NEOADJUVANT T-VEC SHOWS PROMISE IN MELANOMA
LBA66: Primary 2-year (yr) results of a phase 2, multicenter, randomized, open-label trial of efficacy and safety for talimogene laherparepvec (T-VEC) neoadjuvant (neo) treatment (tx) plus surgery (surg) vs surg in patients (pts) with resectable stage IIIB-IVM1a melanoma
Reinhard Dummer
Dr. Reinhard Dummer (University Hospital Zurich, Zurich, Switzerland) discussed the outcomes of melanoma patients treated with neoadjuvant talimogene laherparepvec (T-VEC) compared to patients treated with surgery alone. In this study, patients with resectable stage IIIB-IVM1a melanoma were randomized 1:1 to surgery alone, or six doses of intralesional T-VEC over 12 weeks before surgery. The primary endpoint was recurrence-free survival at two years.
After a median follow-up of 31.2 months, 29.5% of patients receiving neoadjuvant T-VEC were recurrence-free, compared to 16.5% of those treated with surgery alone (HR= 0.75, P= 0.07). An additional sensitivity analysis was also conducted, in which patients who withdrew prior to surgery or had a non-R0 resection were removed from the RFS calculations. After this adjustment, 50.5% of T-VEC and 30.2% of surgery patients were recurrence-free at 2 years. This corresponded to an increase in overall survival for T-VEC patients: two-year OS was 88.9% compared to 77.4%. Increases in CD8+ density and PD-L1 expression were also noted after T-VEC treatment. Since this study closed accrual in 2015, the melanoma treatment landscape has changed drastically; however, the evidence of immune surveillance in T-VEC-treated patients warrants future consideration of this neoadjuvant therapy.
COMBINATION OF IMAGING AND CLINICAL DATA PREDICTS IMMUNOTHERAPY RESPONSE
1176O: Artificial intelligence combining radiomics and clinical data for predicting response to immunotherap
M. Ligero
Marta Ligero, MS (Vall d’Hebron Institute of Oncology, Barcelona, Spain) presented a novel approach for predicting response to immunotherapy, integrating both radiomic and clinical data to create an improved prediction signature. The group first defined the radiomics signature to be employed through a training dataset of patients receiving PD-1 or PD-L1 inhibitors, incorporating radiomic features such as first-order shape and texture of a target lesion on CT. Then, using an elastic-net model, clinical characteristics, including blood counts, were incorporated as well. An external dataset of immunotherapy-treated bladder cancer patients was used for validation of the signature.
The developed radiomics signature alone at baseline associated strongly with response in checkpoint inhibitor patients: in the validation cohort, response could be predicted with an area-under-the-curve (AUC) of 0.76 (p = 0.001). When clinical factors were combined into the signature, the predictive capability was further enhanced (AUC 0.84, p = 5.04x10-9). In this study, tumor responses correlated with tumor homogeneity, hypodensity, and spherical shape, determined from CT; at the same time, clinical aspects including high lymphocyte count and albumin levels and low neutrophils also factored into the predictive signature. With the rising need to predict patients who will respond to immune checkpoint inhibitors, this signature may find a place in non-invasive, cost-effective assessment of patients at baseline, allotting them to proper therapies.
LONG-TERM FOLLOW-UP SUPPORTS CHECKPOINT INHIBITOR COMBO IN MELANOMA
LBA68_PR: 5-year survival outcomes of the CheckMate 067 phase 3 trial of nivolumab plus ipilimumab (NIVO+IPI) combination therapy in advanced melanoma
James M. Larkin
The longest follow-up of checkpoint inhibitor-treated patients to date was presented by Dr. James M. Larkin (Royal Marsden Hospital NHS Foundation Trust, London, UK). The five-year survival outcomes from CheckMate 067 compared three treatment regimens in first-line treatment of advanced melanoma: nivolumab + ipilimumab (1 mg/kg + 3 mg/kg, 4 doses Q3W, then nivolumab 3 mg/kg Q2W); nivolumab alone (3 mg/kg Q2W + placebo); or ipilimumab alone (3 mg/kg Q3W for 4 doses + placebo). The study aimed to evaluate both overall survival and progression-free survival.
Enhanced outcomes were noted in the nivolumab-containing arms of the study after a minimum 60 month follow-up. Median OS was not reached for nivo+ipi, 36.9 months for nivo, and 19.9 months for ipi alone. Progression-free survival and duration of response were similarly enhanced with the combination regimen. While the study was not powered to compare between the combination and nivolumab alone, descriptive analyses indicated a benefit for the combination over nivolumab monotherapy, in terms of OS as well as time to subsequent therapy (NR for combo, 25.2 months for nivo). The long-term follow-up from this study lends strong support to the use of combination nivolumab and ipilimumab in front-line treatment of melanoma.
MEK + PD-L1 CO-INHIBITION OUTPERFORMED BY PD-1 BLOCKADE
LBA69: Combination treatment with cobimetinib (C) and atezolizumab (A) vs pembrolizumab (P) in previously untreated patients (pts) with BRAFV600 wild type (wt) advanced melanoma: primary analysis from the phase 3 IMspire170 trial
Ana M. Arance
Dr. Ana Arance (Hospital Clinic Barcelona, Barcelona, Spain) discussed the primary analysis from the phase III trial, IMspire170, exploring the combination of cobimetinib + atezolizumab vs pembrolizumab in front-line treatment of BRAFV600 wt melanoma patients. Patients were allotted to receive either cobimetinib (a MEK inhibitor, 60 mg, days 1-21) plus atezolizumab (840 mg Q2W) or pembrolizumab (200 mg Q3W), and were followed to assess progression free survival.
After a median follow-up for 7 months, no statistically significant difference was observed for the median PFS between the two cohorts (C+A: 5.5 months; P: 5.7 months; HR 1.15, P = 0.295). This trend was observed across all analyzed subgroups, including PD-L1 and LDH status. Again, disease control rates and overall response rates were similar for both groups (DCR: 46% vs 44%; ORR: 26% vs 32%). A marked difference in the safety profiles was noted between the two treatments, however: a higher incidence of any adverse event as well as high-grade AEs was observed in the combination treatment. Therefore, this study indicates that PD-1 inhibition remains a standard of care for BRAFV600 wt melanoma, and points to the difficulty in identifying synergistic combinatorial therapies.
BENEFIT OF DURVALUMAB COMBINATION IN ES-SCLC
LBA89: PD-L1 expression, patterns of progression and patient-reported outcomes (PROs) with durvalumab plus platinum-etoposide in ES-SCLC: Results from CASPIAN
Luis Paz-Ares – Presented by Marina Chiara Garassino
The application of immunotherapy to small-cell lung cancer was presented by Dr. Marina Chiara Garassino (Fondazione IRCCS Instito Nazionale dei Tumori, Milan, Italy). In the CASPIAN trial, the PD-L1 inhibitor, durvalumab, was added to the standard treatment regimen of etoposide plus platinum for management of treatment-naïve extensive-stage SCLC. Dr. Garassino presented the results of PD-L1 expression analysis, progression patterns, and patient-reported outcomes (PROs).
Throughout the entire study, a benefit was seen for combination treatment (D+EP) over EP treatment alone (median OS: 13.0 vs 10.3 months). Patient-reported outcomes also favored D+EP over EP treatment, with increased time-to-deterioration in all symptoms reported with the combination. For exploratory PD-L1 analysis, 151/265 D+EP patients had evaluable samples, while 126/266 EP patients did as well. Throughout all analyses, PD-L1 expression did not impact treatment outcomes; that is, the benefit for the combination treatment was maintained regardless of PD-L1 expression level or cutoff. The addition of durvalumab to etoposide and platinum therefore represents an important advance in the treatment of extensive-stage small cell lung cancer, warranting continued consideration.
MICROBIOME METABOLITES IMPACT IMMUNOTHERAPY RESPONSE
3O: Systemic gut microbial metabolites limit the anti-tumor effect of CTLA-4 blockade in hosts with cancer
Clelia Coutzac
The impact of the microbiome on CTLA-4 blockade was discussed by Dr. Clelia Coutzac (Gustave Roussy Institute, Villejuif, France). The gut microbiota are well-known producers of short-chain fatty acids (SCFAs), which are thought to have anti-inflammatory properties, causing the group to investigate the influence of these metabolites on response to anti-CTLA-4 therapy in both metastatic melanoma patients and murine models. The presence of F. prausnitzii in stool samples was evaluated by both 16S metagenomic analysis and quantitative PCR, while levels of several SCFAs were measured in both stool and serum samples.
F. prausnitzii enrichment in the stool was found to correlate with systemic levels of butyrate, while higher levels of SCFAs in the blood, in particular propionate and butyrate, were associated with poor response to anti-CTLA-4 therapy. In patients, this increase in SCFAs corresponded to an increase in Treg levels as well. Murine studies helped elucidate some of the mechanisms involved: high levels of butyrate were found to limit CD80/CD86 expression on dendritic cells as well as minimize induction of tumor-specific and memory T cells. Together, this study determined that the metabolites of the gut microbiota, in particular SCFAs, limit the immune response and therefore reduce the benefit of anti-CTLA-4 therapy in cancer.
IMMUNOTHERAPY COMBO IMPROVES OUTCOME IN 1L NSCLC
LBA4_PR: Nivolumab (NIVO) + low-dose ipilimumab (IPI) vs platinum-doublet chemotherapy (chemo) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): CheckMate 227 Part 1 final analysis
Solange Peters
Dr. Solange Peters (Lausanne University, Lausanne, Switzerland) discussed the final analysis of CheckMate 227 Part 1, involving front-line treatment of NSCLC patients with one of three regimens: nivolumab + ipilimumab (3 mg/kg Q2W + 1 mg/kg Q6W), chemotherapy, or nivolumab alone (240 mg Q2W). The study had two co-primary endpoints, and the results of OS in PD-L1 >=1% patients were discussed in this presentation.
PD-L1+ patients experienced significantly enhanced survival when treated with nivolumab + ipilimumab compared to chemotherapy (17.1 months vs 14.9 months; OS HR 0.79, P=0.007). Other methods of treatment response analysis also favored the combination, including PFS, ORR, and DOR. Even in those patients with PD-L1 < 1%, the benefit of the nivolumab + ipilimumab treatment was maintained relative to chemotherapy (mOS: 17.2 months vs 12.2 months). Interestingly, when patients were further stratified by PD-L1 status into groups of >=50%, 1-49%, and <1%, nivolumab + ipilimumab showed benefit only in the >=50% and <1% groups. The combination treatment also resulted in the expected higher irAE incidences than those seen with nivolumab monotherapy, however. Therefore, the combination of nivolumab + ipilimumab may be a first-line treatment option for several groups of NSCLC patients.
FEASIBILITY OF DENDRITIC CELL THERAPY ASSESSED
4O: Novel dendritic cell based immunotherapy for advanced cancer
Aanchal P. Kaur
Aanchal P. Kaur, MS (University of Nottingham, Nottingham, UK) presented a study exploring the potential of dendritic cell-based therapy for advanced cancer patients. To determine feasibility of this approach, the group evaluated levels of natural circulating dendritic cells (nDCs) in both advanced cancer patients and healthy controls. Two specific subsets of nDCs were also investigated: CD1c+ DCs (cDC2) as well as plasmacytoid DCs (pDC), both of which play important roles in immune activation.
In cancer patients, a decreased level of pDC was found relative to healthy controls (1221 vs 2843 pDC/mL, p < 0.01); however, relatively similar amounts of cDC2 were measured in both groups (4475 vs 5053 cDC2/mL). Taken together, advanced cancer patients, on the whole, had high enough levels of DC for this cellular therapy to be feasible. Some differences were noted in the functionality of DCs from patients compared to controls. In particular, patient cDC2 were immune-suppressed, which was found to be controlled by the p38 MAPK signaling pathway. When this pathway was inhibited, IL-2 secretion was restored and immunosuppressive IL-10 secretion was reduced. This study points to the possibility of dendritic cell-based immunotherapy for cancer patients, and a phase I study is thus planned.