publication date: Feb. 8, 2019
Study finds HIV+ cancer patients benefit from immunotherapy
Researchers at Georgetown Lombardi Comprehensive Cancer Center released a study that may show immunotherapy offers similar benefit to cancer patients living with HIV.
The study, published in JAMA Oncology, focused on whether a relatively new class of drugs called checkpoint inhibitors is both safe and effective in patients with advanced cancer who also live with HIV. Because checkpoint inhibitors manipulate the immune system, the concern has been that these therapies might have adverse effects such as virus reactivation in patients with HIV infection.
Investigators searched the medical literature to find 73 HIV patients whose cancer had been treated with checkpoint inhibitors. Only a fraction of patients came from a clinical trial; the rest were mostly case reports and case series from oncologists who chose to treat their patients with cancer and HIV infection with the new cancer drugs.
“Cancer patients with HIV and their oncologists have found themselves in a real conundrum,” the study’s lead investigator Chul Kim, assistant professor at Georgetown Lombardi, attending physician at MedStar Georgetown University Hospital and MedStar Washington Hospital Center, said in a statment. “Because of their HIV infection, they are at higher risk of developing cancer than people who are not infected.”
“In fact, cancer has become one of the leading causes of death in patients with HIV,” Kim said. “But conventional chemotherapies can reverse HIV suppression, and on top of that, these patients are widely excluded from clinical studies that test the next generation of cancer treatments.”
“We hope our finding will lead to increased study of checkpoint inhibitors in patients with HIV and cancer,” says Kim. He adds the checkpoint inhibitors might not just keep cancer in check. “There are signals in this analysis and other studies that suggest these new cancer drugs may restore an immune response against HIV in patients whose immune system is exhausted by its long fight with HIV.”
Kim and co-author, Michael Cook, internal medicine resident at MedStar Georgetown University Hospital, found that checkpoint inhibitors offered similar objective response rates in treating non-small cell lung cancer (30 percent) and melanoma (27 percent) as has been found in non-infected cancer patients.
Additionally, the inhibitor offered benefit in treatment of Kaposi’s sarcoma, a cancer strongly linked to HIV infection for which there are not many effective treatment options. The objective response in this patient population was 67 percent.
HIV patients did not experience increased side effects, compared to the norm, and HIV remained undetectable in 93 percent of patients (26 of 28) known to have undetectable viral load before treatment.
“And we found something that is really intriguing,” Kim said. “In six patients who had a detectable load of HIV in the blood before treatment, five had a decrease in their viral load after treatment. It could be that checkpoint inhibitors are helping to suppress HIV, though this finding needs to be verified in future studies.”
To further investigate these findings, Georgetown plans to launch a clinical trial to test checkpoint inhibitor therapy as first-line therapy in lung cancer patients with HIV or viral hepatitis.
High-dose radiation therapy improves long-term survival in stage IV cancers
The first report from a phase II, multi-center clinical trial indicates that a newer, more aggressive form of radiation therapy, stereotactic radiation, can extend long-term survival for some patients with stage-IV cancers while maintaining their quality of life.
The study is published in the January issue of International Journal of Radiation Oncology • Biology • Physics (Red Journal), the flagship scientific journal of the American Society for Radiation Oncology.
“Despite many advances in cancer care over the last 20 to 30 years, some patients still go on to develop metastatic or stage-IV disease,” said Dwight Heron, senior author of the study and director of radiation services at UPMC Hillman Cancer Center in Pittsburgh. “Generally speaking, radiation therapy in that setting has been used only to make the patient comfortable.
“It also has been the case, however, that a small number of patients with stage-IV disease could have surgery to remove their metastases and live a long time,” Heron said. “And so our question was, could we use highly focused radiation to destroy those tumors and have the same effect as surgery? The initial answer from this large prospective trial is yes.”
Patients in the trial were treated with stereotactic radiation. Increasing evidence points to stereotactic radiation as a viable alternative when patients cannot undergo surgery to remove metastatic tumors.
“With stereotactic radiation, we use a different type of highly precise local therapy to target tumors in the lungs, liver, bones or kidneys with precision that is analogous to surgery, and with very few side effects or harm to the patient’s quality of life,” said Heron.
In this phase II trial, Heron and his colleagues enrolled 147 patients across three large cancer centers to evaluate the safety and feasibility of stereotactic radiation for a variety of oligometastatic cancers. Each patient had up to five metastases — most had either one (71%) or two (19%) — in one to three new sites. The metastases were located most commonly in the lung (52%), followed by lymph nodes (16.5%), bone (15%) or liver (7%).
All patients received stereotactic radiation to all metastatic sites. Radiation dosing and fractionation were dependent on the size and location of each metastasis. All patients had good performance status (ECOG 0-1) and a life expectancy of more than 6 months. Median follow-up time for this report was 41 months (range=14.6-59.0).
Following treatment with stereotactic radiation, more than eight in ten patients (84%) survived at least 1 year, and four in ten (43%) survived 5 years or longer. The median overall survival time was 42.3 months.
Local recurrences were uncommon; half of the patients experienced complete (26%) or partial (26%) remission following treatment. An additional third (32%) had stable disease, meaning their cancer did not progress or recede.
The remaining patients either had local progression following treatment (14%) or their response could not be determined (12%). Distant recurrences were more common, with a median time of 8.7 months until distant progression. The one-year and five-year rates of distant progression free survival were 44 percent and 17 percent, respectively.
The type of primary tumor was associated with both OS (p=0.002) and DPFS (p=0.008). Patients with primary breast (9% of patients), prostate (7.5%) and colorectal (21%) tumors had longer survival than those with primary lung (22%) or head and neck (11%) tumors.
A unique aspect of the trial design was the decision to use patient-reported rather than physician-assessed quality of life. Patients reported no significant changes in their quality of life immediately after completing stereotactic radiation, nor at 6 weeks, 3 months and 9 months follow-up. At the 6- and 12-month marks, QoL was significantly better than before treatment.
Heron said his team plans to continue enrolling patients into the trial, with a goal of expanding the current 147 patients to roughly 200 total patients. Moving forward with additional trials, they also will look at treating patients with larger numbers of metastatic lesions and combining stereotactic radiation with emerging treatments such as immunotherapy.
This trial adds to the growing body of evidence supporting the use of stereotactic radiation for oligometastatic cancers. Two randomized, phase II trials presented at the most recent ASTRO Annual Meeting, for example, also found the treatment may lengthen survival, sometimes dramatically, for patients with stage-IV disease. If validated through larger randomized trials, radiation therapy could be utilized as a safe and effective approach to improve outcomes for patients with cancers that have begun to spread throughout the body.
Combination of Veyonda/radiotherapy delivers clinical benefits
Noxopharm announced interim results from the dose-ranging component of the DARRT-1 study. Some of their key findings include combining Veyonda with low-dose radiotherapy applied to a single metastasis is able to produce an anti-cancer response in both the irradiated and non-irradiated lesions as evidenced by PSA response, pain reduction, and/or tumour measurements.
A dose-response was observed, with the 1200 mg dose confirmed as the therapeutic dose clinical responses were achieved with no serious side-effects related to Veyonda, the company said.
The DARRT treatment regimen involves using Veyonda to trigger a generalised anti- cancer response to radiotherapy against cancer cells throughout the body. This is known as an abscopal response and is thought to involve a generalised immune response.
Veyonda has been shown to activate the body’s innate immune system, an action that the company believes will provide a transformative approach to the use of radiotherapy in oncology, enabling low dosages of focused radiation to be used to create a generalised anti-cancer effect.
The company’s ultimate goal in prostate cancer is to evaluate the DARRT treatment regimen across the full spectrum of prostate cancer from early-stage to late-stage. The DARRT-1 study is the starting point in this program involving end-stage prostate cancer.
The tumor burden in stage IV prostate cancer generally is greatest in the skeleton and is associated with significant pain. Treatment in these men nearing end of life is palliative, with pain relief a major objective through the use of radiotherapy and pain medications.
NOX is developing the DARRT regimen in advanced prostate cancer with the dual objectives of providing better palliation (pain relief) and extending survival and doing so in a well-tolerated way.
The DARRT-1 study has two stages. Stage I involving 12 patients was designed to provide an indication of the benefit:risk profile of three different doses of Veyonda (400, 800, 1200 mg daily) including four patient per dose. Patients included in this phase were required to have at least one soft tissue lesion that was amenable to accurate radiographic measurement (according to RECIST 1.1).
Stage II involved expansion into an additional 12 patients at a dose selected by an independent data safety monitoring board. As previously announced, stage II of the trial was initiated at the 1200 mg dose following DSMB review of the 6-week data.
Stage II includes patients who lack a soft tissue lesion and whose lesion requiring radiatherapy is located in the bone, which often cannot be accurately measured (according to RECIST 1.1).
Determination of a generalised response in such patients will be on the basis of PSA and pain responses. The final 4 patients in this stage have been screened and the study is expected to be fully enrolled within 2 weeks.
All three doses were well tolerated and no serious side-effects were reported as being related to Veyonda. For patients with advanced disease receiving palliative therapy, not doing any harm is a key factor in any new treatment to be introduced, and Veyonda is looking increasingly as meeting this fundamental need.
Efficacy: Efficacy analyses include reported changes from baseline (Day 1 of the study) at 12- and 24-weeks following radiotherapy on three key measures: PSA levels, pain levels, and aggregate lesion sizes.
Falls in PSA of > 50% compared to baseline and reductions in pain severity of > 30% compared to baseline are considered to be significant biochemical/tumour and pain responses respectively.
Apart from pain relief in 2 patients in the 400 mg cohort, this dose did not appear to have any significant anti-cancer effect in this small number of patients.
Efficacy signals were demonstrated in the 800 and 1200 mg cohorts at 12 weeks. Two patients in each cohort had PSA falls > 50% (51-78%). 3/4 patients in the 800 mg cohort and 2/4 patients in the 1200 mg cohort had a pain response of > 30% (52-92%), the company said.
One patient in the 800 mg cohort had a reduction in aggregate tumour diameter of > 30% (RECIST 1.1 partial response); the other three 800 mg patients and 3 of the 1200 mg patients were classified by RECIST 1.1 as having stable disease at 12-weeks.
The changes in PSA levels and total tumour lengths, relative to starting levels across all 11 evaluable stage I patients.
Veyonda (previously known as NOX66) is a dosage formulation of the experimental anti-cancer drug, idronoxil, developed specifically to preserve the anti-cancer activity of idronoxil in the body and to enhance its drug-like behaviour.
Idronoxil inhibits the oncogene, Ecto-NOX disulfide-thiol exchanger type 2, leading to inhibition of the key secondary pro-survival messenger, sphingosine-1-phosphate. This enhances the DNA- damaging effects of radiotherapy and cytotoxic chemotherapy, as well as activating the body’s innate immune system.
The DARRT (Direct and Abscopal Response to Radiotherapy) Program is testing the ability of Veyonda to increase tumour response to palliative dosages of radiotherapy. The DARRT treatment regimen entails a 5-day course of radiotherapy (20-30 Gy) in 5 fractionated dosages targeting a single tumour, and the Veyonda administered daily for up to 3 weeks.
The rationale of DARRT is to combine the radio-enhancing properties of Veyonda that stem from its inhibition of sphingosine-1-phosphate pro-survival functions, combined with its ability to stimulate the body’s first line immune defence cells against cancer.
The clinical outcome being sought is greater shrinkage of irradiated tumours and shrinkage of all non-irradiated tumours. The DARRT treatment regimen is being tested initially in prostate cancer, but in due course is to be extended into other forms of solid cancer that the Company believes will assist the Veyonda marketing approval process.
DARRT-1 is a phase Ib 24-subject study being conducted in Georgia and Australia. The study is in 2 stages, each of 12 subjects. Stage I is dose-finding entailing 3 cohorts of 4 subjects receiving 400 mg, 800 mg and 1200 mg Veyonda respectively. In stage II, the 12 subjects are receiving the 1200 mg Veyonda dose. The subjects are being assessed clinically at 6-, 12- and 24- weeks.
Prolonged time sitting shown to increase risk of colorectal cancer
A study in JNCI Cancer Spectrum has identified a connection between prolonged time spent sitting while watching TV and an increased risk of colorectal cancer for younger Americans.
Young-onset colorectal cancer, diagnosed under age 50, is increasing in the U.S. and globally, sharply contrasting with the dramatic decreases among older people, largely as a result of cancer screening initiatives.
Young-onset colorectal cancer has potentially different molecular characteristics compared to those of late-onset, and is typically more aggressive and found at a more advanced stage than those in older patients, resulting in greater years of life lost. Despite these trends, researchers have identified few risk factors specific to young-onset colorectal cancer.
Researchers here studied sedentary TV reviewing time, as well as other sedentary behaviors, in 89,278 American women in the Nurses’ Health Study II. Of the 118 cases of young-onset colorectal cancer diagnosed over two decades of follow up, more than one hour of daily TV viewing time was associated with a 12% increase in risk compared to those who watched less.
The results were even more striking for those watching more than two hours/day with a nearly 70% increase in risk. This association was independent of BMI and exercise and was consistently observed among women without a family history of colorectal cancer. The association was also more pronounced for rectal cancer compared to colon cancer.
These findings are among the first to link specific sedentary behavioral patterns with risk of young-onsetcolorectal cancer. “This study may help identify those at high risk and who might benefit more from early screening,” said Yin Cao, assistant professor of surgery at Washington University School of Medicine, and the study’s co-senior author. “The fact that these results were independent of BMI and physical activity suggests that being sedentary may be an altogether distinct risk factor for young-onset colorectal cancer.”