Cisplatin/70 Gy IMRT Cemented as SOC for Nonsmoking p16+ Oropharyngeal Cancer

Experimental regimens did not cross the threshold to show superiority vs standard cisplatin plus 70 Gy radiation in those with HPV-associated oropharynx cancer.

The standard schedule of 70 Gy intensity-modulated radiation therapy (IMRT) plus cisplatin was not inferior to a deintensification Gy IMRT schedule or to a regimen using nivolumab (Opdivo) vs cisplatin in patients with p16-positive oropharyngeal cancer, according to results of a futility analysis of the phase 2/3 NRG-HN005 trial (NCT03952585) that was presented at the 2024 American Society for Radiation Oncology (ASTRO) Annual Meeting.¹

Patients were randomly assigned 1:1:1 to received standard 70 Gy IMRT in 6 weeks using 6 fractions weekly plus cisplatin at 100 mg/m2 every 3 weeks for 2 cycles (arm 1), 60 Gy radiation in 6 weeks using 5 fractions weekly plus cisplatin at 100 mg/m2 every 3 weeks for 2 cycles (arm 2), or 60 Gy radiation in 5 weeks using 6 fractions weekly plus nivolumab for 6 cycles (arm 3).

Findings showed that, at a median follow-up of 2.2 years, the 2-year estimated progression-free survival (PFS) rates were 98.1% (95% CI, 95.4%-100%), 88.6% (95% CI, 82.4%-94.7%), and 90.3% (95% CI, 84.5%-96.1%) for arms 1, 2, and 3, respectively. The HRs for arm 2 compared with arm 1 were 7.42 (1-sided 90% upper confidence limit [CL], 19.46) and 5.55 (1-sided 90% upper CL, 14.85) for arm 3 vs arm 1.

Two-year estimated overall survival (OS) rates were 99.0% (95% CI, 97.0%-100%) for arm 1, 98.0% (95% CI, 95.2%-100%) for arm 2, and 96.1% for arm 3 (95% CI, 92.3%-99.9%). The HRs for OS for arm 2 vs arm 1 were 5.58 (95% CI, 0.67-46.41) and 4.87 (95% CI, 0.57-41.74) for arm 3 vs arm 1, respectively.

These results set a new benchmark for PFS expectations in this patient population, lead study author Sue S. Yom, MD, PhD, MAS, FASTRO, said in a press briefing during the meeting, adding that further deintensification trials should be held to this standard in the future.

“While deintensification radiation regimens worked well in the vast majority of patients who were enrolled on this trial […] these current eligibility criteria that we used in the trial selection were not enough to make these 2 experimental arms competitive with the current standard of care within NRG Oncology,” said Yom, the Irwin Mark Jacobs and Joan Klein Jacobs Distinguished Professor in Head and Neck Cancer Radiation Oncology, and professor in the departments of Radiation Oncology and Otolaryngology-Head and Neck Surgery, of the University of California, San Francisco. “I also want to point out that one of the important lessons from this trial, is that the highest rate of cure ever documented in any head and neck cancer national trial now comes from this study. That’s important because we now know that these patients have not just a good prognosis, but an incredible prognosis.”

Seventy percent of new patients with oropharynx cancer in the United States have HPV-positive disease, and because of the long survival outcomes of this patient population, there are concerning long-term adverse effects of chemoradiation.

Prior results seen in the phase 3 RTOG 1016 trial (NCT01302834) showed that standard cisplatin plus radiation therapy in HPV-positive patients with oropharynx cancer did not meet the noninferiority threshold against cetuximab (Erbitux) plus radiation for OS (HR, 1.45; 95% CI, 1.94; P = .5056 for noninferiority; one-sided long-rank P = .0163), cementing cisplatin with radiation as the standard of care for these patients.²

Additionally, the randomized phase 2 NRG-HN002 trial (NCT02254278) explored 60 Gy with or without concurrent cisplatin in patients who were nonsmoking with HPV-positive oropharynx cancer with less extensive disease. To be considered for a phase 3 trial, an arm had to demonstrate a 2-year PFS rate superior to the historical control rate of 85%, along with a 1-year mean composite score of 60 or higher on the MD Anderson Dysphagia Inventory. Data showed that the cisplatin/intensity-modulated radiation therapy (IMRT) arm met both prespecified end points, setting the groundwork for a phase 3 study.³

In the phase 2/3 NRG-HN005 trial (NCT03952585), investigators compared 2 experimental arms that were adapted from the NRG-HN002 trial with the control arm from RTOG 1016. To be eligible for enrollment, patients had to have p16-positive oropharyngeal squamous cell carcinoma with a smoking history of up to 10 pack-years, as well as 8th edition T1-2N1M0 or T3N0-N1M0 stage disease (8th edition stage I-II excluding T0, T1-2N0, or any N2 stage). Patients were stratified by Zubrod performance status (0 vs 1).

Yom noted that for each comparison, investigators conducted a preplanned analysis to test for futility, which would be triggered after 11 events were reported. The phase 3 portion of the study would then proceed if 1 or both experimental arms from the phase 2 portion were not eliminated.

The median age of patients was 60 years; most of them were male (90.6%), White (87.5%), and never smokers (79.4%).

Results showed that through the 2 futility analyses for arm 2 and arm 3, both arms were eliminated. The HRs for both futility analyses were greater than 4, which exceeded the present boundary of HR <less than 2.4, which was required for noninferiority.

“The futility analysis for arm 2 triggered earlier in the trial, so we did not enroll the planned total amount into arm 2. Arm 3 had completely accrued by the time the futility analysis was triggered, so the total results that you’re seeing now are the complete phase 2 accrual with the early elimination of arm 2,” Yom said.

Danielle Margalit, MD, MPH, a senior physician at Dana-Farber Cancer Institute, associate professor of radiation oncology at Harvard Medical School, and vice chair of the ASTRO Oropharyngeal Cancer Guideline Update, provided expert perspective on the data during the press briefing.

“This is a very important study; it’s important because it doesn’t change practice, but it informs practice tremendously,” Margalit said. “What that means for the patients is that 70 Gy radiation and concurrent cisplatin remain the standard of care and now this is the regimen that has the largest body of scientific evidence and highest cure rate as Dr Yom mentioned among all the regimens tested so far for HPV-associated oropharynx cancer in this very favorable patient population. This study also tells us that we can’t de-intensify therapy across the board, so if a patient wants to have the optimal cure rate, this study shows us in this large population setting, 70 Gy and cisplatin is the standard.”

References

1. Yom SS, Harris J, Caudell JJ, et al. Interim futility results of NRG-HN005, a randomized, phase II/III non-inferiority trial for non-smoking p16+ oropharyngeal cancer patients. Presented at the 2024 American Society for Radiation Oncology Annual Meeting; September 29-October 2, 2024; Washington DC. Abstract LBA03.
2. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. The Lancet. 2019;393(10166):40-50. doi:10.1016/S0140-6736(18)32779-X
3. Yom SS, Torres-Saavedra PT, Caudell JJ, et al. Reduced-dose radiation therapy for HPV-associated oropharyngeal carcinoma (NRG Oncology HN002).J Clin Oncol. 2021;39(9):956-965. doi:10.1200/JCO.20.03128