Cardiovascular toxicities seen early in treatment with immune checkpoint inhibitors

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Cardiovascular toxicities seen early in treatment with immune checkpoint inhibitors

In the first large-scale analysis of cardiovascular complications linked to immune checkpoint inhibitors, Vanderbilt researchers have shown that cardiovascular complications include myocarditis, pericarditis, vasculitis and arrhythmias, and that they occur early in the course of treatment.

The study, published online Nov. 12 in The Lancet Oncology, augments previous work by Vanderbilt University Medical Center researchers who first reported in 2016 rare but fatal cardiac side effects from the most widely prescribed class of immunotherapies.

The researchers used VigiBase, a global database of drug complications maintained by the World Health Organization, to track adverse cardiovascular reactions in the latest study.

“When the immune system wakes up to attack the cancer cells, in rare situations it can also attack the heart and vessels, and in some cases, this can result in fatalities,” said Joe-Elie Salem, a Vanderbilt Cardio-Oncology fellow and the study’s first author.

Fatalities occurred in half of myocarditis cases (inflammation of heart muscle), 21 percent of pericardial cases (inflammation of the sac that surrounds the heart) and 6 percent of vasculitis cases (inflammation of blood vessels).

Fatalities with myocarditis occurred more often with combination therapy (65.6 percent) than monotherapy (44.4 percent). The new Vanderbilt study advises clinicians to monitor for pericardial disease and vasculitis.

Javid Moslehi, director of the Cardio-Oncology Program at VUMC and the study’s senior author, presented the study’s findings Nov. 12 at the American Heart Association Scientific Sessions 2018 in Chicago. The cardiovascular complications can also occur simultaneously with neurological complications, including myasthenia gravis, Moslehi said.

“This study suggests a role for a multi-disciplinary group that will help us characterize these novel and diverse side-effects of immunotherapies and identify those at risk,” said Douglas Johnson, director of the melanoma program at Vanderbilt-Ingram Cancer Center and a study author.

Johnson, Moslehi and colleagues are forming an immuno-toxicity group with the hope of utilizing Vanderbilt resources like the REDCap database to track these toxicities. In addition, the group has established a web-based link for physicians nationally to report cases of cardiovascular complications related to immune checkpoint inhibitors, linking these cases to REDCap to collect data on the cases.

While cardiovascular complications have been identified as most likely to result in fatalities, checkpoint inhibitors may also spur reactions in the lungs, liver and colon. Vanderbilt researchers detailed the incidence of these fatal reactions Sept. 13 in JAMA Oncology. With other complications, steroids are prescribed to relieve the resulting inflammation and can be effective.

The study just published in The Lancet Oncology focuses on cardiovascular complications, including myocarditis and pericarditis.

The researchers also found 18 cases of temporal arteritis with a risk for blindness occurring with vasculitis. Visual impairment and blindness occurred with one-third of those cases.

Breast screening linked to 60 percent lower risk of breast cancer death in first 10 years

Women who take part in breast screening have a significantly greater benefit from treatments than those who are not screened, according to a study of more than 50,000 women, led in the UK by Queen Mary University of London.

The research, using data from Sweden, finds that women who chose to participate in an organised breast cancer screening programme had a 60 percent lower risk of dying from breast cancer within 10 years after diagnosis, and a 47 percent lower risk of dying from breast cancer within 20 years after diagnosis.

The authors say that this benefit occurs because screening detects cancers at an earlier stage, meaning that they respond much better to treatment.

The study was co-authored and funded by the American Cancer Society and appears in the American Cancer Society’s peer-review journal Cancer.

In the UK, mammography screening is offered to all women aged 50-70 through the NHS Breast Screening Programme, with participation rates averaging more than 70 per cent but varying dramatically across the country, with lower rates in poorer, inner-city areas.

“Recent improvements in treatments have led to reduced deaths from breast cancer. However, these new results demonstrate the vital role that screening also has to play, giving women a much greater benefit from modern treatments,” said senior author Professor Stephen Duffy, of Queen Mary University of London. “We need to ensure that participation in breast screening programmes improves, especially in socio-economically deprived areas.”

The study involved 52,438 women aged 40 to 69 years in the county of Dalarna, Sweden, during 39 years of the screening era (1977-2015). All patients received stage-specific treatment according to the latest national guidelines, irrespective of the mode of detection.

The investigators, led by Laszlo Tabar, of Falun Central Hospital in Sweden, used a new method to improve the evaluation of the impact of organised mammography screening on death from breast cancer, by calculating the annual incidence of breast cancers causing death within 10 years and within 20 years after breast cancer diagnosis.

The paper can be found here.

Fecal transplant effective against immunotherapy-induced colitis

For the first time, transplanting gut bacteria from healthy donors was used to successfully treat patients suffering from severe colitis caused by treatment with immune checkpoint inhibitors.

The study from MD Anderson Cancer Center, which includes two patients, suggests fecal microbiota transplantation is worth investigating in clinical trials as a therapy for this common side effect of immunotherapy.

The research, led by Yinghong Wang, assistant professor of Gastroenterology, Hepatology & Nutrition and director of Medication Induced Colitis and Enteritis, was published today in Nature Medicine.

“The resolution of colitis in these patients can be confirmed clinically and endoscopically after FMT treatment,” said Wang. “Based on these results, this should be evaluated even as a first-line therapy for ICI-associated colitis because it’s safe, quick, and the effect is durable – from one treatment.”

Immune checkpoint inhibitors, which release a block on the immune system to attack cancer, have been successful in providing durable responses for patients with several cancer types. However, these treatments are often associated with significant immune-related toxicities.

Colitis, inflammation of the colon, is the second most common side effect from ICIs, occurring in up to 40 percent of patients, explained Wang. When ICI-associated colitis is severe, guidelines require a patient to stop ICI treatment until the colitis is in remission.

“If the patient is a good responder to immunotherapy, that means you’ve taken their effective treatment away,” said Wang. “We have a limited amount of time to fix the problem so they can resume ICI treatment, but I feel that we’ve made great progress in this area.”

The researchers chose to investigate the potential for FMT as an alternative, compassionate-use therapy for patients suffering from refractory, or unresponsive, ICI-associated colitis. The two patients included in the study were treated at MD Anderson between June 2017 and January 2018.

FMT has shown promise in treating other types of gastrointestinal diseases, such as recurrent Clostridium difficile infection and inflammatory bowel disease, which shares many clinical and molecular characteristics with ICI-associated colitis.

These conditions typically are treated with steroids and targeted immunosuppressive agents, which result in additional severe side effects and can counteract the effects of immunotherapy.

Both patients in the study had a complete resolution of their colitis following treatment with FMT. The first patient’s colitis resolved within two weeks following a single FMT treatment; the second patient experienced a partial recovery after the first treatment, followed by complete recovery after a second FMT.

With endoscopic evaluation before and after treatment, both patients displayed significant improvements in inflammation and ulcerations, including a reduction of inflammatory immune cells.

Pre- and post-treatment stool analyses revealed patients’ gut microbiomes to be most similar to the donor immediately after treatment, with less resemblance to the donor over time. Still, post-treatment gut bacteria remained distinct from their own pre-treatment microbiome.

Additionally, distinct new populations of bacterial species were evident in these patients following FMT compared to pre-treatment samples, including several species known to be protective or reduce inflammation.

The authors acknowledge significant limitations to this study based on the very small cohort, and they plan to pursue clinical trials to investigate the effectiveness of FMT in treating ICI-associated colitis as compared with standard immunosuppressive therapy. FMT continues to be offered to MD Anderson patients on a compassionate-use basis.

Previous MD Anderson research showed that bacteria in the gut influence patient response to ICI therapy, and other evidence suggests modifying the microbiome in mice can alter their response to immunotherapy.

The current data further suggests there is the potential for many molecular studies to better understand the role of the microbiome in driving ICI-colitis and immunotherapy response more broadly.

The study was supported by the Andrew Sabin Family Fellowship Program; the American Association for Cancer Research – Stand Up to Cancer; the National Institutes of Health (CA219896-01A1, HL124112); the Cancer Prevention & Research Institute of Texas; and the Melanoma Moon Shot, part of MD Anderson’s Moon Shots Program.

Biodesix test predicts response to atezolizumab in lung cancer

Researchers with Biodesix and Genentech presented findings on a test designed to predict response to atezolizumab (Tecentriq) in patients with non-small cell lung cancer.

The blood-based test, which uses expression data from the circulating proteome to classify patients, was found to be predictive for OS and PFS between atezolizumab and docetaxel, the companies said.

Genentech is a member of the Roche Group.

These data suggest a patient’s likelihood of benefiting from PD-L1 checkpoint inhibition can be identified through circulating proteome in blood samples. Researchers presented their findings at the Society for Immunotherapy of Cancer annual meeting in Washington, D.C.

Keytruda significantly improved OS compared to chemotherapy in PD-L1 advanced esophageal or esophagogastric junction carcinoma

Merck announced the phase III KEYNOTE-181 trial investigating Keytruda as monotherapy in the second-line treatment of advanced or metastatic esophageal or esophagogastric junction carcinoma has met a primary endpoint of overall survival in patients whose tumors expressed PD-L1 (Combined Positive Score ≥10).

In this pivotal study, treatment with Keytruda resulted in a statistically significant improvement in OS compared to chemotherapy (paclitaxel, docetaxel, or irinotecan) in patients with CPS ≥10, regardless of histology.

The primary endpoint of OS was also evaluated in patients with squamous cell histology and in the entire intention-to-treat study population. While directionally favorable, statistical significance for OS was not met in these two patient groups.

Per the statistical analysis plan, the key secondary endpoints of progression-free survival and objective response rate were not formally tested, as OS was not reached in the full ITT study population.

The safety profile of Keytruda in this trial was consistent with that observed in previously reported studies. Results will be presented at an upcoming medical meeting and will be submitted to regulatory authorities worldwide.

KEYNOTE-181 is a randomized, open-label, phase III trial (, NCT02564263) investigating Keytruda monotherapy compared to chemotherapy in patients with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or Siewert type I adenocarcinoma of the esophagogastric junction that has progressed after first-line standard therapy.

The primary endpoint was OS (evaluated in all patients as well as in patients with PD-L1 CPS ≥10 and in patients with squamous cell carcinoma). Secondary endpoints were PFS, ORR and safety/tolerability.

The study enrolled more than 600 patients who were randomized 1:1 to receive either Keytruda (200 mg fixed dose every three weeks) or investigator’s choice of any of the following chemotherapy regimens, all given intravenously: docetaxel (75 mg/m^2 on Day 1 of each 21-day cycle), paclitaxel (80-100 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle), or irinotecan (80 mg/m^2 on Day 1 of each 14-day cycle).

Pfizer introduces biosimilar Retacrit injection in the U.S. at a substantial discount

Pfizer Inc. announced the introduction of Retacrit (epoetin alfa-epbx) injection, the first available biosimilar to Procrit (epoetin alfa) and Epogen (epoetin alfa) in the U.S, at a substantial discount.

Pfizer began shipment of Retacrit to wholesalers in the U.S. on Nov. 12.

Retacrit will be introduced at a Wholesale Acquisition Cost of $11.03 per 1,000 units/mL, which is 57.1 percent below the WAC of Procrit (epoetin alfa) [$25.72 per 1,000 units/mL] and 33.5 percent below the WAC of Epogen (epoetin alfa) [$16.58 per 1,000 units/mL], its reference product.

WAC is not inclusive of discounts to payers, providers, distributors and other purchasing organizations.

The Centers for Medicare and Medicaid Services has granted two unique assigned Q codes for Retacrit: Q5105 for End-Stage Renal Disease on dialysis and Q5106 for non-ESRD.

Additionally, Retacrit qualifies for pass-through status under the hospital outpatient prospective payment system.

Retacrit is Pfizer’s third available biosimilar in the U.S. Pfizer also has an extensive biosimilars pipeline, including three biosimilars products currently accepted for review by the FDA. Pfizer has entered into an agreement with Vifor Pharma Inc. for the commercialization of Retacrit in certain channels.

Initial data from AMBER trial of TSR-022 + TSR-042 demonstrates clinical activity in progression following anti-PD-1 treatment

TESARO Inc. presented initial data from the phase I AMBER trial of TSR-022 (anti-TIM-3 antibody) in combination with TSR-042 (anti-PD-1 antibody) in patients who have progressed following anti-PD-1 therapy treatment, in an oral session during the 2018 Annual Meeting of the Society for Immunotherapy of Cancer Conference in Washington, D.C.

Additionally, phase I GARNET data of TSR-042 in patients with previously treated recurrent/advanced non-small cell lung cancer and phase I monotherapy dose-escalation data for TSR-033 (anti-LAG-3 antibody) in a broad range of solid tumors were also highlighted in poster presentations.

AMBER is an ongoing, open-label, phase I study of TSR-022, an anti-TIM-3 antibody, in monotherapy or in combination with TSR-042, an anti-PD-1 antibody. The TSR-022 and TSR-042 combination portion of the study consists of dose-escalation and expansion cohorts.

Data presented at SITC included safety and efficacy data from the combination dose-escalation and two expansion cohorts: NSCLC patients that had progressed following anti-PD-1 treatment and melanoma patients that had progressed following anti-PD-1 treatment. Patients were treated with 100 milligrams or 300 milligrams of TSR-022 in combination with a fixed dose of TSR-042 (500 milligrams) every 3 weeks.

A dose response trend was observed in both the NSCLC and melanoma cohorts based on greater clinical activity observed in patients treated with a 300 milligram dose of TSR-022 as compared to a 100 milligram dose.

At the time of data cutoff, 39 patients with NSCLC who had progressed following anti-PD-1 treatment had received treatment with the TSR-022 and TSR-042 combination, including 14 patients at the 100 milligram dose and 25 patients at the 300 milligram dose of TSR-022.

Among the 11 evaluable patients treated with the 100 milligram dose of TSR-022, 1 had a confirmed partial response by immune related RECIST criteria and 3 had stable disease. Among the 20 evaluable patients treated with the 300 milligram dose of TSR-022, 3 had confirmed partial responses and 8 had stable disease.

All objective responses were in PD-L1 positive (TPS ≥ 1%) patients, indicating potential for biomarker enrichment. Sixteen patients had known PD-L1 positive tumors. Among the 12 evaluable patients with PD-L1 positive tumors treated with either the 100 or 300 milligram dose of TSR-022, 4 patients had confirmed partial responses (3 responses ongoing) and 6 had stable disease.

Preliminary safety findings indicate that the combination of TSR-022 and TSR-042 was generally well-tolerated. Pharmacokinetic analysis showed that a 300 mg dose is not sufficient to maintain maximal pharmacodynamic effect and suggests that a 900 milligram dose of TSR-022 should maintain a maximal effect in the vast majority of patients for the duration of the Q3W dosing interval.

Patients with NSCLC who have progressed following anti-PD-1 treatment are currently being enrolled in the NSCLC expansion cohort at the 900 milligram dose of TSR-022 in combination with TSR-042. Additional data from this cohort (900 milligram dose) and the melanoma cohort (100 and 300 milligram doses) are expected in 2019.

GARNET is an ongoing phase I study evaluating TSR-042 as a monotherapy in patients with advanced solid tumors. The ongoing cohort expansion portion of GARNET is evaluating TSR-042 at a dose of 500 milligrams every 3 weeks for the first 4 cycles and 1,000 milligrams every 6 weeks thereafter in four cohorts: MSI (microsatellite instability)-high endometrial cancer, MSI-high non-endometrial cancer, MSS (microsatellite-stable) endometrial cancer and previously treated recurrent/advanced anti-PD-1 naïve NSCLC.

Data presented at SITC included safety and efficacy data from the cohort of patients with NSCLC, which is fully enrolled.

At the time of data cutoff, 67 patients with previously treated recurrent/advanced anti-PD-1 naive NSCLC had received treatment with TSR-042, and 47 patients had at least one post-baseline tumor assessment or had discontinued treatment prior to first baseline assessment.

Among these 47 patients, 15 had partial responses (including 2 unconfirmed responses that have not yet progressed) by irRECIST criteria for an overall response rate of 31.9 percent; 14 additional patients (29.8%) had stable disease. Responses were durable and nine of the 15 responses are ongoing (60%).

The majority of patients (32 of 34; 94%) with available PD-L1 status had TPS <50% and clinical activity of TSR-042 was observed across all PD-L1 TPS categories. Among the 32 patients with low PD-L1 expression, 13 patients had TPS 1-49%, of which 5 had partial responses (ORR of 38.5%; including one unconfirmed response), and 19 patients had TPS <1%, of which 3 had partial responses (ORR of 15.8%).

Preliminary safety findings indicate TSR-042 was generally well-tolerated, with a safety profile characteristic of approved anti-PD-1 inhibitors for NSCLC.

The GARNET study is intended to support a Biologics License Application submission to the FDA in 2019 for patients with recurrent endometrial cancer.

Data from the monotherapy dose-escalation portion of the CITRINO study were presented and included 30 patients treated with different doses of TSR-033. There were no Grade ≥3 treatment-related treatment emergent adverse events reported. Exposure and peripheral receptor occupancy increased in a dose proportional manner from 20 milligrams to 720 milligrams.

These preliminary findings indicate that TSR-033 was generally well tolerated across multiple dose levels, with a safety profile consistent to those of other immune checkpoint inhibitors.

Enrollment is ongoing for patients treated with TSR-033 in combination with 500 milligrams of TSR-042.

Zymeworks announces updated clinical data for novel bispecific antibody, ZW25

Zymeworks Inc., announced the plenary presentation of updated ZW25 clinical data by Murali Beeram, a clinical investigator at the START Center for Cancer Care in San Antonio.

The data were presented at the Symposium on Molecular Targets and Cancer Therapeutics, sponsored by the European Organization for Research and Treatment of Cancer, NCI, and the American Association for Cancer Research. The title is “Single Agent Activity of ZW25, a HER2-Targeted Bispecific Antibody, in HER2-Expressing Gastroesophageal and Other Cancers.”

Data from Zymeworks’ ongoing multi-center phase I study showed single agent ZW25, a bispecific antibody, induced anti-tumor activity and was well tolerated in heavily pretreated patients with a variety of HER2-expressing cancers.

The plenary presentation includes all 24 gastroesophageal and other cancer patients treated at the phase II recommended dose, of which 17 were response-evaluable (defined as having measurable disease and at least one tumor restaging) at the time of data cut-off.

Of these 17 patients, eight had gastroesophageal cancers, four had colorectal cancer, and five had other HER2-expressing cancers including gallbladder, cholangiocarcinoma, cervical, fallopian tube and salivary gland. The participants in the study were heavily pretreated with a median of three prior cancer treatments.

The overall disease control rate, which includes patients with partial responses and stable disease was 82 percent. There were seven partial responses (41%), seven stable disease (41%) and three progressive disease (18%). The median progression-free survival in all 24 patients was 6.21 months (95% CI 1.94-9.33).

In the eight gastroesophageal cancer patients, who had a median of four prior systemic treatments, the response rate was 50 percent.

In the four colorectal and five other HER2-expressing cancer patients the response rate was 33 percent. Anti-tumor activity was assessed per RECIST every eight weeks.

In the study, ZW25 was well tolerated. All treatment-related adverse events were grade I or II with the exception of one patient with grade III fatigue, and no treatment-related serious adverse events were seen.

There were no grade IV or V adverse events. The most common adverse events (25% or greater) were diarrhea, infusion reaction and nausea.

“The favorable tolerability we have seen with ZW25 supports its use as both a single agent and in combination with approved anti-cancer agents,” said Diana Hausman, Zymeworks’ chief medical officer. “We are excited to be advancing ZW25’s development and have plans to explore its efficacy in a number of tumor types, including gastroesophageal and breast cancer.”

Enrollment in the first portion of the study (the dose-escalation phase) has been completed. The recommended single-agent dose was determined to be 20 mg/kg once every two weeks or 10 mg/kg weekly.

In the second part of the study (the cohort expansion phase), additional patients are being enrolled to further assess ZW25’s single-agent tolerability and anti-tumor activity against a variety of cancer types in different settings.

The third part of the study (the combination phase) is underway and is evaluating ZW25 in combination with selected chemotherapy agents in gastroesophageal and breast cancer patients with HER2 high or lower HER2 expression levels.

ZW25 is a bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding.

This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function and has led to encouraging anti-tumor activity in patients.

Zymeworks is developing ZW25 as a HER2-targeted treatment option for patients with any solid tumor that expresses HER2. FDA has granted Orphan Drug Designation to ZW25 for the treatment of both gastric and ovarian cancers.

Gradalis presents initial data from phase II U.S. trial for Ewing’s sarcoma

Gradalis Inc. presented initial data from its phase II trial for Ewing’s sarcoma at the 2018 Annual Meeting of Children’s Oncology Group.

This is a two-part open-label, non-randomized, single-arm phase PP study in patients with recurrent or refractory Ewing’s Sarcoma. Part 2 of the study was established in order to assess safety and efficacy of Temozolomide / Irinotecan in combination with Vigil. All patients included in the study signed informed consent for tissue procurement treatment on the study according to the requirements of each individual institution.

As of Oct. 5, eight patients were enrolled in Part 2 of the trial, and five patients are still alive. Two patients experienced RECIST partial response and retrospectively confirmed histological complete response. Four patients had durable stable disease as best response for ≥6 months.

All eight patients had histologically confirmed Ewing’s Sarcoma. The mean age was 24 years (range: 12-46 years). All patients were heavily pretreated and failed treatment with Temozolomide and Irinotecan previously, with a mean of 5 lines of systemic treatments prior to study enrollment.

Historical progression-free survival for patients in second relapse (or greater) Ewing’s Sarcoma is 3 months or less. The median progression-free survival of the patients enrolled was 8.2 months.

The combination of Vigil, Irinotecan and Temozolomide in third-line or greater Ewing’s Sarcoma demonstrated favorable safety profile with limited treatment-related toxicities.

Phase II data demonstrates similar results from phase I trial. Previously published data of patients in second relapse (or greater) Ewing’s Sarcoma enrolled and treated with Vigil monotherapy on a phase I study revealed clinical benefit with a median survival of 2 years. While the median OS of patients in the phase II study, treated with the combination of Vigil, Irinotecan, and Temozolomide has not been reached, favorable event-free survival has been observed.

Vigil is a proprietary, investigational cellular immunotherapy technology that combines genetic engineering with the science of immuno-oncology. Vigil is intended to stimulate and enhance the body’s natural mechanism for recognizing and killing cancer cells. It utilizes the patient’s own cancer cells to create a fully personalized cancer immunotherapy.

By utilizing the patient’s own tumor as the antigen source, Vigil is designed to elicit an immune response that is specifically targeted and broadly relevant to each patient’s unique tumor antigens. Vigil is being studied in Ewing’s sarcoma, in gynecological cancer and advanced women’s cancer in combination with PD-L1 inhibitors, and ovarian cancer as a single agent.