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.

A phase II evaluation of the combination of paclitaxel protein-bound and carboplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7127-7127 ◽  
Author(s):  
J. P. Allerton ◽  
C. T. Hagenstad ◽  
R. T. Webb ◽  
G. B. Smith ◽  
R. Birch ◽  
...  
Keyword(s):  
Response Rate ◽  
Performance Status ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Complete Response ◽  
Stage Iiib ◽  
Ecog Performance Status ◽  
Kaplan Meier ◽  
Experienced Grade

7127 Background: Abraxane (A) is a cremophor free, albumin-bound nanoparticle of paclitaxel (P) approved for the treatment of metastatic breast cancer. Belani et al. (JCO 21: 2933–2939, 2003) reported that P 100 mg/m2 days 1, 8 and 15 q 28 days with C AUC 6 on day 1 led to a 32% response rate in 132 patients (pts) with NSCLC. The median time to progression (TTP) was 35 weeks (wks) for stage IIIB and 29 wks for stage IV. Methods: This study was designed to determine if substituting A for P at an identical dose would lead to an improved response rate, TTP or decreased toxicity. Results: Fifty-six pts with stage IIIB/IV NSCLC previously untreated with chemotherapy were enrolled. The median age was 66 (range 37 - 83); 37 were male and median ECOG performance status was 1 (range 0–2). Thirteen pts were stage IIIB. Metastases included bone (17), liver (7), brain (2) and lymph nodes (16). Currently a total of 239 cycles of therapy have been administered with a median of 4 (range 1–8) cycles per pt. In 194 (81%) full dose A was administered on days 1, 8 and 15. The table below shows toxicities compared to P: Seven pts (13%) experienced grade (G) 1 neuropathy and 3 pts (5%) experienced G 2 neuropathy. Five pts were inevaluable for response due to removal from study after <2 cycles of treatment (2 died from progressive disease, 2 because of toxicity - thrombocytopenia and neutropenia - and 1 refused). Of 51 evaluable pts 1 (2%) had a complete response and 23 patients (45%) achieved a partial response. Four of 10 evaluable stage IIIB pts obtained a PR. Twenty-one pts were stable for at least 12 weeks of whom twenty remain stable at 12–29 weeks and one progressed at 23 weeks. A total of 13 pts have progressed and 3 pts have died. The Kaplan-Meier estimate of median TTP is 23 wks and maximum follow up is 34 wks. Conclusions: We conclude that combining A and C is tolerable and active in the treatment of newly-diagnosed NSCLC and antitumor activity compares favorably to that of P/C. Further studies are warranted in this population. [Table: see text] [Table: see text]

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]

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): Interim results of DESTINY-Lung01.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9504-9504 ◽  
Author(s):  
Egbert F. Smit ◽  
Kazuhiko Nakagawa ◽  
Misako Nagasaka ◽  
Enriqueta Felip ◽  
Yasushi Goto ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Clinical Activity ◽  
Antibody Drug Conjugate ◽  
Ecog Performance Status ◽  
Platinum Based Chemotherapy ◽  
Grade 3

9504 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. In a phase I trial, patients (pts) with HER2-mutated NSCLC who received T-DXd had a confirmed objective response rate (ORR) of 72.7% (8/11) (Tsurutani et al, WCLC 2018). DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase II study of T-DXd in pts with non-squamous NSCLC overexpressing HER2 or containing a HER2-activating mutation. We report data for the cohort with HER2 mutations after a median follow-up of 8.0 mo (range, 1.4-14.2 mo). Methods: Pts were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was confirmed ORR (complete response [CR] + partial response [PR]) by ICR. Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety. Results: At data cutoff (25 Nov 2019), 42 pts (64.3% female) had received T-DXd. Median age was 63.0 years (range, 34-83 years; < 65 y, 59.5%); 45.2% had central nervous system metastases; ECOG performance status was 0 in 23.8% of pts and 1 in 76.2%. HER2 mutations were predominantly in the kinase domain (90.5%). Most pts (90.5%) had prior platinum-based chemotherapy and 54.8% had anti–PD-1 or –PD-L1 treatment; median number of prior treatment lines was 2 (range, 1-6). Median treatment duration was 7.75 mo (range, 0.7-14.3 mo); 45.2% of pts remained on treatment. Confirmed ORR by ICR among the 42 pts was 61.9% (95% CI, 45.6%-76.4%); median DOR was not reached at data cutoff; 16 of 26 responders remained on treatment at data cutoff; DCR was 90.5% (95% CI, 77.4%-97.3%); estimated median PFS was 14.0 mo (95% CI, 6.4-14.0 mo). All pts (42/42) had treatment-emergent adverse events (TEAEs); 64.3% were grade ≥ 3 (52.4% drug-related), including decreased neutrophil count (26.2%) and anemia (16.7%). There were 5 cases (11.9%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (all grade 2, no grade ≥ 3) and 1 case of grade 1 ILD is pending adjudication. TEAEs led to dose interruption in 25 pts (59.5%), dose reduction in 16 pts (38.1%), and treatment discontinuation in 10 pts (23.8%). Conclusions: T-DXd demonstrated promising clinical activity with high ORR and durable responses in pts with HER2-mutated NSCLC. The safety profile was generally consistent with previously reported studies. Clinical trial information: NCT03505710 .

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]

Subsequent anticancer medication following first-line lenvatinib: A posthoc responder analysis from the phase 3 REFLECT study in unresectable hepatocellular carcinoma.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 371-371 ◽  
Author(s):  
Angel Alsina ◽  
Masatoshi Kudo ◽  
Arndt Vogel ◽  
Ann-Lii Cheng ◽  
Won Young Tak ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Performance Status ◽  
Objective Response ◽  
Liver Function Tests ◽  
First Line ◽  
Ecog Performance Status ◽  
Responder Analysis ◽  
Unresectable Hepatocellular Carcinoma ◽  
Kaplan Meier

371 Background: Lenvatinib (LEN) was shown to be noninferior to sorafenib (SOR) for overall survival (OS) in REFLECT (median OS [mOS], 13.6 vs 12.3 months [mo]; HR 0.92; 95% CI 0.79–1.06). LEN was superior vs SOR for secondary endpoints including objective response rate (ORR) per mRECIST: 24.1% vs 9.2% by investigator and 40.6% vs 12.4% by independent review (Kudo M et al. Lancet 2018). We report a posthoc responder analysis of patients (pts) who received first-line LEN in REFLECT and subsequent anticancer medication during survival follow up. Methods: In REFLECT, pts with unresectable hepatocellular carcinoma were randomized 1:1 to receive first-line LEN or SOR. Objective response was defined as complete or partial response by mRECIST per investigator. Pts with disease progression and who discontinued treatment were followed for survival every 12 weeks; subsequent anticancer medication during survival follow up were recorded until time of death. Data cutoff: Nov 13, 2016. mOS was calculated using Kaplan-Meier estimates with 2-sided 95% CIs. Results: In REFLECT, one third of the overall study population (156/478 pts randomized to LEN and 184/476 to SOR) received subsequent anticancer medication, most commonly SOR (25% in LEN arm). ECOG performance status and laboratory assessments, including liver function tests, were comparable between arms prior to subsequent treatments. Among these pts, mOS was 21 vs 17 mo and ORR was 27.6% vs 8.7% for LEN vs SOR arms, respectively. In a subset analysis of LEN responders who received any subsequent anticancer medication (n = 43), mOS was 26 mo (95% CI 18.5–34.6). For SOR responders who received any subsequent anticancer medication (n = 16), mOS was 22 mo (95% CI, 14.6–NE). For LEN responders who subsequently received SOR (n = 35), mOS was 26 mo (95% CI 18.2–34.6). Conclusions: In REFLECT, one third of pts randomized to first-line LEN received subsequent anticancer medication, including SOR, with a mOS of 21 mo. In this exploratory, posthoc analysis of pts who responded to LEN and received any subsequent anticancer medication or SOR, mOS was 26 mo. Clinical trial information: NCT01761266.

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 .

scholarly journals 301 Association of response with survival outcomes with atezolizumab in combination with vemurafenib and cobimetinib in the phase 3 IMspire150 study

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A328-A328
Author(s):  
Paolo Ascierto ◽  
Karl Lewis ◽  
Caroline Robert ◽  
Daniil Stroyakovskiy ◽  
Helen Gogas ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Tumor Burden ◽  
Exploratory Analysis ◽  
Survival Outcomes ◽  
Phase 3 ◽  
Link Type ◽  
The Impact

BackgroundThe phase 3 IMspire150 study (NCT02908672) demonstrated improved progression-free survival (PFS) with first-line atezolizumab (A) vs placebo (P) combined with vemurafenib (V) + cobimetinib (C) in patients with BRAFV600 mutation–positive advanced melanoma (15.1 vs 10.6 months; hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.63–0.97; P=0.0249). Objective response has been associated with increased survival with chemotherapy and targeted therapies, but it is unclear whether the association holds for immunotherapy. In this exploratory analysis, we evaluated the impact of response on survival outcomes in patients treated with A+V+C or P+V+C in the IMspire150 study.Methods514 patients were randomized 1:1 to A+V+C (n=256) or P+V+C (n=258). Patients received V+C in cycle 1; A or P was added on days 1+15 from cycle 2 onward. The primary endpoints for this exploratory analysis were PFS and overall survival (OS), estimated using the Kaplan-Meier method. Outcomes were analyzed by investigator-assessed best overall response (BOR) per RECIST v1.1 (complete response [CR] vs partial response [PR] vs stable disease [SD]).ResultsMedian follow-up was 18.9 mo. In the A+V+C arm, BOR was CR (n=41), PR (n=129), and SD (n=58); in the P+V+C arm, BOR was CR (n=46), PR (n=122), and SD (n=58). An imbalance in baseline prognostic factors (eg, lactate dehydrogenase, tumor burden measures) was noted across response categories in both treatment arms, with favorable factors more prevalent in patients with CR and unfavorable factors more prevalent in patients with PR/SD. Improvement in PFS and OS was observed with A+V+C vs P+V+C in patients with PR, with 2-year PFS rates of 42.1% vs 24.6% and 2-year OS rates of 69.1% vs 56.1% with A+V+C vs P+V+C (table 1). In patients with CR, median PFS and OS were not yet reached in either arm, with 2-year PFS rates of 64.6% vs 59.8% and 2-year OS rates of 82.6% vs 82.8% with A+V+C vs P+V+C. PFS and OS outcomes were poor in both treatment arms in patients with SD, with 2-year PFS rates of 10.7% vs not estimable (NE) and 2-year OS rates of 36.6% vs 29.3% with A+V+C vs P+V+C.Abstract 301 Table 1PFS and OS outcomes with A+V+C vs P+V+C by BOR per RECIST v1.1ConclusionsPFS and OS improvement was observed for A+V+C vs P+V+C for patients who achieved PR. CR is associated with improved PFS and OS with both A+V+C and P+V+C. Further follow-up is required to determine the impact of A+C+V vs P+C+V on survival outcomes.Trial RegistrationClinicalTrials. gov, NCT02908672

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.

scholarly journals Real-World Survival in Patients with Metastatic Melanoma after Discontinuation of Anti-PD-1 Immunotherapy for Objective Response or Adverse Effects: A Retrospective Study

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Julie Valentin ◽  
Thomas Ferté ◽  
Valérie Dorizy-Vuong ◽  
Léa Dousset ◽  
Sorilla Prey ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Metastatic Melanoma ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Advanced Melanoma ◽  
Discontinuation Of Treatment

Objective. Anti-PD-1 has dramatically improved the survival of patients with advanced melanoma. However, there is a lack of data on maintenance of the response after treatment discontinuation. We aimed to evaluate the progression-free survival (PFS) of patients with metastatic melanoma after anti-PD-1 interruption for objective response (OR) or limiting toxicity during clinical trials. Methods. All patients with advanced melanoma who stopped single-agent anti-PD-1 antibodies for objective response or toxicity were included between April 2014 and January 2019 in our institution (data cut-off, September 10th, 2019). Clinical and biological factors associated with relapse were studied. Results. The median follow-up after introduction of treatment was 36.5 months [4.6–62.4], and the median follow-up after discontinuation of treatment was 15.7 months (2.5–45.1). Out of 65 patients, 28 patients stopped immunotherapy for limiting adverse effects (AEs) (43.1%), 25 for complete response (CR) (38.4%), and 12 for partial response (PR) or long-term stable disease (SD) (18.5%). Twelve patients relapsed (18.5%) after a median time of 9 months [1.9–40.9 months]. Seven relapsed after discontinuation for AEs, 3 after discontinuation for CR, and 2 after discontinuation for PR/SD. The median PFS after therapy discontinuation was not reached. No statistical association was found between recurrence and age, sex, increased LDH, BRAF status, presence of brain metastases, previous treatments, radiotherapy, or time on anti-PD-1 treatment. Conclusion. This cohort shows a global recurrence rate of 18.5% and confirms a long-lasting response after anti-PD-1 cessation regardless of the cause of discontinuation.

scholarly journals Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma

2021 ◽  
Vol 9 (6) ◽  
pp. e002057
Author(s):  
Yousef Zakharia ◽  
Robert R McWilliams ◽  
Olivier Rixe ◽  
Joseph Drabick ◽  
Montaser F Shaheen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Advanced Melanoma ◽  
Free Survival ◽  
Programmed Death ◽  
Evaluable Population

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

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