Highlights of Cutting-edge NRG Research Underway
These are just some of the important trials and research underway with NRG Oncology. Summaries were provided by the disease site committee leaders and members.
Brain
NRG-BN001 and NRG-BN005
NRG Oncology Brain Tumor Committee Leads the Way in Testing Novel Technologies for Brain Tumors
In 2020, NRG Oncology reported the seminal, practice-changing results from CC-001, a clinical trial that demonstrated the value of hippocampal sparing in neurocognitive protection. In 2021, NRG Oncology is continuing this focus on testing novel technologies in randomized trials. Two trials showcased below represent examples of efforts to generate an develop level 1 evidence for proton therapy:
NRG- BN001: This randomized trial is premised on the hypothesis that circulating lymphocytes represent an organ-at-risk and that daily partial volume brain irradiation contributes to acute significant lymphopenia, which in other clinical series has been associated with inferior outcomes in GBM. Because proton therapy would irradiate a lower volume of brain, and therefore presumably cause less lymphopenia, this trial is attempting to elucidate an answer to the photon versus proton question for GBM, using a novel design where institutions predeclare themselves as proton or photon sites and the randomization is between conventional chemoradiotherapy or dose-intensified chemoradiotherapy, using either IMRT or IMPT. The trial has completed accrual to the IMRT arm and the proton arm is expected to accrual in the next several months. The unique aspect of this trial is the testing of a biological/immunological mechanism driving differences between proton and photon radiotherapy.
NRG BN-005: This randomized trial is testing whether IMPT would result in superior neurocognitive outcomes, compared to IMRT, in IDH-mutant WHO grades 2/3 gliomas treated with combinatorial radiotherapy-chemotherapy. The innate hypothesis is that IMRT would treat more normal brain volume to low doses, compared to IMPT, and that this could drive differences in cognitive outcomes. The trial is early in its accrual phase and could use the assistance of ASTRO membership to promote the trial and recommend suitable patients for trial participation.
Minesh Mehta, MD, FASTRO, is deputy director of Miami Cancer Institute, chief of Radiation Oncology at Baptist Health, S Florida and professor and chair of the Department of Radiation Oncology at Florida International University.
Breast
NRG NSABP B51-RTOG 1304, NRG-BR002 and NRG-BR007
NRG Oncology Breast Committee research focus includes developing local regional management for breast cancer with surgery and radiation tailored to match the risk and specific biology of the disease. Clinical trials for local regional management of breast cancer have been typically based on clinical pathologic criteria, specifically tumor size and axillary nodal status. The biologic subtype of breast cancer and its response to systemic therapy have emerged as equally prognostic for local regional cancer control. Three trials in the NRG portfolio demonstrate trials more specifically tailored to risk and biology: NRG NSABP B51-RTOG 1304, NRG-BR002 and the soon to open NRG-BR007.
NRG B51-1304 evaluates whether response to neoadjuvant chemotherapy (NAC) in the axillary nodes can lead to omission of regional nodal irradiation (RNI). Women who present with clinical axillary node positive disease (confirmed pathologic positive by needle biopsy) that are down-staged by NAC to pathologically axillary node negative at surgical resection are randomized to RNI vs none. This trial recently met its accrual goal of 1,635 in December 2020 and the NRG Breast Committee is grateful to the many radiation oncology facilities who participated. NRG B51-1304 is notable for being the first to require target-based RNI treatment planning, which will provide a robust database for studying outcomes based on radiation quality.
NRG-BR002 is a phase II-III trial focused on oligometastatic breast cancer (one to four metastatic sites) receiving first line of systemic therapy asking whether ablation of all metastasis can improve progression free survival (PFS) in the phase II portion and then overall survival in the phase III portion. It is on hold after meeting accrual for thepPhase II portion to determine if the goals for PFS are met.
The NRG Breast Committee is close to opening NRG-BR007 “DEBRA” trial which is evaluating over treatment with radiation in biologically low risk stage 1 hormone sensitive, HER2 negative breast cancer undergoing breast conserving therapy. Eligible patients are those between the ages of 50-70 years with stage 1 breast cancer that is estrogen/progesterone sensitive, HER2 negative and has an oncotype RS of < 18.
Julia White, MD, FASTRO is a tenured professor of radiation oncology, Klotz Sisters Chair in Cancer Research, and vice-chair of Clinical Research in the Department of Radiation Oncology at Ohio State University.
Gastrointestinal
NRG-GI006 and NRG-GI003
NRG-GI006 is a phase III study comparing proton beam therapy versus intensity-modulated photon therapy in the treatment of esophageal cancer. This study builds upon a randomized phase II study showing a decrease in total toxicity burden with protons compared to photons in patients with esophageal cancer. The hypothesis is that survival can be improved with protons by mitigation of toxicity but also through preservation of immune function through decreased radiation-induced lymphopenia. Similarily, NRG-GI003 is a phase III study evaluating protons versus photons for hepatocellular carcinoma. The key hypothesis is that the lack of exit dose with protons may decrease rates of hepatic compensation after liver-directed radiation. Both studies seek to provide level 1 evidence regarding the utility of protons in these two difficult to treat disease sites with innovative biological hypotheses.
Ted Hong, MD, is director of gastrointestional radiation oncology at Massachusetts General Hospital, co-leader of the Gastrointestinal Malignancies Program at Dana-Farber/Harvard Cancer Center, and professor of radiation oncology at Harvard Medical School.
Genitourinary
NRG-GU006 and NRG-GU009
Over the last few years, the NRG GU group has focused on incorporating novel biomarkers and therapeutics into randomized trials. We just finished accruing to NRG-GU006 (BALANCE), led by Principal Investigators Felix Feng, MD, and Daniel Spratt, MD. This trial is for patients with PSA recurrences after surgery, which stratified patients by a potential predictive biomarker of response to hormone therapy (the PAM50 panel) prior to randomization to radiation +/- the next-generation anti-androgen apalutamide. NRG-GU006 accrued three times faster than expected, largely because of enthusiasm for access to the biomarker and to apalutamide.
More recently, we have activated NRG-GU009 (PREDICT-RT), a 2,478 patient phase III study for patients with high-risk prostate cancer by NCCN criteria, led by Principal Investigators Paul Nguyen, MD, and Oliver Sartor, MD. GU009 selects patients based on their Decipher score (a genomic test) to select patients for a randomized trial of treatment intensification (high Decipher score) or treatment de-intensification (low Decipher score). Patients enrolled on GU009 will have free access to a genomic test, to next generation androgen-directed therapies (on the intensification arm), and to advanced PET imaging approaches (on an optional imaging substudy).
Felix Feng, MD, is a professor of radiation oncology, urology and medicine, vice-chair for translational research in the Department of Radiation Oncology and director at Benioff Initiative for Prostate Cancer Research at the University of California at San Francisco.
Gynecologic
NRG-GY017
Anti PD-L1 (Atezolizumab) as an Immune Primer and Concurrently with Extended Field Chemoradiotherapy for Node-positive Locally Advanced Cervical Cancer
Cervical cancer accounts for approximately 266,000 deaths globally each year and patients diagnosed with locally advanced cervical cancer have a higher risk of recurrence and worse survival than early stage patients. Additionally, patients presenting with para-aortic lymph node (PALN) metastases represent a poor prognostic group with only a five-year survival of approximately 40% across the stages. The NRG Oncology clinical trial NRG-GY017 was designed to address the need for a therapeutic treatment option for this patient population.
NRG-GY017 will be observing the anti PD-L1, atezolizumab, as an immune system activation for women with node-positive, locally advanced cervical cancer. Women on this trial will receive atezolizumab either before and/or concurrent with the standard of care chemoradiotherapy. This trial is currently accruing patients with stage IB2, II, IIIB or IVA cervical cancer that has metastasized to the lymph nodes.
Women who participate on NRG-GY017 will be randomly assigned to one of two potential treatment arms. Participants on treatment arm one will receive atezolizumab, then, if there is no disease progression or unacceptable toxicity, patients will begin to receive concurrent atezolizumab, cisplatin chemotherapy and the standard of care radiotherapy with image-guided brachytherapy. Participants on treatment arm two will receive concurrent atezolizumab, cisplatin chemotherapy and standard of care radiotherapy.
The primary goal of NRG-GY017 is to determine whether the difference in sequencing for the addition of atezolizumab to chemoradiotherapy results in differential immune activation for trial participants. Differential immune activation will be determined by clonal expansion of T cell receptor beta repertoires in peripheral blood on day 21 of treatment.
Other objectives include investigating the feasibility of administrating atezolizumab as an immune primer and concurrent with chemoradiotherapy, the nature and degree of toxicity from atezolizumab prior and concurrent with chemoradiotherapy, changes in the T cell receptor clonality, diversity and frequency in peripheral blood and tissue and the correlation of these changes to clinical outcomes, and lastly the predictive value of baseline and PD-L1 expression in tissue in each treatment arms for clinical outcomes. Exploratory objectives are to explore biomarkers that could predict a response to the combination therapy and to explore the response of assessment on the exploratory and optional post-treatment PET-CT scan, and the clinical two-year disease free survival.
“This trial is of paramount importance to understand the optimal sequencing and underlying immune mechanism when immunotherapy is added to the standard of care chemoradiation in locally advanced cervical cancer,” said the trial’s study chairs, Jyoti Mayadev, MD, of the University of California, San Diego, Russell Schilder, MD, of Thomas Jefferson University, and Dmitiry Zamarin, MD, PhD, of Memorial Sloan Kettering Cancer Center.
Jyoti Mayadev, MD, is associate professor, director of gynecologic brachytherapy and chief of Gynecology Oncology Radiation Services at the University of California San Diego.
Head and Neck
NRG-HN005 and NRG-HN004
NRG-HN005 is a randomized phase II trial leading into a randomized phase III extension, led by Principal Investigator Sue Yom, MD, PhD, FASTRO. One arm, considered the NRG standard of care, consists of 70 Gy in 35 fractions combined with only two cycles of high-dose cisplatin, mildly accelerated to take place over six weeks as was done in RTOG 1016. Two experimental arms are tested in the initial phase II component, consisting of 60 Gy in 30 fractions with two cycles of cisplatin or 60 Gy, mildly accelerated over five weeks and combined with six cycles of nivolumab. NRG-HN005 tests one of the most vexing questions in head and neck radiation oncology: how can we mitigate the toxicity of head and neck irradiation in patients who may live a long time? In the case of HN005, the eligible population consists of p16+ oropharyngeal cancer patients who, due to their lower overall age and lesser comorbidity burden, could live many decades. It also tests one of the most fundamental precepts in all of radiation oncology, the concept that all locoregionally advanced head and neck cancers must be irradiated to 70 Gy in 35 fractions, as the first trial with the potential to examine in the phase III randomized setting whether 60 Gy might be non-inferior to 70 Gy.
NRG-HN004, led by Principal Investigator Loren Mell, MD, is a randomized phase II/III trial for patients with locoregionally advanced head and neck cancer who have a contraindication to cisplatin. It is an exciting trial as it represents NRG's first foray into treating this unique and growing population, addressing an unmet need for patients who are older or have comorbidities. Eligible patients are randomized 2:1 to either experimental therapy or standard therapy. Standard therapy consists of 70 Gy in 35 fractions over seven weeks with concurrent cetuximab (EGF-R inhibitor). Experimental therapy consists of the same RT schedule plus durvalumab (PD-L1 inhibitor). The phase III primary endpoint is overall survival, and we plan to enroll up to 493 patients in total. This trial presents an exciting opportunity to clarify the role of immune checkpoint inhibitors in head and neck cancer and help define standard of care for patients who are unable to receive cisplatin.
Quynh-Thu Le, MD, FASTRO, is the Katharine Dexter McCormick & Stanley McCormick Memorial Professor and chair of the Department of Radiation Oncology at Stanford University.
Lung
NRG-LU002 and NRG-LU005
The NRG Oncology Lung Cancer Committee has 11 ongoing trials for patients with either lung cancer or brain metastases. Nine of these are randomized Phase III or II/III trials that were designed to answer questions that would change practice. The COVID-19 pandemic has decreased enrollment to National Cancer Trials Network trials by about 20% in 2020. We are hoping to recover enrollment in 2021 and beyond. We will focus on two trials today: NRG LU002 and NRG LU005.
LU002 is a phase II/III for patients with oligometastatic non-small cell lung cancer (NSCLC) who are receiving systemic therapy (chemo, immuno or both). After systemic therapy, patients are randomized to +/- radiation therapy to residual disease. This is a very important question to answer. As we see more referrals for patients with oligometastatic NSCLC in radiation oncology, we need to definitely answer this question.
NRG/Alliance LU005 is a phase II/III randomized trial for patients with limited-stage small cell lung cancer (LS-SCLC). It is based on the success of the Impower133 trial in ES-SCLC, which showed a survival improvement with the addition of the PDL1 agent atezolizumab to systemic chemotherapy. LU005 randomizes LS-SCLC patients to chemoradiation +/- atezolizumab. This trial is actually accruing ahead of schedule despite the pandemic.
Jeffrey Bradley, MD, is the Keller Distinguished Professor and interim chair of the Department of Radiation Oncology at Emory University School of Medicine.
