Pembrolizumab shows trend towards improved overall survival in patients with recurrent or metastatic head and neck squamous cell carcinoma (LBA45_PR)
Ezra Cohen, MD (University of California, San Diego Moores Cancer Center, La Jolla, CA) presented results from the global, open-label KEYNOTE-040 phase 3 study (NCT02252042) assessing antitumor activity and toxicity of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). A total of 495 patients with recurrent or progressive R/M HNSCC after platinum-containing treatment were randomized to receive pembrolizumab (n=247, 200mg Q3W) or investigator’s choice (‘standard of care, SOC) of methotrexate (M, n=65), docetaxel (D, n=110), or cetuximab (C, n=73) for 24 months or until progressive disease or intolerable toxicity. After a median follow up of 7.3 months, there was a trend towards increased OS in the pembrolizumab arm but this did not reach statistical significance [HR 0.81 (95%CI: 0.66-0.99); one-sided p=0.02] since the pre-specified efficacy boundary for the trial was not met (one-sided p=0.01). Of note, 12.5% of the SOC cohort was prescribed additional immunotherapy, potentially affecting OS calculations. While PFS was similar between the two cohorts (2 months), pembrolizumab increased ORR by 4.5 months compared to SOC (15 and 10 months, respectively). Pembrolizumab also increased ORR by 12 months in patients with PD-L1 TPS ≥50% (n=64, 26.6 months) compared to the overall population (n=247, 14.6 months). Grade 3/4 TRAEs occurred in 14% of the pembrolizumab and 37% of the SOC cohort, including 1.6% and 0.9% deaths, respectively. Despite missing predetermined endpoints, pembrolizumab reduced the risk of death by 19% in patients with R/M HNSCC, with particular benefit in patients with high tumor PD-L1 expression.
Combination ipilimumab and nivolumab improves clinical outcomes compared to sunitinib in patients with treatment-naïve advanced or metastatic renal cell carcinoma and high PD-L1 expression status (LBA5)
Bernard Escudier, MD (Institut Gustave Roussy, Villejuif, France) reported the first results from the open-label phase 3 CheckMate 214 study (NCT02231749), which compared the efficacy of combination therapy with the anti-CTLA 4 agent, ipilimumab and anti-PD-1 agent, nivolumab, versus the tyrosine kinase inhibitor sunitinib, in patients with treatment-naïve advanced or metastatic renal cell carcinoma. In all, 1096 patients (measurable clear-cell mRCC, Karnofsky performance score ≥70, and available tumor tissue; stratified by IMDC risk and PD-L1 expression) were randomized 1:1 to receive nivolumab (3mg/kg, Q3W) and ipilimumab (1mg/kg, Q3W) for 4 doses, followed by nivolumab monotherapy (3mg/kg, Q2W), or SOC sunitinib (50mg daily for 4 weeks, 2 weeks off, 6-week cycles). Risk of death was reduced by 37% in patients with IMDC intermediate/poor risk disease within the nivolumab/ipilimumab cohort (n=425; median OS not reached [95% CI 28.2 – NR]) compared to the sunitinib cohort (n=422, median OS 26 months [95% CI 22.1 – NR]; hazard ratio 0.63 (99.8% CI, 0.44-0.89, p < 0.0001]). However, in favorable-risk patients sunitinib treatment (n=124) led to longer median PFS (25.1 months [95% CI 20.9 – NR] vs. 15.3 months [95% CI 9.7 - 20.3]; HR 2.18 (1.29 – 3.68, p < 0.0001)) and higher ORR (median ORR = 52% [95% CI 43 – 61]) vs. 29% [95% CI 21 - 38]; p = 0.0002). Observed differences in OS, PFS, and ORR between cohorts seemingly correlated with PD-L1 expression within the IMDC risk groups, as only 11% of IMDC favorable-risk patients in the nivolumab/ipilimumab cohort, and 12% of the sunitinib cohort, had PD-L1 levels ≥1%, compared to 26% and 29% of IMDC intermediate/poor risk patients, respectively, in the same cohorts. Grade 3/4 AEs occurred in 46% (7 deaths) and 63% (4 deaths) of nivolumab/ipilimumab and sunitinib cohorts, respectively. Grade 3/4 immune-related adverse events in the nivolumab/ipilimumab cohort included diarrhea/colitis (5%), hepatitis (6%), and rash (3%). In this important study, combination nivolumab/ipilimumab significantly improved key clinical outcomes compared to sunitinib in patients with poor disease risk and PD-L1 expression ≥1%, but not in patients with favorable IMDC scores.
Epacadostat/pembrolizumab combination therapy provides promising clinical activity and is well tolerated in patients with advanced melanoma (1214O)
Omid Hamid, MD (Angeles Clinic & Research Institute, Los Angeles, CA) discussed the latest results from the open-label, phase 1/2 ECHO-202/KEYNOTE-037 study (NCT02178722) investigating the safety and efficacy of epacadostat, a selective inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), in combination with the PD-1 inhibitor pembrolizumab, in patients with advanced melanoma. In all, 64 patients (70% male, median age 65 years, 30% BRAF+, 52% M1c, no prior checkpoint inhibitor treatment) were included in the study. A total of 22 patients received epacadostat (25-300 mg PO BID) + pembrolizumab (2mg/kg or 200mg IV Q3W) during phase 1. Phase 2 patients (n=42) received 100mg BID epacadostat + 200mg Q3W pembrolizumab. DCR was similar between the overall patient population (71%, 9 CR, 41 PR, 10 SD) and the treatment-naïve subset (72%, 13 CR, 42 PR, 17 SD), regardless of PD-L1 and BRAF status (RECIST v1.1). Median PFS, however, increased by >10 months in treatment-naïve patients compared to the overall patient population (22.8 months vs. 12.4 months, respectively). Median PFS has not been reached in treatment-naïve patients that received 100mg BID epacadostat. Grade 3+ TRAEs were present in 17% of all patients, most commonly increased lipase (n=4), rash (n=3), and increased amylase (n=2). Fatigue (39%), rash (33%), pruritus (27%), and arthralgia (16%) were also observed. These preliminary results suggest combination epacadostat and pembrolizumab is well tolerated in patients with advanced melanoma and exhibits promising clinical activity in patients with advanced melanoma. A phase 3 study is ongoing.
Tumor LAG-3 expression is associated with response to combination LAG-3/PD-1 pathway inhibition in patients with melanoma that has progressed on prior anti–PD-1/PD-L1 therapy (LBA18)
Paolo Ascierto, MD (Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy) described late-breaking results from a phase 1/2a study (NCT01968109) evaluating efficacy and safety of combination therapy with the anti-LAG-3 antibody BMS-986016 (relatlimab) and the anti-PD-1 antibody nivolumab in patients with melanoma that progressed during prior anti-PD-1/PD-L1 immunotherapy. As of June 15th, 2017, 68 patients (57% previously treated with anti-CTLA-4 treatment, 46% ≥ 3 lines of prior therapy) had received treatment with relatlimab (80mg Q2W) and nivolumab (240mg Q2W). ORR (1 CR, 6 PR [1 unconfirmed]) and DCR were 11.5% and 49%, respectively, in 61 evaluable patients. Median DOR was not reached. ORR in patients with LAG-3 expression ≥ 1% (n=33) was more than 3-fold higher than that in patients with LAG-3 expression < 1% (n=22; 18% vs. 5%), and this held true regardless of PD-L1 expression. TRAEs occurred in 41% of patients (4.4% G3/4). These data, from the largest study to date in patients treated with an anti-LAG-3/anti-PD1 combination, suggest that this combination has a similar AE profile to nivolumab alone, with greater efficacy, in heavily pretreated melanoma patients. Increased LAG-3 expression was associated with improved response to therapy, irrespective of PD-L1 expression.
Anti-leukemic activity observed in first-in human study of flotetuzumab, a CD123 x CD3 bispecific DART molecule, in patients with AML or MDS (995O)
Norbert Vey, MD, PhD (Institut Paoli-Calmettes, Marseille, France) presented preliminary results from a phase 1 dose-escalation study (NCT02152956) investigating the safety profile, maximum tolerated dose and schedule (MTDS), and anti-leukemic activity of the novel CD123 X CD3 bispecific DART protein flotetuzumab (MGD006/S80880) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or intermediate-2/high-risk myelodysplastic syndrome (MDS). Patients were treated with 28-day cycles of continuous flotetuzumab ranging from 3 to 1000ng/kg/day. After gradual dose escalation and stabilization during cycle 1, patients entering cycle 2 were treated on a 4-day on/3-day off schedule at the target dose for a maximum of 12 cycles or 2 cycles after complete response, drug-related toxicity, or disease progression. In all, 14/38 (36%) patients experienced ≥ grade 3 TRAEs, predominantly infusion-related reaction/cytokine-release syndrome [29/38; 76%, of which 3/38 (8%) were grade 3]. Flotetuzumab toxicity and corticosteroid use was mitigated through early tocilizumab therapy. Anti-leukemic activity was observed in 57% of patients (8/14) receiving the threshold dose of flotetuzumab (500ng/kg/day) or greater. A total of 4 CR and 1 molecular CR were observed, often after a single cycle of therapy. No MTDS has been defined for either schedule. This small study reveals that flotetuzumab may exhibit anti-leukemic activity while displaying an acceptable safety profile, offering a potential new therapy for patients with R/R AML/MDS.
Efficacy of HPV vaccines against preexisting oropharyngeal cancer is increased by concurrent nivolumab (1136O)
Bonnie Glisson, MD (University of Texas MD Anderson Cancer Center, Houston, TX) presented data from a phase II trial of ISA101 (NCT02426892), a synthetic long-peptide HPV-16 vaccine, investigating the potential of nivolumab to increase the efficacy of HPV vaccine-induced T-cells in patients with incurable HPV-16+ cancer. In all, 24 patients [HPV-genotype 16 tumors (Cervista HPV16/18); 22 oropharyngeal, 1 anal, 1 cervical; ECOG PS 0-1; ≤1 prior regimen for recurrence; 10 treated frontline for recurrence, 14 second line) received ISA101 (100mcgs/peptide, days 1, 22, and 50) and nivolumab (3mg/kg iv, Q2W, beginning day 8) for up to one year. ORR was 33% [8/24; 1 CR, 7 PR (1 unconfirmed), 3 SD, 13 PD] and 36% (8/22) in the oropharnygeal cancer subgroup. Median DOR was ≥30 weeks and 5/8 patients remain in response. Median OS was not reached at 8.6 months, and median PFS was 2.7 months. Grade 3/4 TRAEs occurred in 2 patients (grade 3 elevated transaminase, grade 4 elevated lipase; n=1 each). ORR in patients with HPV-16+ oropharyngeal cancer receiving ISA101/nivolumab combination therapy (36%) compared favorably to ORR with nivolumab monotherapy, as measured in the CheckMate 141 trial (16%). These data suggest that nivolumab may promote HPV vaccine-induced T cell activity against HPV-16+ cancer.