA RAS mutations do not necessarily predict response to panitumumab and should be interpreted with caution. Further work is needed to establish clinically relevant and validated thresholds. Clinical trial information: NCT01001377.

e15169 Background: The Skin Toxicity Evaluation Protocol with Panitumumab (STEPP) and the Japan Skin Toxicity Evaluation Protocol with Panitumumab (J-STEPP) were open-label, randomized trials that were designed to evaluate differences in preemptive versus reactive management of dermatologic toxicities associated with panitumumab among patients with mCRC. The objective of this study was to evaluate if there were differences in the knowledge and application of STEPP and J-STEPP among oncologists who self-identified as primarily managing EGFR rash preemptively or reactively. Methods: A total of 250 practicing oncologists who had treated at least three new or continuing mCRC patients with panitumumab in the last year completed an online survey to report their opinions and perceptions regarding the management strategies for mCRC patients who are treated with panitumumab. Preemptive treatment was described in the survey as beginning treatment “prior to the appearance of rash” and reactive treatment was defined as beginning treatment “after signs of rash.” Results: Of the 250 oncologists who participated in this study, n = 58 (23%) reported treating 100% of their patients preemptively and n = 38 (15%) reported treating 100% of their patients reactively. A significantly higher proportion of preemptive treaters than reactive treaters reported following the skin management strategies from STEPP or J-STEPP when managing panitumumab-related skin toxicity (31% vs 13%, p = 0.02). When asked if skin moisturizer, sunscreen, over-the-counter topical steroids, prescription topical steroids, oral antibiotics, topical antibiotics, or UV protective garments were most critical in the preemptive management of panitumumab-related skin toxicity, preemptive treaters more likely to report using oral antibiotics and reactive treaters more like to report using sunscreen (p = 0.05). Conclusions: The results of this survey highlight the wide variability in the management of EGFR-related rash among mCRC patients who are treated with panitumumab and they highlight the need for heighted education among oncologists who treat mCRC patients with panitumumab.

639 Background: Dermatologic toxicity can be a limiting factor for the use of anti-EGFR therapy such as panitumumab. There is a paucity of real world data regarding the management of dermatologic toxicity among metastatic colorectal cancer (mCRC) patients treated with panitumumab in the United States (U.S.). The objective of this study is to describe oncologist's opinions regarding timing of skin rash management in relation to the initiation of treatment and perceptions regarding rash management strategies. Methods: A total of 125 oncologists were recruited from a national database via a third independent party. Eligible oncologists (i.e.: licensed and practicing oncologist who had treated at least three new or continuing mCRC patients with panitumumab in the last year) completed an online survey to report their opinions regarding the grade and type of dermatologic toxicities seen and their perceptions about management strategies for mCRC patients who are treated with panitumumab. The timing of rash management initiation was defined as pre-emptive (prior to the appearance of the rash) or reactive (after any signs of skin rash). Results: Based upon their collective experience, oncologists expect that 44% of patients will develop acneiform rash while on treatment. More than half (58%) of the oncologists reported they did not follow any practice guidelines regarding the management of dermatologic toxicities. The oncologists reported that they pre-emptively initiated the management of dermatologic toxicities in 53% of their patients. Skin moisturizer and sunscreen were reported to be the most critical preemptive management approach, while skin moisturizer, over-the-counter topical steroids, and oral antibiotics were reported to be the most critical reactive management tools for Grades 1, 2, and 3, respectively. Conclusions: Despite evidence from randomized controlled trials, a majority of oncologists do not follow guidelines for dermatologic management of EGFR-I rash. There is a clear need for better physician education and awareness of mitigation strategies for skin toxicity management in mCRC patients treated with panitumumab.

739 Background: Guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) recommend that all tumors be tested for RAS mutations to identify patients who will most benefit from chemotherapy regimens with biologic agents. The aim of this study was to describe characteristics of patients captured by a large national health claims database who were tested vs those who were not tested for RAS mutations and to identify potential predictors of RAS testing. Methods: Patients with mCRC diagnosed from 2012–2014 (ICD-9 codes 153.x, 154.0x, or 154.1x and 197.x–198.x) were identified from a US healthcare claims database consisting of 129 million unique covered patient lives. Patient demographics and baseline clinical characteristics were compared between patients who were and were not tested for RAS mutations (identified by CPT codes) using chi-square and t-tests. Odds ratios (ORs) were estimated for potential predictors by fitting multivariate logistic regressions to adjust for patient characteristics. Results: Of the 4,527 mCRC patients identified (mean age at diagnosis, 61.2 years; 54% male); 39% (n = 1,787) had a claim for RAS testing during the study period. Patients tested had similar mean age and comorbidity index at diagnosis compared to those not tested (60.8 vs 61.5 years, P = 0.06; 3.98 vs 3.90, P = 0.47). A greater proportion of RAS-tested patients were commercially insured compared to those not tested (37% vs 26%, P < 0.01). Adjusted for other patient characteristics, patients with commercial insurance (OR: 1.62 [95% confidence interval–CI: 1.41–1.87]), metastases to viscera (OR: 1.61 [95% CI: 1.42–1.84]), or diagnosis of colon primary site compared to rectum (OR: 1.32 [95% CI: 1.16–1.51]) had increased odds of receiving RAS testing; all P < 0.01. Conclusions: These observational data show that mCRC patients with commercial insurance, metastases to viscera, and colon cancer have a higher probability of being tested for RAS mutations. Overall, the data suggest that RAS status is underdetermined, with certain subgroups appearing to be more likely to be tested than others.

773 Background: Current clinical guidelines recommend that all patients with mCRC have tumor tissue genotyped for RAS mutations. Tumor RAS testing enables the widest range of treatment options, with potential impact on patient outcomes. The aim of this study was to estimate the impact of RAS testing on the duration of treatment, across multiple lines of chemotherapy in mCRC. Methods: Adults with a diagnosis of mCRC (ICD-9 codes 153.x, 154.0x, or 154.1x and 197.x–198.x) were identified from a database of US public and private insurance claims (129 million covered lives) from 2012–2014. Time to treatment discontinuation, overall and by line of chemotherapy, was compared through univariate analysis between patients who were tested for RAS mutations (identified by CPT codes) to those who were not tested. Multivariate Cox proportional hazard regression model was used to estimate the risk of discontinuation attributable to prior RAS testing (i.e., hazard ratio [HR]), adjusting for patient characteristics. Results: We identified 4,527 mCRC patients (mean age at diagnosis, 61.2 years; 54% male), 39% (n = 1,787) of whom had a claim for RAS testing during the study period. Patients tested for RAS mutations stayed on treatment significantly longer in first-line (1LD), second-line (2LD), and overall treatment (OTD) vs those who were not tested for RAS mutations (1LD: median, 245 days [95% confidence interval–CI: 232–251] vs 196 days [95% CI: 189–205]; 2LD: median, 189 days [95% CI: 168–203] vs 147 days [95% CI: 133–161]; OTD: median, 903 days [95% CI: 815–1,040] vs 305 days [95% CI: 281–337]; all P < 0.01). Adjusting for patient characteristics, RAS testing significantly reduced the risk of discontinuation in 1LD, 2LD, and OTD (HRs: 0.83 [95% CI: 0.76–0.90], 0.80 [95% CI: 0.71–0.91], and 0.32 [95% CI: 0.27–0.37], respectively; all P< 0.01). Conclusions: These observational data show that RAS testing is associated with significantly greater time on treatment for mCRC patients compared to not testing, suggesting that patients under the care of physicians who decide to test for RAS mutations, regardless of test result, are on therapy for a longer period of time than untested patients.

Annals of Oncology 25 (Supplement 4): iv494–iv510, 2014 doi:10.1093/annonc/mdu354.8 sarcoma 1419PD ASSESSMENT OF SURGICAL DOWNSTAGING IN AN OPEN-LABEL PHASE 2 TRIAL OF DENOSUMAB IN PATIENTS WITH GIANT CELL TUMOR OF BONE Aim: Surgical resection, the standard treatment for giant cell tumor of bone (GCTB), may be associated with severe morbidity and may not be curative for all lesions. In an open-label phase 2 study, treatment with denosumab was associated with delayed surgery and/or a less morbid procedure in most patients with resectable GCTB. We report an unplanned, interim analysis of surgical downstaging in patients with Table: 1419PD abstracts Actual On-Study Procedure Planned Procedure Curettage (n=80) Marginal Excision (n=3) En Bloc Excision (n=1) Hemipelvectomy (n=10) Amputation (n=40) Joint/prosthesis replacement (n=25) Joint resection/fusion (n=35) En bloc resection (n=85) En bloc excision (n=8) Marginal excision (n=1) Curettage (n=18) En Bloc Resection (n=20) Joint Resection/ Fusion (n=5) Joint/Prosthesis Replacement (n=6) Amputation (n=1) © European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. Downloaded from http://annonc.oxfordjournals.org/ at University of California, Los Angeles on August 31, 2015 S. Ferrari 1 , P. Rutkowski 2 , R.J. Grimer 3 , P.D. Stalley 4 , S.P.D. Dijkstra 5 , A. Pienkowski 2 , G. Vaz 6 , L.L. Seeger 7 , A. Feng 8 , B.A. Bach 9 Chemotherapy Unit, Istituto Ortopedico Rizzoli, Bologna, ITALY Soft Tissue/bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, POLAND Orthopaedic Oncology Unit, Royal Orthopaedic Hospital, Birmingham, UK Department of Orthopaedic Surgery, Royal Prince Alfred Hospital, Sydney, NSW, AUSTRALIA Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, NETHERLANDS Department of Orthopedic Surgery, Edouard Herriot Hospital, Lyon, FRANCE Department of Radiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, USA Global Development Oncology Therapeutics, Amgen Inc., Thousand Oaks, CA, USA resectable GCTB whose initially planned surgery was expected to result in severe morbidity. Methods: Adults or skeletally mature adolescents with resectable GCTB received denosumab 120 mg SC every 4 weeks and on study days 8 and 15. Planned and actual GCTB surgical procedures after treatment are reported. Procedure selection and timing were based on review of radiographic imaging and clinical response. Results: Overall, 222 patients enrolled and were evaluable for surgical downstaging (men, 46%; median age, 34 y); most had lesions in the lower (n=117) and upper (n=62) extremities or pelvis/sacrum (n=33). In total, 190 (86%) patients had either no surgery (n=106; 48%) or a less morbid procedure (n=84; 38%). All 222 patients received denosumab; median (range) time on denosumab was 14.1 (1.0−57.1) months for all patients and 18.4 (1.0−57.1) months for the 106 patients with no surgery. The proportions of patients with a planned surgical procedure who did not undergo surgery were: hemipelvectomy (n=8/10; 80%), amputation (n=32/40; 80%), joint/prosthesis replacement (n=6/25; 24%), joint resection/fusion (n=14/35; 40%), en bloc resection (n=31/85; 36%), en bloc excision (n=7/8; 88%), curettage (n=8/18; 44%). The native joint preservation rate was 96% in the 25 patients with a planned joint/prosthesis replacement and 86% in 35 patients with a planned joint resection/ fusion. Conclusions: Consistent with initial results, treatment with denosumab was associated with avoidance of invasive surgery or a less morbid procedure than was planned in most patients with resectable GCTB. Disclosure: S. Ferrari: Advisory board (Amgen Inc., GlaxoSmithKline); research funding (MolMed, Pharmar, Morphotek, Amgen Inc.); honoraria (Takeda); P. Rutkowski: honoraria for lectures (Amgen Inc.); R.J. Grimer: Advisory board (Amgen Inc.); S.P.D. Dijkstra: advisory board (Implantcast GmbH); L.L. Seeger: honoraria for advisory boards and travel expenses (Amgen Inc.); A. Feng: employment by and stock ownership in Amgen Inc.; B.A. Bach: employment by and stock ownership in Amgen Inc. All other authors have declared no conflicts of interest.