Median Progression-free Survival For Pts Research Articles

Comparison of Venetoclax Based Treatments for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Background: Venetoclax (Ven) is a BCL-2 inhibitor that produces deep responses with high rates of undetectable minimal residual disease (uMRD) for patients (pts) with chronic lymphocytic leukemia (CLL) (Al-Sawaf et al. 2020). Currently, ven is FDA approved as either monotherapy (mono) or in combination (combo) with rituximab (R) In patients with relapsed/refractory (R/R) CLL (Seymour et al. 2018). However, the optimal ven based treatment (tx) for pts with R/R CLL either as mono, or in combo with anti-CD20 monoclonal antibody (mab), or bruton tyrosine kinase inhibitor (BTKi) is uncertain. We performed a single institution retrospective analysis of pts with R/R CLL treated with ven based regimens evaluating efficacy of different ven based txs. Methods: 98 pts with R/R CLL treated between the years of 2012 and 2023 were evaluated. Ven based treatment consisted of ven mono or in combo with R, obinutuzumab (G), or ibrutinib (BTKi) with standard ven dose ramp up to a maximum dose of 400mg daily. R and G were administered per FDA standard dosing. Ibrutinib was administered as 420mg daily, as either fixed or continuous duration tx. Response assessment was performed using iwCLL criteria. Minimal residual disease (MRD) was assessed by multi-parametric peripheral blood flow cytometry with a sensitivity of 10 -4. Time-to-event analyses were performed with the Kaplan-Meier method, with log-rank test used to assess statistically significant differences between variables. Hazard ratios (HR) were calculated by use of Cox proportional modelling. Results: The pts had a median age of 68 years (range; 46-89). Rai stage at time of tx initiation with ven: I 14.2%; II 36.3%; III 8.8%; Stage IV 40.7%. The median number of previous txs was 4 (range; 1-14). Pts harbored the following cytogenetic abnormalities: del(13q) 50.5%; del(11q) 18.5%; trisomy 12 15.5%; normal 15.5%; del(17p)/TP53 mutation 24.7%; and complex in 33%. Seventy percent of pts harbored an unmutated immunoglobulin heavy chain. 25.5% of pts had genomic complexity, with ≥ 5 gene mutations. 43.9% of pts were treated with ven mono; 19.4% were treated with venR; 25.5% of pts were treated with venG; and 11.2% of pts were treated with ven + BTKi. The median number of months of ven based tx was 16.3 (range; 0.9-118.6). 14.3% of pts currently remain on ven. 60.8% of pts had progression after ven based tx; with 62.2% requiring additional tx. 15.3% of pts developed Richter's Transformation. The best overall response for the cohort was: CR 67%; PR 24.5%; SD 1.1%; and PD 7.4%. The best MRD response for the whole cohort was uMRD 76.8%; low MRD 19.5; and high MRD 3.6%. uMRD as best MRD response occurred in 66.7% of ven mono; 82.4% of venR; 86.4% of venG; and 70% of ven + BTKi treated pts. With a median follow-up of 52 months (mo), the median progression-free survival (PFS) for the whole cohort was 67.8 mo. Ven combo had superior PFS to ven mono; median PFS 76.6 vs 58.9 mo (p = 0.04; HR 0.5037; 95% CI 0.2583 - 0.9635). Among the combination treatment approaches, there was a trend for improved PFS for venG compared to ven mono; median PFS not reached (NR) vs 58.9 mo (p = 0.08; HR 0.4385; 95% CI 0.1608 - 1.0240). Similarly, there was also a trend to improved PFS for ven + BTKi compared to ven mono; median PFS NR vs 58.9 mo (p = 0.07; HR 0.2895; 95% CI 0.0462 - 0.9950). Both the presence of del17p/TP53 mutation; and the presence of MRD (+MRD) 12 months after stopping ven based tx were associated with inferior PFS. The median PFS for pts without del17p/TP53 mutation vs with del17p/TP53 mutation was 118 vs 39.7 mo (p < 0.0001; HR 0.2242; 95% CI 0.0533 - 0.8366). Median PFS for pts with uMRD vs +MRD 12 months after ven was NR vs 42.8 mo (p = 0.0001; HR 0.0689; 95% CI 0.0037 - 0.3810). Conclusions : In a high-risk population of pts with R/R CLL, we found that ven based tx leads to durable remissions, with high rates of uMRD. Combo approaches with the addition of either an anti-CD20mab or BTKi led to improved PFS. While venR is the current FDA approved combo regimen for pts with R/R CLL, we found that there was a trend for improved PFS with either venG or ven + BTKi compared to ven mono. Both the presence of a del17p/TP53 mutation and the presence of MRD 12 months after stopping ven based tx significantly adversely affected PFS. However, pts who maintained uMRD 12 months after completing ven, had exceptionally durable long-term remission. This has possible implications for employing MRD adapted txs for pts with CLL.

High dose ipilimumab (Ipi) plus temozolomide (TMZ) after progression on standard or low dose Ipi in advanced melanoma.

9557 Background: Despite advancements in checkpoint inhibitor-based immunotherapy (IO), patients (pts) with advanced melanoma who have progressed on Ipi + nivolumab (Nivo) continue to have poor prognosis. Several studies support a dose-response activity of Ipi. One promising combination for these pts is Ipi 10mg/kg (Ipi10) + TMZ. TMZ depletes regulatory T cells and suppresses their function, and it may enhance the antitumor activity of Ipi. We studied outcomes of pts with advanced melanoma treated with Ipi10+TMZ in the IO refractory/resistant setting, using a cohort of similar pts treated with Ipi3+TMZ as comparison. Methods: Clinical data of pts with IO refractory melanoma treated with Ipi+TMZ was collected retrospectively following IRB approval. Molecular profiling by WES and RNAseq of tumors harvested throughout one responder’s treatment were analyzed: the primary skin lesion (P1), a liver metastasis (M2) 2 days after low-dose Ipi1+Nivo, and a soft tissue metastasis (M3) after Ipi10+TMZ. Results: Overall 12 pts met eligibility: 6 received Ipi10 and 6 received Ipi3. All pts in Ipi10 cohort had progressed on prior Ipi+Nivo. Two pts (33% ORR) with CNS involvement demonstrated extraordinary near complete responses to Ipi10+TMZ despite progressing on prior therapies, including regular or low dose Ipi+Nivo. With a median follow up of 119 days, pts treated with Ipi10+TMZ had statistically significant longer median progression free survival (PFS) of 144.5 days (range 27–219) vs 44 (26–75) for Ipi3+TMZ, p = 0.04. There is a trend for longer median PFS for pts who had > 1 cycle of treatment, and for those who had progressed on prior Ipi+Nivo. There is a trend for longer median overall survival (OS) of 154.5 days (27–537) with Ipi10 vs 89.5 (26–548) for Ipi3 +TMZ. In those previously exposed to Ipi3+Nivo, median OS in the Ipi10+TMZ group was 154.5 days (27–537) vs 39 (26–55) in Ipi3+TMZ group. WES of one responder’s tumors revealed only 12 shared somatic mutations among P1, M2 and M3, including BRAF V600E, suggesting common lineage but significant clonal evolution. Genes involved in several important immune response pathways were mutated in M2 and M3 but not in P1. RNAseq showed enrichment of inflammatory signatures, including interferon responses in both M2 and M3 compared to P1, and downregulated negative immune regulators such as Wnt and TGFb signaling. M2 is a responding liver lesion to prior Ipi1+Nivo but disease progressed to bones and brain that subsequently responded to Ipi10+TMZ. Conclusions: Ipi10+TMZ demonstrated efficacy including dramatic responses in pts with advanced melanoma refractory to standard or low doses of Ipi + anti-PD1, even with CNS metastases. Molecular data suggest a potential threshold of Ipi dose for activation of sufficient anti-tumor immune response, and higher dose Ipi is required for some pts.

Addressing a New Challenge in Chronic Lymphocytic Leukemia: Outcomes of Therapies after Exposure to Both a Covalent Bruton's Tyrosine Kinase Inhibitor and Venetoclax

Addressing a New Challenge in Chronic Lymphocytic Leukemia: Outcomes of Therapies after Exposure to Both a Covalent Bruton's Tyrosine Kinase Inhibitor and Venetoclax

Subcutaneous epcoritamab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma: Safety profile and antitumor activity.

7518 Background: Epcoritamab is a CD20xCD3 bispecific antibody that induces T-cell–mediated killing of CD20–positive malignant B-cells. We present updated data, including progression-free survival (PFS) from the dose escalation part of the first-in-human phase 1/2 study of epcoritamab in pts with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT03625037). Methods: Adults with R/R CD20+ B-NHL received flat-dose 1 mL SC epcoritamab (step-up dosing approach) in 28-day cycles (q1w: cycles 1–2; q2w: cycles 3–6; q4w thereafter) until disease progression or unacceptable toxicity. Step-up dosing and standard prophylaxis were used to mitigate severity of cytokine release syndrome (CRS). Results: At data cut off (1/31/2021), 68 pts with B-NHL were enrolled across histologies including diffuse large B-cell lymphoma (DLBCL; n = 46 [67.6%]; de novo and transformed), follicular lymphoma (FL; 12 [17.6%]), mantle cell lymphoma (MCL; 4 [5.9%]), and others (6 [8.8%]). Majority were heavily pretreated (median [range] prior lines: DLBCL, 3 [1–6]; FL, 4.5 [1–18]); including prior CAR-T (n = 6) and prior ASCT (n = 10). At median follow-up of 14.1 mo (DLBCL, 10.2 mo; FL, 15.2 mo), treatment was ongoing in 15 (22%) pts. Most common treatment-emergent adverse events (AEs) were pyrexia (69%), CRS (59%), and injection site reaction (47%). CRS events were all grade 1 or 2 and most occurred in cycle 1; neurotoxicity was limited (6%; grade 1: 3%; grade 3: 3%; all transient). One case of tumor lysis syndrome was observed (1.5%; grade 3); there were no cases of febrile neutropenia or treatment-related death. Overall response is shown for DLBCL ≥12 mg and ≥48 mg and FL ≥12 mg, corresponding to the minimal efficacy threshold (Table). Responses deepened over time (PR converted to CR: DLBCL, 6 pts; FL, 3 pts). Median time to response was 1.4 mo (DLBCL) and 1.9 mo (FL). Among DLBCL pts achieving CR with ≥6 mg (n = 11), none relapsed while on treatment. The median PFS for pts with DLBCL ≥12 mg (n = 22) was 9.1 mo (95% CI: 1.6, NE; median follow-up 9.3 mo) and for pts with DLBCL ≥48 mg (n = 11) median PFS was not reached (median follow-up 8.8 mo). Updated analyses will be presented. Conclusions: With longer follow-up, SC epcoritamab demonstrated substantial single-agent activity, inducing deep and durable clinically meaningful responses, with a consistent safety profile. Notably no severe (grade ≥3) CRS events, no febrile neutropenia, and limited neurotoxicity was observed. Clinical trial information: NCT03625037. [Table: see text]

Early circulating tumor (ct) DNA dynamics and efficacy of lorlatinib: Analysis from the CROWN study.

9011 Background: Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, significantly improved progression-free survival (PFS) and overall/intracranial responses vs crizotinib in patients (pts) with previously untreated ALK-positive advanced non-small cell lung cancer (NSCLC) in the ongoing randomized Phase 3 CROWN study (NCT03052608). To identify whether additional molecular biomarker analysis correlated with efficacy, we evaluated early ctDNA dynamics compared with clinical outcomes. Methods: Plasma samples were prospectively collected at screening (SC), week 4 (cycle 2, day 1 [C2D1]), week 24 (C7D1), and end of treatment for ctDNA analysis. ctDNA was analyzed using Guardant360CDx (Guardant Health, Inc., Redwood City, CA, USA). Mean variant allele fraction (VAF) of ALK alterations (fusions and/or mutations) and overall detected alterations at each time point and longitudinal mean change (dVAF) as (VAFC2D1) – (VAFSC) were calculated; dVAF <0 indicated decreased ctDNA at week 4. Objective tumor response and PFS were evaluated according to dVAF. These analyses were repeated vs ctDNA results at week 24. Additional correlation analyses between depth of molecular response and/or ctDNA clearance and clinical outcomes are ongoing. Results: Paired samples were available at SC and week 4 from 232 of 255 pts included in the ctDNA analysis: 118/130 (90.8%) in the lorlatinib arm and 114/125 (91.2%) in the crizotinib arm. ALK alterations were detected in 122/232 (52.6%) pts at SC (62/118 [52.5%] from the lorlatinib arm) but only 19/232 (8.2%) at week 4 (8/118 [6.8%] from the lorlatinib arm). Mean VAF of ALK alterations at week 4 was significantly decreased compared with SC in both treatment arms (lorlatinib -1.54, crizotinib -1.25; both P<0.0001; P=0.4239 between arms). In the lorlatinib arm, mean VAF at week 4 was significantly decreased compared with SC in pts with a complete or partial response (dVAF -1.53; n=47; P<0.0001), or stable disease (dVAF -1.37; n=12; P=0.0304). Similar results were observed in the crizotinib arm. In pts with dVAF <0 for ALK alterations, mean percent change from screening in tumor size was -40.8% with lorlatinib (n=59) and -38.7% with crizotinib (n=58). Only 2 pts had dVAF ≥0, both from the crizotinib arm. Median PFS for pts with dVAF <0 for ALK alterations was not reached in the lorlatinib arm (n=62), and was 7.4 months (95% CI, 7.2–9.3) in the crizotinib arm (n=58). Similar response and PFS data were observed in the analysis of dVAF for ALK alterations at week 24. Conclusions: Early ctDNA dynamics may predict lorlatinib efficacy in pts with previously untreated ALK-positive NSCLC. The magnitude of reduction in ctDNA at 4 weeks may be associated with better responses and potentially longer PFS. These findings further support the utility of dynamic ctDNA monitoring in ALK-positive NSCLC. Reference: Shaw AT, et al. N Engl J Med. 2020;383:2018-2029. Clinical trial information: NCT03052608.

Abstract PS11-18: Ceralasertib (cer) in combination with olaparib (ola) in patients (pts) with advanced breast cancer (BC): Results of phase I expansion cohorts

Abstract Background: Alterations in BRCA1/2 are associated with ~9% of all BCs. Ola (a poly ADP-ribose polymerase inhibitor [PARPi]) is approved for treating pts with HER2-negative metastatic BC with germline BRCA mutation (gBRCAm), demonstrating an improvement in progression-free survival (PFS). Ceralasertib (an ataxia telangiectasia and Rad3-related protein ATR inhibitor) targets DNA damage repair and cell cycle regulation. Preclinical studies show synergistic antitumor effects of ola+cer vs ola monotherapy supporting the clinical evaluation of this combination. Methods: Study 4 is a modular multicenter Phase I study of cer combinations (NCT02264678). Module 2 established the Recommended Phase 2 Dose of ola+cer as ola 300 mg bid daily + cer 160 mg qd D1-7 q 28d. We report the results of two expansion cohorts testing ola+cer in pts with triple negative breast cancer with no alterations in homologous recombination repair (HRR)-related genes (HRR wt group), and pts with advanced HER2- BRCAm BC (BRCAm group), with a data cut-off of 19th June 2019. Eligible pts had to have received 1-2 prior lines of chemotherapy for metastatic disease, and were PARPi naive. Patients may have enrolled directly based on a local BRCAm test result, but all pts submitted a tumor specimen for central confirmation of a deleterious (or suspected deleterious) germline or somatic BRCA1/2 mutation. The primary objective was to investigate the safety and tolerability of the combination; secondary objectives included assessment of objective response rate by RECIST 1.1. Results: Twenty-five pts were enrolled in the HRR wt group: median age 53 (31-75), ECOG PS 0/1 13 (52%)/12 (48%), median number of prior chemotherapy lines 2 of which 8 pts (32%) had received prior platinum. Thirty-seven pts enrolled in the BRCAm group: median age 51 (24-69), ECOG PS 0/1 20 (54%)/17 (46%), median number of prior chemotherapy lines 1 of which 19 pts (51%) had received prior platinum. The most frequent all causality Adverse Events (AEs) were nausea 43 (69%), anemia 36 (58%), diarrhea 20 (32%) and vomiting 20 (32%); CTCAE ≥ Grade 3 AEs included anemia 15 (24%), neutropenia 6 (10%) with few patients discontinuing treatment. In the HRR wt group, no responses were observed, 12 (48%) pts achieved a best response of stable disease and 13 (52%) had disease progression. The median PFS was 3.1 months (80%CI 2.0,3.9). In the BRCAm group, 13 (35%) pts achieved a confirmed response (including 1 complete response), 17 (46%) stable disease and 7 (19%) pts disease progression. The median PFS in pts with a centrally confirmed BRCAm was 11.5 months (80%CI 5.8-14.8, n=30), 7.7 months (80%CI 5.8-11.4, n=37) in all pts enrolled in the BRCAm group. Eleven of the 13 responders in the BRCAm group were on study treatment for a longer duration than their treatment immediately prior to enrollment. As of 18th June 20, preliminary data shows 10 pts are still ongoing with a treatment duration ranging 20 to 35 months. Conclusion: In pts with HER2- BRCAm breast cancer, clinical efficacy was observed with durable radiological response despite adverse prognostic features in this Phase I population. The observations in this study are currently being tested in a global multicenter open-label randomised Phase 2 study: VIOLETTE (NCT03330847). Citation Format: Emma Dean, Matthew G Krebs, Seock-Ah Im, Mario Campone, Sophie Postel-Vinay, Tobias Arkenau, Juanita Lopez, Wassim Abida, Duncan Jodrell, Keun-Wook Lee, SunYoung Rha, Irene Kang, Rebecca Roylance, Graeme Parr, Claire Smith, Andrew Goldwin, Elhan Sanay, Natasha Lukashchuk, Alan Lau, Andrew Pierce, Bienvenu Loembe. Ceralasertib (cer) in combination with olaparib (ola) in patients (pts) with advanced breast cancer (BC): Results of phase I expansion cohorts [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 PS11-18.

Abstract PS2-19: Circulating tumor cell (CTC) enumeration in a phase II trial of pazopanib in addition to endocrine therapy in patients with hormone resistant advanced breast cancer (ABC)

Abstract Background: CTCs are detectable in approximately 50% of pts with metastatic breast cancer, and elevated CTC levels are an independent negative prognostic factor. CTCs have been shown to play a valuable role in predicting outcomes in pts with ABC treated with chemotherapy or endocrine therapy. This phase II trial was conducted to evaluate the clinical benefit (CB) of pazopanib, a VEGF receptor tyrosine kinase inhibitor (TKI) combined with nonsteroidal aromatase inhibitors (NSAIs) in pts with ABC resistant to NSAIs. As an exploratory analysis, we hypothesized that CTC levels might be correlated with response to pazopanib plus endocrine therapy. Methods: Eligibility included postmenopausal women with hormone receptor positive (HR+) ABC and progressive disease after at least one month of NSAIs. Treatment was pazopanib 800 mg/day plus either letrozole or anastrozole. The primary endpoint was clinical benefit rate at 12 weeks (CBR12, wks). Secondary endpoints included progression free survival (PFS), safety, and the impact of pazopanib and NSAI on CTCs. A CBR of 20% was considered a clinically meaningful comparison to the expected CBR of <5% with continued NSAIs after PD. Blood samples were collected for CTC analysis at baseline, then every 4 wks while on treatment. The presence of CTCs was assessed using the FDA-cleared CellSearch System; CTCs were defined as EPCAM-positive, CD45-negative nucleated cells. Samples with 5 CTCs per 7.5 mLs of blood were considered CTC-positive. Results: 32 pts were enrolled; 28 are evaluable for study endpoints. The median age was 58 years (range: 41-77). Pts were heavily pre-treated, with a median of 2 prior hormone therapies (range 1-6) and 1 prior chemotherapy (range 0-8). 8 pts (28.6%) stopped treatment due to adverse events, and 6 pts progressed before wk 12. CBR12 was 46.4% (12 SD, 1 PR), and CBR24 was 25% (5 SD, 2 PR). Safety has been presented (ASCO 2020). Median PFS was 20 wks, and median PFS for pts with CBR12 was 24 wks. Five (22%) of 23 pts with CTC data were CTC-positive (5 CTC/7.5 mL). There was no significant association between CBR12 and CTC status at baseline, or between CBR12 and change in CTC status (baseline to 4 wks after initiation of treatment). 7 pts had non-CBR12 and CTC data; 4 pts (n=4/7; 57%) were CTC positive at either baseline, week 4 or both. 11 pts had CBR12 and CTC data; all patients were CTC negative at baseline and remained negative at 4 wks. 7 pts had PFS >6 months (24, 32, 36, 36, 48, 184 and 274 wks), and 6 had CTC data: all were CTC-negative at baseline and 4 wks, then remained negative at 12 wks. Based on baseline values only, CTC-positive pts had a shorter median PFS compared to CTC-negative pts, but the difference was not statistically significant (11 wks vs 14 wks, p=0.18). Persistently CTC negative patients had significantly longer PFS compared to patients who were CTC positive at any time during study treatment (36 wks vs 11 wks, p=0.01). Conclusions: The addition of pazopanib to NSAIs resulted in a CBR12 of 46.4%, and a CBR24 of 25% in pts with heavily pre-treated ABC resistant to NSAIs. These results support clinical efficacy of antiangiogenic TKI in HR+ ABC and suggest benefit in hormone resistant disease. Consistently negative CTCs correlated with response and response duration. PFS was significantly longer in patients who were consistently CTC negative, further defining the prognostic role of CTCs in HR+ ABC. (NCT01466972) Citation Format: Ozge Gumusay, Mark Jesus M. Magbanua, Melanie C. Majure, Travis Deal, Jonathan R. Renslo, Chiara A. Wabl, Michelle E. Melisko, A. Jo Chien, Andrei Goga, Mark M. Moasser, John W. Park, Jimmy Hwang, Hope S. Rugo. Circulating tumor cell (CTC) enumeration in a phase II trial of pazopanib in addition to endocrine therapy in patients with hormone resistant advanced breast cancer (ABC) [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 PS2-19.

Association of immune-related adverse events (irAEs) with improved clinical outcome in sarcoma patients treated with immune checkpoint blockade (ICB).

11510 Background: IrAEs are associated with improved clinical outcomes after treatment with ICB in select epithelial malignancies. We hypothesized that sarcoma patients (pts) treated with ICB who developed an irAE would have improved outcomes compared to pts who had no irAE. Methods: Adverse events (AEs) from 3 sarcoma-specific ICB trials (nivolumab plus NKTR-214, pembrolizumab plus epacadostat, and pembrolizumab plus T-VEC) were reviewed. AEs probably or definitely related to ICB were classified as immune- or non-immune-related by the principal investigator. Endpoints of interest included best overall response (BOR) by RECIST 1.1 (complete response [CR]/partial response [PR]), durable clinical benefit (DCB; CR/PR/stable disease [SD] ≥ 16 weeks), and progression-free survival (PFS). Outcomes were stratified by the presence or absence of ≥ 1 irAE of any grade and by grade 1-2, grade 3-4, or no irAE (three-category comparison). Results: A total of 124 pts received ICB on these studies. Median pt age was 56 (range: 13-90); 53% were male; all but one pt had a performance status of ≤ 1. BOR was PR in 12 pts, SD in 41, and PD in 69. 2 pts were not evaluable. 40 pts (32%) had ≥ 1 irAE of any grade, 6 of whom had a grade 3-4 irAE. The most common irAEs (≥ 5% of pts) were rash (15%), arthralgia (11%), myalgia (9%), pruritis (8%), and hypothyroidism (6%). The proportion of pts with a CR/PR was higher in pts with than without an irAE (18% vs. 6%, respectively; P = 0.058). A significantly higher proportion of pts with an irAE had DCB compared to those without (53% and 29%, respectively; P = 0.017). The median PFS of pts with an irAE was 16.6 months compared to 10.6 in those without (P = 0.013). The proportion of pts with a grade 3-4 irAE and a CR/PR was highest (33%) compared to pts with grade 1-2 (15%) or no irAE (6%) (P = 0.048). More pts with grade 3-4 irAE achieved DCB (67%) than grade 1-2 (50%) or no irAE (29%) (P = 0.027). Median PFS was 22.6, 15, and 10.6 weeks in the grade 3-4, grade 1-2, and no irAE groups, respectively (P = 0.047). Conclusions: Approximately one-third of advanced sarcoma pts with ICB-based immunotherapy developed an irAE. As reported previously in select carcinomas, sarcoma pts with irAEs were more likely to have clinical benefit than those without irAEs. Further research is needed to understand the mechanism behind this association and to validate these findings prospectively.

An Exploratory Analysis of Brentuximab Vedotin Plus CHP (A+CHP) in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas (ECHELON-2): Impact of Consolidative Stem Cell Transplant

An Exploratory Analysis of Brentuximab Vedotin Plus CHP (A+CHP) in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas (ECHELON-2): Impact of Consolidative Stem Cell Transplant

Four-Year Interim Analysis of Miroir, a French Multicenter, Non-Interventional Study of Pomalidomide in Relapsed/Refractory Multiple Myeloma

BACKGROUND Real-world data on the use of pomalidomide (POM) for the treatment (Tx) of relapsed/refractory multiple myeloma (RRMM) are limited. The MIROIR study was designed to evaluate POM Tx in routine clinical practice in France. Here, we present results from a prespecified 4-year interim analysis. METHODS MIROIR is a multicenter, observational, ambispective, non-interventional study of POM in routine clinical practice. Adult patients (pts) with MM who initiated POM Tx in France between October 1, 2014, and September 30, 2018, were included. All pts were required to be enrolled in the French IMNOVID® registry. Data were collected from medical records of consenting pts. Key exclusion criteria included previous treatment with POM or simultaneous participation in a clinical trial. The primary endpoint is progression-free survival (PFS) at 6 months. Key secondary endpoints include time to next Tx (TTNT), overall survival (OS), and safety. This study is ongoing; targeted enrollment is 3000 pts (ClinicalTrials.gov, NCT02902900). RESULTS A total of 2099 pts were included in this analysis (median follow-up: 23.3 months; data cutoff: February 1, 2019). Median age was 70.0 years, and 655 pts (31.2%) were aged ≥ 75 years; 1134 pts (54.0%) were male. Median time from start of first-line Tx to POM initiation was 51.4 months. Pts had received a median of 3 prior lines of therapy (range: 0-9), with 914 (43.5%), 644 (30.7%), 312 (14.9%) and 229 pts (10.9%) receiving ≤ 2, 3, 4, and ≥ 5 prior lines, respectively. From 2014 to 2016, the median number of prior lines of therapy before POM initiation was 3, and from 2016 to 2018, the median was 2. Nearly all pts received prior lenalidomide (LEN; 97.0%) and bortezomib (96.7%). POM was initiated at 4 mg/day in 1635 pts (77.9%) overall and in 1216 pts (84.2%) aged < 75 years and in 419 pts (64.0%) aged ≥ 75 years. Dexamethasone was prescribed at 20 mg/day and 40 mg/day in 507 (35.1%) and 732 pts (50.7%) aged < 75 years and in 405 (61.8%) and 62 pts (9.5%) aged ≥ 75 years. Overall, the 6-month PFS rate was 51.7% (95% CI, 49.4%-54.1%). Other key PFS data in pt subgroups are reported in the Table. In the overall population, median TTNT, 12-month OS rate, and median OS were 10.4 months (95% CI, 9.7-11.2), 70.6% (95% CI, 68.5-72.6), and 24.6 months (95% CI, 22.9-not reached), respectively. Among 1164 pts (55.5%) with ≥ 1 adverse event (AE), the most common AEs were neutropenia (290 pts; 24.9%), infections (263 pts; 22.6%), thrombocytopenia (99 pts; 8.5%), and asthenia (87 pts; 7.5%). POM dose was reduced due to an AE in 20.7% of pts; POM Tx was interrupted or discontinued due to an AE in 36.2% and 15.2% of pts, respectively. CONCLUSIONS The results of this interim analysis confirm the efficacy of POM reported in clinical trials and underscore its role in Tx of RRMM, including after LEN Tx. Median PFS in pts with ≤ 2 prior Tx lines was numerically longer than in pts who had more Tx lines, supporting earlier Tx with POM. PFS outcomes were similar regardless of the duration of LEN Tx (< or ≥ 6 months) before initiation of POM and whether pts had received LEN or another Tx as their most recent therapy. The latter finding suggests that POM can be used after relapse or resistance to LEN and that there is no need to replace an IMiD agent with another class of treatment. Disclosures Decaux: Celgene Corporation, Janssen, Takeda, Amgen: Honoraria. Macro:Celgene, Janssen, Amgen, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support. Gourgou:Celgene: Employment, Equity Ownership. Lachenal:Celgene: Other: Scientific Comittee's. Stoppa:Celgene: Honoraria. Jaccard:Abbvie: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Perrot:jannsen: Honoraria, Membership on an entity's Board of Directors or advisory committees; takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding. Karlin:AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fohrer:Celgene: Consultancy, Honoraria. Leleu:Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria.

Overall Survival Benefit of Ixazomib, Lenalidomide and Dexamethasone (IRD) over Lenalidomide and Dexamethasone (RD) in RRMM Patients Treated in Routine Clinical Practice: Results from the Czech Registry of Monoclonal Gammopathies (RMG)

Background : Outcomes reported in real-world practice versus controlled clinical trials show markedly shorter treatment durations, progression free survival (PFS) and overall survival (OS). Understanding effectiveness of therapeutic regimens in routine practice is critical for treating physicians as well as for regulatory and reimbursement authorities. We have performed a real-world comparison of two regimens, ixazomib, lenalidomide and dexamethasone (IRD) triplet and lenalidomide and dexamethasone (Rd) doublet in patients with relapsed and/or refractory multiple myeloma (RRMM) treated in seven Czech and one Slovak hematology-oncology centers. Patients and methods: Between 3/2015 and 5/2017, 344 patients with RRMM were treated with either IRD (N=127) or RD (N=217). Patients selected for both cohorts had the same inclusion and exclusion criteria. Patient baseline characteristics were well balanced. The data were collected through the Czech Registry of Monoclonal Gammopathies (RMG), which is an international database gathering data from patients with monoclonal gammopathies within Central Europe. Results: The median follow-up in the IRD vs RD arm was 20.8 vs 15.5 months, respectively. Median PFS in pts with 1-3 prior lines for the IRD cohort was 23.1 months (95% CI 11.8-34.5 months) and 11.6 months (95% CI 8.4-11.8 months) for the RD cohort favoring the all-oral triplet (p=0.001). The median PFS for all patients including 4+ line of therapy was 17.5 months (95% CI 10.3-24.7) in the IRD cohort versus 11.5 months (95% CI 8.6-14.3) in the RD group (p=0.005). Median OS for pts with 1-3 prior lines for IRD cohort was not reached, and was 27.1 months (95% CI 23.1-31.1 months) in the RD cohort (p=0.002). Median OS for all patients, including 4+ lines of treatment was 36.6 months in the IRD vs 26.0 months in the RD cohort (p=0.008). The PFS benefit of IRD over RD was observed in most of the assessed subgroups; in younger pts ≤65 years with hazard ratio (HR) 0.58, in pts 66-75 years HR 0.64. There was a trend towards better PFS in patients with lower ISS stage; ISS1 HR 0.53, ISS2 HR 0.58 and ISS3 the HR was 0.87. Patients in the 1st relapse (HR 0.53) benefited most from the IRD, followed by the 2nd relapse (HR 0.58), 3rd relapse (HR 0.90) and pts relapsing after 4+ therapies (HR 0.88). The PFS benefit of IRD regimen was observed in pts regardless of previous stem cell transplantation; transplant-eligible patients HR 0.51 and transplant-ineligible HR 0.71. Patients who did not benefit from the triplet regimen were those over 75 years of age and pts with the presence of extramedullary disease. The IRD treatment was well tolerated. The safety profile was concordant with previously reported data. Conclusions: This RMG comparative cohort analysis shows PFS benefit of all-oral IRD regimen over RD in the real world setting, and confirms growing evidence that long term outcomes with IRD triplet are comparable with phase 3 TOURMALINE-MM1 trial. Our analysis also shows an overall survival benefit of IRD over RD treatment. Patients older than 75 years, with 4+ lines of therapy and presence of extramedullary disease did not profit from addition of ixazomib to RD doublet.Additional data with larger patient populations confirming RWE effectiveness are warranted. With support of AZV 17-29343A, NV18-03-00500, FNOl 00098892, IGA-LF-2019-001, PROGRES Q40/08, MH CZ-DRO (UHHK, 00179906) Disclosures Minarik: Celgene: Consultancy, Honoraria, Research Funding; Amgen, BMS, Janssen-Cilag, Takeda: Consultancy, Honoraria. Straub:Amgen, Takeda, Celgene: Consultancy. Spicka:Celgene: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Sanofi: Consultancy. Skacel:Millennium Pharmaceuticals, Inc., subsidiary of Takeda Pharmaceutical Company Limited: Employment. Maisnar:Janssen, Amgen, Celgene, Takeda, BMS: Consultancy, Honoraria.

A retrospective analysis of antibiotics usage and effect on overall survival and progressive free survival in patients with metastatic pancreatic cancer.

e15781 Background: Recent studies have shown that the pancreatic ductal adenocarcinoma (PDAC)-associated gut microbiome can play a major in modulating responses to therapies. Antibiotics (ATB) can potentially alter the tumor and gut microbiota diversity and composition leading to modified responses to chemotherapeutic/immune therapy regimens and hence the survival. Methods: We retrospectively analyzed the clinical data of 148 patients (pts) with documented metastatic PDAC seen at MD Anderson Cancer (MDACC) from 2009 to 2017. Along with demographic and chemotherapy regimen details the duration, type and reason for antibiotic consumption for more than 3 days were recorded. Overall survival (OS) and Progression free survival (PFS) were calculated. Log-rank test and Gehan-Breslow-Wilcoxon test were used to check the statistical significance for OS and PFS. Confounding variables were also accounted. Results: We analyzed the data of 148 metastatic pancreatic cancer pts[mean age 62.73, 50.67% males 49.32% females, 75.6% white] out of which 135 patients received antibiotics. The infectious sources consisted of intraabdominal (n = 68), urinary (n = 36), respiratory (n = 57), skin/soft tissue infections (n = 26), blood related (n = 24), and others (n = 76). Beta lactams (n = 96) and Quinolones (n = 96) were the most commonly prescribed antibiotics. When comparing outcomes, we found out that the median OS for pts taking macrolides (n = 24) was 541 days compared to 341 days for pts not taking macrolides (n = 144) (HR = 0.6384, p value = 0.0191) . Median PFS for pts taking macrolides was 178 days versus 124 days in those not taking macrolides (HR = 0.6331, p value = 0.0188). The potential confounders were having a respiratory infection or the type of chemotherapy regimen. Conclusions: Macrolide consumption for > 3 days leads to a prolonged OS and PFS. Consistent with the preclinical evidence our data suggests a potential role for some antibiotics in modulating PDAC-associated gut microbiome. Hence, having implications on the survival of PDAC pts. [Table: see text]

Outcomes with CDK4/6 inhibitors based on endocrine sensitivity in hormone receptor-positive metastatic breast cancer (HR+ MBC).

e12526 Background: PALOMA-3 results demonstrated that patients (pts) with sensitivity to previous endocrine therapy had a substantial benefit with Palbociclib compared to those with intrinsic endocrine resistance (Turner NC et al. NEJM 2018). ESR1 mutation has been associated with decreased response to endocrine therapy (Fribbens C et al. JCO 2016) and NSD3 amplification in breast cancer cells have been correlated with the overexpression of ESR1 (Irish JC et al. Mol Oncol 2016). Here we demonstrate a real-world response to CDK4/6i based on high-risk features and correlation to biomarkers of response. Methods: We retrospectively analyzed 115 HR+MBC pts at a single large community cancer center who received CDK4/6i + endocrine therapy and 40 matched controls treated with endocrine therapy and underwent NextGen Sequencing (NGS) profiling of 592 genes (Caris Life Sciences, Phoenix, AZ). The primary outcome was progression-free survival (PFS). Hazard ratios were calculated from Cox proportional hazards models built using the survival package[1] in R. Results: Among 115 pts in the CDK4/6i cohort, the median PFS for pts treated in the first-line (N=77) versus (vs.) second-line (N=38) was 9.7 and 4.6 months (mo) respectively (HR 2.04, p=0.001). Further, the median PFS in first-line cases who had a Disease-Free Survival (DFS) of >2 years (endocrine sensitive) (N=27) was 11.9 mo, and in pts with DFS < 2years (endocrine resistant) (N=24), it was 7.7 mo (HR 0.71, p= 0.397). Six pts with ESR1 mutations had worse PFS compared to ESR1 wild-type (N=40) when treated with CDK4/6i in 1st line, 6.4 vs. 18 mo (HR: 2.25, p=0.052) and 2nd line 2.5 (N=9) vs. 5.6 mo (N=17) HR: 2.09, p=0.1). NSD3 amplification was the only other genomic alteration showing significance as a negative predictor of PFS (first-line: 6.1 vs. 14.7 mo, HR: 2.40, p=0.04; second-line: 2.8 vs. 6.5 mo, HR: 3.61, p=0.06). NSD3 amplification appeared to have no significant effect in the control cohort 6.5 vs. 4.4 mo, (HR 1.29, p=0.63). Conclusions: In this real-world cohort, CDK 4/6 combination therapy benefits HR+ MBC patients in the first and second-line setting. ESR1 mutation is a predictor of worse outcome. NSD3 gene amplification is a potential biomarker of resistance to CDK4/6i combination therapy. (Therneau T (2015). A Package for Survival Analysis in S version 2.38, https://CRAN.R-project.org/package=survival).

FOLFIRI in advanced biliary tract cancers.

451 Background: Gemcitabine plus platinum (GP) is the standard of care first-line treatment for advanced biliary tract cancers (BTC). There is no established second-line therapy, and retrospective reviews report progression-free survival (PFS) for second-line treatment to be < 3 months. 5-Fluorouracil plus irinotecan (FOLFIRI) is a commonly used regimen in patients (pts) with BTC who have progressed on GP, though there is a paucity of data regarding its efficacy in this population. Methods: We retrospectively evaluated pts with advanced BTC who were treated with FOLFIRI at MD Anderson, University of Michigan and Mayo Clinic in Jacksonville. Data were obtained on pt demographics, type of BTC, PFS, and overall survival (OS). Results: Ninety-eight pts were included of which 74 (76%) had metastatic disease at the time of treatment with FOLFIRI. The median age was 59 (range, 22 to 86) years. The number of pts with extrahepatic cholangiocarcinoma (CCA)/gall bladder (GB)/intrahepatic CCA were 10, 17, and 71. FOLFIRI was used as 1st, 2nd, 3rd or 4th – Nth lines in 8, 50, 36, and 4 pts, respectively. Of the 65 pts whose best responses were documented, 23 (35%) had stable disease and 7 (11%) had a partial response per RECIST v1.1. Median duration on FOLFIRI was 2.2 months. The median PFS and OS were 2.4 (95% CI 1.7 to 3.1) and 6.6 (95% CI 4.7 to 8.4) months, respectively. Median PFS for pts treated with FOLFIRI in 1st, 2nd, 3rd or 4th – Nth lines were 3.1, 2.5, 2.3 and 1.5 months, respectively. Eighteen pts received concurrent bevacizumab (13) or EGFR-targeted therapy (5) with FOLFIRI, and both of groups exhibited a median PFS of 2.7 months. Eastern Cooperative Oncology Group performance status (PS) of 0-1 was associated with improved OS (P = 0.006) compared to PS of 2-3. Conclusions: In this multi-institution retrospective review of 98 pts with BTC treated with FOLFIRI, efficacy of this regimen appears to be modest. While PFS and OS outcomes were similar to what has been previously reported, the 46% disease control rate in this group of predominantly pretreated pts is encouraging. Given the lack of other standard therapies, FOLFIRI may still have a role in this pt population, but these results emphasize the need for more effective treatment options for pts with advanced, pretreated BTC.

Efficacy and Safety of Once-Weekly vs Twice-Weekly Carfilzomib Plus Dexamethasone: Subgroup Analysis of the Phase 3 A.R.R.O.W. Study (NCT02412878) By Prior Lines

Efficacy and Safety of Once-Weekly vs Twice-Weekly Carfilzomib Plus Dexamethasone: Subgroup Analysis of the Phase 3 A.R.R.O.W. Study (NCT02412878) By Prior Lines

Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed Against B-Cell Maturation Antigen, in Patients with Relapsed/Refractory Multiple Myeloma

LCAR-B38M is a bispecific chimeric antigen receptor T cell (CAR T) therapy directed against B-cell maturation antigen (BCMA). The bi-epitope BCMA binding moieties confer high avidity binding and distinguish LCAR-B38M from other BCMA CAR constructs. Preliminary results of LCAR-B38M in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM) showed encouraging efficacy and manageable safety (Fan et al.JCO 2017;35:18_suppl LBA3001). Here we present updated safety and efficacy results of the trial.LEGEND-2 (NCT03090659) is an ongoing phase 1, single-arm, open-label multicenter study evaluating LCAR-B38M in pts (18-80 years) with R/R MM. Lymphodepletion was performed using 3 doses of cyclophosphamide 300 mg/m2 on days -5, -4, and -3. Five days after lymphodepletion, LCAR-B38M CAR T cells (median CAR+ cell dose = 0.5x106 cells/kg, [range, 0.07-2x106]) were given in 3 infusions (20, 30, and 50% of total dose). The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the anti-myeloma response of the treatment. Adverse events (AEs) were graded using the Common Terminology Criteria for AE, v.4.03, and cytokine release syndrome (CRS) was assessed according to Lee et al. (Blood 2014;124:188-95). Response was evaluated using International Myeloma Working Group criteria. This analysis presents data from a single institution.As of June 25, 2018, 57 pts have been infused with LCAR-B38M CAR T cells. The median age was 54 years (range, 27-72), median number of prior therapies was 3 (range, 1-9), and 74% of pts had stage III disease by Durie-Salmon staging. The median duration of follow-up for all pts was 12 months (range, 0.7-25).AEs were reported by all pts; most common were pyrexia (91%), CRS (90%), thrombocytopenia (49%), and leukopenia (47%). Grade ≥3 AEs were reported by 65% of pts; most common were leukopenia (30%), thrombocytopenia (23%), and increased aspartate aminotransferase (21%).CRS was mostly grade 1 (47%) and 2 (35%); 4 pts (7%) had grade 3 cases. Liver function abnormalities were the most common signs of end organ injury among pts with CRS. The median time to onset of CRS was 9 days (range, 1-19). All but 1 CRS events resolved, with a median duration of 9 days (range, 3-57). No clear relationship was demonstrated between dose and CRS; there may be some effect at higher doses, but conclusions are limited by the small number of pts in the grade 3 CRS group (n=4; Figure 1A). Neurotoxicity was observed in 1 pt who had grade 1 aphasia, agitation, and seizure-like activity.The overall response rate (partial response [PR] or better) was 88% (95% confidence interval [CI], 76-95). Complete response (CR) was achieved by 42 pts (74%; 95% CI, 60-85), very good partial response was achieved by 2 pts (4%; 95% CI, 0.4-12), and PR was achieved by 6 pts (11%; 95% CI, 4-22; Figure 1B). Among pts with CR, 39/42 were minimal residual disease (MRD) negative by 8-color flow cytometry. The median time to initial response was 1 month (range, 0.4-4). No clear relationship between LCAR-B38M CAR T cell dose and response was observed (Figure 1C). BCMA expression did not correlate with clinical response.The median duration of response (DOR) was 16 months (95% CI, 12-not reached [NR]). The median DOR for pts who achieved a CR was 22 months (95% CI, 14-NR). At data cutoff, 18 pts (36%) who achieved PR or better progressed. The median progression-free survival (PFS) for all treated pts was 15 months (95% CI, 11-NR); median PFS for pts who achieved CR was 24 months (95% CI, 15-NR). The median overall survival was not reached. Overall, 17 pts died during the study and follow-up period; causes of death were progressive disease (PD; n=14), suicide after PD (n=1), esophagitis (n=1), and pulmonary embolism and acute coronary syndrome (n=1).Peak levels of LCAR-B38M (≥1x104 copies/µg genomic DNA) were observed in a majority of pts with blood samples for analysis (n=32). LCAR-B38M CAR T cells were not detectable in peripheral blood in 71% of pts at 4 months; 5 pts showed CAR T cell persistence up to 10 months.This ongoing first-in-human study has provided initial proof-of-concept that bispecific LCAR-B38M CAR T cells may be a highly effective therapy for R/R MM. LCAR-B38M CAR T cell therapy displayed a manageable safety profile consistent with its known mechanism of action and demonstrated deep and durable responses in pts with R/R MM. A phase 1/2 study of LCAR-B38M in R/R MM has been initiated in the US (NCT03548207). DisclosuresZhuang:Nanjing Legend Biotech: Employment. Fan:Nanjing Legend Biotech: Employment.

Clinical outcome of patients (Pts) with metastatic renal cell carcinoma (mRCC) progressing on front-line immune-oncology based combination (IO-COMBO) regimens.

613 Background: Several IO-COMBO regimens are under investigation in front-line mRCC. The clinical outcome of pts who progress on an IO-COMBO regimen and receive subsequent systemic therapy is unknown. Methods: A retrospective analysis of all pts with clear-cell mRCC enrolled in one of seven clinical trials investigating an IO-COMBO at Cleveland Clinic Taussig Cancer Institute and Barts Cancer Institute was conducted. Clinical outcome of subsequent therapy including best objective response according to RECIST v1.1, progression-free survival (PFS) and adverse events (AEs) using CTCAE v4.0, were collected. Results: From a total of 89 pts enrolled on an IO-COMBO trial, final analysis included 32 pts with PD who received ≥1 line of subsequent therapy, median age 57 (41-77), 83% male, 72% ECOG 0, 78% IMDC fav-/intm- risk. Prior IO-COMBO included atezolizumab/bevacizumab (n = 20), ipilimumab/nivolumab (n = 10) and axitinib/avelumab (n = 2). All except 1 pt received IO-COMBO in the front-line setting. All pts received 1 subsequent therapy (axitinib n = 15; pazopanib n = 9; sunitinib n = 4; cabozantinib n = 3; nivolumab n = 1) after progression on IO-COMBO, 12 pts were treated with a second subsequent therapy and 5 pts were treated with ≥3 subsequent lines of treatment. For pts with available response (n = 26), the overall best response to first subsequent therapy was 27% PR, 50% SD and 15% PD. Median PFS for the first subsequent therapy was 7.9 months (95% CI, 4.5-11.3) with 8 pts remaining on treatment. The median PFS for pts previously treated with a combination of IO plus anti-VEGF was 7.9 months (95% CI, 3.1-12.7) and was 9.3 months (95% CI, 3.5-15.0) for pts treated with a prior IO plus IO combination (p = 0.732). The most frequent G3/G4 treatment-related AEs observed with first subsequent therapy were LFT elevation (9%) and diarrhea (7%); 2 pts discontinued subsequent treatment due to toxicity. Conclusions: VEGF-TKIs have clinical activity in mRCC refractory to IO-COMBO therapy, possibly impacted by the inclusion of an anti-VEGF agent in prior IO-COMBO therapy. Subsequent therapy was in general well tolerated.

Abstract P3-11-03: The impact of dose delays and reductions on toxicity and progression free survival (PFS) in patients receiving palbociclib

Abstract Background: Despite the high rates of neutropenia observed in the PALOMA studies, the incidence of neutropenic fevers remained low. The safety analysis from the PALOMA-3 trial showed no difference in PFS among pts who had dose reductions or delays secondary to neutropenia. We conducted a retrospective study to analyze the impact of dose delays and reductions on toxicity and progression free survival (PFS) in pts receiving palbociclib as standard of care. Methods: Pts with metastatic ER positive breast cancer receiving palbociclib in any line of therapy were identified from a cohort at MD Anderson Cancer Center. Clinical, demographic, baseline labs, comorbidities and recurrence data were collected. Dose delays, dose reductions, and toxicities were recorded up to the first 6 cycles of palbociclib. Early dose delays and reductions were defined as events occurring during the first 2 cycles of palbociclib while late events were defined as cycles 3-6. Data was analyzed using Fischer's exact test for categorized variables and T test/Wilcoxon rank-sum test for continuous variables. PFS was analyzed using the Kaplan Meier method and Cox model was used to analyze factors associated with PFS. Results: 344 pts who met eligibility criteria were included in the analysis. Pts receiving palbociclib on clinical trial were excluded. 109 (31.6%) pts received dose reductions and 153 (44.4%) experienced dose delays. The rate of neutropenic fever was low, occurring in 2.3% of all pts. There was a significant association between pts experiencing dose reductions and Hispanic race, baseline ANC, history of adjuvant endocrine therapy, adjuvant radiation therapy (XRT), and heart disease. History of adjuvant XRT, baseline ANC, and heart disease were associated with dose delays. Toxicities, including neutropenic fever, infections requiring antibiotics, and hospitalizations, were associated with dose reductions and dose delays. Median PFS for the cohort was 263.5 days. There was no significant association between early dose reductions or delays with PFS. Pts experiencing late dose delays (hazard ratio [HR], 0.4, P=0.0001) and reductions (HR, 0.4, P=0.0005) had a significantly longer PFS. Median PFS for pts without late dose delays was 228 days compared to 313.5 days for pts with late dose delays. Median PFS for pts without late dose reductions was 246 days compared to 305.5 days for pts with late dose reductions. In the multivariable analysis, liver metastasis, metastatic line, and higher tumor grade were associated with worse PFS. Pts receiving palbociclib and fulvestrant were found to have worse PFS than pts receiving palbociclib and letrozole. Conclusions: Similar to the PALOMA trials, this study found that while the rate of toxicities such as neutropenic fever were low, dose reductions and delays were common. In pts receiving palbociclib as standard of care, pts with late dose reductions and delays had a longer PFS than those without dose reductions and delays. It is reassuring that the PFS was not negatively affected in pts with dose reductions and delays. As use of palbociclib as standard of care becomes more common, further larger retrospective studies are warranted to examine the impact of dose delays and reductions. Citation Format: Clifton KK, Kimmel J, Yi M, Chad B, Litton J, Debu T, Meghan K. The impact of dose delays and reductions on toxicity and progression free survival (PFS) in patients receiving palbociclib [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-11-03.

Outcomes following progression on BRAF/MEK inhibition in metastatic melanoma.

9537 Background: Restrictions in Australia dictate the prescription of BRAF/MEK inhibitors prior to immunotherapy in BRAF mutant metastatic melanoma (BRMM). We analysed patients (pts) with advanced BRMM after treatment with a BRAF/MEK inhibitor and use of second line immunotherapy (PD-1 inhibitor or CTLA4 inhibitor). Methods: Patients (pts) with BRMM from Princess Alexandra Hospital treated between June 2013 to June 2016 were identified retrospectively. Demographics, treatment pattern and survival were analysed. Results: 92 pts were identified. 50% had an elevated LDH at diagnosis. 30 pts had brain metastasis at diagnosis, of these pts 11 had cerebral progression on BRAF/MEK. 41 pts had radiotherapy, 50% had stereotactic/gamma knife and 50% WBRT. 68 pts progressed giving a median progression free survival (PFS) of 9 months (95% CI 6.4 – 11.6 m). The median PFS for pts with normal LDH was 14 months, opposed to 9 months if elevated. On progression 31 pts (36.5%) were not offered second line immunotherapy due to rapid deterioration or declining performance status. 26 (30.6%) were treated with PD-1 inhibitor; 7 (8.2%) had Ipilimumab, of these, 4 then had PD-1; 1 had combination therapy; 23.5% of pts continued on BRAF/MEK at analysis. Of the patients exposed to immunotherapy, 27 pts experienced disease progression, giving a median PFS survival of 2.5 months (95% CI 1.2 –3.6m). Conclusions: After BRAF/MEK inhibition, due to rapid disease progression and poor performance status a significant proportion of patients do not receive immunotherapy and received best supportive care. Disease control with single agent PD-1 is short after BRAF/MEK inhibitors. These patients may have benefited from first line immunotherapy. This cohort, while small, suggests further data is needed about optimal sequencing of targeted and immunotherapy.

P3.02a-005 The Association between the Percentage of Anaplastic Lymphoma Kinase(ALK)-Positive Cells and Efficacy of ALK Inhibitor: Topic: ALK Biomarkers

The purpose of the study was to explore the association between the percentage of ALK+ cells in fluorescent in situ hybridization (FISH) and the clinical efficacy of ALK inhibitor. A total of 73 patients (pts) with ALK rearrangement who were identified the percentages of ALK+ cells in FISH and were treated with ALK inhibitor, were enrolled at three participating institutions. Retrospectively, we evaluated progression-free survival (PFS) by log-rank test and Kaplan–Meier method. Median % ALK+ cells in FISH was 54% (range 15-100%). Fifty (68.5％) pts used crizotinib (CRZ) and 23 (31.5%) pts used alectinib (ALC) as the first ALK inhibitor. Among 57 pts who were evaluated by immunohistochemical (IHC) staining, 10 had no detectable expression of the ALK protein and the percentage of ALK+ cells was all within 15-29%. The PFS of pts with 15-29% ALK+ cells was shorter than that with 30% or more ALK+ cells (CRZ group: 1.4 months [95% CI: 0.2-4.2] in 15-19% ALK+ cells, 3.25 months [0.47-Not Estimated (NE)] in 20-29%, 6.77 months [4.27-12.6] in 30-100%, p < .001. ALC group: 6.4 months [3.03-16.8] in 20-29%, 23.1 months [7.8-NE] in 30-100%, p = 0.547). Moreover, among pts with 15-29% ALK+ cells, median PFS of pts with IHC- was significantly shorter than that with IHC+ (CRZ group: 1.3 vs 5.6 months, p = 0.009. ALC group: 0.87 vs 40.3 months, p = 0.004). The case in 15-29% ALK+ cells and IHC- could not obtain the benefit of the ALK inhibitor. However, if the case is IHC+, the long PFS could be expected despite the percentage of ALK+ cells in FISH.