SERUM CRP AND IL-6 ARE PROGNOSTIC INDICATORS FOR MELANOMA PATIENTS RECEIVING CHECKPOINT INHIBITORS
On Saturday, Dr. Jeffrey S. Weber (NYU Langone Medical Center, New York, NY) presented a biomarker analysis of melanoma patients receiving nivolumab (N) and/or ipilimumab (I) from the Checkmate 064, 066, and 067 studies. Analysis of sera from these patients at baseline and on treatment for IL-6 and CRP was compared with response or survival.
A number of trends were identified through this study. Notably, across all studied populations, higher baseline IL-6 was associated with worse outcomes for patients. Indeed, multivariate analysis indicated that lower IL-6 was associated with longer overall survival, regardless of treatment, with encouraging hazard ratios: in Checkmate 066, a non-significant but promising HR for N treatment was found at 1.58; at the same time, significantly longer survival for IL-6-low patients was found after treatment with dacarbazine (HR: 1.79). In Checkmate 067, even more encouraging findings were presented: HRs of 3.13, 2.67, and 4.06 were calculated for N, N+I, and I treatment, respectively. Similarly, high serum CRP correlated with poor outcomes in all studies, yielding HRs over 1 in nearly all treatment groups in all three trials. In vitro studies indicated that CRP may dampen immune responses, possibly describing this finding. Overall, this study points to the potential of serum IL-6 and CRP to serve as prognostic factors for checkpoint inhibition.
BIOMARKERS IDENTIFIED FOR RESPONSE TO AVELUMAB + AXITINIB IN ARCC
Abstract 101: Biomarker analyses from JAVELIN Renal 101: Avelumab + axitinib (A+Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC)
A biomarker analysis from the phase III trial of 1st-line treatment of advanced renal cell carcinoma with avelumab + axitinib (A+Ax) vs sunitinib (S) was presented by Dr. Toni K. Choueiri (Dana-Farber Cancer Institute, Boston, MA). Treatment efficacy (PFS) was correlated with molecular analysis of tumor tissues from all patients enrolled in the JAVELIN Renal 101 trial using immunohistochemistry for CD8 and PD-L1, whole-exome sequencing (WES), and RNAseq. Several gene expression signatures (GES) were analyzed by WES and RNAseq.
A number of trends were identified. First, PD-L1 status as measured by IHC did not correlate with outcomes to A+Ax, but patients with high PD-L1 had shortened PFS with S treatment, as expected. The presence of CD8+ cells at the invasive margin of tumor samples indicated longer PFS for A+Ax-treated patients (HR: 0.59), while patients with the same finding fared worse with S treatment (HR: 1.42). The investigators developed a novel 26-gene signature that, when found at a high level, was able to identify patients on A+Ax treatment with longer PFS (HR: 0.60) and also with S treatment, though not significant (HR: 0.89). Finally, the presence or mutation of specific genes was also explored. Mutations in CD163L1 and DNMT1 correlated with extended PFS with A+Ax treatment and shorter PFS with S, while mutant PTEN indicated shorter PFS for both A+Ax and S treatment. Further exploration of these identified biomarkers may lead to improved patient selection for combination immune checkpoint treatments in the future.
NEOADJUVANT ATEZOLIZUMAB SHOWS ENCOURAGING OUTCOMES IN NSCLC, ESPECIALLY IN BIOMARKER-DEFINED SUBPOPULATIONS
Abstract 8503: Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3)
Dr. David J. Kwiatkowski (Dana-Farber Cancer Institute, Boston, MA) discussed the treatment of patients with atezolizumab (1200 mg) before surgical resection in stage IB-IIIB non-small cell lung cancer. In this study, the primary tumor and nodes were biopsied before therapy and at surgery for the analysis of the primary endpoint: major pathologic complete response (MPR, <10% viable tumor cells in the resection specimen). Other goals of the study included safety and response correlations with other markers such as PD-L1 expression, tumor mutational burden (TMB), and gene expression signatures (GES).
In this interim analysis with 101/180 patients enrolled, the MPR rate was 19%. Overall, 5% of patients experienced a pathological complete response, 7% had PR, and 89% had SD. Encouragingly, 49% of enrolled patients had at least 50% pathological regression. No difference in TMB or PD-L1 positivity was noted between patients with or without an MPR in this study to date. All-cause grade 3-5 AEs occurred in 31% of the patient population, and treatment-related AEs of grade 3 or higher occurred in only 6% of patients. The study is still ongoing, with the results pointing toward the potential of neoadjuvant PD-L1 blockade.
ENHANCED PATHOLOGICAL TREATMENT RESPONSES WITH NIVOLUMAB + IPILIMUMAB IN PD-L1+ NSCLC
Abstract 8504: Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study
Results of neoadjuvant nivolumab (N) or nivolumab + ipilimumab (N+I) in resectable NSCLC were presented by Dr. Tina Cascone (MD Anderson Cancer Center, Houston, TX). Patients were randomized to N 3 mg/kg on D1, 15, and 29 or N+I at 1 mg/kg on D1 also, and major pathologic response (MPR) served as the primary endpoint of the study.
Overall, 11/41 patients experienced an MPR (4/23 N and 7/21 N+I). Eight of these MPRs were pathologic complete responses (2 N and 6 N+I). Of patients who underwent resection on-trial, the MPR rate was 30%, and the percent viable tumor in samples was lower after treatment with N+I than with N. The ORR in this study was 20% overall, with MPRs of 19% in N+I-treated patients, and 22% with N alone. An increase in CD3- and CD103-positive TILs was observed in N+I-treated tumors over N-treated, and higher median pre-treatment PD-L1 was noted in responders than non-responders. Responses measured by RECIST and MPRs were correlated as well. A few grade 3-5 treatment-related AEs occurred in this study: a grade 5 bronchopleural fistula post steroid-treated pneumonitis (N), and one each of grade 3 pneumonia, hypermagnesia, and hypoxia with N, and one grade 3 diarrhea and one hyponatremia with N+I. With MPRs in the ITT population of 17% with N and 33% with N+I, this study points to the potential of neoadjuvant checkpoint inhibition in NSCLC, especially in PD-L1 (+) subpopulations.
TMB AND INFG PREDICT RESPONSE TO IMMUNE CHECKPOINT BLOCKADE IN METASTATIC MELANOMA
Abstract 9511: Comprehensive molecular profiling of metastatic melanoma to predict response to monotherapy and combination immunotherapy
Dr. Ines Esteves Domingues Pires Da Silva (Melanoma Institute Australia, Sydney, Australia) described molecular analysis of cutaneous metastatic melanoma tumors using whole genome sequencing (WGS), RNAseq, and immunohistochemistry, and the correlations of these markers with response to PD-1 or dual PD-1 and CTLA-4 blockade.
Through WGS analysis of 77 samples (53 PD-1, 24 PD-1 + CTLA-4), a higher response rate was noted in patients with higher TMB, lower structural variant burden, and higher neoantigen load. While certain genes are reported to confer resistance or response to checkpoint inhibitors, no difference in these signatures was noted for responders vs non-responders. When RNAseq analysis was performed on 53 samples, an enrichment in the IFN and TCR signaling pathways was observed in responders; in addition, T cell proportion (through CIBERSORT), cytolytic activity, and PD-L1 expression were all also higher in responders. After a multivariate analysis, a combination of TMB and INFG expression was found to be a good predictive model of response, indicating that non-responders to checkpoint inhibition may be deficient in immune recognition and/or activation.
PROMISING PHASE I TRIAL OF ANTI-CD19 CAR T THERAPY IN R/R ALL
Abstract 7006: End of phase I results of ZUMA-3, a phase 1/2 study of KTE-X19, anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in adult patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL)
The end of Phase 1 results for ZUMA-3 were reported by Dr. Bijal D. Shah (Moffitt Cancer Center, Tampa, FL). This study evaluated KTE-X19, an autologous anti-CD19 CAR T cell therapy, in adult R/R acute lymphoblastic leukemia; patients received 2, 1, or 0.5 x 106 cells/kg after conditioning chemotherapy, in order to determine the dose-limiting toxicity rate as the primary endpoint, since notable CRS events had been noted in previous studies. Secondary analyses included MRD and CR occurrences, along with incidence of AEs and levels of KTE-X19.
At the time of analysis, 45 patients had been treated with KTE-X19: 6, 23, and 16 patients received 2, 1, and 0.5 x 106 cells, respectively. In all evaluable patients, no DLTs occurred, but the most common grade ?3 AEs were hypotension, pyrexia, and thrombocytopenia, all in >30% of patients. Grade ?3 CRS and neurotoxicity were observed in 29% and 38% of patients, respectively, as well, in a dose-dependent manner. A revised irAE management schedule was implemented in 9 patients treated with 1 x 106 cells, and reduced the incidence of grade 3 CRS and neurotoxicity to 22% and 11%. In all patients with over 2 months of follow-up, 68% experienced CR/CRi, and 100% of patients with any remission were MRD-negative. The dose of 1 x 106 was chosen for further studies, and in this population, 84% had a CR/CRi. This study has laid the groundwork for further evaluation of KTE-X19 in phase II studies at a dose of 1 x 106.