scholarly journals 797 Significant anti-tumor activity of HBI-8000, a class I histone deacetylase inhibitor (HDACi) in combination with nivolumab (NIVO) in anti-PD1 therapy-naïve advanced melanoma (TN-Mel)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A845-A845
Author(s):  
Nikhil Khushalani ◽  
Andrew Brohl ◽  
Joseph Markowitz ◽  
Lyudmila Bazhenova ◽  
Gregory Daniels ◽  
...  
Keyword(s):  
Cytotoxic T Cells ◽  
Performance Status ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Class I ◽  
Institutional Review Boards ◽  
Tumor Infiltration ◽  
Ecog Performance Status ◽  
Phase 1B

BackgroundAnti-PD1 based therapy has been the mainstay of treatment for advanced melanoma for several years. HBI-8000 is a Class I selective oral HDACi with immunomodulatory effects including enhanced cell-mediated toxicity, enhanced tumor infiltration by cytotoxic T-cells and reduced tumor infiltration by T-regulatory cells. In a phase 1b/2 trial in melanoma, kidney cancer and non-small cell lung cancer, the recommended phase 2 dose of HBI-8000 was determined to be 30mg orally twice weekly (BIW) combined with nivolumab administered at the approved dosing schedule (JITC 2018;P346). This report describes the tolerability of this combination in all enrolled melanoma patients, and efficacy in the expansion cohort of anti-PD1 TN-MEL.MethodsPatients with unresectable or advanced melanoma and measurable disease, of ECOG performance status 0-1, and with adequate hematologic and biochemical parameters were enrolled. Treated brain metastases not requiring steroids were permitted. Tumor response was assessed by RECIST v1.1 and iRECIST with staging every 8 weeks; treatment continued for 24 months, disease progression or unacceptable toxicity. Data cut-off was Jan 31, 2020 for the reported analysesResultsForty-nine patients (32 anti-PD1 naïve, 17 with prior anti-PD1 therapy) were treated with HBI-8000 (47 patients at 30 mg BIW; 2 patients at 40mg BIW in Phase 1b) in combination with nivolumab. The median age was 63 years (range 28-84); 57% were male. In the anti-PD1 naïve cohort, most (30/32) had normal LDH. The most common all grade treatment related adverse events (AEs) included fatigue (n=25), diarrhea (n=24), abdominal pain (n=14), and lymphopenia (n=13). Although HBI-8000 related thrombocytopenia (n=25) and neutropenia (n=15) were common, clinically significant bleeding or febrile neutropenia were not observed. The most frequent >/= G3 AEs related to HBI-8000 were hypophosphatemia (n=7), neutropenia (n=4), thrombocytopenia (n=3) and lymphopenia (n=2). Twelve patients discontinued treatment for AEs. Among 31 anti-PD1 naïve patients evaluable for response, there were 23 objective responses (4 CR, 19 PR; ORR 74%), 5 stable disease (disease control rate 90%), and 3 progressive disease. Median time to response was 1.9 months. At a median follow-up for this cohort of 8.9 months (range, 0.9-35.5 months), the median duration of response and median progression-free survival have not been reached.ConclusionsThe combination of HBI-8000 and nivolumab is well tolerated and demonstrates very encouraging efficacy in patients with anti-PD1-naïve advanced melanoma. Follow-up to assess durability of response is ongoing, and further investigation of this promising combination is planned.Trial RegistrationNCT02718066Ethics ApprovalThe study was approved by participating study sites’ Institutional Review Boards and the Sponsor has conducted the trial in full compliance with all GCP and FDA regulations.

Association between complete response and survival in advanced melanoma treated with talimogene laherparepvec (T-VEC) plus ipilimumab (ipi).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10029-10029 ◽  
Author(s):  
Jason Alan Chesney ◽  
Igor Puzanov ◽  
Frances A. Collichio ◽  
Mohammed M. Milhem ◽  
Axel Hauschild ◽  
...  
Keyword(s):  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Tumor Burden ◽  
Advanced Melanoma ◽  
Stage Iiib ◽  
Ecog Performance Status ◽  
Kaplan Meier

10029 Background: This is the first randomized trial testing the addition of an oncolytic virus to an immune checkpoint inhibitor for advanced melanoma. At the 3-year (yr) follow-up, the combination (combo) of T-VEC and ipi demonstrated durable and statistically superior objective response rate (ORR) over ipi alone (36.7% vs. 16.0%; odds ratio, 3.0; 95% Cl, 1.6–6.0; P = 0.002). Complete response (CR) rate was 21.4% with the combo and 6.0% with ipi. Median overall survival (OS) was not reached in either arm. In this post hoc analysis, we utilized the 3-yr landmark data to explore the relationship between CR and OS in the combo arm. Methods: Pts with unresectable, stage IIIB-IV melanoma were randomized 1:1 to receive combo or ipi alone. T-VEC was administered intratumorally on day 1 of week (wk) 1 at 106 plaque-forming units (PFU)/mL followed by subsequent doses at 108 PFU/mL on day 1 of wk 4, and every 2 wks thereafter. Ipi (3 mg/kg) was given every 3 wks starting on day 1 of wk 6 for up to 4 doses. Response was assessed by investigators per immune-related response criteria every 12 wks until disease progression. The primary endpoint was ORR; key secondary endpoints were OS, progression-free survival, and safety. Results: 198 pts were randomized (98 to combo; 100 to ipi). As of February 25, 2019, the median follow-up time was 40.0 mos (range: 0.2–63.7) for the combo arm. Among 98 pts who received combo, 21 (21.4%) had a best overall response of CR including 8 who converted from an initial partial response (PR), 15 (15.3%) had PR, 19 (19.4%) had stable disease, 30 (30.6%) had progressive disease, and 13 (13.2%) were unevaluable. Of 21 pts achieving CR, 17 (81%) had ECOG status of 0, 16 (76.2%) had stage IIIB-IVM1a disease, and 16 (76.2%) had no visceral metastases. Median duration of CR was not reached (range: 5.4[+]–58.2[+] mos); 19 of 21 CRs lasted more than 6 months. The baseline tumor burden was lower in pts with CR than in those with non-CR. Median OS was not reached in pts with CR (range: 25.1[+]–63.7[+] mos) and was 47.6 mos (range: 0.2[+]– 63.7[+] mos) in pts with non-CR (Log-rank P = 0.0005). The Kaplan–Meier estimated 3-year OS rate was 100.0% for patients with CR and 52.3% for those with non-CR. Conclusions: CR rate was higher with T-VEC plus ipi than with ipi alone in pts with advanced melanoma (21.4% vs. 6.0%). In the combo arm, CR was associated with prolonged OS, and pts with CR tended to have better ECOG performance status, earlier-stage disease, and lower baseline tumor burden, as compared with those with non-CR. Clinical trial information: NCT01740297.

First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9000-9000
Author(s):  
Martin Reck ◽  
Tudor-Eliade Ciuleanu ◽  
Manuel Cobo ◽  
Michael Schenker ◽  
Bogdan Zurawski ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Performance Status ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Expression Level ◽  
First Line ◽  
Ecog Performance Status ◽  
Grade 3

9000 Background: In the randomized phase 3 CheckMate 9LA trial (NCT03215706), first-line NIVO + IPI combined with 2 cycles of chemo significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs chemo alone (4 cycles). Clinical benefit was observed regardless of programmed death ligand 1 (PD-L1) expression level and histology. Here we report data with 2 years’ minimum follow-up from this study. Methods: Adult patients (pts) with stage IV / recurrent NSCLC, ECOG performance status ≤ 1, and no known sensitizing EGFR/ALK alterations were stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous) and were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles; n = 361) or chemo alone (4 cycles; n = 358). Pts with non-squamous NSCLC in the chemo-alone arm could receive pemetrexed maintenance. The primary endpoint was OS. Secondary endpoints included PFS and ORR by blinded independent central review, and efficacy by different PD-L1 levels. Safety was exploratory. Results: At a minimum follow-up of 24.4 months for OS (database lock: Feb 18, 2021), pts treated with NIVO + IPI + chemo continued to derive OS benefit vs chemo, with a median OS of 15.8 months vs 11.0 months, respectively (HR, 0.72 [95% CI, 0.61–0.86]); 2-year OS rates were 38% vs 26%. Median PFS with NIVO + IPI + chemo vs chemo was 6.7 months vs 5.3 months (HR, 0.67 [95% CI, 0.56–0.79]); 8% and 37% of pts who had disease progression received subsequent immunotherapy, respectively. ORR was 38% with NIVO + IPI + chemo vs 25% with chemo. Similar clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across the majority of subgroups, including by PD-L1 expression level (Table) or histology. Any grade and grade 3–4 treatment-related adverse events were reported in 92% and 48% of pts in the NIVO + IPI + chemo arm vs 88% and 38% in the chemo arm, respectively. Conclusion: With 2 years’ minimum follow-up, first-line NIVO + IPI + chemo demonstrated durable survival and benefit versus chemo in pts with advanced NSCLC; no new safety signals were identified. Clinical trial information: NCT03215706. [Table: see text]

Randomized phase II trial of carboplatin combined with weekly paclitaxel (CP) and docetaxel alone (D) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): NJLCG 0801.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7565-7565
Author(s):  
Shunichi Sugawara ◽  
Makoto Maemondo ◽  
Toshiyuki Harada ◽  
Akira Inoue ◽  
Nobumichi Matsubara ◽  
...  
Keyword(s):  
Performance Status ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Toxicity Profile ◽  
Ecog Performance Status ◽  
Loss To Follow Up ◽  
Lethal Arrhythmia ◽  
Grade 3

7565 Background: Standard first-line chemotherapy for elderly NSCLC pts has been considered as a monotherapy with vinorelbine or gemcitabine globally. However, we have demonstrated the high efficacy of CP for elderly pts in our previous trial (Ann Oncol 2010). Meanwhile, D has been considered as an alternative option for this population in Japan according to the result of WJTOG9904 (JCO 2006). Thus we compared the two regimens to select the proper candidate for future phase III trial. Methods: Eligible pts were aged 70 years or older with newly diagnosed stage IIIB/IV NSCLC; ECOG performance status 0-1; adequate organ function; written informed consent. Pts were randomized to receive carboplatin (AUC 6) on day 1 and paclitaxel (70mg/m2 on day 1, 8, and 15) every 4 weeks or D (60mg/m2 on day 1) every 3 weeks. The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival, and toxicity profile. Assuming that ORR of 40% would be potential usefulness while ORR of 20% would be the lower limit of interest, 40 pts in each arm were required if expect 10% loss to follow up. Results: Between July 2006 and September 2010, 84 pts were enrolled and 41 pts in CP arm and 42 pts in D arm were eligible (median age, 76 years; 75% male; 72% stage IV). Median treatment cycle was 4 in each arm (CP, range 1-6; D, range 1-8). ORRs were 51% (95%CI: 36-66%) and 26% (95%CI: 12-39%) in the CP and D arm, respectively. With a median follow-up of 18.4 months, median PFS were 6.5 and 3.9 months in the CP and D arm, respectively (Logrank, P=0.0027). Grade 3 or severer toxicities were as follows: neutropenia (CP, 56% and D, 79%), anemia (CP, 15% and D, 7%), thrombocytopenia (CP, 10% and D, 0%), infection (CP, 20% and D, 25%). One treatment-related death due to neutropenia, pneumonia, and lethal arrhythmia occurred in D arm but none in CP arm. Conclusions: The platinum doublet CP achieved higher activity with an acceptable toxicity profile for elderly pts with advanced NSCLC compared to monotherapy with D. The superiority of CP to the monotherapy in this trial is consistent with results of recent IFCT-0501 trial (Lancet 2011).

An observational study of patients with advanced melanoma receiving pembrolizumab in a real-world U.S. community oncology practice.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21015-e21015
Author(s):  
Charles Lance Cowey ◽  
Frank Xiaoqing Liu ◽  
Jenny Black-Shinn ◽  
Kendall Lee Stevinson ◽  
Marley Boyd ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastases ◽  
Real World ◽  
Performance Status ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Ecog Performance Status ◽  
Study Results ◽  
Line Of Therapy ◽  
Oncology Practice

e21015 Background: PD-1 monoclonal antibodies are promising immunotherapies approved for treatment of patients (pts) with advanced melanoma. As the first US FDA approved PD-1 antibody, pembrolizumab (pembro) has demonstrated efficacy and safety in clinical trial settings. However, patterns of real world utilization and pt outcomes associated with pembro are limited. Methods: Adult pts with advanced melanoma who initiated pembro between 9/1/ 2014-3/31/2016 were identified retrospectively fromelectronic health records (EHR) of McKesson Specialty Health and followed through 9/ 30/2016. Pts in clinical trials were excluded. Demographic, disease, treatment characteristics and reasons for treatment discontinuation of pembro were abstracted from structured data elements of the EHR with further supplementation of unstructured data within the patient chart (progress notes, radiology scan reports). Overall survival (OS) and physician-reported progression free survival (PFS) from pembro initiation were analyzed using Kaplan Meier analysis. Results: 182 pts, with a median follow-up of 9.9 mos (range = 0.0-25.0), were included. Median age at pembro initiation was 66.0 yrs; 30.8% had an elevated lactate dehydrogenase (LDH); 23.6% had brain metastases and 65.4% had an ECOG performance status of 0 or 1. The most common reason for pembro discontinuation was progression (45.5%) followed by treatment-related toxicity (24.4%). In the overall population, median PFS from pembro initiation was 4.2 mos (95% CI = 3.2-5.3). Median OS was 19.4 mos (14.0-NR) with 12 and 24-month survival probabilities of 61.4% (95% CI = 53.4-68.5) and 43.9% (95% CI = 31.1-55.9). In multivariable analyses, characteristics predictive of worse survival included receipt of pembro at a later line of therapy (HR = 3.36, p = 0.0013 for 3L+), presence of brain metastases (HR = 2.67, p = 0.0007) and elevated LDH (HR = 4.10, p < 0.0001). Conclusions: The study results are consistent with those from pembro clinical trials (KeyNote001) and are in support of the effectiveness of pembro in real world treatment of advanced melanoma. Presence of brain metastases, elevated LDH, and use of pembro 3L+ were associated with worse survival outcome.

Efficacy and safety of bevacizumab (BEV)-based combination regimens in patients with metastatic colorectal cancer (mCRC): Randomized phase II study of BEV + FOLFIRI versus BEV + XELIRI (FNCLCC ACCORD 13/0503 study)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4086-4086
Author(s):  
M. Ducreux ◽  
A. Adenis ◽  
J. Mendiboure ◽  
E. François ◽  
E. Boucher ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
Ecog Performance Status ◽  
Free Survival ◽  
First Line Therapy ◽  
Number Of Cycles ◽  
Combination Regimens

4086 Background: The combination of BEV and chemotherapy is highly effective in patients with mCRC and improves response rate, progression-free survival and overall survival compared with chemotherapy alone. This randomized non-comparative phase II trial evaluated the efficacy and safety of BEV in combination with either XELIRI or FOLFIRI as first-line therapy for mCRC. Methods: Patients were eligible for inclusion in this study if they had histologically proven measurable mCRC, were aged 18–75 years, and had an ECOG performance status (PS) of 0–2. Patients were treated with 8 cycles of XELIRI (irinotecan 200 mg/m2 on Day 1 and capecitabine 1000 mg/m2 bid on Days 1–14) + BEV 7.5 mg/kg on Day 1, every 3 weeks or 12 cycles of FOLFIRI (irinotecan 200 mg/m2 on Day 1 + 5-fluorouracil (5-FU) 400 mg/m2 + folinic acid 400 mg/m2 on day 1 followed by 5-FU 2400 mg/m2 via 46-h infusion) + BEV 5 mg/kg on day 1, every 2 weeks. BEV was continued to disease progression. Patients aged ≥65 years received a lower daily dose of capecitabine (800 mg/m2 bid). The primary endpoint was crude progression-free survival (PFS) at 6 months. Results: In total, 145 patients were entered in the study between March 2006 and January 2008; 72 patients received BEV + XELIRI and 73 patients received BEV + FOLFIRI (male 64%/48%; median age 61/61 years; 35/36% aged >65 years). Preliminary results from the first 6 months of follow-up are reported here. A total of 491/783 cycles was administered, 63%/67% receiving at least the initially planned number of cycles (8 cycles for BEV + XELIRI and 12 for BEV + FOLFIRI). Main results are given in the table . Conclusions: This randomized non-comparative study has shown that BEV + XELIRI and BEV + FOLFIRI are similarly effective treatments for patients with mCRC, with manageable toxicity profiles. Results with updated follow-up will be presented at the Meeting. [Table: see text] [Table: see text]

Real-world outcomes with immuno-oncology (IO) therapies: A prospective, observational cohort study in patients (pts) with advanced melanoma (OPTIMIzE).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14144-e14144
Author(s):  
John M. Kirkwood ◽  
Lisa A. Kottschade ◽  
Robert R. McWilliams ◽  
Nikhil I. Khushalani ◽  
Sekwon Jang ◽  
...  
Keyword(s):  
Real World ◽  
Cox Model ◽  
Performance Status ◽  
Objective Response ◽  
Advanced Melanoma ◽  
Ecog Performance Status ◽  
Treatment Naïve ◽  
The Difference ◽  
Grade 3

e14144 Background: There is little real-world evidence evaluating treatment patterns and outcomes with IO therapies for pts with advanced melanoma (aMEL). We present results from the OPTIMIzE (NCT02780089) study in pts with aMEL receiving IO therapies. Methods: OPTIMIzE is a US-based multisite (150 sites), community-based study of adult pts with aMEL. Pts receiving first-line (1L) nivolumab (NIVO)+ipilimumab (IPI), anti-PD-1 (NIVO/pembrolizumab), or IPI between 2011-2018 with a minimum 1 y of follow-up were included. Baseline characteristics, objective response rate (ORR), overall survival (OS), treatment-related adverse events (TRAEs), and quality of life (QoL) were analyzed. QoL assessments included the Functional Assessment of Cancer Therapy–Melanoma (FACT-M), EQ-5D index, and visual analog scale (VAS). Results: Cohort size: 81 NIVO+IPI, 147 anti-PD-1, and 16 IPI (IPI arm not included in the analysis). Overall, mean age was 64.5 y; 42% had BRAF mutation. Mean follow-up was 14.1 mo. Pts in the NIVO+IPI group were younger, had better ECOG performance status, and a higher likelihood of M1c disease and elevated LDH vs the anti-PD-1 group. ORR was higher for pts treated with NIVO+IPI vs anti-PD-1 (48% vs 33%, P= 0.08). Unadjusted 1-y OS was 78.4% for NIVO+IPI and 73.1% for anti-PD-1. In multivariate Cox model analysis, the hazard ratio for OS for NIVO+IPI vs anti-PD-1 was 0.78 (95% CI, 0.46–1.33; P= 0.36). Grade 3/4 TRAEs occurred in 53% and 22% of pts in the NIVO+IPI and anti-PD-1 groups, respectively ( P˂0.001). QoL changes from baseline were clinically meaningful for EQ-5D VAS and FACT-M in the NIVO+IPI group at 12 mo (Table). After adjusting for baseline covariates, the difference at 12 mo between NIVO+IPI vs anti-PD-1 was 6.7 ( P= 0.04) for EQ-5D VAS and 8.8 ( P= 0.02) for FACT-M. Conclusions: Safety and efficacy outcomes from this prospective real-world study are consistent with those reported in prior clinical trials in treatment-naive aMEL pts. No clinically meaningful deterioration in QoL measures was observed in either group. Clinical trial information: NCT02780089. [Table: see text]

Results of a phase II study to evaluate the safety and efficacy of RX-0201 in combination with everolimus in subjects with metastatic renal cell carcinoma (mRCC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 646-646 ◽  
Author(s):  
Neeraj Agarwal ◽  
Sumanta K. Pal ◽  
Richard C. Lauer ◽  
Gurkamal S. Chatta ◽  
Sanjay Goel ◽  
...  
Keyword(s):  
Phase 1 ◽  
Performance Status ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Ecog Performance Status ◽  
Safety And Efficacy ◽  
Prior Therapy ◽  
Phase 1B ◽  
Vegfr Inhibitor

646 Background: RX-0201 is a novel 20-mer oligonucleotide that binds to mRNA coding for AKT-1, preventing AKT-1 expression and limiting the amount of downstream p-AKT. In vitro RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth. RX-0201, in combination with everolimus, to treat mRCC was evaluated in a Phase 1b/2 clinical study. Methods: This Phase 1b/2 study (2‐stage design, NCT02089334 ) evaluated the efficacy and safety of RX‐0201 in combination with everolimus in eligible subjects with mRCC. Eligible subjects must have had confirmed histologic or cytologic evidence of renal cancer with a clear cell component, measurable disease as defined by RECIST, received at least 1 course of therapy with a VEGFR inhibitor and progressed within 6 months of planned first dose of on study treatment. In Phase 1 subjects were enrolled at increasing doses of RX-0201 (delivered via continuous IV for 14 days) in combination with 10 mg/day everolimus in a modified 3+3 design. The target dose of RX-0201 identified in Phase 1, 250 mg/m2/day, was further evaluated in Phase 2. Primary objectives included the safety and efficacy at the recommended Phase 2 dose. The Phase 2 primary endpoint was progression free survival (PFS) benefit for at least 4.5 months. Results: Eleven subjects (7 males, 4 females) with mRCC were treated with RX-0201 (250 mg/m2/day) + everolimus (10 mg/ day) in Phase 2. The median age was 63 years, ECOG performance status at screening was 0 to 1, and 55% received ≥ 3 prior therapies. The median PFS in evaluable subjects was 4.9 months. Four subjects had stable disease after 6 months of treatment. The most frequent related adverse events ( > 15%) were G1/2 epistaxis, G3 fatigue, G1/2 nausea and G1 vomiting. Conclusions: In this mRCC population with extensive prior therapy, RX‐0201 in combination with everolimus was safe, well-tolerated, and showed promising efficacy. The results also support the therapeutic significance of the AKT-1/mTOR pathway in mRCC. Clinical trial information: NCT02089334.

Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9501-9501 ◽  
Author(s):  
Martin Reck ◽  
Tudor-Eliade Ciuleanu ◽  
Manuel Cobo Dols ◽  
Michael Schenker ◽  
Bogdan Zurawski ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Interim Analysis ◽  
Advanced Nsclc ◽  
Performance Status ◽  
Randomized Study ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Ecog Performance Status

9501 Background: NIVO + IPI was shown to improve overall survival (OS) and durability of response vs chemo in 1L advanced NSCLC in CheckMate 227 Part 1, regardless of PD-L1 expression. We hypothesized that a limited course of chemo combined with NIVO + IPI could provide rapid disease control while building on the durable OS benefit seen with dual PD-1 and CTLA-4 inhibition. CheckMate 9LA (NCT03215706) is a phase 3 randomized study evaluating NIVO + IPI + 2 cycles chemo vs chemo in 1L stage IV/recurrent NSCLC. Methods: Adults with tx-naive, histologically confirmed stage IV/recurrent NSCLC, ECOG performance status 0–1, and no known sensitizing EGFR/ALK alterations were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles) (n = 361) or chemo (4 cycles) alone (n = 358), stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous). Chemo was based on histology. Pts with non-squamous NSCLC in the chemo-only arm could receive optional pemetrexed maintenance. Pts were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 y. The primary endpoint was OS; the interim analysis using Lan–DeMets alpha spending function with O’Brien–Fleming boundary was planned at ~80% information fraction (ie, after observing ~322 total events). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability. Results: Baseline characteristics were balanced across arms. At a preplanned interim analysis (minimum follow-up 8.1 mo), OS was significantly prolonged with NIVO + IPI + chemo vs chemo (HR 0.69, 96.71% CI: 0.55–0.87; P = 0.0006); statistically significant improvements in PFS and ORR were seen. With longer follow-up (minimum 12.7 mo), NIVO + IPI + chemo vs chemo continued to provide longer OS; median 15.6 vs 10.9 mo (HR 0.66, 95% CI: 0.55–0.80); 1-y OS rates were 63 vs 47%. Clinical benefit was consistent across all efficacy measures in key subgroups including by PD-L1 and histology. Grade 3–4 tx-related adverse events were reported in 47 vs 38% of pts in the NIVO + IPI + chemo vs chemo arms, respectively. Conclusions: CheckMate 9LA met its primary endpoint: a statistically significant improvement in OS was observed with NIVO + NSCLC-optimized IPI + a limited course of chemo vs chemo (4 cycles) in 1L advanced NSCLC. No new safety signals were reported. Clinical trial information: NCT03215706 .

A phase Ib/II study evaluating the efficacy of doxorubicin (D) with or without a human anti-PDGFRα monoclonal antibody olaratumab (IMC-3G3) in the treatment of advanced soft tissue sarcoma (STS).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS10099-TPS10099
Author(s):  
William D. Tap ◽  
Brian Andrew Van Tine ◽  
Anthony D. Elias ◽  
Michael B. Livingston ◽  
Mark Agulnik ◽  
...  
Keyword(s):  
Performance Status ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Dose Schedule ◽  
The United States ◽  
Phase 2 ◽  
Ecog Performance Status ◽  
Develop Disease Progression ◽  
Phase 1B ◽  
Randomized Methods

TPS10099 Background: PDGFRα is a receptor commonly overexpressed in STS. Olaratumab is a fully human IgG1 MAb which specifically binds to human PDGFRα and blocks PDGFR-mediated signaling pathways. Olaratumab demonstrated significant tumor inhibition as a monotherapy and in combination with standard chemotherapy in preclinical human sarcoma xenograft models. A Phase 1b/2 clinical trial for patients with advanced or metastatic STS is currently enrolling patients in 9 sites across the United States; approximately 45 patients have been randomized. Methods: In Phase 1b, patients received olaratumab (15 mg/kg) via intravenous infusion on Days 1 and 8 of each 21-day cycle and D (75 mg/m²) 1 hour after olaratumab on Day 1. Phase 1b was completed without encountering dose-limiting toxicities; enrollment into Phase 2 has begun. The primary endpoint of the Phase 2 portion is to compare progression-free survival in patients with advanced STS when treated with D plus olaratumab versus D alone. Planned enrollment goal for Phase 2 is 130 patients. Patients are required to be ≥ 18 years old with ECOG 0-2, have appropriate organ function and histologically confirmed, measurable, and advanced STS. There is no restriction on the number of prior therapies. Patients are randomized 1:1 to either D plus olaratumab (Arm A) at same dose/schedule as in Phase 1b or D alone (Arm B). All patients can receive dexrazoxane. Upon completion of 8 cycles, patients in Arm A continue with olaratumab monotherapy. Patients in Arm B who develop disease progression during or after treatment can subsequently receive olaratumab monotherapy. Patients are stratified to treatment arms according to PDGFRα expression (positive vs. negative), number of previous lines of treatment, sarcoma subtype, and ECOG performance status. Response assessment occurs every 6 weeks. Exploratory analyses include biomarkers of olaratumab pharmacodynamic activity including PDGF ligands, PDGFR downstream molecules, VEGF, and changes in vascularity of tumor specimens.

Safety evaluation of combined PD-1+CTLA4 inhibition concurrently to chemoradiotherapy (CRT) in localized muscle invasive bladder carcinoma (MIBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4531-4531
Author(s):  
Ben-Max de Ruiter ◽  
Jons Wouter van Hattum ◽  
Theo Maria De Reijke ◽  
Jorg Reinier Oddens ◽  
Maarten C.C.M. Hulshof ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Performance Status ◽  
Safety Evaluation ◽  
Clinical Trial Data ◽  
Ecog Performance Status ◽  
Grade 5 ◽  
Phase 1B ◽  
Muscle Invasive ◽  
Dose Reductions

4531 Background: Neoadjuvant nivolumab (nivo) + ipilimumab (ipi) prior to radical cystectomy showed efficacy in localized MIBC. The safety of PD-1 and PDL-1+CTLA4 inhibition concurrent with CRT in localized MIBC has not been assessed. We present the first clinical trial data on concurrent 3 doses of q4w nivo 480mg (cohort1) and concurrent 4 doses of q3w nivo 3mg/kg + ipi 1kg/mg (nivo3+ipi1, cohort2) in combination with Mitomycin C/Capecitabin (MMC/Cape) CRT. Methods: We report the first 2 cohorts of a phase 1b, EC approved, study with nivo only or nivo3+ipi1 added to MMC/Cape CRT. CRT consists of MMC i.v. on day 1 with Cape 750mg/m2 on days of radiotherapy. Radiotherapy schedule comprises a 20x2Gy whole bladder irradiation with a simultaneous tumorboost of 20x0.75Gy. Patients with MIBC, T2-4N0-1, ECOG performance status <2 were included. A dose escalation scheme, with a staggered enrollment is used. The first 10 patients received nivo 480mg on week 1, 5, 9. Cohort2 of 10 patients received nivo3+ ipi1 at week 1, 4, 7 and 10. Relevant severe Adverse Events (AEs) were registered as Dose Limiting Toxicity (DLT) when they occurred within 6 weeks after start of treatment. Clinical efficacy is evaluated by cystoscopy and CT at week 12 and 24. Results: Both cohorts enrolled 10 patients. Median age was 68 [IQR 61-75] and 70 [IQR 66-75] years in cohort1 and 2, respectively. In cohort1 no patients experienced DLT. No dose reductions were applied. In cohort2, 2 patients experienced DLT, 1 trombocytopenia (grade 4) and 1 asystole (grade 5). 50% of patients did not receive all 4 q3w nivo3+ipi1 infusions, due to AEs. Table 1 reports an overview of AEs. In cohort2 6 SAE’s occurred in 3 patients. Median follow up is 71 [IQR 59-86] and 30 weeks [IQR 12-45] in cohort1 and 2, respectively. 1year OS and DFS is 100% in cohort1. Conclusions: Concurrent 3 doses nivo 480mg q4w added to MMC/Cape based CRT is feasible with a favorable toxicity profile and shows promising efficacy in MIBC patients. An escalated regimen with 4 doses nivo 3mg/kg + ipi 1mg/kg q3w concurrent to CRT shows acceptable toxicity. Cohort3 with ipi 3mg/kg and nivo 1mg/kg is enrolling. Clinical trial information: NCT03844256. [Table: see text]

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