WASHINGTON, USA. In a new study, reduced doses of radiation therapy and immunotherapy did not work as well as standard chemoradiation for early-stage human papillomavirus-associated oropharyngeal cancer.
These findings, which prompted the suspension of the study, underscore the effectiveness of the current standard of care and highlight the challenges in de-intensifying treatment for this patient population, said Sue Yom, MD, Ph.D., professor at Bakar Precision Cancer. Medicine Center, University of California, San Francisco, United States, in the Annual Congress of the American Society for Radiation Oncology (ASTRO) 2024.[1]
Dra. Sue Yom
Human papillomavirus-associated oropharyngeal cancer has been on the rise, with nearly 70% of newly diagnosed oropharyngeal cancer patients in the United States likely having a virus-driven etiology. These patients generally have a favorable prognosis, but concerns about long-term treatment-related toxicities have driven research into de-escalation strategies, Dr. Yom noted.
The specialist presented the preliminary futility results of the trial NRG-HN005. The phase 2/3 non-inferiority study compared de-escalation strategies with standard chemoradiation in patients with human papillomavirus-associated oropharyngeal cancer.
Rationale and design of the study
The NRG-HN005 trial enrolled patients with p16-positive oropharyngeal squamous cell carcinoma at stage T1-2N1M0 or T3N0-N1M0 (8th edition of the American Joint Committee on Cancer) and smoking history ≤10 pack-years.
Patients were randomly assigned 1:1:1 to three treatment groups:
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Group 1: intensity-modulated radiotherapy of 70 Gy for 6 weeks in combination with cisplatin 100 mg/m2 every 3 weeks (standard of care as control).
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Group 2: intensity modulated radiotherapy of 60 Gy for 6 weeks in combination with cisplatin 100 mg/m2 every 3 weeks.
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Group 3: intensity-modulated radiotherapy of 60 Gy for 5 weeks in combination with 6 cycles of nivolumab.
The primary outcome criterion for the phase 2 portion of the study was noninferiority of progression-free survival with de-escalation therapy compared with the control group.
Two futility analyzes were performed to evaluate the noninferiority status of the experimental groups.
Patient recruitment and patient characteristics for phase 2
Dr. Yom reported that the trial enrolled patients from July 2019 to November 2023 for the Phase 2 portion of the study. Recruitment was suspended from February 2023 to May 2023 to discontinue group 2 after the first futility analysis. From May to November 2023, cumulative patients were randomly assigned 1:1 to groups 1 and 3.
The reviewed phase 2 trial accrued 382 patients in total (men: 90.6%; white race: 87.5%; stage I disease: 84.9%). Additionally, 79.4% of participants had never smoked, while 20.3% had a smoking history of ≤10 pack-years. The median age of the patients was 60 years.
Results
The first futility analysis was performed at a mean follow-up of 1.1 years after eleven progression-free survival events (two in group 1 and nine in group 2). He hazard ratio Estimated HR (HR) for progression in group 2 was 4.34.
The second futility analysis was performed after eleven progression-free survival events (three in group 3) with a median follow-up of 1.7 years. He hazard ratio estimate for disease progression was 4.51. By then patient recruitment for phase 2 had ended.
Patients in the control group demonstrated exceptionally high progression-free survival rates, higher than those in the two de-escalation treatment groups, Dr. Yom said. With a median follow-up of 2.2 years, the 2-year progression-free survival estimates are: group 1: 98.1% (95% confidence interval [IC 95 %]: 95.4 to 100, standard treatment as control), group 2: 88.6% (95% CI: 82.4 to 94.7) and group 3: 90.3% (95% CI: 84.5 to 96.1).
The 2-year overall survival rates are 99.0% (95% CI: 97.0 to 100), 98.0% (95% CI: 95.2 to 100%), and 96.1% (95% CI: 95.2 to 100%). 95%: 92.3 to 99.9), respectively, in groups 1, 2 and 3.
None of the de-escalation treatments met the non-inferiority criteria. During her presentation, Dr. Yom explained: “The failure of the experimental groups to meet the non-inferiority criteria is due in part to the highly favorable outcome of the radiotherapy plus cisplatin regimen, which demonstrated a progression-free survival rate of 98%. at 2 years.”
Implications for clinical practice
The doctor added that these results establish a new benchmark for progression-free survival expectations in human papillomavirus-associated oropharyngeal cancer. Dr. Danielle Margalit, MPH, Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, United States, who was not involved in the study, had a similar take on the findings.
“This study creates a new progression-free survival target that future research should incorporate into the statistical design, because previous phase 2 studies used progression-free survival targets that are in the high 80% or low 90% to affirm no inferiority,” added Dr. Margalit.
Both Dr. Yom and Dr. Margalit agreed that the study confirms that 70 Gy radiation and concurrent cisplatin should remain the standard of care for the patient group included in the study.
“Control treatment produces exceptional results that should be reinforced in standard guidelines. The moral of the long history of NRG/RTOG studies in this population is that standard treatment among these very favorable prognosis groups produces extremely high progression-free survival “said Dr. Yom.
Challenges in de-escalation
Dr. Margalit highlighted that the study results highlight the difficulties in finding a de-escalation scheme that maintains the high cure rates of standard therapy.
“The study tells us that we cannot de-escalate therapy across the board. Therefore, if a patient wants an optimal cure rate, the study shows us that 70 Gy and cisplatin is the standard therapy,” he said.
However, both doctors emphasized that these results should not discourage additional research on de-escalation strategies.
“The majority of patients in these experimental groups had good results with de-escalation. This tells us that de-escalation can preserve high cure rates if we can find a generalizable mechanism to identify patients who should or should not receive it,” said Dr. .Yom.
Future perspectives
The specialists pointed out that future studies should focus on identifying subgroups of patients who could benefit from de-escalation therapy without compromising results.
“It will be very interesting to know what kind of secondary analysis comes out of this study to see if there is a segment of the study population that seems to do just as well even with the lowest dose of radiation or with immunotherapy instead of cisplatin,” she added. Dr. Margalit.
Dr. Yom echoed the need for future studies to refine patient selection criteria.
“Whether we can devise selection criteria to find patients who can safely receive deintensification would be a separate future question from how to integrate immunotherapy into future deintensification efforts,” he added.
Dr. Yom concluded: “The main takeaway is that our usual therapies work very well and our bar must be high for deintensification studies. These findings illustrate that we need rigorous phase 3 data before we can comfortably use deintensification as a standard of care.”
This content was originally published in the English edition of Medscape.
