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Tuesday, September 27, 2016

NEW YORK—Among patients with stage IV melanoma who were being treated with the immunotherapeutic pembrolizumab (Keytruda), the ratio of a particular subset of immune cells in the blood to tumor burden correlated with clinical response, according to data presented at the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival, held Sept. 25-28.

Pembrolizumab was approved by the FDA for treating metastatic melanoma in September 2014. Although some patients have remarkable and durable responses to treatment, the majority do not, according to Alexander Huang, MD, a clinical fellow in the Division of Hematology/Oncology and Institute for Immunology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

"We set out to investigate whether we could monitor and predict a patient's response to pembrolizumab by tracking the effect of pembrolizumab on immune cells in blood samples from the patients," said Huang. "We found that we could, which is important because it opens up the possibility that we might one day be able to use blood-based assays to inform clinical care. However, we need to validate our findings in a larger group of patients before this can become a reality."

Huang and colleagues analyzed blood samples from 29 patients with stage IV melanoma taken before and at 3, 6, 9, and 12 weeks after starting treatment with pembrolizumab. They measured levels of the proliferation marker Ki67 in immune cells called exhausted-phenotype CD8-positive (CD8+) T cells.

"After a prolonged battle with tumor cells, CD8+ T cells become progressively more dysfunctional, or exhausted," said Huang. "Exhausted-phenotype CD8+ T cells have high levels of the protein PD-1 on their surface. Pembrolizumab targets PD-1. In preclinical models, pembrolizumab targeting of PD-1 can reinvigorate exhausted-phenotype CD8+ T cells, something that we can measure by increased levels of proliferation markers like Ki67."

The researchers found that levels of Ki67 were significantly greater in CD8+PD-1+ T cells (exhausted-phenotype CD8+ T cells) in posttreatment blood samples compared with pretreatment blood samples for 78 percent of patients. A clinical response, as measured by immune-related RECIST criteria, occurred in 38 percent of patients.

Huang and colleagues measured the level of Ki67 in CD8+PD-1+ T cells before and after treatment, with the peak Ki67 after treatment considered the measure of the extent of reinvigoration of exhausted-phenotype CD8+ T cells. They then found that the ratio of CD8+PD-1+ T cell reinvigoration to pretreatment tumor burden correlated with clinical response. In one cohort of patients, all those who had a ratio greater than 1.94 were alive after 11 months of follow-up compared with 50 percent of patients with a ratio of less than 1.94. In a second cohort, 75 percent of patients with a ratio greater than 1.94 were alive at two years, compared with 29 percent with a ratio less than 1.94.

"We were excited to find that patients with a balance in favor of the immune response compared to tumor burden were more likely to have clinical benefit," said Huang. "If validated in larger studies, this could provide a way to predict early on after starting pembrolizumab treatment whether a patient should continue this treatment or either change to a different treatment or add an additional treatment.

"The fact that we were able to track the immune effect of pembrolizumab in the peripheral blood of patients opens up many doors in terms of research opportunities," added Huang. "We want to put our findings in context with what is known about other biomarkers of response, such as tumor PD-L1 expression."

According to Huang, the main limitation of the study is the small sample size, which means that the correlation between response to pembrolizumab and the ratio of exhausted-phenotype CD8+ T cell reinvigoration to tumor burden needs to be validated in a larger cohort of patients.

Tuesday, September 27, 2016

NEW YORK—A combination of the immunotherapies AM0010 and the immune checkpoint inhibitor pembrolizumab was well tolerated and resulted in durable objective tumor responses in some patients with renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC), according to data from a phase Ib clinical trial presented at the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival, held Sept. 25–28.

"Immunotherapy has improved the prospects for many cancer patients by providing long-term benefit, but not all patients respond to the currently available immuno-oncology drugs," said Aung Naing, MD, an associate professor in the department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston. "Rational combinations of immune therapies are likely to expand the tumor-specific immune activation and lead to more durable tumor responses."

Naing and colleagues are investigating a novel immunotherapy, AM0010, which is a PEGylated form of the recombinant human cytokine IL-10. This therapy has specific immune-stimulating effects that induce the activation, proliferation, and survival of cytotoxic CD8-positive (CD8+) T cells present within the tumors of patients, Naing explained.

The targets of AM0010 and pembrolizumab, IL-10 receptor and PD-1, respectively, are both present on CD8+ T cells. AM0010 enhances the survival and tumor cell-killing activity of CD8+ T cells and complements the activity of pembrolizumab that blocks the immune-suppressive PD-1/PD-L1 pathway, thus providing a rationale for this combination, Naing said.

"In this clinical trial, we found that the two immunotherapies were well tolerated, without overlapping toxicity or severe autoimmunity, while providing strong antitumor responses," Naing said. "In addition, we detected new, expanding T-cell clones in the blood of all patients who received AM0010. Many of those T-cell clones were not detectable before treatment. This is reminiscent of tumor-specific vaccination."

In this multi-cohort phase I clinical trial, the investigators enrolled 19 patients with advanced melanoma, RCC, or NSCLC to a cohort in which patients received one of the two doses of AM0010 daily and 2 mg/kg body weight pembrolizumab every three weeks.

After 10-15 months of observation, two of the eight patients with renal cell carcinoma had a complete reduction of their tumor burden (complete responses) and two had a 77 and 92 percent reduction (partial responses (PR)), respectively. Of the six melanoma patients, two had PR, and two others had an initial increase in tumor volume followed by a decrease (known as pseudoprogression).

The most common side effects associated with AM0010 were anemia, thrombocytopenia, and fatigue, which were all manageable. Importantly, AM0010 did not lead to autoimmune side effects.

The weapons used by CD8+ T cells in killing cancer cells are the cytotoxic molecules—granzymes, FasL and lymphotoxin beta. With AM0010 treatment, the levels of these cytotoxic molecules were elevated in the serum of the patients, which provides further evidence of the systemic activation of the cytotoxic arm of the immune system, according to Naing.

Effects such as the elevation of cytotoxic molecules and the expansion of T-cell clones in the blood were also observed in patients from other cohorts in this clinical trial in which AM0010 was tested as monotherapy or in combination with chemotherapies.

The main limitation is that this is a study with a small number of patients with RCC and NSCLC; however, the immunological profiles and early results support the interpretation, Naing said.



Tuesday, September 27, 2016

American Society of Radiation Oncology Annual Meeting

BOSTONFor men with early stage, low-risk prostate cancer, treatment with hypofractionated radiation therapy (RT) offers comparable health-related quality of life outcomes in one-third less treatment time than conventional RT, according to research presented at the 58th Annual Meeting of the American Society for Radiation Oncology (ASTRO) (Abstract 4).

While efficacy results from NRG Oncology/RTOG 0415 were reported previously, this study is the first to report patient-reported outcomes from the trial, which included patients from across the U.S. and Canada. This trial assessed the differences in health-related quality of life (HRQoL), including bowel, urinary, sexual and hormonal side effects, following a conventional or fractionated RT schedule. Compared to conventional (C) RT, hypofractionated (H) RT is delivered in larger doses over a shorter period of time.

"Studies have suggested that higher amounts of radiation over shorter periods of time might be more effective in destroying cancer cells, but the concern has been that stronger doses might also cause quality of life issues such as more diarrhea or decrease in sexual function," said lead study author Deborah Watkins Bruner, PhD, a Professor at the Nell Hodgson Woodruff School of Nursing and a Professor of Radiation Oncology at Emory University School of Medicine in Atlanta.

Patients in the study were randomly assigned to receive either conventional RT, consisting of 73.8 Gy in 41 daily treatments delivered over 8.2 weeks, or hypofractionated RT, consisting of 70 Gy in 28 daily treatments delivered over 5.6 weeks. A total of 962 patients reported HRQoL data, including 478 men from the C group and 448 men from the H group. The median patient age was 67 years, and baseline characteristics were similar between the treatment groups.

HRQoL was assessed with the Expanded Prostate Index Composite (EPIC), a comprehensive instrument designed to evaluate patient-reported side effects after prostate cancer treatment. The questionnaire measured side effects in each of EPIC's four domains – bowel, urinary, sexual, and hormonal. EPIC assesses prostate cancer-specific HRQoL on a Likert scale with responses transformed to 0-100, where higher scores indicate a better HRQoL. Participant feedback was collected at baseline, six months after treatment began and one year post-treatment, with change scores compared between the C and H groups. A Wilcoxon test was used to assess differences.

At baseline, there were no statistically significant differences between treatment groups in any of the HRQoL domains. Results indicated that, compared to men without prostate cancer, most patients in both groups reported poor baseline EPIC sexual domain scores, with the C group's score averaging 47.5 and the H group's score averaging 44.2. At baseline, the groups reported only slightly lower than average bowel and urinary scores.

Following treatment, patients who received higher doses of RT in fewer sessions (the H group) reported similar HRQoL as the patients who received conventional RT (the C group). There were no differences in change scores for either group on any EPIC domain at six months follow-up. At 12 months follow-up, hypofractionation patients reported a larger decline in the bowel domain compared to those who received conventional RT, with an average from baseline of -3.6 vs. -1.8, respectively, (p = 0.0037), but the change was not deemed clinically significant to patients.

"This research shows that hypofractionated radiation therapy offers patients value-based care for their disease. If patients with low-risk prostate cancer choose radiation therapy, they can live equally long and have the same quality of life outcomes with 28 daily treatments, compared to what has been the standard care of 41 daily treatments," said Bruner. "This reduction of treatment time by almost a third translates into other types of value for patients, such as decreased drive time, lower transportation costs and fewer days off of work."

Monday, September 26, 2016

American Society of Radiation Oncology Annual Meeting

BOSTONAlthough approximately 50 percent of cancer patients in developing countries need radiation therapy (RT) to treat their disease, up to half of these patients do not have access to it, according to research presented at the 58th Annual Meeting of the American Society for Radiation Oncology (ASTRO) (Abstract 82​). Examining nine middle-income countries, researchers found that between 18 and 82 percent of patients who can benefit from RT in these countries do not receive the treatment.

Researchers at the International Atomic Energy Agency conducted this project to assess levels of optimal and actual RT utilization (RTU) and calculated unmet RT need in developing countries. This study is the first scientific analysis of RTU in middle-income countries. Findings reflect data from nine countries, including Costa Rica, Ghana, Malaysia, the Philippines, Romania, Serbia, Slovenia, Tunisia, and Uruguay.

Optimal and actual RTU rates were determined for each country. The optimal RTU rate is the proportion of all newly diagnosed cases of cancer who have an indication for RT at least once in their lifetime. An indication for RT was defined as a clinical scenario for which RT is recommended as the treatment of choice because there is evidence of its superiority to alternative modalities and/or no treatment (e.g., better survival, local control, or quality of life profiles). In clinical situations where RT was equivalent to other treatment options, all comparable modalities were included in the model, and a subsequent sensitivity analysis was conducted to determine the proportion of these patients who indicated for RT.

Indications for RT for each cancer site were derived from treatment guidelines published by reputed national and international organizations. An evidence-based computation model was used based on data from high income countries, and researchers developed optimal RTU models for each cancer site by combining clinical scenarios and epidemiological data. The distribution of tumor types for each country was obtained from Globocan-2012, and patients were counted only once even if they subsequently developed repeated indications for RT.

Actual RTU rate was calculated dividing the total number of new cases of cancer treated with RT for the first time in 2012 ("new RT cases"), by the total number of new cases of cancer diagnosed in the same year ("incident cases"). The total number of new RT cases for each country was reported to the research team by the individual country coordinators who gathered the data from their own center, and all other RT centers in their respective countries. Incident cases were obtained from cancer incidence data from Globocan-2012.

The case-mix for each country was determined by prospectively registering 300 consecutive patients receiving RT at a leading RT center in each country and by capturing detailed data on patient, tumor and treatment characteristics from this sample.

The median optimal RTU for all countries was 52 percent. Optimal RTU rates ranged from a low of 47 percent for Costa Rica to a high of 56 percent for Tunisia. Differences in optimal RTU rates are attributable to varying incidence rates of cancer types in each country.

Median actual RTU rate was roughly half of optimal utilization, suggesting that nearly half of cancer patients across these nine countries combined may not be receiving adequate care for their disease. The median actual RTU rate was 28 percent, with a much broader range than for optimal RTU. The lowest rates of utilization were in Ghana (9%) and the Philippines (10.3%), while the highest utilization rates were in Tunisia (46%) and Uruguay (37%).

Actual RTU rates were lower than optimal RTU rates for all nine countries, with the smallest difference in Tunisia and the widest gap in Ghana at nearly 43 percentage points. Median level of unmet need was 47 percent for all countries combined.

Ghana and the Philippines had the highest levels of unmet need, at 82.3 and 80.5 percent, respectively. In the majority of cases in Romania (57.6%) and Serbia (54%), RT is not utilized, though indications for it exist. Costa Rica and Tunisia had the lowest levels of unmet need, at 25.5 and 18 percent, respectively. Unmet need in RT utilization indicates that RT is not administered when needed.

"Access to radiation therapy remains limited in low-and middle-income countries," said Elena Fidarova, MD, a researcher at the International Atomic Energy Agency in Vienna and co-author of the study. "In Ghana and the Philippines, for example, about eight in 10 cancer patients who need radiation therapy will not receive needed treatment. To eradicate this disparity, efforts should be made to improve access to radiation therapy. National radiation therapy strategy with realistic short-, mid-, and long-term goals should be developed and incorporated into comprehensive national cancer control plans. Existing obstacles to RT access should be systematically addressed in the planning phase."

The unmet need was particularly substantial (in the order of 80%) in countries with limited resources and a large population. The number of teletherapy machines per 1,000 cancer cases ranged from a high of 1.3 in Tunisia to a low of 0.19 in Ghana. The strong correlation between the actual RTU rates and the number of teletherapy machines per 1,000 cancer cases/year in each country confirms that, although other access factors may be at play, availability of RT machines is an important factor in RT utilization.

"Our findings strongly support the call for action from the Lancet Oncology Commission, which requires a worldwide effort to expand global access to radiation therapy," said Fidarova. "Differences between optimal and actual RTU rates and the high percentage of unmet RT need likely stem from a number of complex reasons, although inadequate capacity for radiation therapy is the most obvious factor. As obstacles in access to existing RT services, such as inadequate referral patterns, affordability of treatment and geographical distribution of centers, differ by country, so does the ideal mix of solutions." 

Monday, September 26, 2016

American Society of Radiation Oncology Annual Meeting

BOSTONStereotactic radiosurgery (SRS) for cancer patients who receive the treatment for brain metastases decreases the likelihood of local recurrence but shows no positive difference in terms of overall survival (OS) or distant brain metastases (DBMs) rates, when compared to observation alone following surgical resection of brain metastases, according to research presented at the 58th Annual Meeting of the American Society for Radiation Oncology (ASTRO) (Abstract 3).

Brain metastases occur in a large number of patients with common cancers and are more prevalent than many primary tumors, including primary brain tumors, lymphoma, and colon cancer. Rates of brain metastasis have risen in recent years, as well. When cancer spreads to the brain, surgical resection can be employed to confirm the diagnosis, remove the lesion(s) or to reduce pressure in the brain. After resection, whole brain radiation therapy (WBRT) to the surgical cavity limits the growth of new lesions in the brain, yet radiation to healthy brain tissue can lead to cognitive decline and other toxicities. With SRS, oncologists deliver a single fraction of precise, high-dose radiation while preserving surrounding brain tissue.

"Over the past several years, with advances in technology, radiation to only the surgical bed of the resected lesion has become of interest," said Anita Mahajan, MD, Professor of Radiation Oncology at MD Anderson Cancer Center in Houston and lead author of the study. "While oncology teams see the potential of radiosurgery, its novelty means that we have limited prospective evidence of its efficacy."

Study participants included 132 patients (128 eventually analyzed) with one to three metastatic brain tumors who wished to avoid or delay WBRT following complete surgical resection of at least one brain metastasis. The median patient age was 59, and there were no relevant demographic differences between the treatment groups. Patients were randomly assigned to one of two arms, either SRS to the surgical cavity (or cavities for patients with more than one lesion removed) (SRS-cav, n = 63) or observation alone (OBS, n = 65). Patients were stratified by number of brain metastases (1 vs. 2-3), primary cancer type (melanoma vs. other histology) and pre-operative tumor size (less than vs. greater than three centimeters). Researchers assigned radiation dose for the SRS-cav group (12, 14 or 16 Gy) based on cavity volume at time of radiosurgery.

Failure of local control (LC), the primary endpoint of the study, was assessed through follow-up magnetic resonance imaging by the study neuro-radiologist to determine whether local tumors recurred in the area treated with SRS. Researchers also examined the rates of overall survival (OS), development of distant brain metastases (DBM), time to WBRT, and complications following SRS. Hazard ratios (HR) and corresponding confidence intervals (CI) were computed to compare treatment arms. The median follow-up time was 13 months, with a range of 0.3 to 71 months.

Radiosurgery to the surgical bed significantly reduced local recurrence of the resected tumor. At six months following treatment, LC rates were 83 percent for the SRS-cav group and 57 percent for the OBS group. At 12 months follow-up, the LC rates were 72 percent for the SRS-cav group, compared to 45 percent for the OBS group (HR, 0.46; p = 0.01).

Although SRS improved LC, there were no differences between treatment arms for regional recurrence, overall survival or time to WBRT. At 12 months after treatment, 58 percent of the SRS-cav patients had developed DBMs, compared to 67 percent in the OBS group, though the difference was statistically non-significant (HR, 0.79; p = 0.29). Median OS was 17 months for both groups (HR, 1.22; p = 0.37). WBRT was given to 24 of the 64 patients in the SRS-cav group within an average timeframe of 16.1 months, compared to 30 of 67 patients in the OBS group within an average timeframe of 15.2 months (HR, 0.8; p = 0.42). No significant complications were noted in the SRS-cav patients.

In terms of non-treatment factors, only tumor size impacted LC, as determined by multivariate Cox regression analysis. A pre-surgery tumor size of greater than three centimeters was associated with worse LC, but local recurrence was not significantly affected by the number of brain metastases or the patients' histology or graded prognosis assessments.

"Our research shows that radiosurgery in this patient cohort does reduce the incidence of local recurrence, although the findings for overall brain control, overall survival and time until whole brain radiation therapy limit our ability to conclude an obvious clinical benefit," said Mahajan. "In addition, it appears that smaller tumors may not-need post-operative radiosurgery after resection, since the local failure rate for tumors smaller than 2.5 centimeters was very low."

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