ESMO 2017 Congress Highlights

Published: Sept. 18, 2017

The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in immunotherapy emerging from the European Society for Medical Oncology (ESMO) 2017 Congress held in Madrid, Spain Sept. 8-12, 2017.

Durvalumab improves PFS in patients with stage III advanced, unresectable NSCLC and few remaining treatment options (LBA1_PR)

Luis Paz-Ares, MD, PhD (Hospital Universitario Doce de Octubre, Madrid, Spain) detailed new results from the double-blind Phase 3 PACIFIC trial (NCT02125461) investigating the PD-L1 inhibitor durvalumab as consolidation therapy in patients with stage III locally advanced (non-metastatic) NSCLC patients without progression following concurrent platinum-based chemoradiation (cCRT). In all, 709 patients (any PD-L1 status, WHO PS 0-1) were randomized 2:1 to receive durvalumab (n=473, 10mg/kg iv, Q2W) or placebo (n=236) 1-42 days post-cCRT, for up to 12 months. Median follow-up time was 14.5 months as of Feb 13, 2017. Based on an increase in median PFS of 11.2 months (16.8 vs. 5.6 months with durvalumab versus placebo), associated with a hazard ratio of 0.52 (95% CI, 0.42–0.65; P < 0.0001), treatment with durvalumab reduced risk of disease progression by 48% over placebo. Consistent with this, ORR for the durvalumab and placebo groups was 28% and 16%, respectively, with median DOR not reached with durvalumab, and 14 months with placebo. Median TTDM was significantly longer for patients treated with durvalumab (23 months) than placebo (14.6 months). The trial has not yet matured sufficiently for generation of OS data. Grade 3/4 AEs, most commonly pneumonia, occurred in 30% and 26% of durvalumab and placebo patients, respectively. Durvalumab and placebo patients also experienced immune-related adverse events including pneumonitis (34% and 25%, respectively), hyperthyroidism (12% and 2%, respectively), and rash (12% vs. 7%, respectively). Deaths occurred in 4.4% and 5.6% of durvalumab and placebo groups, respectively. This study suggests that durvalumab treatment is well tolerated and provides clinically meaningful improvement in PFS, ORR, and DOR, irrespective of PD-L1 status, in patients with stage III NSCLC who have few remaining treatment options.

Adjuvant nivolumab provides superior safety and survival compared to adjuvant ipilimumab in patients with resected stage III/IV melanoma. (LBA8_PR)

Jeffrey Weber, MD, PhD (Perlmutter Cancer Center, New York, NY) presented results from the phase 3 CheckMate 238 trial (NCT02388906) comparing efficacy of adjuvant nivolumab versus ipilimumab in patients with resected stage III/IV melanoma at high risk of recurrence. In all, 906 patients (age ≥15 years; completely resected stage IIIb [34%], IIIc [47%] or IV [19%] melanoma; 32% ulcerated primary, 48% macroscopic lymph node, 42% BRAF mutation) were randomized 1:1 to receive 4 doses of adjuvant nivolumab (n=453, 3mg/kg Q2W) or ipilimumab (n=453, 10mg/kg Q3W) over 24 weeks. Study medication was then given every 12 weeks for up to one year, or until disease recurrence or unacceptable toxicity.  Nivolumab increased 18-month RFS by 35% [HR: 0.65 (95% CI: 0.5-0.8) compared to ipilimumab [nivolumab RFS = 64% (95% CI: 62-71) vs. ipilimumab RFS 53% (95% CI: 48-57)]. Biomarker analysis supported the greater benefit with nivolumab in improving RFS at 12 months, irrespective of PD-L1 status (nivolumab: PD-L1 < 5%, RFS = 64%; PD-L1 ≥ 5%, RFS = 82% vs. ipilimumab: PD-L1 < 5%, RFS = 54%; PD-L1 ≥ 5%, RFS = 74%). Median RFS was not reached in either cohort. TRAEs were observed in 14% and 46% of the nivolumab and ipilimumab groups, respectively, including G3/4 gastrointestinal (2% vs. 17%), hepatic (2% vs. 11%), and skin (1% vs. 6%) disorders. No deaths were reported in the nivolumab group, while 2 deaths (0.4%) occurred within the ipilimumab group (colitis and medullary aplasia) >100 days post-treatment. These data suggest that adjuvant nivolumab provides superior RFS and safety compared to the FDA-approved adjuvant ipilimumab in patients with resected stage III/IV melanoma, regardless of tumor PD-L1 status.


AE = adverse event

AML= Acute myeloid leukemia

BID = twice daily

cCRT = concurrent chemoradiation therapy

CR = complete response

DCR = disease control rate

DOR = duration of response

ECOG = Eastern Cooperative Oncology Group

G/GEJ = gastric or gastroesophageal

G3/4 = grade 3 or 4

HPV = human papillomavirus

IDO1 = indoleamine 2,3-dioxygenase 1

IMDC = International Metastatic Renal Cell Carcinoma Database Consortium

LAG-3 = lymphocyte activation gene-3

MDS = myelodysplastic syndrome

MTDS = maximum tolerated dose and schedule

nab-P = nab-paclitaxel

NR = not reached

NSCLC = non-small cell lung cancer

OS = overall survival

ORR = objective response rate

PD = progressive disease

PFS = progression-free survival

pNET = pancreatic neuroendocrine tumor

PO = by mouth

PR = partial response

PS = performance score

Q2W = every 2 weeks

Q3W = every 3 weeks

RFS = recurrence-free survival

R/M = recurrent or metastatic

R/R = Relapsed/refractory

SCC = squamous cell carcinoma

SCCHN = squamous cell carcinoma of the head and neck

SD = stable disease

TPS = tumor proportion score

TRAE = treatment-related adverse event

Treg = regulatory T cell

TTDM = time to death or distant metastasis

WHO = World Health Organization

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.


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