publication date: Sep. 14, 2018
Study details incidence and timing of immunotherapy-related fatalities
Vanderbilt-Ingram Cancer Center researchers have answered questions about the incidence and timing of rare but sometimes fatal reactions to the most widely prescribed class of immunotherapies.
Their research, which appeared in JAMA Oncology, is the largest evaluation of fatal immune checkpoint inhibitor toxicities published to date. They determined that although these severe events can happen, the risks are “within or well below” fatality rates for more common cancer treatments, including chemotherapy, stem cell transplants, and complex cancer surgeries.
The study was supported by NIH, NCI, The Cancer ITMO of the French National Alliance for Life and Health Sciences, the James C. Bradford Jr. Melanoma Fund and the Melanoma Research Foundation.
When fatal reactions did occur, they tended to happen early after starting treatment, on average 15-40 days, depending upon the type of immune checkpoint inhibitor. Their study further characterized the fatal toxicities and timing of reaction by type of cancer and specific drug.
“These drugs are quite transformative,” said Douglas Johnson, senior author of the article. “The benefits outweigh the risks, but patients and doctors should be aware of their toxicities. These side effects can be quite severe, and they are something that we really need to pay attention to.”
The team sorted through more than 16 million adverse drug reaction reports in a World Health Organization database searching for those related to immune checkpoint inhibitors. They also reviewed the records from seven academic centers, including Vanderbilt, that have been at the forefront of immunotherapy research. Additionally, they conducted a meta-analysis of published trials for the drugs.
Checkpoint inhibitors unleash the immune system to attack cancer, but they may also spur an attack on organs, including the heart, lungs, liver and colon. Steroids are prescribed to relieve myocarditis, pneumonitis, hepatitis, and colitis, and are usually extremely effective. Timely treatment with steroids is crucial, Johnson said.
“Some of the patients who died had a long delay before they received steroids,” Johnson said. “In some cases, the patient didn’t call in to report their symptoms or experienced a very unusual presentation that was difficult to diagnose.”
The data also showed that older patients were more prone to experience fatal toxicities, although the occurrence was still rare.
“We don’t necessarily think that older patients have more side effects, but when they do have toxicities, they can potentially have more complications,” Johnson said.
The team found 613 fatal immune checkpoint inhibitor toxicities within the more than 16 million reports in the WHO pharmacovigilance database (Vigilyze) from 2009 to 2018.
Myocarditis had the highest fatality rate, as nearly 40 percent of patients with this side effect died.
The review of records from the seven academic centers revealed a 0.6 percent fatality rate. The meta-analysis of data from 112 clinical trials showed a fatality death rate ranging from 0.36 percent to 1.23 percent, depending upon the specific type of immune checkpoint inhibitor.
The study notes that this range is “dramatically lower than the near 100 percent fatality rate for metastatic solid tumors.” The FDA has at this point in time approved immune checkpoint inhibitors for 13 different types of metastatic cancers.
“We have clinics full of patients now who received these treatments who are alive today because they responded to these treatments,” Johnson said.
CARsgen Therapeutics and CrownBio complete CAR-T study for gastric cancer
Crown Bioscience has completed a joint study with CARsgen Therapeutics and Shanghai Cancer Institute, demonstrating the elimination of gastric tumors in mice using CLDN18.2 targeting CAR-T cells. The work was recently published in the Journal of the National Cancer Institute.
CAR-T cells were engineered to target Claudin18.2 and tested in gastric adenocarcinoma PDX models expressing high levels of Claudin 18.2.
“Humanized antibodies were developed and tested for their ability to redirect CAR-T cells on our PDX models. Tumor elimination was observed with no deleterious effect on normal gastric tissue in the mice, further validating it as high value CAR-T target and demonstrating a promising result for gastric and other CLDN18.2 positive tumors,” said Henry Li, a co-author on the paper and senior vice president of research and innovation at Crown Bioscience.
Bavencio + Inlyta improved PFS in advanced RCC
Merck KGaA and Pfizer Inc. announced positive top-line results from the pivotal phase III JAVELIN Renal 101 study evaluating Bavencio (avelumab) in combination with Inlyta (axitinib), compared with Sutent (sunitinib) as initial therapy for patients with advanced renal cell carcinoma.
As part of a planned interim analysis, an independent Data Monitoring Committee confirmed that the trial showed a statistically significant improvement in progression-free survival by central review for patients treated with the combination whose tumors had programmed death ligand-1 positive expression greater than 1 percent (the primary objective), as well as in the entire study population regardless of PD-L1 tumor expression (the secondary objective).
According to the statistical analysis plan, if PFS was statistically significant in the PD-L1+ subgroup, then PFS in the entire study population was to be analyzed for statistical significance. JAVELIN Renal 101 will continue as planned to the final analysis for the other primary endpoint of overall survival.
No new safety signals were observed, and adverse events for Bavencio, Inlyta, and Sutent in this trial were consistent with the known safety profiles for all three medicines. The alliance intends to pursue a regulatory submission in the U.S. based on these interim results, and these results will be discussed with global health authorities. A detailed analysis will also be submitted for presentation at an upcoming medical congress.
In Dec. 2017, the FDA granted Breakthrough Therapy Designation for Bavencio in combination with Inlyta for treatment-naïve patients with advanced RCC. Despite available therapies, the outlook for patients with advanced RCC remains poor. About 20 to 30 percent of patients are first diagnosed at the metastatic stage. The five-year survival rate for patients with metastatic RCC is approximately 12 percent.
JAVELIN Renal 101 is a global Phase III, multicenter, randomized (1:1) study investigating the efficacy and safety of Bavencio in combination with Inlyta as a first-line treatment option compared with SUTENT monotherapy in 886 patients with advanced RCC across all risk groups.
The primary objectives are to demonstrate that Bavencio in combination with Inlyta is superior to Sutent monotherapy in prolonging PFS or OS in patients with PD-L1+ tumors. Bavencio was administered at 10 mg/kg IV every two weeks in combination with Inlyta at 5 mg orally twice daily; Sutent was administered at 50 mg orally once daily, four weeks on/two weeks off.
The combination of Bavencio and Inlyta is under clinical investigation for advanced RCC, and there is no guarantee this combination will be approved for advanced RCC by any health authority worldwide.
In the US, INLYTA is approved as monotherapy for the treatment of advanced RCC after failure of one prior systemic therapy. Inlyta is also approved by the European Medicines Agency for use in the EU in adult patients with advanced RCC after failure of prior treatment with Sutent or a cytokine.
IMV Inc. and Merck to evaluate DPX-Survivac + Keytruda
IMV Inc. said it has expanded its clinical program with a phase II basket trial evaluating its lead candidate, DPX-Survivac, in combination with low dose cyclophosphamide and Merck’s anti-PD-1 therapy, Keytruda (pembrolizumab) in patients with select advanced or recurrent solid tumors.
“The clinical data from our recent ASCO meeting presentation demonstrated for the first time the unique potential of DPX-Survivac to generate solid tumor regressions in ovarian cancer,” said Frederic Ors, chief executive officer of IMV Inc.
The open-label, multicenter, phase II basket study will evaluate the safety and efficacy of the immunotherapeutic combination agents in patients with bladder, liver (hepatocellular carcinoma), ovarian, or non-small cell lung cancers as well as tumors shown to be positive for the microsatellite instability high biomarker.
Investigators plan to enroll more than 200 patients across five indications at multiple medical centers in Canada and the United States. IMV expects to initiate trial enrollment in the 4th quarter of 2018.
This is the third clinical trial evaluating the combination of DPX-Survivac, low dose cyclophosphamide, and pembrolizumab in advanced recurrent cancers. Two ongoing investigator-sponsored phase II trials are evaluating this combination in patients with advanced ovarian cancer and diffuse large B-cell lymphoma.
DPX-Survivac is the lead candidate in IMV’s new class of immunotherapies that programs targeted T cells in vivo. It has demonstrated the potential for industry-leading targeted, persistent, and durable T cell activation against cancer.
This mechanism of action is key to generating durable regressions in solid tumors, IMV said. DPX-Survivac consists of survivin-based peptide antigens formulated in IMV’s proprietary DPX drug delivery platform. DPX-Survivac is believed to work by eliciting a prolonged cytotoxic T cell attack on cancer cells presenting survivin peptides.
Survivin, recognized by NCI as a tumor-associated antigen, is broadly over-expressed in most cancer types, and plays an essential role in antagonizing cell death, supporting tumor-associated angiogenesis, and promoting resistance to anti-cancer therapies. IMV has identified over 15 cancer indications in which the over-expression of survivin can be targeted by DPX-Survivac.
DPX-Survivac has received Fast Track designation from FDA as maintenance therapy in advanced ovarian cancer, as well as orphan drug designation status from the U.S. FDA and the European Medicines Agency in the ovarian cancer indication. It is currently being evaluated in multiple phase Ib/II clinical trials.
Clinical trial shows best outcomes to date for older Hodgkin lymphoma patients
Recently published results of a phase II clinical trial have shown the best outcomes to date for newly diagnosed older Hodgkin lymphoma patients treated with brentuximab vedotin given before and after doxorubicin, vinblastine and dacarbazine (AVD) chemotherapy, which is the standard of care.
Causes of poor outcomes for older Hodgkin lymphoma patients are not well understood although inability to tolerate full doses of chemotherapy, the existence of co-morbidities, disease biology, and other factors have often been attributed.
The aim of this multicenter, investigator-initiated study was to improve outcomes for this difficult to treat population. Results of the work were published in the September 4 online edition of the Journal of Clinical Oncology (doi: 10.1200/JCO.2018.79.0139).
In this study, participants who were initially untreated for their disease received two ‘lead-in’ doses of single-agent brentuximab vedotin, which were followed by six cycles of standard AVD chemotherapy. Responding subsequently patients received four brentuximab vedotin consolidation cycles. Enrolled were 48 patients with a median age of 69; 82 percent had advanced stage disease and 60 percent had high-grade co-morbidities.
The overall response rate to the initial brentuximab vedotin lead-in dose was 82 percent with a complete remission rate of 36 percent. After first-line chemotherapy was administered, the overall response rate and remission rates were 95 percent and 90 percent, respectively.
Additionally, the two-year progression-free survival rate was 84 percent with an associated overall survival rate of 93 percent on intent-to-treat analyses. In addition, baseline assessment of geriatric measures including activities of daily living and presence of co-morbidities was strongly prognostic for patient outcome in this study.
The authors said study limitations include the inability of some patients to complete therapy as planned (23 percent did not receive the prescribed six AVD cycles; 48 percent did not complete brentuximab vedotin consolidation cycles). Strategies to decrease the length of the therapy, either through individual drugs or number of cycles administered, should also be explored.
The research was funded as an investigator-initiated clinical trial via Seattle Genetics. An earlier version of the work was presented at the December 2017 American Society of Hematology Annual Meeting; and in part at the 10th International Symposium on Hodgkin Lymphoma in October 2016 in Cologne, Germany. Additional details including information on conflicts of interest can be found at: doi: 10.1200/JCO.2018.79.0139.
Children who develop ALL may have dysregulated immune function at birth
A study has found that neonatal concentrations of eight detectable inflammatory markers were significantly different in children later diagnosed with B-cell precursor acute lymphoblastic leukemia compared with controls.
The study, published in Cancer Research, a journal of the American Association for Cancer Research, was conducted by Signe Holst Søegaard, a fellow in the Department of Epidemiology Research at Statens Serum Institut in Copenhagen, Denmark.
“Our findings suggest that children who develop ALL are immunologically disparate already at birth,” said Søegaard. “This may link to other observations suggesting that children who develop ALL respond differently to infections in early childhood, potentially promoting subsequent genetic events required for transformation to ALL, or speculations that they are unable to eliminate preleukemic cells.
Prior research indicates that ALL could develop in children because of an overreaction to infections in childhood, Søegaard said. This may hold promise for the prevention of childhood ALL through early immune modulation.
Søegaard and colleagues used data from Denmark’s Neonatal Screening Biobank and nationwide registers to assess baseline characteristics of the immune system of children born in Denmark from 1995 to 2008, who at ages 1–9 years were diagnosed with B-cell precursor ALL, the most common ALL subtype in children.
They measured the concentrations of inflammatory markers, including cytokines and acute inflammatory proteins, on neonatal dried blood spots from 178 childhood ALL patients and 178 matched leukemia-free controls.
Inflammatory markers included interleukin-6, its soluble receptor sIL-6R, IL-8, IL-10, IL-12, IL-17, IL-18, transforming growth factor-1, monocyte chemotactic protein-1, and C-reactive protein.
“These markers were chosen to provide a broad picture of the neonatal immune response,” Søegaard said.
The study found children who later developed B-cell precursor ALL had statistically significantly different neonatal concentrations of eight of the nine analyzed inflammatory markers, compared with controls. IL-10 concentrations were too low for accurate measurement.
Neonatal concentrations of sIL-6R, IL-8, TGF-1, MCP-1, and CRP were statistically significantly lower, while concentrations of IL-6, IL-17, and IL-18 were statistically significantly higher among B-cell precursor ALL patients, compared with controls.
“We also demonstrated that several previously shown ALL risk factors, namely birth order, gestational age, and sex were associated with the neonatal concentrations of inflammatory markers,” Søegaard said. “These findings raise the interesting possibility that the effects of some known ALL risk factors partly act through prenatal programming of immune function.”
Limitations of the study include the small number of studied inflammatory markers and the limited sample size, which made it impossible to detect potential differences in the association with inflammatory markers between subtypes of B-cell precursor ALL, Søegaard said.
“Importantly, our study does not inform about the nature of the associations observed, i.e., whether they are causal or consequential. Accordingly, further studies are needed both to confirm the findings and to identify the underlying mechanisms,” she said.
The study was conducted in collaboration with researchers at Statens Serum Institut in Copenhagen, University Hospital Rigshospitalet, Copenhagen, and University of Southern California, Los Angeles. The research was sponsored by the Dagmar Marshall Foundation, the A.P. Møller Foundation, the Danish Childhood Cancer Foundation, the Arvid Nilsson Foundation, and the Danish Cancer Research Foundation. Søegaard declares no conflict of interest.
Drug for pancreatic cancer targets two genes at a time
A University of Houston researcher has developed a synthetic compound, MA242, that can inhibit two of the major pathways of highly aggressive pancreatic cancer.
Ruiwen Zhang, a Robert L. Boblitt Endowed Professor in Drug Discovery, has published his findings, along with research associate professor of pharmacology Wei Wang, in Cancer Research Journal.
The drug may be a first-in-class, new therapy for pancreatic cancer and a new conceptual framework for developing other drugs.
“We developed a synthetic compound that we call MA242, and it can deplete both proteins at the same time increasing specificity and efficiency of tumor killing,” said Zhang. “In our molecular modeling study, MA242 is a potent dual inhibitor.” Though man-made, the new compound is based on a type of sea sponge.
Stromal depletion and immunotherapy also have been proposed to offer substantial promise for treating advanced pancreatic cancer, but their therapeutic impact remains unclear.
The two cancer-causing genes linked in pancreatic cancer are nuclear factor of activated T cells 1 and murine double minute 2, a gene that regulates, and depletes, the tumor suppressor gene called p53. If there is no tumor suppressor p53 present, MDM2 will cause cancer on its own. NFAT1 up-regulates MDM2 expression and encourages tumor growth.
Patients with pancreatic cancer have too much MDM2 and NFAT1, which has left these genes as open targets for cancer therapy. Numerous studies have shown reduced MDM2 can lead to decreased tumor growth and progression. Healthy individuals have low levels of MDM2 and NFAT1, but diet, nutrition and environment can cause higher levels in cells, said Zhang.