Induction chemotherapy response–guided selection for hypoxia-directed major radiation de-escalation in T3–T4 HPV-positive oropharyngeal cancer.

6103 Background: De-escalation trials in human papillomavirus associated oropharyngeal carcinoma (HPV+ OPC) often exclude patients with very locally advanced disease. We previously demonstrated in several Phase II study that for patients with T1-T2 HPV+OPC, de-escalation to 30Gy of definitive chemoradiation based on lack of hypoxia on 18 F-FMISO (fluoromisonidazole) PET (30-ROC Study) is associated with excellent outcomes (JNCI 2021; JCO 2024). Here, we hypothesized that induction chemotherapy (ICT) response could be used to select appropriate locally advanced (T3-T4) HPV+OPC for de-escalation while simultaneously improving tumor hypoxia. Methods: We conducted a pilot study in HPV+ OPC patients with AJCC v7 T3-T4 and/or large volume N2b-N2c-N3 disease (who were ineligible for 30-ROC Study (NCT03323563)). ICT – carboplatin (AUC2), paclitaxel (90 mg/m2), and cetuximab (250 mg/m2 after 400 mg/m2 loading dose) weekly for 6 weeks. To be eligible for de-escalation (30-ROC), after ICT, patients needed to be down-staged (<=T2 and <=N3 disease). 18 F-FMISO PET scan done prior to ICT, after ICT, and, if eligible for ROC study, about 2 weeks after start of radiation therapy. If an 18 F-FMISO PET scan showed no hypoxia prior to the start of chemoradiation, no further scans were necessary and patients received 30Gy of radiation therapy with 2 cycles of chemotherapy concurrently. Primary outcome is 2-year local control rate in 20 evaluable patients. Results: 20 patients were accrued 3/2023-12/2023. Median age - 70 years old (46-88); Male – 95%; ECOG PS 0 – 80%. Tumor stage – T3 (70%); T4a (30%); N2b (70%); N2c (30%). All 20 patients had pretreatment hypoxia by 18 F-FMISO. All 20 patients had sufficient downstaging to be treated by 30-ROC Study and converted to no hypoxia by 18 F-FMISO. The estimated progression free survival and local control rate at 2 years is 90% (95% CI 76.9%-100%). There were no distant failures. The median follow up is 23 months (range 12-29 months). All patients were alive and without evidence of disease at last follow up. Conclusions: Preliminary results suggest that ICT can allow more advanced tumors (T3/T4), that are typically excluded from de-escalation studies, to be de-escalated and may eliminate tumor hypoxia in a large proportion of cases. This small pilot study shows similar results seen in the larger ROC studies published to date, but a larger study is needed to confirm these results and is currently ongoing. Clinical trial information: NCT05491512 .