De-escalation of Adjuvant Therapy in Operatively Managed HPV Associated Oropharyngeal Carcinoma: Current Status and Future Directions

Ignatiadis M., Bailey A., McArthur H., El-abed S., de Azambuja E., Metzger O., Chui S.Y., Dieterich M., Perretti T., Shearer-Kang E., Molinero L., Steger G.G., Jassem J., Lee S.C., Higgins M., et. al.

ImportanceTriple-negative breast cancer is an aggressive subtype with a high incidence in young patients, a high incidence in non-Hispanic Black women, and a high risk of progression to metastatic cancer, a devastating sequela with a 12- to 18-month life expectancy. Until recently, one strategy for treating early-stage triple-negative breast cancer was chemotherapy after surgery. However, it was not known whether the addition of immune therapy to postsurgery chemotherapy would be beneficial.ObjectiveTo evaluate the addition of immune therapy in the form of atezolizumab to postoperative chemotherapy in patients with the high-risk triple-negative breast cancer subtype.Design, Setting, and ParticipantsIn this open-label international randomized phase 3 trial conducted in more than 330 centers in 31 countries, patients undergoing surgery as initial treatment for stage II or III triple-negative breast cancer were enrolled between August 2, 2018, and November 11, 2022. The last patient follow-up was on August 18, 2023.InterventionsPatients were randomized (1:1) to receive standard chemotherapy for 20 weeks with (n = 1101) or without (n = 1098) the immune therapy drug atezolizumab for up to 1 year.Main Outcomes and MeasuresThe primary end point was invasive disease-free survival (time between randomization and invasive breast cancer in the same or opposite breast, recurrence elsewhere in the body, or death from any cause).ResultsThe median age of enrolled patients was 53 years and most self-reported as being of Asian or White race and neither Latino nor Hispanic ethnicity. The study independent data monitoring committee halted enrollment at 2199 of 2300 planned patients. All patients stopped atezolizumab following a planned early interim and futility analysis. The trial continued to a premature final analysis. With invasive disease-free survival events in 141 patients (12.8%) treated with atezolizumab-chemotherapy and 125 (11.4%) with chemotherapy alone (median follow-up, 32 months), the final stratified invasive disease-free survival hazard ratio was 1.11 (95% CI, 0.87-1.42; P = .38). Compared with chemotherapy alone, the regimen of atezolizumab plus chemotherapy was associated with more treatment-related grade 3 or 4 adverse events (54% vs 44%) but similar incidences of fatal adverse events (0.8% vs 0.6%) and adverse events leading to chemotherapy discontinuation. Chemotherapy exposure was similar in the 2 treatment groups.Conclusions and RelevanceThe addition of the immune therapy drug atezolizumab to chemotherapy after surgery did not provide benefit among patients with triple-negative breast cancer who are at high risk of recurrent disease.Trial RegistrationClinicalTrials.gov Identifier: NCT03498716

Campo F., Paolini F., Terrenato I., Blandino G., Pascale V.D., Locca O., Moretto S., Manciocco V., Vidiri A., Venuti A., Pellini R.

we evaluated the hypothesis that level of ctHPVDNA on the first postoperative day (POD-1); and at 15 days (POD-15) could be associated with the need for adjuvant therapy and the presence of recurrence. this is a prospective observational study on biomarkers, focusing on the longitudinal monitoring of ctHPVDNA in a cohort of HPV-OPSCC patients undergoing TORS. Blood samples were collected according to the following schema: (1) pretreatment; (2) on first postoperative day (POD 1); and (3) at 15 days (POD 15). Plasma samples were analyzed with ddPCR assay comprising E6 of HPV16, HPV 33 and HPV 35. Present study was conducted on 44 OPSCC patients and revealed a ctHPVDNA sensitivity of 100% (95%CI: 89-100%) in blood samples at first diagnosis. Data demonstrated a significant different of ctHPVDNA levels at POD-1 among patients who received observation vs. adjuvant treatment and among patients who remained disease-free at the last follow-up, compared to those who experienced recurrence. In the next years, studies on larger patients’ surgical cohorts focused on ctHPVDNA levels at POD-1 and continued improvements in assay methodology could allow the implementation of ctHPVDNA in routine clinical use. Liquid biopsy could identify residual molecular disease after surgery and guide clinicians choosing adjuvant treatment.

Black J.R., Bartha G., Abbott C.W., Boyle S.M., Karasaki T., Li B., Chen R., Harris J., Veeriah S., Colopi M., Bakir M.A., Liu W.K., Lyle J., Navarro F.C., Northcott J., et. al.

Abstract Circulating tumor DNA (ctDNA) detection can predict clinical risk in early-stage tumors. However, clinical applications are constrained by the sensitivity of clinically validated ctDNA detection approaches. NeXT Personal is a whole-genome-based, tumor-informed platform that has been analytically validated for ultrasensitive ctDNA detection at 1–3 ppm of ctDNA with 99.9% specificity. Through an analysis of 171 patients with early-stage lung cancer from the TRACERx study, we detected ctDNA pre-operatively within 81% of patients with lung adenocarcinoma (LUAD), including 53% of those with pathological TNM (pTNM) stage I disease. ctDNA predicted worse clinical outcome, and patients with LUAD with <80 ppm preoperative ctDNA levels (the 95% limit of detection of a ctDNA detection approach previously published in TRACERx) experienced reduced overall survival compared with ctDNA-negative patients with LUAD. Although prospective studies are needed to confirm the clinical utility of the assay, these data show that our approach has the potential to improve disease stratification in early-stage LUADs.

Rettig E.M., Schoenfeld J.D., Miller J., Sargent B., Carey E., Margalit D.N., Sehgal K., Sethi R.K., Uppaluri R., Tishler R.B., Goguen L.A., Annino D.J., Sim E.S., Jo V.Y., Wong K.S., et. al.

Abstract Purpose: Observational studies suggest circulating tumor human papillomavirus (HPV) DNA may facilitate early detection of recurrent HPV-positive oropharynx cancer. We prospectively investigated whether biomarker-guided surveillance detects recurrence earlier than the standard-of-care methods. Patients and Methods: We enrolled patients evaluated for HPV-positive oropharynx cancer at a single center from November, 2020, to April, 2023, undergoing curative-intent treatment in a single-arm cohort study. Pretreatment plasma and/or tumor tissue were tested for tumor tissue–modified viral (TTMV) HPV DNA from HPV subtypes 16/18/31/33/35 using a droplet digital PCR–based commercial assay. Posttreatment plasma TTMV was assessed periodically. Detectable/indeterminate tests prompted imaging. The primary outcome was the proportion of recurrences first detected by TTMV. Results: Median follow-up was 23 months, with median six posttreatment TTMV tests for 155 subjects. Fifteen subjects (9%) experienced recurrence. Among these, six [40%, 95% confidence interval (CI) = 16%–68%] were “early true-positives,” for whom TTMV detection predated and prompted the imaging and clinical workup that diagnosed recurrence (median lead time = 132 days; range = 47–280). Another five subjects (33%) were “confirmatory true-positives,” for whom detectable TTMV confirmed suspicious standard-of-care imaging findings. Finally, four subjects (27%) with recurrence had undetectable TTMV at diagnosis (“false-negatives”). False-negatives had low or undetectable pretreatment TTMV, and 2/4 had non-HPV16 genotypes. Finally, three subjects had prolonged detectable TTMV without disease (“false-positives”); all had immunologic comorbidities. Overall, the sensitivity of TTMV for recurrence was 73% (95% CI = 45%–92%). Among 117 subjects with HPV16 and detectable pretreatment TTMV, sensitivity was higher (91%, 95% CI = 59%–100%). Conclusions: TTMV-guided surveillance facilitates early detection of many HPV-positive oropharynx cancer recurrences, with the highest sensitivity for HPV16 and detectable pretreatment TTMV. Clinical implementation should be carefully informed by the limitations described in this study.

Mell L.K., Torres-Saavedra P.A., Wong S.J., Kish J.A., Chang S.S., Jordan R.C., Liu T., Truong M.T., Winquist E.W., Takiar V., Wise-Draper T., Robbins J.R., Rodriguez C.P., Awan M.J., Beadle B.M., et. al.

Nichols A.C., Theurer J., Prisman E., Read N., Berthelet E., Tran E., Fung K., de Almeida J.R., Bayley A., Goldstein D.P., Hier M., Sultanem K., Richardson K., Mlynarek A., Krishnan S., et. al.

Radiotherapy (RT) and transoral robotic surgery (TORS) are both curative-intent treatment options for oropharyngeal squamous cell carcinoma (OPSCC). Herein, we report the final outcomes of the ORATOR trial comparing these modalities, 5 years after enrollment completion. We randomly assigned 68 patients with T1-2N0-2 OPSCC to RT (with chemotherapy if node-positive) versus TORS plus neck dissection (± adjuvant RT/chemoradiation). The primary end point was swallowing quality of life (QOL) assessed with the MD Anderson Dysphagia Inventory (MDADI). Secondary end points included overall and progression-free survival (OS, PFS), adverse events (AEs), and other QOL metrics. The primary end point has been previously reported (Nichols 2019). In this report, the median follow-up was 5.1 years (IQR, 5.0-5.3 years). MDADI total scores converged by 5 years and were not significantly different across the follow-up period ( P = .11). EORTC QLQ-C30 and H&N35 scores demonstrated differing profiles, including worse dry mouth in the RT arm ( P = .032) and worse pain in the TORS arm ( P = .002). Grade 2-5 AE rates did not differ between arms (91% [n = 31] v 97% [n = 33] respectively, P = .61), with more neutropenia and hearing loss in the RT arm, and more dysphagia and other pain in the TORS arm based on grades 2-5 (all P < .05). There were no differences in OS or PFS. In conclusion, toxicity and QOL profiles differ in some domains between RT and TORS, but oncologic outcomes were excellent in both arms. Choice of treatment should remain a shared decision between the patient and their providers.

Blank C.U., Lucas M.W., Scolyer R.A., van de Wiel B.A., Menzies A.M., Lopez-Yurda M., Hoeijmakers L.L., Saw R.P., Lijnsvelt J.M., Maher N.G., Pulleman S.M., Gonzalez M., Torres Acosta A., van Houdt W.J., Lo S.N., et. al.

Kiser K., Apicelli A., Brenneman R.J., Gay H.A., Moravan M.J., Rammohan N., Jackson R.S., Pipkorn P., Puram S., Adkins D., Oppelt P., Thorstad W.L.

Yom S.S., Harris J., Caudell J.J., Geiger J.L., Waldron J., Gillison M., Subramaniam R.M., Yao M., Xiao C., Kovalchuk N., Martino R., Jordan R., Henson C., Echevarria M., Lominska C.E., et. al.

Bratman S.V., Karam I., Waldron J.N., Butler J., Olson R.A., Pochini C.M., Berthelet E., de Almeida J., McNiven A.L., Fitzgerald T., Cheung W., Gaudet M., Metser U., Yu E., Gauthier I., et. al.

Margalit D.N., Anker C.J., Aristophanous M., Awan M., Bajaj G.K., Bradfield L., Califano J., Caudell J.J., Chapman C.H., Garden A.S., Harari P.M., Helms A., Lin A., Maghami E., Mehra R., et. al.

PurposeHPV-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct disease from other head and neck tumors. This guideline provides evidence-based recommendations on the critical decisions in its curative treatment, including both definitive and postoperative radiation therapy (RT) management.MethodsThe American Society for Radiation Oncology convened a task force to address 5 key questions on the use of RT for management of HPV-associated OPSCC. These questions included indications for definitive and postoperative RT and chemoradiation; dose-fractionation regimens and treatment volumes; preferred RT techniques and normal tissue considerations; and post-treatment management decisions. The task force did not address indications for primary surgery versus RT. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength.ResultsConcurrent cisplatin is recommended for patients receiving definitive RT with T3-4 disease and/or one node >3 cm, or multiple nodes. For similar patients who are ineligible for cisplatin, concurrent cetuximab, carboplatin/5-fluorouracil, or taxane-based systemic therapy are conditionally recommended. In the postoperative setting, RT with concurrent cisplatin (either schedule) is recommended for positive surgical margins (PSM) or extranodal extension (ENE). Postoperative RT alone is recommended for pT3-4 disease, >2 nodes, or a single node >3 cm. Observation is conditionally recommended for pT1-2 disease and a single node ≤3 cm without other risk factors. For patients treated with definitive RT with concurrent systemic therapy, 7000 cGy in 33 to 35 fractions is recommended, and for patients receiving postoperative RT without PSM and ENE, 5600-6000 cGy is recommended. For all patients receiving RT, intensity modulated RT over 3-D techniques with reduction in dose to critical organs-at-risk (including salivary and swallowing structures) is recommended. Reassessment with positron emission tomography-computed tomography (PET-CT) is recommended approximately 3 months following definitive RT/chemoradiation, and neck dissection is recommended for convincing evidence of residual disease; for equivocal PET-CT findings, either neck dissection or repeat imaging is recommended.ConclusionsThe role and practice of RT continues to evolve for HPV-associated OPSCC, and these guidelines inform best clinical practice based on the available evidence.

Henson C., Abou-Foul A.K., Yu E., Glastonbury C., Huang S.H., King A.D., Lydiatt W.M., McDowell L., Nagelschneider A.A., Nankivell P.C., O’Sullivan B., Rhys R., Xiao Y., Andrew D., Asmussen J.T., et. al.

Extranodal extension of tumour on histopathology is known to be a negative prognostic factor in head and neck cancer. Compelling evidence suggests that extranodal extension detected on radiological imaging is also a negative prognostic factor. Furthermore, if imaging detected extranodal extension could be identified reliably before the start of treatment, it could be used to guide treatment selection, as patients might be better managed with non-surgical approaches to avoid the toxicity and cost of trimodality therapy (surgery, chemotherapy, and radiotherapy together). There are many aspects of imaging detected extranodal extension that remain unresolved or are without consensus, such as the criteria to best diagnose them and the associated terminology. The Head and Neck Cancer International Group conducted a five-round modified Delphi process with a group of 18 international radiology experts, representing 14 national clinical research groups. We generated consensus recommendations on the terminology and diagnostic criteria for imaging detected extranodal extension to harmonise clinical practice and research. These recommendations have been endorsed by 19 national and international organisations, representing 34 countries. We propose a new classification system to aid diagnosis, which was supported by most of the participating experts over existing systems, and which will require validation in the future. Additionally, we have created an online educational resource for grading imaging detected extranodal extensions.

Rosenberg A.J., Agrawal N., Juloori A., Cursio J., Gooi Z., Blair E., Chin J., Ginat D., Pasternak-Wise O., Hasina R., Starus A., Jones F.S., Izumchenko E., MacCracken E., Wolk R., et. al.

ImportanceImmune checkpoint inhibitors improve survival in recurrent and/or metastatic head and neck cancer, yet their role in curative human papillomavirus−positive oropharyngeal cancer (HPV+ OPC) remains undefined. Neoadjuvant nivolumab and chemotherapy followed by response-adaptive treatment in HPV+ OPC may increase efficacy while reducing toxicity.ObjectiveTo determine the deep response rate and tolerability of the addition of neoadjuvant nivolumab to chemotherapy followed by response-adapted locoregional therapy (LRT) in patients with HPV+ OPC.Design, Setting, and ParticipantsThis phase 2 nonrandomized controlled trial conducted at a single academic center enrolled 77 patients with locoregionally advanced HPV+ OPC from 2017 to 2020. Data analyses were performed from February 10, 2021, to January 9, 2023.InterventionsAddition of nivolumab to neoadjuvant nab-paclitaxel and carboplatin (studied in the first OPTIMA trial) followed by response-adapted LRT in patients with HPV+ OPC stages III to IV.Main Outcomes and MeasuresPrimary outcome was deep response rate to neoadjuvant nivolumab plus chemotherapy, defined as the proportion of tumors with 50% or greater shrinkage per the Response Evaluation Criteria in Solid Tumors 1.1. Secondary outcomes were progression-free survival (PFS) and overall survival (OS). Swallowing function, quality of life, and tissue- and blood-based biomarkers, including programmed death-ligand 1 (PD-L1) expression and circulating tumor HPV-DNA (ctHPV-DNA), were also evaluated.ResultsThe 73 eligible patients (median [range] age, 61 [37-82] years; 6 [8.2%] female; 67 [91.8%] male) started neoadjuvant nivolumab and chemotherapy. Deep responses were observed in 51 patients (70.8%; 95% CI, 0.59-0.81). Subsequent risk- and response-adaptive therapy was assigned as follows: group A, single-modality radiotherapy alone or transoral robotic surgery (28 patients); group B, intermediate-dose chemoradiotherapy of 45 to 50 Gray (34 patients); and group C, regular-dose chemoradiotherapy of 70 to 75 Gray (10 patients). Two-year PFS and OS were 90.0% (95% CI, 0.80-0.95) and 91.4% (95% CI, 0.82-0.96), respectively. By response-adapted group, 2-year PFS and OS for group A were 96.4% and 96.4%, and group B, 88.0% and 91.0%, respectively. Lower enteral feeding rates and changes in weight, as well as improved swallowing, were observed among patients who received response-adapted LRT. Pathologic complete response rate among patients who underwent transoral robotic surgery was 67.0%. PD-L1 expression was nonsignificantly higher for deeper responses and improved PFS, and ctHPV-DNA clearance was significantly associated with improved PFS.Conclusions and RelevanceThis phase 2 nonrandomized controlled trial found that neoadjuvant nivolumab and chemotherapy followed by response-adapted LRT is feasible and has favorable tolerability, excellent OS, and improved functional outcomes in HPV+ OPC, including among patients with high-risk disease. Moreover, addition of nivolumab may benefit high PD-L1 expressors, and sensitive dynamic biomarkers (eg, ctHPV-DNA) are useful for patient selection.Trial RegistrationClinicalTrials.gov Identifier: NCT03107182

Huang C., Zhang N., Jiang W., Xie F., Pei X., Huang S.H., Wang X., Mao Y., Li K., Liu Q., Li J., Liang S., Qin G., Hu W., Zhou G., et. al.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We previously reported comparable 3-year regional relapse–free survival (RRFS) using elective upper-neck irradiation (UNI) in N0-1 nasopharyngeal carcinoma (NPC) compared with standard whole-neck irradiation (WNI). Here, we present the prespecified 5-year overall survival (OS), RRFS, late toxicity, and additional analyses. In this randomized trial, patients received UNI (n = 224) or WNI (n = 222) for an uninvolved neck. After a median follow-up of 74 months, the UNI and WNI groups had similar 5-year OS (95.9% v 93.1%, hazard ratio [HR], 0.63 [95% CI, 0.30 to 1.35]; P = .24) and RRFS (95.0% v 94.9%, HR, 0.96 [95% CI, 0.43 to 2.13]; P = .91) rates. The 5-year disease-free survivors in the UNI group had a lower frequency of hypothyroidism (34% v 48%; P = .004), neck tissue damage (29% v 46%; P < .001), dysphagia (14% v 27%; P = .002), and lower-neck common carotid artery stenosis (15% v 26%; P = .043). The UNI group had higher postradiotherapy circulating lymphocyte counts than the WNI group (median: 400 cells/μL v 335 cells/μL, P = .007). In conclusion, these updated data confirmed that UNI of the uninvolved neck is a standard of care in N0-1 NPC, providing outstanding efficacy and reduced long-term toxicity, and might retain more immune function.

Hirayama S., Al-Inaya Y., Aye L., Bryan M.E., Das D., Mendel J., Naegele S., Faquin W.C., Sadow P., Fisch A.S., Lin D., Varvares M.A., Feng A., Emerick K.S., Deschler D.G., et. al.

6010 Background: Prediction of minimal residual disease (MRD) following surgery, and thus the need for adjuvant therapy, is currently based on clinicopathologic risk factors which have poor individual prognostic capacity. We previously reported that MRD detection by ctHPVDNA droplet digital (dd)PCR as early as post-operative day (POD) 1 is predictive of recurrence in stage I-II HPV+HNSCC patients. Here, we applied a significantly more sensitive custom whole genome hybrid-capture-based next generation sequencing assay, termed HPV-DeepSeek, to validate the prognostic capacity of ctHPVDNA detection and explore the optimal timing of MRD testing in HPV+HNSCC patients. We tested the primary hypothesis that patients with MRD detection within 6 weeks of surgery would have inferior PFS at 2 years and the secondary hypothesis that patients with ctHPVDNA positivity detected at any point following treatment completion would have inferior PFS at 2 years. Methods: 98 patients with HPV+HNSCC were prospectively enrolled with a mean follow-up of 712 days. All patients underwent surgery as primary treatment and clinicopathologic adjusted adjuvant treatment. 10ml blood samples were collected before surgery, in the post-operative period (POD 1-42), and serially in follow-up. MRD was defined as a lack of ctHPVDNA clearance during the 6 weeks following surgery. Cell free DNA was extracted from plasma and run on HPV-DeepSeek, and on existing ddPCR assays for head to head comparisons. Results: 96/98 (98%) of patients had detectable ctHPVDNA pre-treatment. 30/98 patients (31%) were MRD positive. Patients who were MRD positive had significantly worse 2 years PFS compared to MRD negative patients (78% vs 98%, P=0.0009). Predictive performance improved by limiting time points to POD 7-42 (2 year PFS 60% vs 97%, P<0.0001) as significantly fewer patients were MRD positive >1 week after surgery, suggesting the use of an ultra-sensitive assay such as HPV-DeepSeek requires adjustment of MRD time points. Patients with detectable ctHPVDNA following completion of all treatment had significantly worse 2-year PFS compared to patients without detectable ctHPVDNA (0% vs 97%, P<0.0001). 7/98 patients had cancer recurrence during follow-up that was detected by ctHPVDNA with a mean lead time of 207 days (35-518) to clinical diagnosis. Conclusions: ctHPVDNA detection by HPV-DeepSeek is a highly specific biomarker of MRD in HPV+HNSCC, accurately predicts disease progression and detects recurrence earlier than standard care clinical.