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Wednesday, April 26, 2017

The American Society for Radiation Oncology (ASTRO) issued a new clinical guideline for the management of oropharyngeal cancer. The guideline, "Radiation therapy for oropharyngeal squamous cell carcinoma: An ASTRO Evidence-based Clinical Practice Guideline," is available as a free access article in Practical Radiation Oncology, ASTRO's clinical practice journal.

Drawing on data from clinical trials and other prospective studies, recommendations address the use of radiation therapy (RT) to treat tumors of the oropharynx in a variety of scenarios. The new clinical practice guideline covers optimal radiation dose and fractionation schedules, the integration of chemotherapy with RT, and the role of induction chemotherapy.

Oropharyngeal squamous cell cancer (OPSCC) is rapidly becoming the most commonly diagnosed head and neck malignancy. The demand for radiation oncologists to treat head and neck cancer is projected to increase nearly 20 percent by 2020 over 2010 rates (J Clin Oncol 2010;28(35):5160-5165). The profile of the typical OPSCC patient has changed in the past several decades. From 1988 to 2004, the rates of human papillomavirus (HPV)-associated OPSCC rose more than 200 percent, while the rates of HPV-negative disease dropped by half (J Clin Oncol 2011;29(32):4294-4301). The estimated risk of death for HPV-positive OPSCC patients is 50 percent lower than for those with HPV-negative disease, in large part due to the more favorable biology of HPV-driven disease, but also because these patients tend to be younger and healthier when they are diagnosed (J Natl Cancer Inst 2008;100(6):407-420).

"Advances in treatment planning and technology, as well as a shift in the 'typical' oropharyngeal cancer patient over the past several decades, have led to a significant improvement in treatment outcomes for these patients," said David J. Sher, MD, MPH, Co-Chair of the task force that authored the guideline and a radiation oncologist at the University of Texas Southwestern in Dallas. "Despite these advances, however, treatment in this sensitive and complex region of the head and neck often leads to short-term, long-term and potentially lifelong side effects—which become even more salient as this patient population trends younger."

"Radiation therapy is the most commonly used curative option for the primary treatment of oropharynx tumors," added Avraham Eisbruch, MD, also Co-Chair of the task force and a radiation oncologist at the University of Michigan in Ann Arbor. "We developed the current guideline to address critical topics facing radiation oncologists who treat oropharyngeal cancer, including when to use chemotherapy, as well as appropriate dose and fractionation schedules for definitive and post-surgical RT settings."

The guideline first addresses the addition of chemotherapy to curative RT for oropharyngeal cancer, recommending concurrent chemoradiation for patients with stage IV disease or stage III disease with large-volume tumors, but not for patients with stage I-II disease. Recommendations by disease stage are as follows:

  • Stage IV: Patients with stage IVA-B tumors receiving definitive RT should receive concurrent high-dose intermittent cisplatin. Advanced-stage patients who are medically unfit for high-dose cisplatin should receive concurrent cetuximab or carboplatin-fluorouracil; weekly cisplatin may be considered for these patients with the caveat that there is limited prospective evidence to support its use. Concurrent cetuximab should not be co-delivered to patients receiving definitive chemoradiation (CRT), nor should intra-arterial chemotherapy be used in this population.
  • Stage III: Patients with stage III OPSCC receiving definitive RT should receive concurrent systemic therapy for T3 N0-1 tumors. CRT may be considered for larger volume T1-T2 N1 tumors that are at substantial risk for locoregional recurrence. Systemic therapy for other stage III patients may convey unnecessary toxicity.
  • Stage I-II: Concurrent systemic therapy is not recommended for patients with stage I-II OPSCC receiving definitive RT, due to a lack of evidence supporting its use for early-stage disease.

The guideline also provides guidance for the use of radiation and chemoradiation following primary surgery for OPSCC. Adjuvant RT is recommended for patients who show pathologic risk factors for disease recurrence, such as positive surgical margins or positive lymph nodes following surgery, although concurrent chemoradiation is strongly recommended only for high-risk patients.

Recommendations by treatment type and risk level are as follows:

  • Concurrent systemic therapy for high-risk patients: Systemic therapy, specifically high-dose intermittent cisplatin, should be delivered with post-surgical RT for patients with positive surgical margins and/or extracapsular extension. Weekly cisplatin may be delivered to post-operative patients who are unable to tolerate high-dose cisplatin. Post-operative patients who are unable to tolerate cisplatin-based chemoradiotherapy should not routinely receive concurrent chemotherapy. Existing prospective data do not support the use of cetuximab, concurrent weekly carboplatin or routine concurrent weekly docetaxel with post-operative RT, although clinical trials are underway to examine these alternative agents.
  • Adjuvant therapy for lower-risk patients: Concurrent chemoradiation should not be routinely used in intermediate-risk disease. Adjuvant RT is strongly recommended for post-operative OPSCC patients at significant risk of locoregional recurrence but only conditionally recommended in scenarios (e.g. pathologic N1 disease, perineural invasion, lymphovascular invasion) with a more uncertain risk of locoregional failure. Adjuvant radiotherapy may be delivered to patients without conventional adverse pathologic risk factors only if the clinical and surgical findings imply a particularly significant risk of locoregional recurrence.

The guideline also outlines optimal dosing and fractionation schedules based on treatment approach, disease profile and risk of recurrence. Recommendations by treatment setting are as follows:

  • Definitive RT: Patients with stage III-IV OPSCC should receive a cumulative dose of 70 Gray (Gy) delivered to the primary tumor site and positive nodes in 2-Gy daily fractions over 7 weeks, as well as an equivalent dose of 50 Gy delivered in 2-Gy daily fractions to the surrounding region at risk for tumor spread. For stage IV A-B patients not receiving concurrent systemic therapy, altered fractionation schedules (either accelerated or hyperfractionated) are recommended. For Stage IV A-B patients undergoing concurrent CRT, either standard or accelerated fractionation may be implemented. Altered fractionation also should be used for patients with T3 N0-1 disease not receiving concurrent chemoradiation, and it may be used for patients with T1-2 N1 or T2 N0 disease at high risk for recurrence.
  • Post-surgical/Adjuvant RT: Post-operative OPSCC patients at high risk for recurrence (e.g., those with positive surgical margins) should receive a total dose of 60 to 66 Gy delivered to the positive margins and region of extranodal extension in 2-Gy daily fractions. High-risk patients not undergoing concurrent systemic therapy should receive the upper limit of this range, while the 60-Gy total dose is recommended for patients with negative margins following surgery.
  • Early T-stage tonsillar carcinoma: Ipsilateral RT, which involves treating only one side of the oropharyngeal area, is strongly recommended for the subset of OPSCC patients with early-stage tonsillar cancer, specifically well-lateralized T1-2 N0-1 tumors. It is conditionally recommended for patients with lateralized T1-2 N0-2a disease without evidence of extra-capsular extension.​

The guideline also addresses the role of induction chemotherapy (IC) in treating OPSCC, examining the three existing published randomized trials examining IC followed by CRT for the disease.

Because none of these trials found an improvement in overall survival yet all found increased toxicity following IC, the guideline strongly recommends that IC should not be delivered routinely to patients with OPSCC.

The guideline was based on a systematic literature review of studies published from January 1990 through December 2014. A total of 2,615 abstracts were retrieved from PubMed, and the 119 articles that met inclusion criteria were abstracted into evidence tables and evaluated by a 16-member task force of experts in oropharyngeal cancer, including radiation oncologists, medical oncologists, otolaryngologists, and a patient representative. The Clinical Practice Statement was approved by ASTRO's Board of Directors following a 6-week period of public comment. The guideline has been endorsed by the European Society for Radiotherapy & Oncology (ESTRO) and ASCO.

Friday, April 21, 2017

​A vaccine targeting cytomegalovirus (CMV) antigen pp65, combined with high-dose chemotherapy (temozolomide), improved both progression-free survival and overall survival for a small group of glioblastoma (GBM) patients, according to a study published in Clinical Cancer Research (2017; doi:10.1158/1078-0432.CCR-16-2057).

"The clinical outcomes in GBM patients who received this combination were very striking," said lead author of the study Kristen Batich, MD, PhD, a researcher in the lab of senior author John Sampson, MD, PhD, Chair of the Department of Neurosurgery at Duke University. 

The cohort of 11 patients who received this combination therapy demonstrated a median progression-free survival of 25.3 months and a median overall survival of 41.1 months, and three patients remain progression-free more than 7 years after diagnosis, Batich said.

By contrast, the typical median survival for GBM patients is less than 15 months. To overcome these poor numbers, the researchers took advantage of CMV's affinity for GBM, with the viral proteins being expressed in roughly 90 percent of these tumors. Building on previous research, they used CMV as a proxy for GBM, targeting the virus with pp65-specific dendritic cells to spotlight the tumor for the immune system.

Previous work had shown that temozolomide generates profound lymphopenia or the loss of immune cells, which offers a unique opportunity to retrain the immune system, Batich explained. The researchers administered dose-intensified TMZ as a strategy to further enhance the immune response.

"The dose-intensified temozolomide induces a strong state of lymphopenia," said Batich. "With that comes an opportune moment to introduce an antigen-specific vaccine, which redirects the immune system to put all hands on deck and fight that target."

One of the noteworthy results from the study was the excellent response rate despite the high proportion of regulatory T cells, which dampen the immune response and rebounded sharply following TMZ administration. This finding may actually be cause for optimism, Batich noted.

"If we could preclude this regulatory T-cell rebound, it could have additionally enhancing effects on the pp65 vaccine response," said Batich.

Though the survival results are quite encouraging, the authors caution that this was a single-arm study without a control group. In addition, the cohort was quite small. Though the outcomes far outpaced historical controls, a more robust trial will be needed to confirm these results.

In addition, the team wants to better understand the mechanisms that underlie the strong response rate and refine this combination therapy to produce even better results. "We want to understand why some patients do better than others," concluded Batich. 

Tuesday, April 4, 2017

WASHINGTON, D.C.—Adding the investigational immunotherapy indoximod to the FDA-approved immunotherapy pembrolizumab increased the proportion of patients with advanced melanoma who responded to treatment compared with previously reported response rates for pembrolizumab monotherapy, according to interim results from a phase I/II clinical trial presented at the AACR Annual Meeting 2017, April 1-5 (Abstract CT117).

"In the phase III KEYNOTE-006 clinical trial that led the FDA to approve the immune checkpoint inhibitor pembrolizumab as an initial treatment for patients with advanced melanoma, the overall response rate was 33 percent, meaning 33 percent of patients had partial or complete shrinkage of their tumors," said Yousef N. Zakharia, MD, Assistant Professor in the Department of Internal Medicine at the University of Iowa, Iowa City. "We set out to investigate whether we could improve upon this response rate by adding an inhibitor of the IDO pathway to pembrolizumab treatment.

"We are excited to share interim results from the phase II portion of this clinical trial, because the data show that 52 percent of patients treated with a combination of pembrolizumab and the IDO-pathway inhibitor indoximod had a partial or complete response without significant added toxicities," continued Zakharia, who is also Co-Leader of the early phase clinical trials program at the Holden Comprehensive Cancer Center at the University of Iowa.

"It is noteworthy that this trial did not exclude ocular melanoma, which has been shown to be more aggressive and less responsive to available systemic treatment," added Zakharia. "Most comparable trials do not allow patients with ocular melanoma. When the results are considered without the ocular melanoma patients (9 out of 60), the response rate in cutaneous and nonocular melanoma is actually 59 percent. These robust data are very promising, but we need to confirm the clinical benefit in a larger, randomized trial."

Zakharia explained that the normal function of the IDO pathway is to keep the immune system in check, preventing it from responding inappropriately; for example, it helps prevent the immune system of a pregnant woman from attacking her baby. "However, some tumors hijack the pathway, using it to prevent the immune system from attacking and destroying the tumors, suggesting that it could be a good target for cancer immunotherapy," he said.

Previously reported results from the phase Ib portion of the clinical trial showed that the combination of indoximod and an FDA-approved immune checkpoint inhibitor called ipilimumab was well tolerated and caused no increase in toxicity compared with the immune checkpoint inhibitor used alone.

In the phase II portion of the clinical trial, patients received indoximod and FDA-approved immune checkpoint inhibitor therapy of the treating physician's choice, either ipilimumab, pembrolizumab, or nivolumab (Opdivo). Most patients received indoximod (1200 mg orally twice every day) with pembrolizumab, which was infused at the standard dose of 3 mg/kg every 21 days.

The new data being reported were obtained with a January 2017 cutoff data. After a median follow up of 10.5 months, six of 60 patients had a complete response and 25 had a partial response, giving an overall response rate of 52 percent. The most common adverse events were fatigue, diarrhea, and nausea.

"The trial is still accruing patients and we are continuing to monitor all of the patients enrolled so far," said Zakharia. "This interim analysis represents the largest reported number of melanoma patients treated with the combination of an IDO-pathway inhibitor and standard checkpoint inhibitors to date." ​

According to Zakharia, the main limitation of the study is that the clinical trial had no control arm, which means that a large-scale, placebo-controlled randomized clinical is needed to confirm the current results.

Tuesday, April 4, 2017

WASHINGTON, D.C.—Tumors with mutations in the proteins isocitrate dehydrogenase-1 or -2 (IDH1/2) exhibited features similar to BRCA-mutant tumors and were more likely to respond better to PARP inhibitors than to IDH inhibitors, according to preclinical data presented at the AACR Annual Meeting 2017, April 1-5 (Abstract LB-290).

"IDH is an enzyme that plays a role in the citric acid cycle, the energy-producing unit of the cells, and IDH mutations are commonly found in brain tumors and some leukemias," said Ranjit Bindra, MD, PhD, Assistant Professor of Therapeutic Radiology and Experimental Pathology at Yale School of Medicine and Yale Cancer Center in New Haven, Conn. "We found that the oncometabolites produced by IDH mutations induce a state in the cell where DNA repair is profoundly inhibited. This essentially makes them quite similar to breast and ovarian cancers which harbor mutations in key DNA repair genes such as BRCA1 and BRCA2.

"Our data strongly suggest that exploiting this DNA repair deficiency in IDH-mutant tumors, rather than inhibiting the function of the mutant IDH proteins, likely will be a better strategy for treating brain tumors with these specific mutations, a devastating disease with an urgent need for better therapies," he added.

IDH mutations are neomorphic, meaning that they change the normal function of the encoded protein, Bindra explained. Instead of making molecules that produce energy in the cell, the mutant IDH proteins start making an oncometabolite, 2-hydroxyglutarate (2HG), which is thought to be important for tumorigenesis.

Based on this knowledge, therapeutics that block the mutant IDH1 and IDH2 proteins and decrease the levels of 2-HG are being developed and tested in clinical trials. However, it is not entirely clear whether these therapeutics have been effective in shrinking solid tumors, according to Bindra.

"The remarkable thing is that we are proposing a therapy which does exactly the opposite of what IDH inhibitors are designed to do," Bindra said. Laboratory research led by his team showed that by suppressing DNA repair, the IDH mutations essentially create an Achilles' heel in the tumor cell, and that this weakness can be exploited by treating these tumors with PARP inhibitors, instead of IDH inhibitors. "In fact, small molecule inhibitors of mutant IDH actually reverse PARP inhibitor sensitivity."

A PARP inhibitor is a DNA repair inhibitor, and when applied to a tumor that has a DNA repair defect, the effects of the defect and inhibitor are synergistic, as a result of a process known as "synthetic lethality," leading to tumor cell death. Therapeutics developed based on this approach have been effective in treating hereditary breast and ovarian cancers, and the FDA has approved two PARP inhibitors, olaparib and rucaparib, to treat certain BRCA-mutant ovarian cancers.

Bindra, Peter Glazer, MD, PhD, and colleagues conducted a series of laboratory experiments to show that IDH-mutant patient-derived glioma cells, bone-marrow cultures of IDH-mutant acute myeloid leukemia, and mice bearing IDH-mutant human tumor cells were all susceptible to PARP inhibition. Results from these studies were published recently in Science Translational Medicine.

Since then, the investigators have conducted a series of experiments in genetically matched IDH-wild type (normal form of the protein) and IDH-mutant cancer cell line models to directly compare the efficacy of IDH inhibitors and PARP inhibitors in inhibiting IDH-mutant tumor cell viability. "When you carefully control the conditions and simply ask the question of which drugs best target solid tumor cell lines with IDH mutations, we do not see a significant effect of mutant IDH inhibitors on viability, however, we do see profound differences with PARP inhibitors," said Bindra.

They also found that in addition to R-2HG, the other form of 2HG, S-2HG, also induced a similar DNA repair deficiency, which made the brain tumor cell lines doubly sensitive to PARP inhibitors. S-2HG is produced in response to tumor hypoxia, and also at baseline levels in subsets of renal cell cancers and pediatric gliomas.

"We believe that exploiting oncometabolite-induced defects in IDH-mutant cancers may be the best path forward," said Bindra. "We will be presenting for the first time the schema for a multicenter, biomarker-driven NCI-sponsored phase II trial across approximately 35 centers in the United States, which will directly translate our recent discovery to patients," Bindra said. ​

Limitations of the study include that their hypothesis has not been tested specifically in patient-derived, intracranial glioma xenograft animal models, Bindra said.

Tuesday, April 4, 2017

WASHINGTON, D.C.—Treatment with a combination of ipilimumab and Coxsackievirus A21 (CVA21) led to durable responses in a number of patients with advanced melanoma, including some whose melanoma had progressed despite prior treatment with an immune checkpoint inhibitor, and fewer than anticipated adverse events, according to results from a phase Ib clinical trial presented at the AACR Annual Meeting 2017, April 1-5 (Abstract CTT114).

"In recent years, the number of treatment options for patients with advanced melanoma has increased with the development of immune checkpoint inhibitors such as ipilimumab," said Brendan D. Curti, MD, Director of the Clinical Biotherapy Program and Co-Director of the Melanoma Program at the Earle A. Chiles Research Institute of Providence Cancer Center in Portland, Oregon. "However, not all patients respond to these immunotherapeutics and some who respond go on to have disease progression later. These patients have few treatment options and a poor outlook.

"We are excited that the ipilimumab–CVA21 combination has yielded responses greater than 6 months for a number of patients, both those whose melanoma has progressed after immune checkpoint inhibitor therapy and those who have not yet been treated with these immunotherapeutics," continued Curti. "Based on these promising preliminary data and the urgent need for new treatments for advanced melanoma patients refractory to immune checkpoint inhibitors, we are expanding the trial up to 70 patients."

CVA21 is bioselected, nongenetically altered common cold RNA virus. According to Curti, it can directly infect many different cancer cells and as such it can boost adaptive and innate anticancer immune responses.

Curti and colleagues are enrolling up to 70 patients with advanced melanoma in the melanoma intratumoral CVA21 and ipilimumab (MITCI) clinical trial. Patients who have and who have not received immune checkpoint inhibitors are eligible for the trial. CVA21 is injected directly into melanoma lesions, while ipilimumab is infused intravenously.

At data cutoff for this presentation, 25 patients were evaluable for safety and 22 were evaluable for response. The overall response rate was 50 percent, with four patients having a complete response and seven patients having a partial response. The median duration of response has not been reached, with a number of responses greater than 6 months and several still ongoing.

Among the 11 patients who had disease progression despite prior treatment with an immune checkpoint inhibitor, four had a response. The other seven patients who had a response had not previously received treatment with an immune checkpoint inhibitor.

"The preliminary overall response rate of 50 percent is very positive because previous reports indicate an 11 percent overall response rate for ipilimumab alone and an approximately 28 percent overall response rate for CVA21 alone," said Curti.

Among the 25 patients evaluable for safety, two had grade 3 or higher ipilimumab-related adverse events. Thus far, there have been no CVA21-related adverse events of grade 3 or higher. ​

"While still a small data set, we are encouraged by the low frequency of severe adverse events," said Curti. "Historically, about 25 percent of patients treated with ipilimumab have treatment-related grade 3 or higher adverse events. We have seen this in just 8 percent of patients treated with the combination, but we will need larger numbers of patients to confirm this finding."