The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in immunotherapy emerging from the ESMO Immuno-Oncology Virtual Congress 2020. Below is a recap of highlighted research presented from Wednesday, Dec. 9 through Saturday, Dec. 12, 2020.
BIOMARKER ANALYSIS INDICATES PATIENTS WHO MAY BENEFIT FROM ADJUVANT ATEZOLIZUMAB
Clinical outcomes in post-operative ctDNA-positive muscle-invasive urothelial carcinoma (MIUC) patients after atezolizumab adjuvant therapy
Dr. Thomas Powles (Barts Cancer Centre) presented an analysis of a subpopulation of patients with muscle-invasive urothelial cancer from the IMvigor010 study who had evaluable circulating tumor DNA (ctDNA). ctDNA has been associated with recurrence in other cancers, and so in this analysis the investigators analyzed the responses of patients with or without detectable ctDNA as well as the dynamics of ctDNA over the course of adjuvant atezolizumab treatment for patients with muscle invasive urothelial cancer.
Of the ITT population, 581 patients (72%) in IMvigor010 were biomarker-evaluable. Of these patients, 37% were ctDNA+, and the presence of ctDNA was associated with nodal status at baseline. ctDNA+ patients appeared to derive more benefit from adjuvant atezolizumab than ctDNA-, with both disease-free survival (HR: 0.58) and interim overall survival (HR: 0.59) benefits compared to observation. Patients without ctDNA present did not derive benefit from adjuvant atezolizumab compared to observation. ctDNA was cleared more rapidly with atezolizumab treatment than with observation alone. In ctDNA+ patients treated with atezolizumab, further improvements in survival outcomes were associated with either PD-L1 positivity (HR: 0.52) or TMB-high tumors (HR: 0.34). This study points to a possible subpopulation of urothelial cancer patients who may benefit from adjuvant immunotherapy treatment, and highlights the importance of biomarker selection.
QUALITY-OF-LIFE IMPROVEMENTS REPORTED FOR PATIENTS WITH MPM TREATED WITH COMBINATION IMMUNOTHERAPY
First-line nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) for the treatment of unresectable malignant pleural mesothelioma (MPM): Patient-reported outcomes (PROs) from CheckMate 743
Dr. Arnaud Scherpereel (University of Lille) presented patient-reported outcomes from the CheckMate 743 trial, which investigated the combination of nivolumab and ipilimumab for the treatment of malignant pleural mesothelioma compared to standard-of-care chemotherapy. The exploratory PRO endpoints were measured using four scales (two for symptom burden and two for HRQoL): disease-related symptom burden through the Lung Cancer Symptom Scale (LCSS)-Meso average symptom burden index (ASBI) and the three-item global index (3-IGI); while health-related quality of life was assessed with the EQ-5D-3L utility index (UI) and visual analogue scale (VAS).
Patients were evaluated before each dose of therapy on day 1 of each cycle for 12 weeks, then every 6 weeks for one year, and every 12 weeks thereafter, if still on study. This led to data being collected for nivo/ipi patients for up to 96 weeks, while chemotherapy data was collected for 36 weeks. Over the course of the trial, patients treated with immunotherapy reported improved disease symptoms by both the ASBI and 3-IGI scales, though the difference from the chemotherapy arm did not meet statistical significance. The only symptom that was not improved with immunotherapy treatment was cough, which remained stable. HRQoL was also improved with nivo/ipi treatment; in fact, patients who were treated for at least two years reported scores on the EQ-5D-3L VAS that were similar to the general UK population. Time-to-definitive deterioration was improved with nivo/ipi, with a HR of 0.52 using ASBI. Overall, the study emphasizes the benefits beyond cancer responses for patients treated with combination immunotherapy.
CYTOKINE-INDUCED KILLER CELLS DEMONSTRATE BENEFITS FOR NSCLC
Randomized, multicenter, open-label trial of autologous cytokine-induced killer cell immunotherapy plus chemotherapy for squamous non-small cell lung cancer
A clinical trial of cytokine-induced killer cells (CIKs) for patients with untreated squamous non-small cell lung cancer was discussed by Dr. Xiubao Ren (Tianjin Medical University Cancer Institute and Hospital). Ninety patients were randomized to receive CIKs in combination with gemicitabine and cisplatin, or chemotherapy alone, with the primary endpoint of progression-free survival. The CIKs are CD3+CD56+ cells that were expanded ex vivo.
A benefit was noted for the CIK + chemotherapy group in major measures of efficacy. Overall response rates also favored the combination, doubling from 31.1% with chemotherapy alone, to 62.2% with the combination in this trial. In the cellular therapy combination group, PFS was extended by 4.7 months (8.7 vs. 4.0 months, HR: 0.26), and the median OS was also longer (21.0 vs. 10.3 months, HR: 0.22). Any grade adverse events occurred in 93.3% of patients in the CIK arm and 100% in the control. Notably, nausea and/or vomiting was reduced in the CIK arm, while fever was increased, compared to chemotherapy treatment alone. A few outstanding questions remain with this therapy, including the impact of chemotherapy treatments given after the CIK infusion, and whether pre-treatment lymphodepletion should be considered in the future.
You can read about other methods for improving the success of adoptive cellular therapy in a recent article from the Journal for ImmunoTherapy of Cancer (JITC).
CHECKPOINT INHIBITION + CHEMOTHERAPY MAY BE NEOADJUVANT OPTION FOR NSCLC
A randomised, controlled, multicenter phase II trial of camrelizumab combined with albumin-bound paclitaxel and cisplatin as neoadjuvant treatment in locally advanced NSCLC
Dr. Jie Lei (Fourth Military Medical University, Xi’an) presented an interim analysis of a phase 2 study of the anti-PD-1 antibody camrelizumab in combination with chemotherapy as neoadjuvant treatment for patients with resectable stage III NSCLC. Patients were randomized to either camrelizumab with albumin-bound paclitaxel and cisplatin or chemotherapy alone, each for three cycles followed by surgery. The primary endpoint was pathologic complete response rate.
At the time of interim analysis, 27 of 94 planned patients were enrolled and 14 patients had completed the full neoadjuvant regimen and underwent surgery. More pathological complete responses (pCR) were noted in the immunotherapy-containing arm, with 57% of patients demonstrating a pCR compared to 14% with chemotherapy alone. Overall response rate was also higher in the camrelizumab arm, at 85% compared to 28%. The investigators observed similar rates of adverse events in the two arms, with no grade 4-5 events recorded. The combination of immune checkpoint inhibition and chemotherapy may therefore be a potential option for neoadjuvant management of NSCLC, although survival outcomes need to be elucidated.
PI3K INHIBITOR MAY BE EFFECTIVE TREATMENT FOR B-CELL CANCERS
A phase I study of SHC014748M capsules in patients with relapsed or refractory indolent B-cell malignancies
An orally available PI3K-delta inhibitor, SHC014748M, was explored in patients with B cell malignancies in a trial reported by Dr. Wei Xu (Nanjing Medical University). The dose escalation phase of the trial enrolled three patients into each of five dose levels from 50-250 mg QD, while 12 patients were enrolled into the expansion cohorts of 150 and 200 mg QD. Primary endpoints of the trial included safety and tolerability, and pharmacokinetics, and secondary outcomes included ORR.
Patients in the trial had different types of B cell malignancies, including most commonly follicular lymphoma and CLL/SLL. No dose-limiting toxicities were observed; the most common any-grade adverse events were neutropenia, elevated LDH and decreased platelet counts. Grade 3+ events included neutropenia, diarrhea, pneumonitis, rash and anemia. After 28 days of exposure, pharmacokinetic studies found the Tmax to be between 1-2 hours, and the half-life ranged from 14 to 22 hours. Across all dose levels, the ORR was 59.0%, with a higher response rate of 66.7% in the 200 mg expansion cohort. The highest rates were seen among patients with follicular lymphoma, reaching 72.7% in the 200 mg dosing level. The investigators propose further investigation of this agent in follicular lymphoma as a result of this study.
VACCINATION AND PD-L1 BLOCKADE MAY BENEFIT HPV+ MALIGNANCIES
TG4001 therapeutic vaccination combined with PD-L1 blocker avelumab remodels the tumor microenvironement (TME) and drives antitumor responses in human papillomavirus (HPV)+ malignancies
The combination of an HPV E6/E7 vaccine, TG4001, with the PD-L1 inhibitor avelumab was tested in a trial presented by Dr. Christophe Le Tourneau (Institut Curie) for patients with HPV-related malignancies. Patients had oropharyngeal, anal, cervical, or vulvar/vaginal cancers and were treated with the vaccine subcutaneously weekly for six weeks, Q2W up to month 6, and then Q12W in addition to avelumab Q2W throughout the whole study.
T cells reactive against HPV E6, E7 or both were observed in 7/11 evaluable patients following vaccination. The overall response rate in all patients was 23.5%. Patients without liver metastases had an ORR of 34.8% and a median PFS of 5.6 months, leading to a PFS HR of 0.2 when comparing patients with or without liver metastases. One patient with a CR demonstrated strong HPV T cell responses that persisted past 6 months. Several baseline patient characteristics correlated with likelihood of response, including higher levels of PD-L1 expression and CD3 or CD8-positive T-cell infiltration. The inflammation and immune infiltration of tumors was increased over the course of treatment, indicating vaccine-induced immune responses. This therapeutic approach is being further tested in later-stage trials, particularly for patients with limited liver involvement.
UVEAL MELANOMA MAY BE TREATABLE WITH TEBENTAFUSP
A phase (ph) II, multi-center study of the safety and efficacy of tebentafusp (tebe) (IMCgp100) in patients (pts) with metastatic uveal melanoma (mUM)
Dr. Joseph Sacco (Clatterbridge Cancer Center) presented a study of tebentafusp for patients with metastatic uveal melanoma. Tebentafusp is able to redirect T cells to gp100+ cells, including melanoma cells and melanocytes, through an affinity-enhanced TCR fused to an anti-CD3 effector. This trial investigated tebentafusp in 127 pretreated patients with the primary endpoint of ORR.
Partial responses and stable disease were observed in 5% and 45% of patients, respectively. A reduction in target lesions was noted in 44% of evaluable patients. The ORR was 5%; median OS was 16.8 months, and a 12-month OS rate of 62% was observed in all patients. Consistent with the mechanisms of tebentafusp, the majority of treatment-related adverse events were cutaneous or cytokine-mediated, and included pyrexia, pruritus and chills. Common grade 3+ events included rash, hypotension, increased AST and hypophosphatemia, and the incidence of higher-grade events decreased after the first few doses of therapy. Mostly low-grade CRS was noted in 86% of patients. One marker for potential response was the appearance of a rash within a week of starting therapy, potentially indicating immune activation. A randomized control trial of tebentafusp is underway with the endpoint of overall survival.
A recent JITC article discussed the role of checkpoint inhibitors in uveal melanoma.
IPILIMUMAB AND NIVOLUMAB REGIMEN SAFE IN GLIOBLASTOMA
A phase I clinical trial on intratumoural (IT) administration of ipilimumab (IPI) plus nivolumab (NIVO) followed by intracavitary (IC) administration of nivolumab in patients with recurrent glioblastoma
Dr. Julia Katharina Schwarze (Universitair Ziekenhuis Brussel) presented results from the GlITIpNi trial, investigating ipilimumab and nivolumab as management for recurrent glioblastoma. Patients with unresectable disease were enrolled in cohort 3 (n=17), while cohort 4 included resectable disease (n=15). Intratumoral delivery of ipilimumab and nivolumab was followed by intracavitary plus intravenous nivolumab.
All patients received the full dose of intratumoral therapy, with a median of 4-5 doses of IC/IV nivolumab as well. Common adverse events included fatigue, headache, fever and seizures, with no grade 4 or 5 adverse events reported. No dose-limiting toxicities occurred. One patient responded in the unresectable cohort, with an ongoing response after 92 weeks. The rest of the enrolled patients all had progressive disease. There was evidence of lymphocytic pleocytosis and increased protein levels in 5/17 and 6/15 patients in cohorts 3 and 4, respectively, although accumulation of nivolumab and ipilimumab in the CSF was not evident. The investigators aim to further improve the efficacy of this therapy through additional combinations and further studies.
Biomarkers for immunotherapy in glioblastoma were investigated in a recent JITC paper.