Search

9508 Background: Preliminary data from the ABC (76 pts) and CheckMate 204 (94 pts) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report updated 5-yr data from all pts enrolled on the ABC trial (NCT02374242). Methods: This open-label ph2 trial enrolled 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014-Apr 2017. Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Key secondary endpoints were IC PFS, overall PFS, OS, & safety. Results: A total of 76 pts (med f/u 54 mo) were enrolled; median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19%; V600BRAF 54%, 56% and 81%; prior BRAFi 23%, 24%, 75%. Efficacy and toxicity are shown in the table. There were no treatment-related deaths. 1/17 deaths in cohort A & 4/16 in cohort B were due to IC progression only. Conclusions: Nivo monotherapy and ipi+nivo are active in melanoma brain mets, with durable responses in the majority of patients who received ipi+nivo upfront. A study of upfront ipi+nivo+/-SRS is underway (NCT03340129). Clinical trial information: NCT02374242. [Table: see text]

103 Background: Rare cancers (RCs) often lack proven treatments and consequently have poorer outcomes. Identification of molecular biomarkers can facilitate treatment selection and trials access for RC patients (pts) where histology-based trials are not feasible. We assessed the potential for next-generation sequencing (NGS) to impact RC care. Methods: Pts with a rare histology, poor-prognosis solid-tumor and no standard of care therapy underwent NGS genomic profiling of paired FFPE tumor and blood (PMCC comprehensive cancer panel; 391 genes). A virtual molecular tumour board (MTB) reviewed curated results regarding diagnosis, actionability (OncoKB) and treatment recommendations. Results: Between July 2017 and Nov 2019, 121 pt were prospectively enrolled across 4 Australian sites. 109 (91%) pts had a tumour with an incidence of < 1/100,000 person/years with 83 diverse RC histologies represented. 100 (83%) cases were successfully sequenced. The most commonly aberrant genes ( > 10%) were: TP53 (45%), CDKN2A/B, RB1, PTEN and NF1. 51 (51%) had at least one potentially actionable finding, with 27 matched to a clinically validated drug (OncoKB level 3 or better) [Table]. In 6 cases NGS resulted in a revised diagnosis (includes 4 with FDA approved therapy). Actionable germline mutations were detected in 3 individuals of which 2 were previously known. The majority of pts remain in follow-up, however, 8 died prior to or within 28 days of NGS result availability. Drug access remains a limitation with only 12 receiving therapy based on NGS/MTB guidance. Clinical trial information: ACTRN12616001000493 . Conclusions: NGS in RCs is feasible with potential impact in half of cases. Earlier testing and improved off-label/trial drug access is necessary to increase the likelihood that RC patients may benefit from molecularly guided therapy. [Table: see text]

9514 Background: KEYNOTE-029 cohort 1B showed substantial efficacy for standard-dose pembro + 4 doses of ipi 1 mg/kg with lower rate of grade 3-5 toxicity than reported for standard-dose nivolumab + ipi in patients (pts) with advanced melanoma. In KEYNOTE-029 cohort 1C, we assessed the toxicity and antitumor activity of standard-dose pembro plus 2 alternate ipi doses (NCT02089685). Methods: Eligible pts with previously untreated stage III/IV melanoma, ECOG PS 0-1, and no active CNS metastases were randomized 1:1 to pembro 200 mg Q3W for 24 mo + 4 doses of ipi 50 mg Q6W (arm A) or pembro 200 mg Q3W for 24 mo + 4 doses of ipi 100 mg Q12W (arm B). Primary endpoints were the grade 3-5 treatment-related AE (TRAE) rate and ORR (RECIST v1.1, central review). With 50 pts per arm and compared with other anti–PD-1 + ipi regimens, a grade 3-5 TRAE rate ≤26% would suggest a meaningful reduction in toxicity and an ORR ≥48% would suggest no decrease in efficacy. Data cutoff date was Jul 17, 2018, and will be updated. Results: 102 pts were randomized: 51 to each arm. Median age was 63.5 y, 70% were male, 15% had ECOG PS 1, 34% had BRAF mutation, and 30% had elevated LDH at baseline. With 9.4 mo median follow-up, 69% of pts in arm A and 71% in arm B remained on treatment. All pts in arm A and 96.1% in arm B had ≥1 TRAE; grade 3-5 TRAE rates were 22% in arm A and 33% in arm B. 1 pt had a grade 5 TRAE (autoimmune myocarditis; arm A). ORR was 49% (95% CI 35-63) in arm A, including 7 CRs and 18 PRs, and 53% (95% CI 39-67) in arm B, including 6 CRs and 21 PRs. An additional 16 pts in each arm had SD or non-CR/non-PD, leading to a DCR of 80% and 84%, respectively. Median response duration was not reached in either arm (range 1.4+ to 9.6+ in arm A, 1.4+ to 9.8+ in arm B). Updated data based on longer follow-up will be presented. Conclusions: Standard-dose pembro + ipi 50 mg Q6W and standard-dose pembro + ipi 100 mg Q12W showed robust antitumor activity in this initial analysis. Both regimens appeared to have a lower rate of grade 3-5 TRAEs than previously observed. Longer follow-up and randomized studies are needed to confirm that these regimens reduce toxicity without compromising efficacy compared with other anti–PD-1 and ipi combinations. Clinical trial information: NCT02089685.

TPS9600 Background: Nivolumab combined with ipilimumab is active in melanoma brain metastases, with intracranial response rates > 55% and durable survival in treatment naïve patients (pts) (Long GV et al Lancet Onc 2018; Tawbi H et al NEJM 2018). We seek to determine if the addition of stereotactic radiotherapy (SRS) results in improved intracranial outcomes. Methods: This is a multisite, open-label, phase 2 trial in systemic treatment-naïve pts with melanoma brain metastases. Pts must have ≥1 asymptomatic brain metastases that are ≥5mm and ≤40mm as per modified RECIST 1.1, on gadolinium-enhanced MRI, and no history of previous treatment with SRS. Eligible pts are randomly assigned to either receive nivolumab plus ipilimumab with SRS or nivolumab plus ipilimumab alone. Nivolumab (1mg/kg) and ipilimumab (3mg/kg) are given every 3 weeks for 4 doses. Following induction, 480mg nivolumab is given every 4 weeks until progression, unacceptable toxicity, or a maximum of 2 years. SRS is administered as single fraction of 16-22Gy, or hypofractionated for larger lesions (24-27Gy in 3 fractions), within 7 days of immunotherapy commencement. Pts will be evaluated for intracranial and extracranial tumour response, and overall response, every 6 weeks to week 24 and 12 weekly thereafter until overall disease progression or death. The primary endpoint is neurologic specific survival (NSS) at 12 months. Secondary endpoints include intracranial response rate, intracranial PFS, overall PFS, overall progression free survival, overall survival, neurocognitive function and incidence of radiation necrosis. 109 patients in each cohort (218 total) will achieve > 80% power at the significance level (alpha) of 0.10 to detect a minimum absolute increase of 9% in the NSS rate at 12 months. Clinical trial information: NCT03340129.

9508 Background: Nivolumab (nivo) and the combination of nivo + ipilimumab (ipi) improve response rates (RR) and progression-free survival (PFS) compared with ipi alone in clinical trials of metastatic melanoma pts, but pts with untreated brain mets were excluded. Brain mets are a major cause of morbidity and mortality in melanoma and their management is critical. We sought to determine the antitumour activity and safety of nivo and nivo+ipi in pts with active melanoma brain mets (NCT02374242). Methods: This open-label, ph II trial enrolled 3 cohorts of pts naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014 - Feb 2017. Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥ wk12. Secondary endpoints were best extracranial response (ECR), best overall response (OR), IC PFS, EC PFS, overall PFS, OS, and safety. Results: A total of 66 pts (med f/u 14 mo) were included in this analysis of total 76 planned; median age 60y, 77% male. For cohorts A, B and C: elevated LDH 48%, 58% and 19%; V600BRAF 44%, 56% and 81%; prior BRAFi 24%, 24%, 75%. Table shows RR, PFS and OS. ICR in cohort A treatment naïve vs prior BRAFi was 53% vs 16%. Treatment-related gd 3/4 toxicity in cohorts A, B and C were 68%, 40% and 56%, respectively. There were no treatment-related deaths. Conclusions:Nivo monotherapy and ipi+nivo and are active in melanoma brain mets. Ipi+nivo had reduced activity in pts who progressed on BRAFi. Pts with symptomatic brain mets, leptomeningeal mets or previous local therapy responded poorly to nivo alone. Clinical trial information: NCT02374242. [Table: see text]

3083 Background: PG545 (pixatimod, pINN) is a novel immunomodulatory agent which stimulates dendritic cells (DC) via TLR9/IL-12 pathway to activate natural killer (NK) cells. It also inhibits tumour-associated macrophages in cancer models. We report on safety, PK, PD, and antitumor activity of PG545 monotherapy. Methods: In this dose escalation (3+3 design) study, eligible pts (ECOG≤1) with advanced solid malignancies who failed standard therapies received PG545 once weekly as a 1-hour i.v. infusion until disease progression or discontinuation due to intolerability. The primary objective was determination of the maximum tolerated dose (MTD). Secondary objectives evaluated safety, antitumor activity based on RECIST (1.1) criteria, PK and PD (plasmacytoid DC & NKp46+NK cells from PBMC, and plasma cytokines/chemokines). Results: The study recruited 23 subjects across four cohorts (25, 50, 100 & 150 mg). Three dose limiting toxicities (DLTs) - hypertension (2), epistaxis (1) - occurred in the 150 mg cohort, which was identified as a non-tolerated dose level. No DLTs occurred in the 100 mg cohort, which was identified as the MTD. Six SAEs were reported to be possibly or likely related to PG545 treatment. No RECIST 1.1 objective responses were reported; best response was prolonged stable disease up to 24 weeks (mCRC), with disease control rate in evaluable subjects of 38% (6/16) at eight weeks. Exposure (AUC0-last) was proportional up to 100mg and mean half-life was 144 hours. At 50 and 100mg dose levels, two subjects in each cohort exhibited up to 4-fold increased numbers of NKp46+NK cells, IFN-α-producing pDCs, and increases (up to 25-fold) in plasma IFN-γ, TNF-α, IP-10 and MCP-1. Conclusions: PG545 is well tolerated up to 100 mg once-weekly via i.v. infusion. Human exposure data at 50mg and 100mg reach exposures consistent with those required for preclinical efficacy. Preliminary PD data support the proposed mechanism of action, which represents a promising approach to improve the efficacy of existing therapies. These data, and the absence of toxicities associated with chemo- or immunotherapies, support the development of PG545 in combination clinical trials. Clinical trial information: NCT02042781.

e19089 Background: Lung cancer is a common malignancy with NSCLC comprising the majority of the cases. Previous studies have demonstrated a role for both the estrogen pathway and mammalian target o...

9045 Background: In a phase 3 trial, nab-paclitaxel significantly improved progression-free survival (PFS) compared with DTIC (4.8 vs 2.5 months; hazard ratio [HR] 0.792; P = 0.044) in chemotherapy...

9046 Background: Vemurafenib (VEM), a BRAF kinase inhibitor, has demonstrated high response rates and improved progression-free and overall survival in pts with BRAFV600mutation–positive metastatic melanoma (mM). We present interim results from predefined subgroups from a large multicenter, open-label safety study of VEM in pts with mM (NCT01307397). Methods: Pts with BRAFV600mutation–positive histologically confirmed mM received VEM (960 mg BID) as first-line therapy or subsequent to previous therapies. Assessments for safety and efficacy were made every 28 days. Results: As of Feb 29, 2012, 2,265 pts have received VEM. Pts had a median age of 54.0 (13-95) yrs and median time since diagnosis of mM of 6.2 (0-351.9) mos. 59% had received prior systemic therapy. Median time of exposure to VEM as of the cut-off date was 3 (0.03-11.24) mos for the overall population and majority of subgroups, and approximately 2.5 mos for pts with ECOG ≥2 and age ≥75 yrs. 1537 (68%) pts were still receiving VEM at the cut-off date. 728 (32%) pts discontinued, most frequently because of PD (538/728 pts; 74%). Adverse events (AEs) were reported for 87% of all patients, with arthralgia (32%) and rash (26%) the most frequent. The incidences of AEs in the subgroups are summarized (Table). Although efficacy analyses are limited by the short duration of follow-up, six-month OS rate was 76% (95% CI 72-79%) and median PFS was 4.1 mos (95% CI 3.9-4.5 mos). Postbaseline tumor assessments were available for 63% and 30% of pts at wk 8 and 16, respectively. At wk 8 CR: 2%, PR: 57%, SD: 30%, PD: 6%. At wk 16 CR: 3%, PR: 46%, SD: 31%, PD: 15%. Conclusions: Although the overall safety profile of VEM in this study was consistent with previous clinical data, interim analyses of subgroups suggest that very elderly pts may be at higher risk of G3 AEs. Clinical trial information: NCT01307397. [Table: see text]

e20025 Background: Peripheral neuropathy (PN) is a common side effect associated with taxane treatment. In a phase III trial, nab-paclitaxel vs dacarbazine demonstrated a significant improvement in progression-free survival (4.8 vs 2.5 months; P = 0.044) and at the interim survival analysis, a trend toward prolonged overall survival (12.8 vs 10.7 months; P = 0.094) for the treatment of chemotherapy-naive patients with metastatic melanoma. Here we report on the PN profile of nab-paclitaxel in this phase III trial. Methods: Pts (median age, 63 years) with chemotherapy-naive stage IV melanoma (M1c stage, 65%; elevated LDH, 28%) and an ECOG performance status 0-1 were randomized to nab-paclitaxel 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n = 264) or dacarbazine 1000 mg/m2on day 1 of each 21-day cycle (n = 265). PN events were defined based on the Standardized MedDRA Query (V 12.1, broad scope). Results: As expected, a higher proportion of pts receiving nab-paclitaxel vs dacarbazine had ≥ 1 treatment-related PN event (68% vs 8%; P < 0.001). Treatment-related grade ≥ 3 PN was more frequent with nab-paclitaxel vs dacarbazine (25% vs 0%; P < 0.001); 2 grade 4 events were reported in the nab-paclitaxel arm. Treatment-related grade ≥ 3 PN was 15% in pts who received up to the median of 3 cycles of nab-paclitaxel. PN led to dose reduction in 13% or discontinuation in 15% of nab-paclitaxel–treated pts. The median time to onset of grade ≥ 3 PN was 101 days (95% CI, 85 - 113). Most early-onset PN events, occurring within the first 3 cycles, were grade 1. Grade ≥ 2 PN events peaked by cycle 4 and subsided by cycle 9. Forty-one of the 64 (64%) pts with a grade ≥ 3 PN event had an improvement of ≥ 1 grade, with a median time to improvement of 28 days (95% CI, 17 - 64), and 33 of 64 (52%) pts had improved to grade 1 or better by a median of 67 days from onset (95% CI, 22- upper limit not estimable); 30 of 64 (47%) pts resumed treatment with nab-paclitaxel. Conclusions: In this phase III trial, grade ≥ 3 PN was the main treatment-related toxicity with nab-paclitaxel as observed in other studies. However, PN was rapidly reversible; a majority of pts had improvement of PN symptoms within 1 month and resumed treatment. Clinical trial information: NCT00864253.

9030 Background: Activating mutations of BRAF V600 can be found in 40%-50% of melanomas and are related to poor prognosis. In a phase 3 trial for the treatment of metastatic melanoma (MM) in chemotherapy-naive patients, nab-paclitaxel (nab-P) vs dacarbazine (DTIC) demonstrated a significant improvement in the primary endpoint of progression-free survival (PFS), assessed by independent radiological review (IRR), and a trend toward prolonged overall survival (OS) at the interim survival analysis. The study also explored the effect of BRAF status on the efficacy parameters. Methods: Chemotherapy-naive patients with stage IV melanoma (M1c stage 65%; elevated LDH 28%) and ECOG performance status 0-1 were randomized to nab-P 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n = 264) or DTIC 1000 mg/m2 on day 1 of each 21-day cycle (n = 265) independent of BRAF status. Prespecified subgroup analyses of final PFS and interim OS in subgroups by BRAF status (V600E mutant, wild-type, or unknown) were performed. Results: BRAF mutation status was balanced between the treatment arms, with 36% and 38% of patients with known BRAF mutation status in the nab-P and DTIC arms, respectively. Patient characteristics were also balanced within BRAF subgroups. As shown in the Table, advantage in the nab-P arm vs DTIC arm was observed for both PFS and interim OS regardless of BRAFmutation status. Poststudy BRAF inhibitor treatment was also balanced. Conclusions: In this phase III trial, treatment effect was independent of BRAF mutation status, benefiting all patients who received nab-P vs DTIC. Therefore nab-P should be considered in the armamentarium for all chemotherapy-naive patients with MM. Clinical trial information: NCT00864253. [Table: see text]

8517 Background: Vemurafenib, a BRAF inhibitor, is associated with improved PFS and OS in patients (pts) with BRAFV600-mutant metastatic melanoma (mM). We present preliminary safety and efficacy findings from a safety study of vemurafenib in pts with unresectable stage IIIC/IV mM with BRAFV600 mutations. Methods: Pts with untreated or previously treated stage IIIC/IV BRAFV600 mutation-positive (cobas 4800 BRAF V600 Mutation Test) melanoma were enrolled. Pts received continuous oral vemurafenib 960 mg bid. Primary study endpoint was safety; efficacy (RECIST V 1.1) was a secondary endpoint. Results: Of 1,964 screened pts between Mar and Sep 2011, 914 (47%) were enrolled and 834 were evaluable for safety. Median age was 53 (21–88 years), 55% males. Median time since first mM diagnosis was 7.6 months (0–18 years). At baseline, 80% of pts had ECOG PS 0–1, 11% ECOG PS 2 (missing 9%); 27% of pts had brain metastases, and 31% had elevated LDH. Most pts had received prior systemic therapy (70%) including ipilimumab (14%), MEK and BRAF inhibitors (2%). At data cut-off (Sep 30, 2011), median treatment duration was 68 days (1–223 days) with 87% of pts still on treatment. Of 834 pts, 553 (66%) to date have reported AEs. Of 553 pts reporting AEs, 88% were related to vemurafenib, 33% Grade 3, and 1.9% Grade 4. The most common (>1%) Grade 3/4 AEs were rash (3.6%), arthralgia (3.1%), and cutaneous squamous cell carcinoma/keratoacanthoma (4.3%). Most common AEs (>10%) of any grade were arthralgia (31%), rash (29%), fatigue (22%), photosensitivity (21%), nausea (15%), and were similar irrespective of brain metastases and ECOG PS. AEs caused treatment interruption in 141 (17%) pts. Of 109 pts who discontinued treatment (13%), main reasons for withdrawal were progressive disease (60%), death (20%), AEs (6%; most commonly arthritis and abdominal pain). Tumor assessments at Week 8 of treatment were available for 302/834 (36%) pts, 61% pts achieved CR or PR, and 29% had SD. Conclusions: In a setting representative of routine clinical practice, vemurafenib is seen to be well tolerated and both safety profile and activity resemble the phase I–III data although this analysis is limited by the study duration.

553 Background: Sensorial peripheral neuropathy (PNP) is a major limitation for pts receiving oxaliplatin-based ctx for CRC. Pregabalin is widely used for treatment of oxaliplatin-induced PNP. We evaluated the efficacy of pregabalin vs. placebo for the prevention of paresthesia from the onset of oxaliplatin-based ctx over each cycle. Methods: Rd, db, placebo-controlled study in adult CRC pts with ECOG 0-2 to undergo a new oxaliplatin/5-FU/FA-based ctx. Pts were excluded if they had neuropathic pain or other of painful paresthesia prior to baseline. Paresthesia, dysesthesia, and pain were rated on a numerical scale (NRS 0-10) every day. Primary endpoint was the time of onset of persistent symptoms (NRS >4). Results: Of the 69 screened pts, 64 were randomized and 61 received study medication (32 pregabalin vs. 29 placebo). Pts were balanced in both arms regarding age, sex, stage, and ctx. There were no differences between both treatment groups for all PNP parameters at any cycle. One pt in both arms developed paresthesia (5.3%) after 9 cycles of ctx, 1 pt had persistent pain (placebo arm). During the follow-up period persistent paresthesic, dysesthesic, and persistent pain developed in 2 vs. 1, 2 vs. 2, and 0 vs. 2 pts, respectively. The study was terminated after a blinded data review found that there were very few events of persistent symptoms, which was then confirmed an interim analysis. Nausea and anorexia were the most frequently reported AE in both groups. Conclusions: The results of this study, which was terminated early at interim analysis, is that too few patients developed persistent symptoms to allow any meaningful treatment difference for prevention of neuropathic pain related to oxaliplatin by pregabalin. There remains an unmet need for oxaliplatin-induced PNP with new trial design issues in this field urgently needed. No significant financial relationships to disclose.

8503 Background: GSK2118436 is a highly potent and selective ATP competitive BRAF inhibitor with > 100-fold selectivity for mutant (mut) BRAF over wild type (wt) in cell lines. It displays dose-dependent inhibition of MEK and ERK phosphorylation in mut BRAF cell lines and tumor regression in xenograft models. Methods: This is a first-time in human, dose escalation study to identify the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in cohorts of 1 to 20 patients (pts). Pts were treated with oral GSK2118436 once to three times daily. Once safety was established in cohorts of 3 to 4 pts, cohorts were expanded to determine the optimal dose based on efficacy and tolerability. Results: 61 pts (52 mut BRAF melanoma) received 12–400 mg daily. Plasma concentrations were dose-proportional and exceeded the minimal therapeutic target at doses > 35 mg BID. 1 pt reported dose-limiting toxicity of syncope (200 mg BID) and resumed reduced dosing. AEs included skin change...

8541 Background: Tasisulam is a novel anticancer agent that induces apoptosis through the intrinsic pathway and has antiangiogenic properties in vitro. The mechanism of action is being further eval...

TPS164 Background: Combretastatin A1 diphosphate (CA1P, OXi4503) is a novel vascular disrupting agent (VDA) that is a reversible tubulin-binding agent with direct cytotoxic activity when bioactivated to its reactive orthoquinone metabolite. Several oxidative enzymes have been shown to catalyze this reaction including myeloperoxidase (MPO), tyrosinase, and hepatic peroxidases. Based on these findings it is expected that OXi4503 should be more active in tissues and tumors containing high levels of these and other oxidative enzymes. Nonclinical blood flow studies in tumor-bearing SCID mice showed that OXi4503 treatment (1 to 50 mg/kg) produced a decrease in tumor-associated blood volume. A dose of 50 mg/kg resulted in approximately 100% reduction in tumor vascular volume, compared with control mice. Tumor growth inhibition has been observed in single- and repeat-dose xenograft studies in multiple tumor models including breast cancer (MDA-MB-231), colorectal, renal (Caki-1), hepatocellular (HEP-G2), melanoma ...