Chemoradiation Best in HPV-associated Oropharyngeal Cancer

WASHINGTON — Reduced doses of radiation therapy and immunotherapy did not work as well as the standard chemoradiation for early-stage HPV-associated oropharyngeal cancer, in a new study.

These findings, which caused the study to be suspended, underscore the efficacy of the current standard-of-care treatment and highlight the challenges in de-intensifying therapy for this patient population, said Sue Yom, MD, PhD, at the American Society for Radiation Oncology (ASTRO) 2024 Annual Meeting.

HPV-associated oropharyngeal cancer has been on the rise, with approximately 70% of patients with newly diagnosed oropharyngeal cancer in the United States likely having HPV-driven etiology. These patients generally have a favorable prognosis, but concerns about long-term treatment-related toxicities have driven research into de-escalation strategies, said Yom, who is professor at the University of California, San Francisco, Bakar Precision Cancer Medicine Center.

Yom presented interim futility results from the NRG-HN005 trial at the meeting. The phase 2/3 non-inferiority study compared de-escalation strategies to standard chemoradiation in patients with human papillomavirus (HPV)-associated oropharyngeal cancer.

Study Rationale and Design

The NRG-HN005 trial enrolled patients with p16-positive, stage T1-2N1M0 or T3N0-N1M0 (American Joint Committee on Cancer Eighth edition) oropharyngeal squamous cell carcinoma and a smoking history of ≤ 10 pack-years.

Patients were randomized 1:1:1 to three treatment arms:

• Arm 1 — 70 Gy intensity-modulated radiation therapy (IMRT) over 6 weeks in combination with cisplatin 100 mg/m² every 3 weeks (the standard of care as control)
• Arm 2 — 60 Gy IMRT over 6 weeks in combination with cisplatin 100 mg/m² every 3 weeks
• Arm 3 — 60 Gy IMRT over 5 weeks in combination with six cycles of nivolumab

The primary endpoint for the phase 2 portion of the study was non-inferiority of progression-free survival (PFS) with de-escalation therapy compared with the control arm.

Two futility analyses were conducted to evaluate the non-inferiority status of the experimental arms.

Phase 2 Accrual and Patient Characteristics

Yom reported that the trial accrued patients from July 2019 to November 2023 for the phase 2 part of the study. The accrual was suspended from February 2023 to May 2023 to discontinue arm 2 after the first futility analysis. From May to November 2023, accrued patients were randomized 1:1 to arms 1 and 3.

The revised phase 2 trial accrued 382 patients in total (90.6% men, 87.5% White, and 84.9% with stage I disease). Moreover, 79.4% of the participants had never smoked, whereas 20.3% had a smoking history of ≤ 10 pack-years. The median patient age was 60 years.

Results

The first futility analysis was conducted at a median follow-up of 1.1 years after 11 PFS events (two in arm 1 and nine in arm 2). The estimated hazard ratio (HR) for progression in arm 2 was 4.34.

The second futility analysis was conducted after 11 PFS events (three in arm 3) at a median follow-up of 1.7 years. The estimated HR for disease progression was 4.51. By then, the phase 2 accrual had finished.

Patients in the control arm demonstrated exceptionally high PFS rates, which were higher than those in the two de-escalation treatment arms, said Yom. At a median follow-up of 2.2 years, the 2-year PFS estimates are: Arm 1 — 98.1% (95% CI, 95.4%-100%; standard treatment as control), arm 2 — 88.6% (95% CI, 82.4%-94.7%), and arm 3 — 90.3% (95% CI, 84.5%-96.1%).

The 2-year overall survival rates are 99.0% (95% CI, 97.0%-100%), 98.0% (95% CI, 95.2%-100%), and 96.1% (95% CI, 92.3%-99.9%), respectively, in arms 1, 2, and 3.

Both de-escalation treatments failed to meet the non-inferiority criteria. During her presentation, Yom explained, “The failure of the experimental arms to satisfy non-inferiority is partly due to the highly favorable outcome for the radiotherapy plus cisplatin regimen, which demonstrated a 98% PFS rate through 2 years.”

Implications for Clinical Practice

According to Yom, these results set a new benchmark for PFS expectations in HPV-associated oropharyngeal cancer.

Danielle Margalit, MD, MPH, who was not involved in the study, gave a similar take on the findings, during a media briefing.

“This study creates a new target PFS that future studies need to incorporate in the statistical design because prior phase 2 studies used PFS goals that are in the high 80% or the low 90% to claim non-inferiority,” said Margalit, of the Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston.

Both Yom and Margalit also 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.

“The control treatment produces outstanding outcomes, which should be reinforced in standard guidelines,” Yom said. “The take-home message from the long history of NRG/RTOG studies in this population is that the standard-of-care treatment among these very favorable prognostic groups produces extremely high PFS.”

Challenges in De-Escalation

According to Margalit, the study results highlight the difficulties in finding a de-escalation regimen that maintains the high cure rates of standard therapy.

“The study tells us that we can’t de-intensify therapy across the board. So if a patient wants an optimal cure rate, the study shows us that 70 Gy and cisplatin is the standard therapy,” she noted during the press briefing session.

However, both Yom and Margalit emphasized that these results should not discourage further research into de-escalation strategies.

“The majority of patients in these experimental arms did well with de-intensification. This tells us that de-intensification can preserve high cure rates if we can find a generalizable mechanism to identify patients who should or should not have it,” Yom said, during an interview.

Future Directions

Yom and Margalit said future studies should focus on identifying subgroups of patients who might benefit from de-escalated therapy without compromising outcomes.

“It will be very interesting to see 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 lower dose of radiation or with immunotherapy instead of cisplatin.” Margalit said.

Yom echoed the need for future studies to refine patient selection criteria.

“If we can come up with selection criteria to find patients who can safely receive de-intensification, it would be a separate future question of how to integrate immunotherapy into future de-intensification efforts,” she said.

Yom concluded: “The key takeaway is that our usual therapies work very well, and our bar should be high for de-intensification studies. These findings illustrate that we need rigorous phase 3 data before we can comfortably use de-intensification as a standard of care.”

Yom reported financial relationships with EMD Serono, Nanobiotix, Bristol Myers Squibb, and Merck (institutional research contracts); NRG Oncology UC Tobacco-Related Disease, National Institutes of Health (institutional grants); UpToDate, Springer (book royalties); and ASTRO, Elsevier (honoraria). Margalit reported financial relationships with the American Radium Society Appropriate Use Committee (guideline committee/chair) and the IJROBP (section editor).