DART Demonstrates Noninferiority to Historical Controls in HPV-Related OPSCC

In human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma (OPSCC), data from a pooled analysis back the use of de-escalated adjuvant radiation therapy (DART), meeting the noninferiority threshold for progression-free survival (PFS) compared with historical data.¹

Compared with PFS results from the HN055 trial (NCT03952585), the 2-year PFS rates of 91.1% (95% CI, 87.2%-95.3%) was within the acceptable threshold of noninferiority, according to Daniel J. Ma, MD, who presented the data at the 2022 Multidisciplinary Head and Neck Cancers Symposium hosted by the American Society for Radiation Oncology (ASTRO).

“Progression-free survival is the aim to see if [DART] meets the metric that was set as clinically acceptable by the head and neck community,” Ma, coleader of the Oropharynx Multidisciplinary Clinic at Mayo Clinic, said during the presentation. “This is the largest prospective cohort of [patients treated with] de-escalated adjuvant therapy and represents the only prospective cohort of extranodel extension [ENE]–positive disease with radiation dose de-escalation.”

Background of MC1273 and MC1675

Due to the severity of adverse effects associated with therapies for HPV-related oropharyngeal cancers, investigators set out to examine a 2-week course of 30 to 36 Gy adjuvant radiation therapy for selected patients by way of the phase 2 MC1273 (NCT01932697) and phase 3 MC1675 trials (NCT02908477).

MC1273 examined patients with surgically resected p16-positive OPSCC who had no evidence of metastases and less than a 10 pack-year smoking history and stratified them by adjuvant risk factors. Patients who had intermediate risk factors only, defined by lymphovascular or perineural invasion, were in cohort A and were administered 30 Gy delivered in 1.5 Gy increments twice daily over 12 days with docetaxel at 15 mg/m2 on days 1 and 8; those with extranodal extension who were in cohort B and were given 36 Gy delivered in 1.8 Gy increments twice daily over 12 days with docetaxel.²

Positive results led to MC1675, in which the DART regimens described above were randomized against standard therapy in a 2:1 fashion. In cohort A, 53 patients were treated with DART whereas 26 were given 60 Gy delivered in 2 Gy doses; cohort B consisted of 77 patients on DART and 38 who were given 60 Gy as 2 Gy doses plus 40 mg/m² of cisplatin weekly.³

“Results from MC1675 have demonstrated excellent overall survival, locoregional control, and progression-free survival metrics,” Ma said.

However, questions about the DART regimen remain, such as whether the PFS results are clinically acceptable, leading to the current pooled analysis of both trials.

“This is a bit of a philosophical question about what is meant by clinically acceptable. The gold standard is a randomized phase 3 trial powered for noninferiority,” said Ma. He then pointed out that to achieve statistically significant results in a trial like MC1675, 4000 patients would be needed to achieve a 1% noninferiority margin. “This is more than all the patients with TORS [transoral robotic surgery] across all the academic centers across the United States with a year.”

Ma then referred to the HN005 trial with hierarchical co-primary end points of PFS and quality of life, in which patients were first analyzed for PFS noninferiority vs a comparable population treated in RTOG 1016 (NCT01302834). When the end point was reached, subsequent comparisons for global MD Anderson Dysphagia Inventory (MDADI) were performed between arms.

“The design for this pre-planned joint analysis is to repeat the HN005 composite design, but in reverse,” said Ma. Given the toxicity results of MC1675 have been presented, the composite analysis is being performed based on efficacy results of MC1675 and MC1273 pooled results.

DART Efficacy Noninferiority

Accrual across the 2 trials occurred from 2013 to 2020 with a median follow-up time of 36.6 months. Those who were included in the pooled analysis received DART in either MC1675 (n = 130) or MC1273 (n = 72). One patient was lost to follow-up due to incarceration around the 12-month time point.

Using the 2-year PFS rate of 92.3% and the lower acceptable threshold of 86.9% from HN005, the investigators for the current analysis determined that DART meet noninferiority.

Looking at subgroups, the ENE-negative cohort remains above the pre-determined PFS threshold with a 2-year rates of 97.7% (95% CI, 94.6%-100.0%); however, patients with ENE-positive status drop below the threshold with a rate of 85.2% (95% CI, 78.6%-92.5%).

Drilling down into each subgroup further, all prespecified cohorts met the noninferiority margin except those with ENE-positive pN2 disease, with a 2-year PFS rate of 54.5% (95% CI, 36.4%-81.7%). Corresponding rates were 97.5% (95% CI, 94.7%-100.0%) with ENE-negative pN0-1 disease, 100.0% for ENE-negative pN2, and 92.5% (95% CI, 86.9%-98.5%) in ENE-positive pN1 disease. Ma cautioned against interpretation of the ENE-negative pN2 cohort, as there were only 2 patients enrolled.

“Most of the events of progression happened in the ENE-positive, pN2 cohort,” Ma said.

Further, the extent of ENE—either values of less than 1 mm vs 1 mm or more—had no appreciable contribution on PFS.

For the combined cohort, rates of overall survival and locoregional control at 2 years were 97.8% (95% CI, 95.7%-100.0%) and 96.9% (95% CI, 94.5%-99.4%), respectively.

“Going back to the question we posed and understanding that this is somewhat controversial, are the results of the DART regimen clinically acceptable? I’ll leave that to the community to define, but I will say that the DART regimen does meet the HN005 PFS noninferiority target. This is combined with the fact that there is a substantial toxicity benefit seen with the DART regimen,” Ma concluded.

_References

_{1. Ma DJ, Price K, Moore EJ, et al. Non-inferiority margin and nodal analysis of de-escalated adjuvant radiation therapy (DART) for HPV-related oropharyngeal squamous cell carcinoma (OPSCC): a preplanned pooled analysis of MC1273 & MC1675. Presented at: 2022 Multidisciplinary Head and Neck Cancers Symposium. Phoenix, AZ. Abstract 2. https://bit.ly/33PnToW}

_{2. Ma DJ, Price K, Moore EJ, et al. Long-Term results for MC1273, a phase II evaluation of de-escalated adjuvant radiation therapy for human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC). Intl J Rad Oncol Biol Phys. 2021;111(3):S61. doi: 10.1016/j.ijrobp.2021.09.012}

_{3. Ma DJ, Price K, Moore EJ, et al. MC1675, a phase III evaluation of de-escalated adjuvant radiation therapy (DART) vs. standard adjuvant treatment for human papillomavirus associated oropharyngeal squamous cell carcinoma. Intl J Rad Oncol Biol Phys. 2021;111(5):LBA-1. doi: 10.1016/j.ijrobp.2021.09.012}