Blockade of immune modulator GDF-15 combined with nivolumab for advanced solid tumors
2501. Initial results from the phase 2A trial of visugromab (CTL-002) + nivolumab in advanced/metastatic anti-PD1/-L1 relapsed/refractory solid tumors (The GDFATHER-TRIAL).
Ignacio Melero Bermejo (Clinica Universitaria de Navarra, Pamplona, Spain) reported initial results from the GDFATHER-TRIAL, a phase IIa trial of visugromab (CTL-002) combined with nivolumab for advanced or metastatic solid tumors. CTL0-002 blocks GDF-15, an immune modulating molecule that inhibits the infiltration of immune cells into the tumor microenvironment and limits the efficacy of cancer immunotherapy. CTL-002 is a monoclonal antibody that binds with high affinity and specificity to GDF-15. Studies of CTL-002 in non-human primates yielded no toxicology findings. The dose escalation phase consisted of five dose levels with a mono-/combo-exploration in which patients received CTL-002 monotherapy followed by CTL-002 combined with nivolumab. Biopsies taken from patients after monotherapy and combination therapy indicated an increase of T-cell tumor infiltration after monotherapy that was maintained during combination therapy. Levels of Ki67+ T cells and GrzB+ T cells increased more than two-fold, providing proof of concept that CTL-002 promotes T cell infiltration of the TME. Of 18 patients dosed at 3-5 levels in the dose escalation, 6 experienced clinical benefit. Three patients (17%) achieved confirmed partial responses (PR) with durations up to 24 months, and one response is ongoing. A response-predictive biomarker that was present in all three patients with PR and one patient with stable disease was identified and is being validated in ongoing phase IIa cohorts. The safety profile was manageable and similar to profiles previously observed for nivolumab monotherapy. Preliminary data indicate visugromab + nivolumab combination produced lasting and confirmed responses in heavily pretreated patients with advanced-stage solid tumors with prior exposure to anti-PD(L)-1 therapy. Phase IIa safety and efficacy data and biomarker correlative analyses are ongoing.
For related research on GDF-15, read this article from Wang et al in JITC.
Live bacterial product CBM588 combined with immune checkpoint blockade and targeted therapy for renal cell carcinoma
LBA104. Effect of CBM588 in combination with cabozantinib plus nivolumab for patients (pts) with metastatic renal cell carcinoma (mRCC): A randomized clinical trial.
Hedyeh Ebrahimi (City of Hope Comprehensive Cancer Center, Duarte, CA) presented results from a small prospective trial of live bacterial product CBM588 in combination with kinase inhibitor cabozantinib (cabo) and immune checkpoint inhibitor nivolumab (nivo) for metastatic renal cell carcinoma (mRCC). CBM588 contains a specific strain of Clostridium butyricum. Previous studies indicate that it has complex effects on immune activity and may augment clinical outcomes in patients with mRCC receiving first-line therapy with dual immune checkpoint inhibitors for non-small cell lung cancer. 30 patients participated in the trial, and Hispanic and Latino patients were highly represented. 10 patients received control treatment of cabo + nivo, and 20 patients received cabo + nivo + CBM588. Metagenomic analyses of stool samples taken at baseline and week 12 of treatment indicate a decrease in gut microbiome diversity in patients receiving cabo + nivo, but no decrease was associated with the cabo + nivo + CBM588 group. Addition of CBM588 significantly increased progression free survival (PFS): PFS was 5.8 months for the cabo + nivo group and not reached for the cabo + nivo + CBM588 group. Response rate was also improved in the cabo + nivo + CBM588 group compared to the cabo + nivo group, at 63% and 33%, respectively. No significant difference in adverse events was observed between the two groups. Although this trial featured a small sample size, these results support previous clinical results that CBM588 improves patient response to immune checkpoint blockade. A potential phase III trial of CBM588 for mRCC is currently being discussed within the NCI Cooperative Groups.
Large-scale analysis of tumor mutational burden and real-world overall survival from immune checkpoint blockade
2503. Tumor mutational burden (TMB) measurement from an FDA-approved assay and real-world overall survival (rwOS) on single-agent immune checkpoint inhibitors (ICI) in over 8,000 patients across 24 cancer types.
David R. Gandara (UC Davis Comprehensive Cancer Center, Sacramento, CA - SITC Member) presented a study of a large real-world patient cohort evaluating the performance of FDA-approved tumor mutational burden (TMB) algorithms to identify patients with favorable overall survival (OS) after treatment with single-agent immune checkpoint inhibitors (ICI). Although ICIs have produced favorable results in treating certain cancers, the predictive value of TMB is limited, partly because variation in TMB algorithms have produced discordant results. Using a combined database of over 100,000 patients, data from 8,440 patients with high TMB who received single-agent ICI were analyzed. Increasing TMB was associated with decreasing hazards of death (i.e., improved OS), independent of prognostic variables. In 9 of 10 tumor types examined, a TMB >=10 mutations/Mb was associated with improved OS with ICI. TMB ranges varied greatly by tumor type. For example, low TMB (< 5 mut/MB) was observed in only 20% of melanomas but in 90% of pancreatic tumors. Real-world OS trended higher with TMB levels in multiple tumor types, and the data were consistent with the FDA-approved CDx assay for TMB. These findings indicate that as TMB assays change and improve as more information becomes available. The new TMB assays should be compared to FDA-approved assays to maintain consistency among different TMB algorithms. These findings also underscore the need to investigate TMB assays in completed and ongoing clinical trials of ICIs and to include TMB in composite biomarker panels to identify patient populations who are more likely to respond.
Evaluating association of changes in tumor burden with survival outcomes in patients treated with immune checkpoint inhibitors
2504. Evaluation of change in RECIST tumor size and survival in patients with rare cancers treated with checkpoint inhibitor therapy (SWOG S1609).
Megan Othus (Fred Hutchinson Cancer Center, Seattle, WA) presented a study investigating the utility of using Response Evaluation Criteria in Solid Tumours (RECIST) to categorize quantitative data of patient response (tumor size) to treatment with immune checkpoint inhibitors. Data from the S1609/DART basket trial, in which patients with rare cancers were treated with anti-CTLA-4 and anti-PD-1, was evaluated to identify the association between quantitative change in tumor burden, evaluated by RECIST, and survival among patients treated with checkpoint inhibitor therapy. A high degree of variability in progression free survival (PFS) and overall survival (OS) was observed among patients identified as responders and non-responders, and there was no inflection point at the tumor change sizes based on classical criteria for progressive disease or objective response. A strong linear association between change in tumor size and one-year OS was observed (R = -0.90). These data underscore the challenges associated with dichotomizing continuous variables like changes in tumor size and indicate that current procedures like RECIST criteria may mask inherent variability within patient subgroups, especially groups with a non-response or stable disease.
For more research from Othus and colleagues, read this article in JITC.
Phase I study of a novel tri-specific NK cell engager against advanced solid tumors
2508. Phase 1/2 Study of DF1001, a novel tri-specific, NK cell engager therapy targeting HER2, in patients with advanced solid tumors: Phase 1 DF1001 monotherapy dose-escalation results.
Howard Safran (Brown University School of Medicine-Rhode Island Hospital, Providence, RI) presented results of a phase I dose escalation study of DF1001, a tri-specific NK cell engager therapy (TriNKET), targets HER2. DF1001 potently stimulates NK cells and gamma delta T cells through NKG2d and CD16a agonism, inducing NK- and T cell-mediated killing of cancer cells expressing HER2. By stimulating NK cells and T cells, DF1001 also stimulates the release of interferon gamma and other inflammatory chemokines and cytokines, recruiting additional effector immune cells to the tumor microenvironment. Preclinical studies indicate that DF1001 increased immune infiltration of mouse tumor models and stimulates release of inflammatory cytokines and chemokines by NK cells in vitro. 106 patients who had received an average of 4 prior lines of therapy (ranging from 1 to 18) were enrolled in the study, and a range of cancers were represented in the cohort. Treatment is ongoing in one patient, and the majority of patients discontinued the study due to progressive disease. DF1001 monotherapy was safe and well-tolerated. No dose-limiting toxicities were observed, 10% of treatment related adverse events (TRAEs) were grade 3, and no grade 4 or 5 TRAEs were observed. In the subgroup of patients receiving >= 1.6 mg DF1001/kg, 5 partial responses were observed, and they occurred in patients with non-small cell lung cancer (n=1) and metastatic breast cancer (n=4). Responses occurred in heavily pre-treated patients and in patients with HER2-low and with HER2-high expressing cancers. Responses were durable, lasting up to 56 weeks. These preliminary clinical results are encouraging and justify further evaluation of DF1001 as monotherapy as well as in combination with other treatments and in defined patient populations.
Preliminary analysis of SWOG S1826: nivolumab-AVD as a new standard therapy for advanced classic Hodgkin lymphoma
LBA4. SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin(BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL).
Alex Francisco Herrera (City of Hope National Medical Center, Duarte, CA) presented results from the second interim analysis of SWOG S1826, which compared nivolumab (N) with doxorubicin, vinblastine, and dacarbazine (AVD) versus brentuximab vedotin (BV)-AVD for stage III or IV classic Hodgkin lymphoma (cHL). PET-adapted combination chemotherapy was the standard treatment for cHL, but approaches differ globally and when treating adults and children. cHL disproportionately affects adolescents and young adults, and this patient population was at increased risk of late effects from chemotherapy and radiation. Bv-AVD improves outcomes in advanced stage cHL, but it is associated with relapse and toxicities. In the S1826 trial, 25% of patients were ages 12 to 17, high-risk patients were included, and adult and pediatric patients received the same treatment, either N-AVD (n = 489) or Bv-AVD (n = 487). The N-AVD arm exhibited no increased risk of infectious toxicities, and rates of immune-related adverse events were low. 8% of patients in the N-AVD arm and 12% of patients in the Bv-AVD arm discontinued treatment. Less than 1% of patients received radiotherapy, potentially reducing the risk of late effects in the younger patient population. At a median follow-up of 12.1 months, the one-year progression free survival (PFS) rate for the N-AVD and Bv-AVD arms were 95% and 86%, respectively, with a hazard ratio (HR) of 0.48. The PFS benefit associated with N-AVD was observed across all subgroups. One-year event free survival rates were 91% and 84% for N-AVD and Bv-AVD, respectively. Overall survival data is not yet mature, and at the median follow-up of 12.1 months there were 4 deaths in the N-AVD arm and 11 deaths in the Bv-AVD arm. Follow-up to confirm durability of PFS and to assess long-term safety, overall survival, and patient-reported outcomes is ongoing. Although the PFS and safety data are preliminary, they are strong indicators for N-AVD as a new standard therapy for advanced cHL, providing a well-tolerated, consistent therapeutic option for adult and pediatric patients.
For related research about Hodgkin lymphoma, read this article by Hochberg et al published in JITC.