Central Nervous System Mets Research Articles

Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive melanoma with central nervous system (CNS) metastases (mets): Final results and exploratory biomarker analysis from the phase 2 TRICOTEL study.

9550 Background: Primary analysis results from the phase 2 TRICOTEL study showed intracranial activity with the triplet combination of A + C + V in pts with BRAFV600-mutated melanoma with CNS mets (1). Here, we report final analysis results and exploratory biomarker analyses for pts with BRAFV600-mutated melanoma in the triplet combination cohort from TRICOTEL. Methods: Eligible pts were aged ≥18 y and had melanoma, MRI-confirmed CNS mets ≥5 mm in ≥1 dimension, and no prior systemic treatment for metastatic disease. Pts received A (840 mg on days 1 and 15 of each 28-d cycle) + C (60 mg once daily for 21 d on, 7 d off) + V (720 mg twice daily) except in cycle 1, during which A was withheld. Tumor tissue and circulating tumor DNA (ctDNA) samples collected at baseline (cycle 1, day 1) and ctDNA at the time of progressive disease (PD) were profiled for mutations using next-generation sequencing. Tumor tissue was profiled using a pipeline programmed for MelArray, and ctDNA was measured based on the tissue genetic profile. Results: A total of65 pts were enrolled in the triplet combination cohort. At final analysis, median follow-up was 12.4 mo. Per independent review committee (IRC) assessment, intracranial ORR (confirmed by assessments ≥4 wk apart) was 38% (95% CI, 27–51) and median intracranial PFS was 5.1 mo (95% CI, 3.7–6.9) (Table). Median OS was 13.4 mo (95% CI, 10.7–16.9). No new safety signals were observed since primary analysis. Mutations were detected in baseline ctDNA samples of 60 pts (5 pts not reported) and showed high prevalence of NF1, NRAS, and GNAI2 mutations; relative to tumor tissue, 11 additional BRAF mutations were detected in ctDNA at baseline. Acquired mutations in AKT1 were detected in ctDNA at PD. Median OS shortened in pts with >2 versus ≤2 mutated MAPK pathway genes in ctDNA at baseline (9.1 vs 14.5 mo; hazard ratio, 2.0 [95% CI, 1.0–3.7]; p<0.05). In tumor tissue, baseline mutations in PIK3C2A and PLEKHG4 were enriched in nonresponders, while RAD51B mutations were enriched in responders. Conclusions: Combination A + C + V had clinical intracranial activity in pts with BRAFV600-mutated melanoma with CNS mets. Exploratory biomarker analyses in this small cohort demonstrate the presence of ctDNA in pts with melanoma and CNS mets and provide insight into mutations associated with response and resistance to the triplet combination. 1. Dummer R et al, Lancet Oncol 2023. Clinical trial information: NCT03625141 . [Table: see text]

Clinical outcomes and genomic landscape of patients (pts) with EGFR-mutant lung cancer (EGFR+ LC) with central nervous system (CNS) metastases (mets).

e21146 Background: CNS mets are a major cause of morbidity and mortality in pts with LC. Up to 50% of pts with EGFR+ LC develop CNS mets over their disease course despite improvements in anti-EGFR therapies. The genomics alterations present in CNS mets in pts with EGFR+ LC and how these may compare to paired systemic samples has not been reported. Furthermore, it is unknown whether there are baseline clinicogenomic features that differ between EGFR+ LC pts with or without (w/wo) CNS mets. Methods: From an institutional database of LC pts with available next-generation sequencing (NGS) completed by MSK-IMPACT, we identified all EGFR+ LCs with molecularly characterized CNS tumor samples (CTS). We subsequently identified all pts with EGFR+ LCs with available paired CTS and systemic tumor samples (STS) profiled with MSK-IMPACT. All pts treated with 1L osimertinib with MSK-IMPACT available on their STS were also identified. We assessed clinicogenomic features of all selected EGFR+ LCs. Comparisons of frequencies of genes altered by somatic alterations were performed using Fisher’s exact test and logistic regression. Results: From 2014 to 2022, 90 EGFR+ LC pts with NGS performed on CTS were identified [brain metastasis (BrM), n = 38; leptomeningeal w/wo BrM (LM), n = 52]. 69 pts (77%) were female, median age 59 (IQR range:53-66 years), and 51 pts (57%) were never smokers. Patterns of EGFR+ were exon 19del (n = 43), L858R (n = 27) and atypical (n = 20). No genomic mutations were differentially altered in pts with LM vs BrM. Paired CTS and STS were available for 28 pts, where numerically higher rates of CDKN2A, CDKN2B loss and RAC1 amplification were seen in the CTS (respectively 43% vs 18%, 43% vs 18%, and 21% vs 0%, q > 0.05 for all). A total of 263 pts on 1L osi had NGS on their STS performed:136 pts (52%) had CNS mets during their disease course to date [94 pts (69%) de novo CNS mets; 42 pts with on-treatment CNS mets with median time to CNS mets of 25 mo (IQR: 13.5-35.3 mo)]. Between pts w/wo a lifetime history of CNS mets, there were no differences in sex, smoking history, EGFR alterations and co-alterations. CARD11 alterations were numerically higher in STS in pts with CNS mets (12% vs 2%, q > 0.05). Conclusions: In patients with EGFR+ LC, there were no genomic alterations that were significantly enriched in CNS mets compared to systemic disease, and no systemic genomic alterations that differentiate pts w/wo CNS mets.

Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive melanoma with central nervous system (CNS) metastases (mets): Primary results from phase 2 Tricotel study.

9515 Retraction The abstract by Dummer et al entitled, “Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive melanoma with central nervous system (CNS) metastases (mets): Primary results from phase 2 Tricotel study,” ( Journal of Clinical Oncology 40, no. 16, suppl 9515) published on June 2, 2022, has been retracted due to corrected data that has led to a change in the conclusions of the abstract. The updated results have been published online by Lancet Oncology in July 2023. See Dummer R, Queirolo P, Gerard Duhard P, et al: Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol doi: 10.1016/S1470-2045(23)00334-0. This abstract was retracted on August 7, 2023. Background: Despite recent advances in the treatment of melanoma, there remains an urgent need to improve outcomes in pts with CNS mets. To date, studies evaluating intracranial activity of immunotherapies and targeted therapies have included limited numbers of pts with symptomatic CNS mets. Cohort 2 of the phase 2 Tricotel study evaluated the safety and efficacy of A + C + V in BRAFV600-mutated melanoma with CNS mets, including symptomatic pts receiving corticosteroids. Methods: Eligible pts were aged ≥18 y and had melanoma, MRI-confirmed CNS mets ≥5 mm in ≥1 dimension, and no prior systemic treatment for metastatic disease. Pts received A (840 mg on days 1 and 15 of each 28-d cycle) + C (60 mg once daily for 21 d on, 7 d off) + V (720 mg twice daily) except in cycle 1, during which A was withheld. Primary outcome was intracranial objective response rate (ORR; confirmed by assessments ≥4 wk apart per independent review committee [IRC]). Secondary end points were investigator-assessed intracranial ORR, extracranial ORR, overall ORR, duration of response (DOR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. Prespecified subgroup analyses were performed in pts receiving corticosteroids (>2 mg/d dexamethasone) and/or with CNS-related symptoms at baseline vs asymptomatic pts. Results: This study enrolled 65 pts (median age, 55 y; 63% male). At baseline, 37% were on corticosteroids and/or were symptomatic; 49% had elevated lactate dehydrogenase. Median follow-up was 9.7 mo for all pts, 10.0 mo for pts on corticosteroids and/or symptomatic at baseline (n = 24), and 9.7 mo for asymptomatic pts (n = 41). Intracranial ORR was 42% by IRC and 51% by investigator (BOR concordance: 68%). Intracranial DOR and PFS are listed in the Table. In pts on corticosteroids and/or symptomatic at baseline, ORR was 58%, DOR was 10.2 mo, and PFS was 7.2 mo by investigator; in asymptomatic pts, ORR was 46%, DOR was 5.7 mo, and PFS was 5.5 mo. Additional secondary efficacy end points will be presented. In 60 pts who received A + C + V, grade 3/4 adverse events (AEs) occurred in 70% of pts; most commonly lipase increased (27%) and blood CPK increased (17%). Serious AEs occurred in 30% of pts. AEs led to discontinuation of any study treatment in 27% of pts. Conclusions: Addition of A to C + V provides promising intracranial activity in pts with BRAFV600-mutated melanoma with CNS mets, particularly in those receiving corticosteroids and/or in symptomatic pts. The safety profile of A + C + V is consistent with that observed in the IMspire150 study. Clinical trial information: NCT03625141. [Table: see text]

Abstract P3-13-04: Clinical features and genetic alterations in patients (pts) with HER2-positive breast cancer (BC) and central nervous system (CNS) metastases (mets) in the real world

Abstract P3-13-04: Clinical features and genetic alterations in patients (pts) with HER2-positive breast cancer (BC) and central nervous system (CNS) metastases (mets) in the real world

Survival time in urban center breast cancer patients with CNS metastasis with or without visceral metastasis.

1088 Background: There is limited data about the role of isolated central nervous system (CNS) metastasis (mets) in patients with breast cancer (BC), since prior studies evaluated BC patients with CNS plus visceral mets. Furthermore, though Black race is associated with worse BC outcomes, there are few studies on CNS mets that predominantly included racial and ethnic minorities in their cohorts. Our study compares overall survival (OS) in BC patients with CNS involvement with and without visceral mets in an underrepresented patient population. Methods: This is a retrospective case series study. We used Montefiore’s Clinical Looking Glass software to identify patients. Inclusion criteria were females age ≥18 years at our institution with the diagnosis of BC and CNS mets between 3/31/1997 to 3/31/2019. Chart review was conducted to obtain clinical-pathological features, including date of diagnosis, treatment, clinical course, and survival status. Patients with BC and CNS mets were divided into two cohorts, those with additional mets limited to bone and lymph nodes but without further visceral spread (CNS-NV), and those with CNS mets plus visceral mets (CNS-V). Kaplan-Meier methods were used to analyze the median OS. Results: Our study included a high proportion of underrepresented minorities (n=177); 46.3% were Black, 10.7% were White, and 34.5% were Other Race; besides, 28% were Hispanic. Mean age at diagnosis of CNS mets was 58 years (SD = 12.9). 62.1% were estrogen receptor (ER) and/or progesterone receptor (PR) positive, 27.1% were HER2 positive; and 19.8% were ER, PR and HER2 negative. Mean number of chemotherapy and endocrine therapy lines before CNS mets were 2 (IQR = 1-2) and 1 (IQR = 1-2), respectively. CNS-NV and CNS-V cohorts included 35 and 142 patients, respectively. Patients with CNS-NV had longer OS than CNS-V (2118 vs. 1120 days, p=0.02). Further subgroup analysis for group CNS-NV was performed based on treatment modality. In this cohort, OS was not significantly different between patients who did and did not receive chemotherapy (n =35, mean OS 1509 vs. 960 days, p = 0.49). In addition, OS was not significantly different between patients who received and did not receive endocrine therapy (n = 24, mean OS 857 vs. 1394 days, p = 0.4). Finally, OS did not significantly differ between patients who did and did not receive anti HER2 treatment (n = 11, 1753 vs. 849 days, p = 0.15). Conclusions: Minimal research has been conducted on breast cancer patients with CNS mets and distal involvement limited to the bones or lymph nodes. In a heterogenous racial and ethnic population, patients with BC and CNS mets have prolonged OS if the extent of distal involvement is limited to the bones or lymph nodes, compared to those with visceral mets. More research with larger sample sizes is needed to confirm our findings, which may help to de-escalate and tailor treatment for patients with CNS mets.

Impact of BRAF mutations on outcomes in metastatic melanoma with central nervous system metastases treated with immune checkpoint inhibitors.

e21500 Background: Half of patients (pts) with melanoma (mel) develop central nervous system (CNS) metastases (mets), leading to death in over 90% in the pre-immune checkpoint inhibitor (ICI) era. Overall survival (OS) has improved in the ICI era for those with CNS mets, yet the association of survival with ICI treatment for those with tumors harboring genomic variants (var) remains unclear. Methods: We retrospectively reviewed our electronic medical records to identify pts with mel and CNS mets who received ICI from 2010 to 2018. Treatment history, systemic and CNS responses, and genomic data were recorded. Genomic var were categorized as BRAFV600E (BRAF), NRAS, cKIT, other var, and no var. Concurrent RT (CRT) was defined as RT to CNS mets within 30 days of ICI. OS was calculated from date of first ICI or RT to date of death or last follow up, and comparison analyses made using Kaplan-Meier estimate. Fisher's exact or Chi-squared tests were used to compare categorical variables and Wilcoxon or Kruskal-Wallis tests to compare continuous variables. A two-sided p-value of < 0.05 was considered statistically significant. Results: A total of 49 pts were identified; 37 had var results available. BRAFV600E was the most common var identified (32%), followed by NRAS (19%), cKIT (5%), and other (5%); 38% had no var. BRAFV600K was not identified. Pts with BRAF had lower rates of CNS progression on ICI at 3 and 6 months than all other pts (17% vs 50%, p< 0.01 and 12.5% vs 40%, p< 0.01, respectively). Of 38 pts (10 BRAF) who had CNS mets at the start of ICI, 6-month OS was 50% in pts with BRAF, compared to 0% in pts with non-BRAF var ( p= 0.01) and 36% in pts with no var ( p= 0.7). 4 of the 10 pts with BRAF who had CNS mets at start of ICI received BRAF-targeted therapy after ICI. On ICI, only 30% of pts with BRAF developed new CNS mets, compared to 57% of all other pts ( p= 0.08). Pts who developed new CNS mets on ICI had worse OS than pts who did not (median OS (mOS) 314 days vs 662 days, p= 0.04). A majority of pts (55%) received anti-CTLA4 monotherapy as first ICI, and 39% received anti-CTLA4 plus anti-PD1. Pts with BRAF were just as likely to receive dual anti-CTLA4/PD-1 as pts without BRAF (33% vs 40%, p= 0.74). 40 pts underwent RT for CNS mets, of whom 22 received CRT. There was no difference in mOS between pts who received CRT and non-concurrent RT/no RT (468 days vs 314 days, p= 0.8). Rates of CRT between pts with BRAF and pts without BRAF were similar ( p> 0.9), and there was no difference in mOS between these groups (400 days vs 536 days, p= 0.9). Conclusions: Pts with BRAF-mutated mel with CNS mets receiving ICI had lower rates of progression in CNS and improved OS compared to other var. CRT was not associated with improved survival over non-concurrent RT. There has been significant improvement in OS of pts with mel CNS mets in the era of ICI and additional studies are warranted to understand the biology of BRAF var and the host immune system response in the CNS.

Association between sites of metastases (mets) and outcomes with immune checkpoint inhibitor (ICI) therapy for advanced urothelial carcinoma (aUC).

445 Background: Different metastatic sites have variable prognostic implications in aUC. However, details on response and outcomes with ICI for particular mets is still unknown. We hypothesized that bone and liver mets would have poor response and outcomes with ICIs. Methods: We performed a retrospective cohort study in patients (pts) with aUC who received ICI. We compared overall response rate (ORR) and overall survival (OS) between pts with different mets at ICI initiation. We developed 4 different models: 1) lymph node (LN) only vs other; 2) visceral mets (bone, lung, liver) vs other; 3) bone + liver mets vs bone without liver vs liver without bone vs neither and 4) 6 factor model: a. LN +/- soft tissue/locoregional recurrence b. lung +/- (a) c. bone +/- (b) d. liver +/- (c) e. central nervous system (CNS) +/- (d) and f. other. ORR and OS were compared among groups using multivariable (adjusting for ECOG PS and hemoglobin<10g/dl) logistic regression and cox regression, respectively. Results: We identified 984 pts (24 institutions); 703 and 696 were included in OS and ORR analyses, respectively. Median age at ICI start was 71 (range 32-93), 77% white race, 74% men, 67% ever smokers, 72% pure UC, 18% upper tract UC, 55% extirpative surgery. Prevalence of LN, lung, bone and liver mets at ICI start was 74%, 32%, 27% and 21%, respectively. LN-only mets had significantly higher ORR (44% vs 22%, OR 2.6, p<0.05) and longer mOS (22 vs 8 months, HR 0.5, p<0.05) vs other mets. Visceral mets had significantly lower ORR (21% vs 35%, OR 0.5, p<0.05) and shorter mOS (7 vs 17 months, HR 1.8, p<0.05) vs non-visceral mets. Pts with bone and liver mets had significantly lower ORR and shorter OS vs those with bone or liver mets, which both had significantly lower ORR and shorter OS vs those with neither and with LN +/- local recurrence (Table). Conclusions: In the context of ICI treatment, bone, liver, lung or CNS mets were associated with lower ORR and/or shorter OS, and bone and liver mets were particularly associated with low ORR and short OS. LN-only mets were associated with higher ORR and longer OS. Further work is needed to interrogate site-specific tumor-host immune interactions and identify biomarkers. Research Sponsor: None[Table: see text]

Abstract PD13-06: Incidence and management of central nervous system metastases in patients with inflammatory breast cancer

Abstract Background: Patients (pts) with inflammatory breast cancer (IBC) have a high risk of central nervous system (CNS) metastasis (mets) with their associated impact on longevity and quality of life. Given evolving CNS-directed treatments, including focal radiation (RT), we compared the proportion of pts diagnosed with asymptomatic CNS mets before and after 2012 as data from Phase III trials in the preceding years (yr) increasingly supported the use of stereotactic radiosurgery (SRS). Specific attention was paid to pts treated with tri-modality therapy (TMT), defined as preoperative systemic therapy, surgery, and RT to determine whether screening for asymptomatic CNS mets would be beneficial. Methods: We retrospectively reviewed the records of pts diagnosed with IBC 1997-2019 and enrolled in an IRB-approved registry at a dedicated IBC center. CNS met-free survival time was defined as the time from IBC diagnosis to date of CNS mets. Alive CNS met-free pts were censored at their latest survival date and death was treated as a competing risk. Cumulative CNS mets incidence was computed. Analyses were stratified based on stage at diagnosis (III vs. de novo IV) and receipt of TMT. For pts completing TMT, the completion date was the starting point for cumulative incidence calculations. Overall survival (OS) was estimated as the time from CNS mets diagnosis to death, with censoring for pts who were still alive. Results: A total of 531 pts were identified; 372 (70%) with stage III; 159 (30%) with de novo Stage IV disease. The median follow-up for pts presenting with stage III and stage IV disease at diagnosis was 5.6 yr and 1.8 yr, respectively. 124 pts had CNS mets; 5 of them at diagnosis. CNS was the first site of mets or progression in 50 pts (9.4%). The cumulative incidence of CNS mets stratified by stage at diagnosis and receipt of TMT is seen in Table 1. Among the 50 de novo Stage IV pts who completed TMT, 4 developed CNS mets prior to surgery. The median overall survival (mOS) after CNS mets was 0.6 yr (IQR: 0.2 - 1.4). Results stratified by tumor subtype were: HER2+ disease (n=51) 1.4 yr (IQR: 0.6 - 3.7); hormone receptor+/HER2- (n=27) 0.6 yr (IQR: 0.2 - 1.2); triple negative (n=40) 0.2 yr (IQR: 0.1 - 0.5). Most pts with CNS mets (87/124, 70%) had neurologic symptoms prompting imaging. There was no difference in the proportion of asymptomatic pts diagnosed with CNS mets prior to or after 2012. Management of CNS mets was as follows: 47 pts (38%) received whole brain RT (WBRT) alone, 22 (18%) SRS alone, 15 WBRT + SRS (12%), 6 resection + WBRT (5%), and 5 resection + SRS (4%). The remaining pts received several of these modalities with or without intrathecal chemotherapy (13, 11%) or CNS treatment was not documented (16, 13%). A total of 258/531 pts have died (49%). Of these pts, 103 (40%) had CNS mets. 67/103 (65%) died due to CNS mets. Conclusions: Among pts with IBC completing TMT, the incidence of CNS mets is as high as 20% both in de novo Stage IV pts at 1 yr and in Stage III pts within 5 yrs, supporting routine surveillance brain MRI among pt with Stage IV disease. The majority of pts continue to receive WBRT with its resultant toxicities. Efforts should be made to identify CNS mets early to facilitate more focal therapy. Future research on systemic therapy with CNS penetrance for IBC patients should be pursued. These data support an ongoing prospective study of screening brain MRI in pts with Stage III IBC to quantify the incidence of CNS mets, utilization of WBRT and impact on neurologic quality of life (NCT04030507). Cumulative Incidence of CNS MetsNo.1 year (95% CI)2 year (95% CI)3 year (95% CI)Stage III (All)3725% (3-7)9% (6-12)18% (14-23)Stage IV (All)15417% (12-24)30% (22-37)42% (32-51)Stage III (TMT)3045% (3-8)11% (8-16)19% (14-24)Stage IV (TMT)4621% (10-34)28% (16-43)35% (20-50) Citation Format: Laura Warren, Samuel M Niman, Marie Claire Remolano, Jean Landry, Faina Nakhlis, Jennifer R Bellon, Meredith M Regan, Beth A Overmoyer. Incidence and management of central nervous system metastases in patients with inflammatory breast cancer [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 PD13-06.

Abstract PS11-28: Efficacy and safety of entrectinib in NTRK fusion-positive (NTRK-fp) breast cancer

Abstract Neurotrophic tyrosine receptor kinase genes (NTRK1/2/3) act as oncogenic drivers across a range of tumors. NTRK fusions occur at low frequency (<5%) in all breast cancer types, including >90% of secretory breast carcinomas. Furthermore, up to 30% of patients (pts) with breast cancer will develop central nervous system (CNS) metastases (mets). Entrectinib is a potent, oral TRKA/B/C, ROS1 and ALK inhibitor, specifically selected for its CNS penetration properties. Entrectinib was evaluated in 3 global phase 1/2 clinical trials (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]), where it demonstrated strong and durable systemic and intracranial efficacy in pts with NTRK-fp solid tumors, including those with breast cancer. We present updated data from this integrated analysis (data cut-off: 31 October 2018) focusing on pts with breast cancer. The entrectinib trials were conducted at >150 sites in 15 countries, and enrolled pts with locally advanced/metastatic NTRK-fp tumors (with or without baseline CNS mets) confirmed by nucleic acid-based methods. Tumor assessments were performed at the end of cycle 1 (4 weeks) and every 8 weeks thereafter, and evaluated by blinded independent central review (BICR) using RECIST v1.1. Primary endpoints were objective response rate (ORR) and duration of response (DoR) by BICR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. At clinical cut-off, the overall efficacy-evaluable population included 74 adults from the 3 trials, with 12 different NTRK-fp tumor types and >25 histopathologies. In these pts, ORR by BICR was 63.5% (95% CI 51.5-74.4), including five complete responses (CR) and 42 partial responses (PR). Median (95% CI) DoR, PFS and OS were 12.9 (9.3-not estimable [NE]), 11.2 (8.0-15.7) and 23.9 (16.0-NE) months, respectively. The efficacy-evaluable NTRK-fp breast cancer cohort included 6 pts with a median age of 63 (range 36-67) years; most had an Eastern Cooperative Oncology Group performance status of 0 (3/6; 50%) or 1 (1/6; 17%). Breast cancer tumors were classified as secretory (4/6; 67%; all NTRK3-fp) or non-secretory (2/6; 33%; all NTRK1-fp). Pts had received 0 (3/6; 50%), 1 (1/6; 17%) or ≥4 (2/6; 33%) lines of prior therapy for metastatic disease. At data cut off, the median survival follow-up was 17.4 (range 1.7-23.9) months. ORR was 100% (2 CR, 2 PR; 95% CI 39.8-100.0) in pts with secretory and 50% (1 PR, 1 missing/unevaluable; 95% CI 1.3-98.7) in pts with non-secretory histology. Median (95% CI) DoR, PFS, and OS were 12.9 (4.2-NE), 10.1 (5.1-NE), and 23.9 (5.1-23.9) months, respectively. At baseline, 2 pts had CNS mets per investigator assessment; 1 of these pts had missing response data. CNS mets were confirmed by BICR in the other pt (non-secretory); this pt had received whole brain radiotherapy 2-6 months before starting entrectinib treatment, and had systemic PR and intracranial non-CR/non-progressive disease (non-measurable CNS lesion). The overall integrated safety-evaluable population comprised 504 pts with any gene fusion who received ≥1 dose of entrectinib. Most treatment-related adverse events (TRAEs) were Grade ≤3 (96.1%); the most frequently reported TRAEs were dysgeusia (39.7%) and fatigue (31.5%). Seven breast cancer pts were evaluated for safety, of whom six (85.7%) reported TRAEs; all were Grade ≤3. The most frequently reported TRAEs (each occurring in 3/7 pts; 42.9%) were nausea, anemia, and increased alanine or aspartate aminotransferase. Dose reductions and interruptions due to TRAEs were each reported in 3/7 pts (42.9%); no discontinuations or deaths due to TRAEs were recorded. In this updated integrated analysis, entrectinib induced objective responses in all pts with NTRK-fp breast cancer who had data available, and was generally well tolerated with no discontinuations due to TRAEs. Citation Format: Janice Lu, Collin M. Blakely, Christophe Le Tourneau, Saiama N. Waqar, Todd M. Bauer, Filippo de Braud, David S. Hong, Alexander Spira, Tira Tan, Samuel McCallum, Stuart Osborne, Brian Simmons, Minal Barve. Efficacy and safety of entrectinib in NTRK fusion-positive (NTRK-fp) breast cancer [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 PS11-28.

A phase II study evaluating atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAF-mutant melanoma and central nervous system (CNS) metastases (mets).

TPS10081 Background: CNS mets, a common complication of melanoma, are associated with poor survival prognosis (median of 4-5 months). The rationale for combining PD-L1 pathway blockade using atezolizumab (A) with the small molecule BRAF pathway–targeted inhibitors cobimetinib (C) and vemurafenib (V) for the treatment of BRAFV600 mutation–positive melanoma is based on preclinical and translational evidence supporting the synergistic antitumoral effects of these approaches. Recently, the phase 3 IMspire150 study (NCT02908672) demonstrated improved progression-free survival outcomes with A + C + V vs C + V. Methods: This phase 2 study (NCT03625141) is currently evaluating A + C + V in pts with BRAFV600 mutation–positive advanced melanoma and CNS mets. The study originally included a parallel cohort evaluating A + C in pts with BRAFV600wild-type advanced melanoma and CNS mets. This cohort was closed at an enrollment of 15 pts after the primary analysis of the phase 3 IMspire170 study (NCT03273153), which showed no added benefit with A + C vs pembrolizumab in pts with BRAFV600 wild-type disease. Eligible pts are aged ≥18 years with histologically confirmed melanoma and magnetic resonance imaging–confirmed brain mets ≥5 mm in at least 1 dimension. In addition, pts should not have received prior systemic treatment for metastatic disease; they were required to have ECOG performance status ≤2 and adequate hematologic and end organ function. Prior stereotactic or surgical therapy of ≤10 brain mets is allowed. The primary endpoint is intracranial objective response rate (ORR) with A + C + V in BRAFV600mutation–positive melanoma as assessed by an independent review committee. Key secondary endpoints include investigator-assessed intracranial ORR, extracranial ORR, overall ORR, safety, and quality of life. Exploratory biomarker analyses are planned. The sample size for the cohort will be approximately 60 pts. No formal statistical hypothesis is being tested in this study. The primary study analysis and the analyses of all efficacy endpoints and safety summaries will be based on data collected ≤6 months after the last pt is enrolled. Clinical trial information: NCT03625141.

Time to central nervous system (CNS) metastases (mets) with atezolizumab (A) or placebo (P) combined with cobimetinib (C) + vemurafenib (V) in the phase III IMspire150 study.

10023 Background: The phase 3 IMspire150 study (NCT02908672) demonstrated improved progression-free survival with first-line combination treatment with A+C+V vs P+C+V in patients (pts) with previously untreated BRAFV600 mutation–positive advanced melanoma. Here we report incidence and time to development of CNS mets with A+C+V vs P+C+V in the IMspire150 study. Methods: Eligible pts were randomized 1:1 to receive A+C+V or P+C+V. A or P were given on day 1 and 15 of each 28-day cycle after an initial cycle of C+V. Incidence and time to development of CNS mets were evaluated in pts with no history of CNS mets at baseline confirmed by magnetic resonance imaging/computed tomography (MRI/CT). On study MRI/CT assessments were performed as clinically indicated. Time-to-event outcomes were estimated using the Kaplan-Meier method and competing risks analysis. Sensitivity analyses were conducted using landmark analysis at time of initiation of A or P. Results: 514 pts were randomized to receive A+C+V (n = 256) or P+C+V (n = 258); 244 and 247 pts, respectively, had no history of CNS mets at baseline. After a median follow-up of 18.9 months, CNS mets had developed in 52/244 pts (21%) in the A+C+V arm and 62/247 pts (25%) in the P+C+V arm. In both arms, pts with CNS mets were more likely to have other known unfavorable prognostic factors: elevated LDH, presence of liver mets, and/or higher tumor burden. Cumulative incidence of CNS mets as first site of progressive disease with A+C+V vs P+C+V was 8% vs 9%, 16% vs 19%, 20% vs 24%, and 23% vs 26% at 6, 12, 18, and 24 months, respectively (hazard ratio [HR] 0.87; 95% CI 0.60-1.26). Estimated CNS mets-free survival rates for A+C+V vs P+C+V were 91% vs 90%, 81% vs 75%, 74% vs 66%, and 69% vs 62% at 6, 12, 18, and 24 months, respectively, with a trend for improved CNS mets-free survival with A+C+V (HR 0.79; 95% CI 0.55-1.14). Results of landmark analyses for CNS mets-free survival and cumulative incidence of CNS mets were similar to those in the overall analysis. Conclusions: The addition of anti–programmed death-ligand 1 to C+V is associated with numerically lower rates of interval development of CNS mets, consistent with the overall benefit observed for A+C+V in the study. This finding requires further follow-up to fully assess the magnitude of benefit of A+C+V on CNS mets-free survival. Clinical trial information: NCT02908672.

Abstract 1642: Alectinib in treatment-naïve anaplastic lymphoma kinase-positive (ALK+) metastatic non-small-cell lung cancer (mNSCLC): Systematic literature review (SLR) and network meta-analysis (NMA)

Abstract Background: The standard of care for treatment-naïve ALK+ mNSCLC patients (pts) is an ALK tyrosine kinase inhibitor (TKI). Pts treated with crizotinib generally experience disease progression within 1 year, often within the central nervous system (CNS). As such, there is a high unmet need for CNS-active ALK TKIs. Phase III data from 2 ALK TKIs, alectinib and ceritinib, showed improved efficacy vs crizotinib and chemotherapy, respectively; however, no studies have directly compared these TKIs. We report a NMA to compare the efficacy/safety of these therapies. Methods: A SLR was conducted to identify ALK+ mNSCLC randomized controlled trials (RCTs) in treatment-naïve pts. Efficacy/safety endpoints were extracted and the feasibility of using the data in a NMA was assessed. Data were analyzed using a fixed effect analysis in WinBUGs following NICE guidelines. Results: 1194 citations were identified, of which 4 RCTs were in treatment-naïve pts (ALEX [NCT02075840], ASCEND-4 [NCT01828099], PROFILE 1014 [NCT01154140] and PROFILE 1029 [NCT01639001]). All were open-label, phase III RCTs and pts were similar in terms of age, ECOG PS, disease stage, sex and smoking status. More pts had baseline CNS metastasis (mets) in ALEX (40%) vs the other trials (26-32%). PROFILE 1029 was conducted in East Asian pts and only included in a sensitivity analysis. Chemotherapy arms differed in that pemetrexed maintenance was included in ASCEND-4 but not in the PROFILE studies. Key efficacy/safety results are shown in the Table. Data from the sensitivity analyses were similar. Conclusion: Alectinib significantly improved progression-free survival compared with other treatments in the ITT population including in pts with baseline CNS mets. Alectinib showed significantly fewer grade 3-4 AEs than ceritinib. The difference in chemotherapy arms of the 2 trials may have impacted the NMA efficacy results. Table. NMA results in treatment-naïve ALK+ mNSCLC patientsComparisonEfficacy/Safety Endpoints PFS by IRC* HR (95% CrI)Subgroup CNS Mets at Baseline* PFS by IRC HR (95% CrI)OS* HR (95% CrI)Grade 3 or 4 AEs§OR (95% CrI)Alectinib vs chemotherapy0.23 (0.15-0.34)0.21 (0.10-0.44)0.63 (0.34-1.15)0.81 (0.44-1.52)Alectinib vs crizotinib0.50 (0.36-0.70)0.37 (0.22-0.63)0.76 (0.49-1.20)0.65 (0.41-1.04)Alectinib vs ceritinib0.41 (0.25-0.67)0.31 (0.13-0.71)0.85 (0.42-1.73)0.36 (0.17-0.79)Crizotinib vs chemotherapy0.45 (0.35-0.58)0.57 (0.35-0.93)0.82 (0.54-1.24)1.24 (0.81-1.91)Ceritinib vs chemotherapy0.55 (0.42-0.72)0.70 (0.44-1.11)0.73 (0.50-1.06)2.25 (1.42-3.61)Ceritinib vs crizotinib1.22 (0.84-1.79)1.22 (0.62-2.43)0.90 (0.52-1.57)1.82 (0.96-3.44)Statistically significant differences indicated in bold based on 95% CrI; *Hazard ratio <1 indicates lower hazard (higher likelihood of PFS or OS) compared with control; §Odds ratio <1 indicates lower odds of an event compared with control. AEs, adverse events; CNS, central nervous system; CrI, credible interval; HR, hazard ratio; IRC, independent review committee; Mets, metastases; OR, odds ratio; OS, overall survival; PFS, progression-free survival Citation Format: Anna Steenrod, Michelle Orme, Katherine S. MacGilchrist, Rachel Rosenthal, Juliane Schaefer, Vlatka Smoljanovic, Emmanuel Mitry, Parneet K. Cheema. Alectinib in treatment-naïve anaplastic lymphoma kinase-positive (ALK+) metastatic non-small-cell lung cancer (mNSCLC): Systematic literature review (SLR) and network meta-analysis (NMA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1642.

Real-world study to quantify the symptom and disease burden of central nervous system (CNS) metastases (mets) in non-small-cell-lung cancer (NSCLC).

e14019Background: Many lung cancer patients (pts) with CNS mets are excluded from clinical trials. To better understand the symptomatic and disease burden in such pts, we designed a prospective rea...

Relationship between human epidermal growth factor receptor 2 (HER2) status and central nervous system metastases in gastroesophageal cancer.

145 Background: Central nervous system (CNS) metastases (mets) in gastroesophageal (GE) cancers are rare. There have only been limited studies examining the role of HER2 status in CNS mets in GE cancers. Methods: A retrospective analysis was performed for patients (pts) treated for GE cancers at the Princess Margaret Cancer Centre from 2011-2016. Quantitative and qualitative data were collected for all pts with CNS mets. Kaplan-Meier method was used to calculate overall survival (OS) and CNS progression free survival (PFS) for CNS mets pts. Results: Of 34 GE cancer pts diagnosed with CNS mets, 11 were HER2+, 11 HER2- and 12 had unknown HER2 status. Median time from initial cancer diagnosis to CNS mets was 10.3 months (13.4 in HER2+, 5.8 in HER2-, 11.7 in HER2 unknown). Characteristics at CNS mets diagnosis included: median age 63; 85% male; 74% had extracranial systemic mets; performance status ECOG 0-1 (64%), 2 (12%), 3-4 (24%). Treatment for CNS mets is shown in Table 1. Median OS from diagnosis of CNS mets was 6.1 months (95%CI 3.2-16.4) for all pts, 17.1 (95%CI 9.9-NA) in HER2+, 1.8 (95%CI 0.6-NA) in HER2-, 6.0 (95%CI 1.9-NA) in HER2 unknown, p=0.01. Median OS from initial cancer diagnosis was 18.5 months (95%CI 13.6-33.7) for all pts, 28.9 (95%CI 21.32-NA) in HER2+, 10.8 (95%CI 6.37-NA) in HER2-, 18.6 (95%CI 10-NA) in HER2 unknown, p=0.015. The 1 year CNS PFS rate was 35% (95%CI 22.1 – 55.5%) for all pts, 53% (95%CI 29.9 – 94%) in HER2+, 18.2% (95%CI 5.3 – 63.7%) in HER2-, 33% (95%CI 15 – 74.2%) in HER2 unknown, p=0.053. Conclusions: HER2+ pts tended to develop CNS mets later than HER2-. HER2+ pts were more likely to receive CNS-directed interventions, with more HER2+ pts having surgery for CNS mets while more HER2- had supportive care. This analysis is the first to suggest that in pts with CNS mets, HER2+ pts had longer survival than HER2-, both from initial diagnosis and after developing CNS metastases.[Table: see text]

1308PD - Preliminary efficacy and safety of lorlatinib in patients (Pts) with ROS1-positive non-small cell lung cancer (NSCLC)

Background: Most pts with ROS1-rearranged NSCLC achieve initial benefit with crizotinib but subsequently develop resistance, and further treatment options are limited. In Phase 1 of this study, lorlatinib, a potent and brain-penetrant TKI, was associated with a response rate of 50% in ROS1-positive NSCLC pts, most of whom had central nervous system (CNS) metastases (mets) and a majority of whom had received prior crizotinib. Antitumor activity and safety were explored at the recommended Phase 2 dose. Methods: In this ongoing, Phase 2 study (NCT01970865), pts with ROS1+ NSCLC, ± asymptomatic untreated or treated CNS mets were enrolled with no restriction on the type or number of prior lines of therapy. Pts received lorlatinib 100 mg QD. The primary objective was overall and intracranial (IC) antitumor activity, measured as overall and IC response by independent central review. Results: 23 pts with ROS1+ NSCLC were treated; 12 had CNS involvement, 16 had received prior crizotinib and 1 had received prior crizotinib and ceritinib. The overall response rate (ORR) by investigator assessment for this cohort was 8/23 (34.8%; 95% CI: 16.4, 57.3). The best overall response was SD in 11 pts (47.8%) and progressive disease (PD) in 2 pts (8.7%). The disease control rate at 12 weeks was 17/23 (73.9%; 95% CI: 51.6, 89.8). Of 8 pts with a confirmed response, 3 have progressed (after a range of 3.5–7.0 mos) and the remainder are in follow-up (range: 5.6–8.3 mos). The IC-ORR was 3/12 (25%) (95% CI: 5.5, 57.2). The most commonly reported treatment-related adverse events (TRAEs) were hypercholesterolemia (95.7%) and hypertriglyceridemia (69.6%) both managed with statins or other lipid lowering agents. Additional TRAEs included peripheral edema (34.8%) and cognitive effects (30.4%). Treatment-related dose interruptions and dose reductions occurred in 26.1% and 17.4% of pts, respectively; there were no treatment-related discontinuations or deaths. Most pts remain on treatment. Conclusions: Lorlatinib has shown clinical activity in ROS1+ NSCLC pts, a majority of whom had CNS involvement and most of whom had received prior crizotinib. Overall, lorlatinib was well-tolerated with lipid elevations being the most common TRAEs. Clinical trial identification: NCT01970865 Legal entity responsible for the study: Pfizer Funding: Pfizer Disclosure: B. Besse: Corporate sponsored research: Pfizer. A.T. Shaw: Advisory board or board of directors: Blueprint medicines, KSQ Therapeutics (scientific advisory board). Consulting/Honoria Pfizer, Novartis, Ariad, Genentech/Roche, Ignyta, Daiichi-sankyo, Taiho, LOXO, Blueprint medicines, EMD Serono, Foundation Medicine. B.J. Solomon: Membership of an advisory board or board of directors: Advisory Boards: Pfizer, Novartis, Roche-Genentech, AstraZeneca, Merck, Bristol Myers Squibb. M. Satouchi: Corporate sponsored research: Pfizer Honoraria: Pfizer. J.S. Clancy: Employed by inVentiv clinical but under contract position with Pfizer. L.P. James, A. Abbattista: Employee and stock owner of Pfizer. E. Felip Font: Advisory boards: Eli Lilly, Pfizer, Roche, MSD, Boehringer Ingelheim Speaker's bureau/lectures fees: AstraZeneca, BMS, Novartis. All other authors have declared no conflicts of interest.

The effect of nivolumab treatment for central nervous system metastases in non-small cell lung cancer.

e20601 Background: Central nervous system (CNS) metastases (mets) occur in 30% of patients with advanced non-small cell lung cancer (NSCLC) and are associated with poor overall survival (OS). Although nivolumab, a programmed death-1 immune checkpoint inhibitor antibody, has demonstrated a longer survival benefit compared with docetaxel in previously treated NSCLC patients (CheckMate 017 and 057; N Engl J Med, 2015), patients with symptomatic or untreated CNS mets were excluded in these trials. In CheckMate 012 Arm M, 2 of 12 patients (16.7%) with untreated CNS mets showed intracranial responses, but the effect of nivolumab treatment for CNS mets was not fully investigated. Methods: To investigate the effect and safety of nivolumab for CNS mets in NSCLC patients, we retrospectively analyzed 48 patients with NSCLC who were treated with nivolumab from February 2016 to December 2016 at Okayama University Hospital. Results: Twenty-nine patients (60%) had no CNS lesions (group A) and 19 patients (40%) had brain mets (BM) (group B). In group B, 15 patients (79%) received radiotherapy (RT) for BM, including 5 patients who received RT just before nivolumab treatment. The responses of extra-CNS lesions to nivolumab are shown in the table. The PFS was longer in group A than in group B (p=0.14). In group B, the PFS of patients who received prior RT tended to be longer than in those without RT (p=0.42); OS was not reached in either group. In group B, the effects of nivolumab treatment for CNS mets were evaluated in 12 patients: SD occurred in 3 patients (25%), PD in 4 patients (33%), and NE in 5 patients (42%). All 4 patients with PD in the CNS lesion also showed PD in the extra-CNS lesion. In group A, no patients showed progression only in the CNS lesion. Conclusions: In this retrospective study, there were no patients treated only with nivolumab who showed a response to CNS mets. RT prior to nivolumab might be more effective, so future investigations should involve additional cases and prospective studies. [Table: see text]

Nivolumab (nivo) in patients (pts) with advanced (adv) NSCLC and central nervous system (CNS) metastases (mets).

9038 Background: CNS mets occur in 20%–40% of pts with adv NSCLC and are associated with poor overall survival (OS; median ≈7 mo). We evaluated nivo in this subgroup by: 1) pooling nivo-treated pts with adv NSCLC and pretreated (pretx) stable CNS mets at baseline (BL) across CheckMate 063 (phase [ph] II), 017 (ph III), and 057 (ph III); and 2) comparing OS with nivo vs docetaxel (doc) in pts with stable BL CNS mets in CheckMate 017 and 057. Methods: 1) Nivo-treated pts with adv NSCLC and pretx BL CNS mets from CheckMate 063 (n = 3), 017 (n = 9), and 057 (n = 34) were pooled to assess BL characteristics, safety, and CNS progression. 2) OS was analyzed in pts with pretx BL CNS mets and squamous (SQ; CheckMate 017) or non-SQ (NSQ; CheckMate 057) NSCLC treated with nivo 3 mg/kg Q2W vs doc 75 mg/m2 Q3W. Results: Of 46 nivo-assigned pts with pretx CNS mets, 74% had prior CNS-site radiotherapy and 85% had ≥ 2 extra-CNS sites of mets. Median follow-up was 8.4 mo (range: 0.3, 23.4); median treatment duration (n = 45; 1 pt not treated) was 2.3 mo (range: 0.03, 23.3). Any grade (gr) treatment-related (TR) adverse events (AEs) occurred in 67% of pts; gr 3–4 TRAEs occurred in 7%, with no TR deaths. CNS TRAEs occurred in 5 pts (11%) and were all gr 1–2 (paresthesia, n = 2; dizziness, somnolence, and tremor, n = 1 each). At time of overall disease progression (PD) or last tumor assessment, 33% of pts had no evidence of CNS progression (stable/decreased CNS lesions) and 52% had unequivocal progression in the CNS (15% had no post-BL CNS assessment). In pts with pretx CNS mets from CheckMate 017, median OS (events, n; HR) with nivo (n = 9) vs doc (n = 8) was 4.99 mo vs 3.86 mo (6 vs 8; not determined); in CheckMate 057, median OS with nivo (n = 34) vs doc (n = 34) was 7.61 mo vs 7.33 mo (30 vs 27; 1.04, 95% CI: 0.62, 1.76). Conclusions: Nivo was well-tolerated in pts with adv NSCLC and pretx CNS mets, with generally low-grade toxicities. One-third of pts had no evidence of CNS progression at time of PD/last assessment. In pts with SQ and NSQ NSCLC with pretx CNS mets, median OS was similar with nivo vs doc. Additional results (including OS and CNS progression rates in pts with/without pretx CNS mets and safety/efficacy of nivo in pts with untreated BL CNS mets from CheckMate 012) will be presented. Clinical trial information: NCT01721759; NCT01642004; NCT01673867.

Safety and efficacy of lorlatinib (PF-06463922) from the dose-escalation component of a study in patients with advanced ALK+ or ROS1+ non-small cell lung cancer (NSCLC).

9009Background: Most patients (pts) with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) NSCLC develop resistance to tyrosine kinase inhibitor (TKI) therapy, with the central nervous system (CNS) as a common site of relapse. Lorlatinib is a selective brain-penetrant ALK/ROS1 TKI active against most known resistance mutations. Methods: In Ph. I of the ongoing Ph. I/II study NCT01970865, eligible pts had ALK+ or ROS1+ NSCLC with/without brain metastases (mets) and were treatment naive or had disease progression after ≥1 TKIs. Pts received lorlatinib on day –7 and daily from day 1. Primary objective was to identify the MTD and recommended Ph. II dose (RP2D). Other objectives were safety and efficacy by RECIST v1.1, including intracranial activity. Results: Of 54 pts treated in Ph. I as of Nov 30 2015, 41 were ALK+, 12 ROS1+; and 1 with mutation status not recorded at cut-off date. Pts were heavily pretreated:27 had received >1 prior TKI, 20 1 prior TKI and 7 were TKI naive; 39 pts had CNS mets a...

LBA11 - Cerebel (EGF111438): An Open Label Randomized Phase III Study Comparing the Incidence of CNS Metastases in Patients (PTS) with HER2+ Metastatic Breast Cancer (MBC), Treated with Lapatinib Plus Capecitabine (LC) Versus Trastuzumab Plus Capecitabine (TC)

ABSTRACT Background In HER2+ MBC, central nervous system (CNS) metastases (mets) occur in 28 - 43% of cases. Systemic therapies with potential to prevent or reduce CNS mets are of current interest. Based on lapatinib promising activity in CNS mets, CEREBEL evaluated the prophylactic impact on CNS mets incidence in HER2+ MBC pts treated with Lapatinib plus capecitabine (LC) in comparison to Trastuzumab plus capecitabine (TC). Methods CEREBEL was a multicenter study in HER2+ MBC pts without CNS mets at baseline, confirmed centrally by MRI. Prior treatment must include anthracyclines or taxanes in (neo)adjuvant or metastatic setting. Pts were randomized to LC (L-1250 mg daily + C-2000 mg/m2/day for 14 days [21-day cycle]) or TC (T loading dose 8 mg/kg followed by 6 mg/kg q3weekly + C-2500 mg/m2/day for 14 days [21-day cycle]). Primary endpoint was incidence of CNS as first site of relapse. Secondary endpoints were progression free survival (PFS), overall survival (OS), CNS progression at any time, overall response rate (ORR), clinical benefit response rate, duration of response and safety. Results A pre-specified interim analysis (IA) including 475 pts was performed by an IDMC convened on June 2012. A total of 43% and 46% of pts had not received prior treatment for MBC, 38% and 40% of pts had not received prior T, in LC and TC arms, respectively. Adverse events were similar in both arms with the exception of diarrhoea, nausea and rash (higher with LC). The incidence of CNS metastasis as site of first relapse was 3% for LC versus 4% for TC (OR 95% CI = 0.75 (0.25, 2.20) in modified ITT population (N = 218 pts per arm). The median PFS was 6.6 and 8.0 months in LC and TC arms (HR: 1.3; 95% CI: 1.0, 1.7; ) and median OS was 22.4 and 27.3 months (HR:1.58; 95% CI:1.07,2.32)(ITT) Conclusions Based on these results, the IDMC recommended study termination. Final results and updated survival data will be presented at ESMO with the 535 patients included in CEREBEL. EudraCT number 2008-000673-38 Disclosure X. Pivot: I am consultant and I have received honorariums for the sponsor GSK. R. Allerton: Roche advisory boad for use of Pertuzumab in breast cancer. R. Parikh: Employee of GSK M. DeSilvio: Employee of GSK S. Santillana: Employees of GSK, Director Clinical Development R. Swaby: Employee of GSK. All other authors have declared no conflicts of interest.

Phase I study of nab-paclitaxel (NP) in combination with biochemotherapy (BCT) in patients (pts) with metastatic melanoma (MM).

e19009 Background: NP has shown anti-tumor activity in MM in a phase II trial. The objective of this study was to determine MTD of NP as part of BCT, consisted of cisplatin (C), temozolomide (T), interleukin-2 (IL2) and interferon-alpha (IFN). Secondary objectives were to evaluate the anti-tumor activity of this combination in MM, and its benefit in preventing central nervous system (CNS) metastasis (mets). Methods: Previously untreated MM patients evaluable by RECIST 1.0 with no history of CNS mets between the ages of 18 and 65 and with ECOG 0-1 were enrolled. NP was given intravenously (IV) on Day (d) 1 and 5 of each cycle. The starting dose on d1 was 100 mg/ m2, and the dose on d5 was 70 mg/ m2, if toxicities permitted. The remainder of the regimen consisted of IV C 20 mg/ m2 daily d1-4, oral T 250 mg/ m2 d1-3, 9 million international units (MIU)/m2 of IL2 via continuous IV infusion for 96 hours, and IFN 5 MIU/m2 via subcutaneous injection d1-5. Treatment was repeated in cycles of 21 d to a maximum of 6 cycles. Prophylactic hematologic growth factors were not allowed in the first cycle. A standard 3+3 escalation method was used for NP d1 dose. Results: Ten pts were enrolled and evaluable for toxicities. Five completed six courses. Because 2 of 5 pts at the starting dose level had dose-limiting toxicities (DLTs) (diarrhea; transaminasemia-TA), the next cohort received d1 NP dose of 80mg/m2. Two of 5 pts at that dose level had DLTs (TA; neutropenia). Overall, the day 5 dose was omitted in 3 patients post third cycle due to thrombocytopenia (TP). There was no grade 5 toxicity. Common grade 3 and 4 toxicities were leucopenia, neutropenia, lymphopenia, anemia, TP, hyponatremia, diarrhea, skin rash, infection, tinnitus, neuropathy and TA. Five of 9 evaluable pts had partial response (PR). The median time-to-progression was 5.3 months (m). The median overall survival was 8.73 m. Six pts developed CNS mets with an overall median time of 5.33 m from treatment start. Conclusions: Additional studies are needed to determine the optimal dosing and schedule of NP as a part of BCT. Despite significant antitumor activity on sites outside the CNS, this combination therapy did not prevent the development of CNS mets.