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A Consensus Statement on the Administration of Systemic Bevacizumab in Patients with Recurrent Respiratory Papillomatosis Simon R. Best, MD ; Jonathan M. Bock, MD ; Nicole B. Fowler, PhD; Eric H. Raabe, MD, PhD; Adam M. Klein, MD; Theodore W. Laetsch, MD; Kim McClellan, BS; Rico N.P.M. Rinkel, MD, SLP; Nabil F. Saba, MD, FACP; Douglas R. Sidell, MD ; James B. Tansey, MBA; David E. Tunkel, MD ; Geoffrey D. Young, MD; Karen B. Zur, MD Objective: To provide detailed guidance on the administration of systemic bevacizumab in patients with recurrent respi ratory papillomatosis (RRP) based on a detailed review of the scienti fi c literature and a consensus of experts with real-world clinical experience. Methods: A bevacizumab consensus working group ( N = 10) was composed of adult and pediatric otolaryngologists, adult and pediatric oncologists, and a representative from the RRP Foundation (RRPF), all with experience administering sys temic bevacizumab in patients with RRP. After extensive review of the medical literature, a modi fi ed Delphi method-based sur vey series was utilized to establish consensus on the following key areas: clinical and patient characteristics ideal for treatment candidacy, patient perspective in treatment decisions, treatment access, initial dosing, monitoring, guidelines for tapering and discontinuation, and reintensifying therapy. Results: Seventy-nine statements were identi fi ed across nine critical domains, and 45 reached consensus [clinical bene fi ts of bevacizumab (3), patient and disease characteristics for treatment consideration (7), contraindications for treatment (3), shared decision-making (incorporating the patient perspective) (5), treatment access (3), initial dosing and administration (8), monitoring (7), tapering and discontinuation (6), and reintensi fi cation (3)]. Conclusion: This consensus statement provides the necessary guidance for clinicians to initiate systemic administration of bevacizumab and represents a potential paradigm shift toward nonsurgical treatment options for patients with RRP. KeyWords: administration, Avastin, consensus, systemic bevacizumab. Level of Evidence: 5 Laryngoscope , 134:5041 – 5046, 2024

INTRODUCTION Recurrent Respiratory Papillomatosis (RRP) is a rare chronic disease caused by infection of the respiratory epithelium by human papillomavirus (HPV) types 6 and 11 resulting in the formation of squamous papillomas in the larynx, trachea, and lungs. 1 The estimated incidences

in children and adults in the United States are 4.3 and 1.8 per 100,000, respectively. 2 – 4 In countries with robust vaccination efforts, the prevalence of juvenile-onset RRP (JORRP) is changing. 5,6 Age of onset for RRP displays a trimodal disease distribution with peaks at age 7, 35, and 64 years and is traditionally designated as either JORRP

From the Department of Otolaryngology – Head and Neck Surgery ( S . R . B ., D . E . T .), Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.; Department of Otolaryngology and Communication Sciences ( J . M . B .), Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.; Recurrent Respiratory Papillomatosis Foundation ( N . B . F ., K . M ., J . B . T ., G . D . Y .), Lawrenceville, New Jersey, U.S.A.; Division of Pediatric Oncology, Department of Oncology ( E . H . R .), Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.; Sidney Kimmel Comprehensive Cancer Center ( E . H . R .), Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.; Department of Otolaryngology-Head and Neck Surgery, Emory Voice Center ( A . M . K .), Emory University School of Medicine, Atlanta, Georgia, U.S.A.; Department of Pediatrics ( T . W . L .), Children ’ s Hospital of Philadelphia/University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.; Department of Otorhinolaryngology/Head and Neck Surgery ( R . N . P . R .), Amsterdam UMC, Amsterdam, The Netherlands; Department of Hematology and Medical Oncology ( N . F . S .), Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, U.S.A.; Department of Otolaryngology, Head and Neck Surgery ( D . R . S .), Stanford Children ’ s Health Aerodigestive and Airway Reconstruction Center and Stanford University, Stanford, California, U.S.A.; Department of Head and Neck Surgery ( G . D . Y .), Miami Cancer Institute, Miami, Florida, U.S.A.; and the Department of Otolaryngology ( K . B . Z .), Children ’ s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. E.H.R, N.P.M.R., D.E.T., and D.R.S. declare no con fl icts of interest. S.R.B. reports clinical consultancy for Inovio Pharmaceuticals and participation in Inovio Pharmaceuticals clinical trial. J.M.B. reports consultancy for Merck. A.M.K. reports participation in Inovio Pharmaceuticals clinical trial. T.W.L reports consultancy for Advanced Microbubbles, AI Therapeutics, Bayer, ITM Oncologists, Jazz Pharmaceuticals, and MassiveBio. The RRPF (N.B.F, K.M., J.B.T., and G.D.Y.) reports research funding from Merck. G.D.Y. reports being a caregiver for a patient being treated with systemic bevacizumab. N.F.S. reports compensation for advisory role or honoraria from: Astra Zeneca, P fi zer, Merck, GSK, Novartis, Inovio, EMD Serono, Vaccinex, Kura Oncol ogy, BioNTech, honoraria from Onclive, Reach MD, Uptodate, WebMD, Springer, and research funding from BMS, Exelixis, and NIH. K.B.Z. reports clinical consultancy for Inovio Pharmaceuticals. Send correspondence to Simon R. Best, Department of Otolaryngology – Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. Email: sbest2@jhmi.edu. Additional supporting information may be found in the online version of this article. Editor ’ s Note: This Manuscript was accepted for publication on July 10, 2024. The authors have no other funding, fi nancial or relationships to disclose.

DOI: 10.1002/lary.31670

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15314995, 2024, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/lary.31670 by Readcube (Labtiva Inc.), Wiley Online Library on [25/08/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

or adult-onset RRP (AORRP) based on age of symptom onset. 7 Due to growth of papillomas in the upper aerodigestive tract, patients with RRP can experience dysphonia and dyspnea, as well as serious complications like pneumonia, malignant transformation, and acute respiratory distress requiring tracheostomy in severe cases. 1 Variability in disease behavior and progression contributes to the challenges related to its management. Traditional standard of care for patients with RRP is repeated debulking surgeries to remove the papillomas to relieve dysphonia and restore airway patency. 1 Subse quent activity or reactivation of latent HPV in remaining or adjacent tissues leads to papilloma recurrence. Patients can undergo hundreds of surgeries throughout their lifetime. These repeated surgeries, regardless of skillful execution, inevitably damage the anatomy of the underlying larynx leading to glottic scarring, webbing, or stenosis. 8,9 The trauma of repeated medical procedures can lead to long-term effects such as post-traumatic stress disorder, anxiety, and depression. 10 A recent study using data from the RRP Foundation (RRPF)/Coordination of Rare Diseases at Sanford (CoRDs) Patient Registry indi cated high mental, social, and fi scal burden impacting the quality-of-life of patients. 11 In many cases, the surgical treatment for this disease also contributes to its morbidity. The RRPF conducted a qualitative survey to capture individualized disease burden for patients and caregivers JORRP 18 + years [ n = 13], caregivers of children with JORRP under 18 years [ n = 10], and individuals with AORRP [ n = 38] ( communication from Kim McClellan of the RRPF in August 2022 ). When asked what an end to surgical treatment would mean to them, the impact was clear: any reduction in the number of surgeries would be impactful. Given the signi fi cant negative effect of repeated sur geries on patient quality of life, there is a need for non surgical treatments for RRP. Historically, local adjuvant therapies, including intralesional cidofovir and bevacizumab, 12,13 as well as systemic interferon 14,15 have had inconsistent clinical bene fi t in RRP. There is ongoing evaluation of the potential ef fi cacy in the adjuvant setting of the HPV vaccine and two other therapeutic vaccines. 16 – 18 Vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis. 19 Bevacizumab is a monoclonal antibody against VEGF that is FDA-approved for the treatment of multiple cancer types. Bevacizumab blockade of VEGF signaling disrupts existing tumor vas culature and prevents the formation of new blood ves sels. 20 The potential utility of bevacizumab in reducing the growth or regrowth of papillomas is based on the vas cular nature of the lesions. 21 Laryngeal tissues from patients with RRP express higher levels of VEGF as com pared with normal tissue making them a potential target for this therapy. 22,23 Treatment with systemic bevacizumab demonstrated ef fi cacy in patients with RRP in terms of a reduction in surgeries. 13,23 – 29 Previously, Sidell and colleagues issued an International Consensus Statement on key points supporting the use of systemic bevacizumab for the treatment of RRP and providing pre liminary guidance surrounding treatment modality. 30

This initial statement was not intended to provide guid ance regarding speci fi c dosing, evaluation, or manage ment of patients in the setting of remission or recurrence. Instead, it sought to provide guidance around patient selection and the setting of administration. Since that time, use of systemic bevacizumab has expanded, and clinical experience has increased. With use of systemic bevacizumab in more patients and with longer treatment durations, a group of expert clinicians sought to expand the recommendations of the previous consensus statement. The objective of this consensus statement is to pro vide speci fi c guidance to clinicians treating patients with RRP regarding the decision to initiate treatment with systemic bevacizumab, details of its administration, and monitoring. It is the authors ’ opinion that this non surgical treatment option is under-utilized, and this statement provides an important opportunity for quality improvement in the care of patients with RRP. A consensus working group was established during the inaugural RRP Roundtable meeting in November 2022. Although many members were authors on the original consensus state ment, the group felt it was imperative to include oncologists with the necessary expertise to advise on administration and monitor ing. The group was composed of adult otolaryngologists ( n = 4 [note: one member treats both adult and pediatric patients]), pediatric otolaryngologists ( n = 3 [note: one member serves both adult and pediatric patients]), adult oncologist ( n = 1), pediatric oncologists ( n = 2), and one representative from the RRPF (head and neck surgeon and caregiver for a patient with RRP), all expe rienced with the use of systemic bevacizumab in patients with RRP. One additional pediatric otolaryngologist served as a meth odologist and did not participate in the consensus survey voting. To ensure that the patient perspective was captured, one care giver from the RRPF participated in the fi rst round of the surveys. Literature Review A literature review was completed before study initiation and distributed to group members. It was conducted using PubMed between January 30, 2023 and March 1, 2023 and included case studies/series, reviews, retrospective studies, let ters, and expert consensus statements regarding treatment of patients with RRP with systemic bevacizumab (no date restric tions) (Material S1). The review was comprehensive in terms of pregnancy (all time periods) and pediatric safety pro fi les, includ ing studies in other patient populations treated with systemic bevacizumab pediatric patients with hereditary hemorrhagic tel angiectasia (HHT), neuro fi bromatosis (NF2), low-grade glioma, and refractory/recurrent pediatric solid tumors (search date range: 2018 – 2023). The results of this literature review are avail able in Material S2. MATERIALS AND METHODS Study Participants

Modi fi ed Delphi Process The methodology applied for this study was consistent with the modi fi ed Delphi method outlined in the Consensus State ment Development Manual published by the American Academy

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of Otolaryngology-Head and Neck Surgery (AAO-HNS). 31 The Delphi methodology aims to seek consensus on a series of state ments through a systematic and iterative approach. 32 The scope de fi ned at initiation included critical topics for clinicians to successfully administer bevacizumab: patient per spective in treatment decisions, clinical and patient characteris tics ideal for treatment candidacy, treatment access, initial dosing, guidelines for tapering and reintensifying therapy, and monitoring. Each member submitted topic questions within scope, and following priority ranking of collated topics, the initial survey was drafted. A 9-point Likert scale was used to measure agreement, with the following anchors: strongly disagree (1), dis agree (3), neutral (5), agree (7), and strongly agree (9). Consistent with the AAO-HNS manual, statements were categorized based on mean score and number of outliers (any rating ≥ 2 Likert points from the mean in either direction) with the following criteria: Consensus = ≥ 7.00 mean score and ≤ 1 outlier, Near Consensus = ≥ 6.50 mean score and ≤ 2 outliers, No Consensus = <6.50 mean score or ≥ 3 outliers. Efforts were made to ensure that language in each statement was clear and unam biguous. To this end, two additional iterations of the survey were issued to determine agreement on fi nal revised language. Statistical Analysis Statistical analysis was performed using Excel for Microsoft 365 (Microsoft Corp, Redmond, Washington). Web-based surveys were generated and distributed via email using Survey Monkey (San Mateo, California). 33 De fi nitions and Assumptions Disease severity was de fi ned by rate of progression beyond the larynx, requirement for emergent airway management more than one time prior to performing operative treatment to remove papillomas, and the number of events of respiratory distress. High disease severity was de fi ned as rapid progression of disease beyond the larynx, requirement for emergent airway manage ment more than one time prior to performing operative treat ment to remove papillomas, or recurrent or multiple documented events of respiratory distress. A patient with highly recurrent, high frequency, or frequent disease should meet the following criteria: disease requiring ≥ 2 surgeries within a 12-month period. Quality-of-life impact was de fi ned as patient-reported negative impact on academic/work participation and/or performance, or on ability to participate in social activities. For the purpose of this study, pre-infusion workup was previously de fi ned by Sidell and colleagues. 30 RESULTS The group identi fi ed nine critical domains needed for clinicians to select candidates for and successfully admin ister systemic bevacizumab: (1) Clinical bene fi ts of bevacizumab, (2) Patient and disease characteristics for treatment consideration, (3) Contraindications for treat ment, (4) Shared decision-making (incorporating the patient perspective), (5) Treatment access, (6) Initial dos ing and administration, (7) Monitoring, (8) Tapering and discontinuation, and (9) Reintensi fi cation. Within the nine domains identi fi ed, 79 statements were drafted and included in the fi rst survey. Following revisions and two additional iterations to clarify and re fi ne, 45 statements met consensus criteria and 13 statements met near

consensus criteria (Table S1). Twenty-one statements that did not meet consensus criteria and one statement that met consensus criteria were eliminated (Table S2). Domain 1 described the clinical bene fi ts of bevacizumab based on the accumulated real-world evi dence and the clinical experience of group members. Importantly, the group reached consensus on the ability of systemic bevacizumab to reduce or eliminate surgical debridement in patients with RRP. Domain 2 focused on an expansion of the initial patient and disease criteria outlined out by Sidell and colleagues. 30 All patients with RRP, juvenile- and adult onset, should be evaluated for candidacy regardless of dis ease severity, surgical frequency, anatomic location of papillomas, or HPV subtype. Correspondingly, state ments that restricted the candidacy of patients for treat ment reached no consensus. Domain 3 addressed contraindications for the use of systemic bevacizumab which align with the United States package insert warnings and precautions. Based on safety data with the use of bevacizumab during pregnancy, the group suggests that pregnancy tests be conducted prior to administration. Consensus was reached on the need to make timing adjustments to administration around planned surgical or invasive procedures. Domain 4 focused on the importance of gathering the patient perspective when making treatment decisions, particularly due to the heterogeneous disease course. Consensus was reached on statements promoting shared decision-making, education, and quality-of-life conversa tions, including the negative impact of recurrent surgeries. Domain 5 focused on treatment access logistics and the challenges associated with insurance coverage for an off-label therapy. Guidance is provided regarding supple mental evidence submission to support positive coverage decisions. To mitigate the geographical barriers preventing treatment access, the group reached consen sus on care coordination among otolaryngologists and quali fi ed oncologists administering systemic bevacizumab at any infusion setting. Domain 6 outlined the procedures for initial admin istration of bevacizumab including coordination with medical oncologists, pre-infusion workup and assess ments, initial dose, and dosing interval. The prior workup was initially outlined by Sidell and colleagues 30 and the following considerations were added: monitor renal func tion and blood pressure with each dose, and obtain a chest CT to evaluate for pulmonary involvement. The standard initial dose and interval is 10 mg/kg adminis tered every 3 – 4weeks. Domains 7 – 9 provided guidance on monitoring for treatment response, discontinuation/tapering, and reintensi fi cation of therapy. Because bevacizumab should be administered with a frequency as low as possible to maintain disease control, outcomes for each individual patient should be reviewed to monitor trends and identify the minimal effective dose. A holistic approach to moni toring treatment response is optimal, as opposed to single-outcome criteria. Speci fi cally, response should be monitored by periodic, objective, anatomical assessment

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Chest CT

Initial dose (10 mg/kg)

Dose (10 mg/kg)

Renal function tests

3–4-week interval

Blood pressure

In 3-4 cycles, assess disease burden with laryngoscopy/bronchoscopy and patient-reported symptoms

Pregnancy test

Every 1-2 years

No, continue another 3-4 cycles and reassess

Disease response

Yes, taper

Dose (10 mg/kg)

Interval + 3-4 weeks

Interval + 3-4 weeks Interval + 3-4 weeks

Periodic laryngoscopy/bronchoscopy and patient-reported symptoms to assess whether disease response is maintained

Yes, consider increasing interval by 3-4 weeks

No, reintensify therapy

Disease response maintained

Fig. 1. Consensus dosing regimen outlining initial dose, interval, tapering, monitoring, and reintensi fi cation.

of affected disease sites by laryngoscopy or bronchoscopy, patient-reported symptoms, symptom severity scores, sur gical frequency, and annual or biannual chest CT in patients with pulmonary disease. These treatment responses and any observed adverse reactions should be rigorously and systematically recorded, preferably through an international patient registry. An overview of dosing and monitoring considerations is provided in Figure 1. DISCUSSION Non-surgical Treatment of Patients with RRP This consensus statement serves as a milestone in the paradigm shift toward the early use of bevacizumab as a non-surgical treatment for patients with RRP. Systemic bevacizumab could be considered a potential fi rst-line therapy as this group of experts encourages the evaluation of all patients with RRP for treatment candi dacy, as the HPV-driven etiology and pathophysiology in pediatric and adult patients is indistinguishable. All published series show an almost universal clinical response to bevacizumab that eliminates or greatly reduces the need for surgical management of RRP. 13,23 – 29,34 By reducing the need for surgery, there is a sub stantial impact on patient quality of life and a signi fi cant reduction in the risk of iatrogenic laryngeal injury. With the accumulation of additional real-world evidence since its publication, this guidance expands on the patient candidacy criteria originally outlined by Sidell et al. 30 Because of the variable disease course and

quality-of-life impact, the group encourages clinicians to make individualized treatment decisions with their patients, supported by education and risk – bene fi t discussions.

Treatment Access Use of systemic bevacizumab requires a coordinated multidisciplinary approach, and the group encourages otolaryngologists to work closely with their medical oncol ogy colleagues on patient selection, treatment, and moni toring. By the treating provider collaborating with more accessible local infusion centers, some of the geographic restrictions to treatment access may be safely circum vented. Bevacizumab and biosimilars are off-label thera pies for the treatment of patients with RRP. There are currently fi ve FDA-approved biosimilars for bevacizumab, including Avzivi (bevacizumab-tnjn; Bio-Thera Solutions), Vegzelma (bevacizumab-adcd; Celltrion, Inc), Alymsys (bevacizumab-maly; Amneak Pharmaceuticals), Zirabev (bevacizumab-bvzr; P fi zer), Mvasi (bevacizumab-awwb; Amgen). 35 Without randomized controlled trial data, pro viders can leverage available case studies, expert consen sus statements, and retrospective data to support appeals for insurance coverage. Dosing Adjustments and Monitoring No consensus was reached on a statement indicating that the initial dosage should align with disease severity. Instead, the group suggests a standard starting dose of 10 mg/kg with fl exibility to modify the dosing interval

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Areas of Future Research The group emphasized the importance of data shar ing to further bolster the evidence base for the ef fi cacy and safety of systemic bevacizumab in the RRP patient population. Leveraging these data to assess effectiveness and safety of systemic bevacizumab aligns with the pri mary uses for patient registries outlined by the Agency for Healthcare Research and Quality. 42 These data will also aid in the identi fi cation of trends that will inform the minimal effective doses and ideal intervals in pediatric and adult patients. The existing Global RRPF/CoRDS RRP Patient Registry can be leveraged for the collection of these data. 43 The consensus panel recognized a need to develop formal tools to collect patient-reported outcomes data. The following statement met criteria for consensus (mean score = 8.2; outliers = 1): Patient-reported outcomes mea sures should be included when monitoring for treatment response . Because of the lack of standardized patient reported outcomes tools in this population, the group ulti mately chose not to include this statement. However, it is important to note that other statements were included regarding shared decision-making and disease monitor ing. The group strongly supports speci fi c conversations with patients and caregivers regarding disease impacts on social, mental, fi nancial, and emotional health. Regardless of the current de fi cit in tools, the group advo cates for surveillance of patient-reported symptoms dur ing treatment with bevacizumab. CONCLUSION This consensus statement provides guidance for cli nicians treating patients with RRP regarding the admin istration of systemic bevacizumab for clinicians treating patients with RRP. The statement highlights the impor tance of consultative discussions with patients and care givers regarding bevacizumab as a possible nonsurgical treatment. This group has outlined speci fi c considerations for the systemic administration of bevacizumab including the clinical and patient characteristics ideal for treatment candidacy, patient perspective in treatment decisions, treatment access, initial dosing, monitoring, guidelines for tapering and discontinuation, and reintensifying ther apy. The authors urge clinicians to offer bevacizumab as an early non-surgical treatment option for patients withRRP. ACKNOWLEDGEMENTS Funding provided by the RRPF as a Chan Zuckerberg Initiative (CZI) Rare as One-funded Organization. This study and manuscript were made possible by the incep tion of the Bevacizumab Working Group during the inau gural RRPF Roundtable meeting held in Bentonville, AR in November 2022. We would like to acknowledge Mir Pawlak for logistical support on survey execution and project management, and Lisa Tansey from the RRPF for her input on this project.

based on disease severity. This guidance is paired with an approach of tapering and reintensifying therapy based on patient response. Reinstensi fi cation would be appro priate either in patients with recurrence who have either completely stopped therapy or extended their tapering interval. The group encourages a holistic approach to assessing treatment response by combining objective assessments with patient-reported symptoms. It is imper ative to include objective anatomical visualization and imaging when monitoring progression. Because pulmo nary involvement occurs in approximately 9% of patients and is associated with a 32% increased lifetime risk of malignancy compared with the overall RRP population, 36 it is important to evaluate all patients prior to initiation of treatment with bevacizumab. In addition, patients with pulmonary involvement at the start of treatment should be monitored periodically during treatment. Treatment duration with bevacizumab is presumed to be inde fi nite and supported by a recent systematic lit erature review indicating universal rapid response (within days) upon resumption of therapy following recurrence with a mean time to recurrence of 5.4 months after treatment was ceased. 23 There is experience in other diseases regarding long-term treatment with bevacizumab, including NF2and HHT. A meta-analysis of 247 patients with NF2 treated with systemic bevacizumab (5 – 10 mg/kg every 2 weeks) for a median duration ranging from 6 to 75 months noted the follow ing adverse events; menstrual disorders 44% [95% CI, 16% – 73%], proteinuria 30% [95% CI, 18% – 44%], hyper tension 29% [95% CI, 23% – 35%], hemorrhage 14% [95% CI, 4% – 26%], and grade 3/4 events 12% [95% CI, 4% – 22%] with 12% of these adverse events being grade 3/4. 37 A multicenter retrospective study of 238 patients with HHT treated with systemic bevacizumab for a median of 12 (range of 1 – 96) months noted the following treatment-emergent adverse events with ≥ 5% incidence: hypertension (18%), fatigue (10%), proteinuria (9%), and myalgia and/or arthralgia (6%). 38 Of the 41 patients with hypertension, 26 had new-onset hypertension whereas the remaining 15 had worsening hypertension from base line. Of the 21 patients with proteinuria, one patient had baseline chronic kidney disease and three patients had baseline diabetes mellitus. Biosimilars Because the group thought there was a need for additional systematic data, no consensus was reached on a speci fi c statement regarding biosimilars. However, the group remained neutral regarding the use of biosimilars, neither discouraging nor endorsing their use. It is impor tant to note that both the United States Food and Drug Administration and the European Union European Medi cines Agency de fi nitions and requirements for approval state that biosimilars are highly similar to the reference product and have no clinically meaningful differences in terms of safety, quality, and effectiveness from the refer ence product. 39 – 41

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22. Rahbar R, Vargas SO, Folkman J, et al. Role of vascular endothelial growth factor-a in recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol . 2005;114(4):289-295. 23. Ryan MA, Leu GR, Upchurch PA, Tunkel DE, Walsh JM, Boss EF. Systemic bevacizumab (Avastin) for juvenile-onset recurrent respiratory papillomatosis: a systematic review. Laryngoscope . 2021;131(5):1138-1146. 24. Ballestas SA, Hidalgo Lopez J, Klein AM, et al. Long-term follow-up of parenteral bevacizumab in patients with recurrent respiratory papillomatosis. Laryngoscope . 2023;133(10):2725-2733. 25. Best SR, Mohr M, Zur KB. Systemic bevacizumab for recurrent respiratory papillomatosis: a national survey. Laryngoscope . 2017;127(10):2225-2229. 26. Evers G, Schliemann C, Beule A, et al. Long-term follow-up on systemic bevacizumab treatment in recurrent respiratory papillomatosis. Laryngo scope . 2021;131(6):E1926-E1933. 27. So RJ, Hidalgo Lopez JC, Ballestas SA, et al. Ef fi cacy of systemic bevacizumab for recurrent respiratory papillomatosis with pulmonary involvement. Laryngoscope . 2024;134(2):577-581. 28. Tkaczuk A, Trivedi S, Mody MD, et al. Parenteral bevacizumab for the treatment of severe respiratory papillomatosis in an adult population. Laryngoscope . 2021;131(3):E921-E928. 29. Zhao X, Wang J, Chen Q, et al. Systemic bevacizumab for treatment of recurrent respiratory papillomatosis. Eur Arch Otorhinolaryngol . 2024; 281(4):1865-1875. 30. Sidell DR, Balakrishnan K, Best SR, et al. Systemic bevacizumab for treat ment of respiratory papillomatosis: international consensus statement. Laryngoscope . 2021;131(6):E1941-E1949. 31. Rosenfeld RM, Nnacheta LC, Corrigan MD. Clinical consensus statement development manual. Otolaryngol Head Neck Surg . 2015;153(2 Suppl): S1-S14. 32. Dalkey NC. The Delphi Method: An Experimental Study of Group Opinion . Santa Monica, CA: Rand Corp; 1969. https://www.rand.org/pubs/research_ memoranda/RM5888.html 33. SurveyMonkey Inc. http://www.surveymonkey.com 34. So RJ, Rayle C, Joo HH, et al. Systemic bevacizumab for recurrent respira tory papillomatosis: a single institution ’ s experience. Laryngoscope . 2024; 134:3253-3259. 35. FDA Biosimilar Product Information. https://www.fda.gov/drugs/biosimilars/ biosimilar-product-information 36. Pai SI, Wasserman I, Ji YD, et al. Pulmonary manifestations of chronic HPV infection in patients with recurrent respiratory papillomatosis. Lan cet Respir Med . 2022;10(10):997-1008. 37. Shi J, Lu D, Gu R, et al. Reliability and toxicity of bevacizumab for neuro fi bromatosis type 2-related vestibular schwannomas: a systematic review and meta-analysis. Am J Otolaryngol . 2021;42(6):103148. 38. Al-Samkari H, Kasthuri RS, Parambil JG, et al. An international, multicen ter study of intravenous bevacizumab for bleeding in hereditary hemor rhagic telangiectasia: the InHIBIT-bleed study. Haematologica . 2021; 106(8):2161-2169. 39. European Medicines Agency. Statement on the scienti fi c rationale supporting interchangeability of biosimilar medicines in the EU. https:// www.ema.europa.eu/en/documents/public-statement/statement-scienti fi c rationale-supporting-interchangeability-biosimilar-medicines-eu_en.pdf 40. European Medicines Agency. Biosimilar medicines: marketing authorisa tion. https://www.ema.europa.eu/en/human-regulatory-overview/marketing authorisation/biosimilar-medicines-marketing-authorisation 41. United States Food and Drug Administration. Biosimilars: review and approval. https://www.fda.gov/drugs/biosimilars/review-and-approval 42. Gliklich RE, Leavy MB, Dreyer NA. Registries for Evaluating Patient Out comes: A User ’ s Guide . 4th ed. Agency for Healthcare Research and Qual ity; 2020. 43. Global RRPF/CoRDS RRP Patient Registry. https://rrpf.org/cords-global patient-registry/

Laryngoscope 134: December 2024

Best et al.: Administration of Bevacizumab in RRP

5046

Article

https://doi.org/10.1038/s41467-025-56729-6

DNA immunotherapy for recurrent respiratory papillomatosis (RRP): phase 1/2 study assessing ef fi cacy, safety, and immunogenicity of INO-3107

A list of authors and their af fi liations appears at the end of the paper

Received: 1 August 2024

Accepted: 29 January 2025

Recurrent respiratory papillomatosis (RRP) is a chronic airway disease caused by Human Papillomavirus (HPV). INO-3107, DNA immunotherapy designed to elicit T-cells against HPV-6 and HPV-11, was evaluated in a 52-week Phase 1/2 study for ef fi cacy, safety, and immunogenicity (NCT04398433). Thirty-two eligible adults with HPV-6 and/or HPV-11 RRP, requiring ≥ 2 surgical interven tions in the year preceding dosing were enrolled between October 2020 and November 2021 and administered 4 INO-3107 doses by intramuscular injection followed by electroporation. The primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary end points included surgical intervention frequency and change in RRP Severity Score (modi fi ed) post-INO-3107 and assessment of immune responses. 81% (26/32) of patients experienced surgery reduction following INO-3107 com pared with the year prior to treatment. Blood assessments revealed HPV-6 and HPV-11 antigen-speci fi c T-cell induction. RNA sequencing identi fi edan in fl ammatory response in papillomas, inclusive of cytolytic CD8 + T-cell sig natures. T-cell receptor sequencing revealed emergent T-cell clones in blood andcon fi rmed traf fi cking to papillomas. Treatment-related adverse events (AEs) were reported in 13/32 (41%) patients, all low-grade. INO-3107 provides clinical bene fi t to HPV-6 and/or HPV-11-associated RRP adults and is well tolerated. Importantly, treatment-induced peripheral T-cell responses traf fi c to airway tissue and are associated with clinical response.

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with substantial patient burden. Repeated surgical removal of papil lomas for symptomatic management remains the mainstay of treat ment and can result in signi fi cant morbidity considering the number of surgical procedures required, impact on voice, effects of repetitive anesthesia, as well as psychological impact, and fi nancial burden 7 . Additionally, the risk of laryngeal injury increases with each surgery 8 . Current treatment of HPV-6- and HPV-11-related RRP could be improved with the addition of HPV-speci fi c immunotherapy, which has the therapeutic potential to control or eliminate papillomas by

Human Papillomavirus (HPV)-associated diseases are an emerging global epidemic 1,2 . The role of HPV-6 and HPV-11 in the etiology of recurrent respiratory papillomatosis (RRP), the most common benign tumor of the laryngeal epithelium, is well-established 3,4 . RRP lesions can occur in the oropharynx, larynx, and elsewhere in the respiratory tract 5 , signi fi cantly impacting voice production and even breathing in severe cases. Rarely, papillomas can undergo malignant transforma tion in the pulmonary tract, most notably in the pulmonary parenchyma 6 . RRP is a chronic, debilitating disease that is associated

e-mail: Matthew.Morrow@inovio.com

Nature Communications | (2025)16:1518

Article

https://doi.org/10.1038/s41467-025-56729-6

(10, 31.3%) were infected with HPV-11 only, and two (2, 6.3%) were co infected with both HPV-6 and HPV-11. Four (4, 12.5%) patients ’ geno types could not be distinguished between HPV-6 and HPV-11 per assay standards at Screening but were known from prior diagnostic history to be HPV-6 and/or HPV-11 positive, which was subsequently con fi rmed through on-study assessment. All patients in the trial had complete follow-ups for ef fi cacy and safety data. Of the 32 patients, 26 had a clinical response (81.3%), de fi ned as a reduction of at least one surgical procedure in the year following Day 0 (overall clinical response; OCR). Nine patients (28.1%) had a complete response (CR), de fi ned as no surgical interventions in the year fol lowing Day 0, and 14 additional patients (43.8%) had a partial response (PR),de fi ned as a reduction in the number of surgical interventions by 50 – 99% in the year following Day 0 (Fig. 1). Together this represents an overall response rate (ORR) of 71.9%; 23 of 32 patients. Reduction in surgical frequency was independent of HPV genotype as responses were noted for patients exhibiting HPV-6 and/or HPV-11 per genotypic assessment (ORR of 66.7% for HPV-6, ORR of 83.4% for HPV-11). When comparing the median number of surgeries in the year prior to treatment with the year following Day 0, in the year prior, patients had a median of four surgeries (range 2 – 8), while in the year following treatment, there was a median decrease of three surgeries with a 95% con fi dence interval of 2 to 3, which indicates a statistically signi fi cant decrease. INO-3107 improves RRP severity scores in adults with RRP Treatment with INO-3107 resulted in reductions in RRP Severity Score (modi fi ed) from pretreatment through the treatment assessment period, as assessed by laryngoscopy throughout the trial. Anatomical disease severity was measured by a modi fi ed Derkay Score. Scores were obtained prior to surgery at or near Day 0, and again at each visit when laryngoscopy was performed. Between Day 365 and Day 0, there was a mean change in total site score of − 10.7 (95% CI − 16.3, − 5.0)anda mean change in total symptom score of − 0.4 (95%CI − 0.7, 0.0). The mean change in total clinical score (total site and total symptom score) was − 11.0 (95% CI − 16.7, − 5.3). INO-3107 is well tolerated in adults with RRP Treatment with INO-3107 was well tolerated in this trial. Twenty patients (62.5%) reported treatment-emergent adverse events (TEAEs), most of which were treatment-related (35/58 events), and almost all of which were Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2 in severity (54/58 events (Table 2)). All related TEAEs were Grade 1 or 2 in severity, and the most common related TEAE was injection site pain (10 patients); all other related TEAEs were seen in three patients or fewer (Table 2). Grade 3 TEAEs were observed in four (4) patients (12.5%), all of which were unrelated. Serious adverse events (SAE) were observed in three (3) patients (9.4%), none of which were considered treatment related. No patient experienced a Grade 4 or 5 TEAE or TEAE leading to treatment discontinuation or death. INO-3107 reduces or eliminates surgical intervention in the treatment of RRP INO-3107 induces HPV-6 and HPV-11-speci fi c T-cell responses and drives peripheral T-cell clonal expansion T-cell responses induced by INO-3107 were fi rst gauged via ex vivo interferon gamma (IFN γ ) ELISpot. T-cell reactivity against INO-3107 antigens was noted in 94% of patients (30/32) over the course of the trial and reactivity was con fi rmed individually for HPV-6 as well as HPV 11 (Fig. 2A and Supplementary Fig. 2). Upon con fi rmation of antigen-speci fi c T-cell responses in blood, multiparametric fl ow cytometry was employed to further elucidate

generating immunity against HPV itself. Patients suffering from RRP have been characterized as exhibiting suppressive or regulatory immune-related functions within papillomas, as opposed to mounting a cytotoxic response against HPV infected cells 9 – 13 . Our previous stu dies of DNA immunotherapies directed against HPV have demon strated the induction of potent immune responses for HPV in a pilot trial of adults with HPV-6-related RRP and in HPV-related head and neck squamous cell carcinoma as well as cervical disease, inclusive of the generation of HPV-speci fi c cytotoxic T-cells as well as CD8+ immune cell in fi ltration into tumors 14 – 18 . Additionally, other groups have conducted clinical studies of RRP treatment from an immuno logical approach via antibody and T-cell-related platforms, with results that support an immune-based impact on disease state 19,20 . INO-3107 is a DNA immunotherapy encoding for antigens from both HPV-6 and HPV-11 as well as encoding for an interleukin-12 (IL-12) immune adju vant. Here, we report full study results from a DNA-based therapy in development for RRP from a completed Phase 1/2 trial demonstrating the safety, ef fi cacy, and immune responses of INO-3107. Results Patient demographics A total of 32 patients were enrolled between October 2020 and November 2021, with follow-up completed through December 2022; seven (7) patients had juvenile-onset (JO) RRP and 25 had adult-onset (AO) RRP (Table 1). All patients completed all clinical trial visits up to Week 52. Demographics of the trial population are presented in Table 1. Sixteen (16, 50.0%) patients were infected with HPV-6 only, ten

Table 1 | Demographics and baseline characteristics (mITT population)

Parameter

Patients ( N =32)

Median age (range), years

47.3 (25-82)

Male, n (%) Race, n (%) Asian

24 (75.0)

1 (3.1)

Black or African American

4 (12.5)

White Other

26 (81.3)

1 (3.1)

Ethnicity, n (%)

Hispanic or Latino

3 (9.4)

Not Hispanic or Latino

29 (90.6)

Type, n (%) Juvenile Onset RRP (age at diagnosis <12years) Adult Onset RRP (age at diagnosis ≥ 12years) Number of surgeries in prior year, n (%) 2

7 (21.9)

25 (78.1)

6 (18.8)

3 to5

18 (56.3)

≥ 6

8 (25.0)

HPV genotype, n (%) 6

16 (50.0)

10 (31.3)

6and 11

2 (6.3)

6and/or 11 a

4 (12.5)

Median (range) number of surgeries in the year prior to dosing

4 (2 – 8)

mITT modi fi ed intention-to-treat, N or n number of patients; % percentile, RRP recurrent respiratory papillomatosis, HPV human papillomavirus. a Of the 32 patients, three (3) did not have papilloma tissue collected at Baseline and one (1) had the HPV genotyping assay fail. HPV-6 and/or 11 was con fi rmed prior to the study based on documentation provided by the clinical site for these four (4) patients, but the genotype was not speci fi ed.

Nature Communications | (2025)16:1518

Article

https://doi.org/10.1038/s41467-025-56729-6

Patients

0 0 0 0

-25

-2

-50

-3

-4

-2 -4

PR CR OCR

-75

-3

-4

-100 Percent (%) Change in Surgeries On Study As Compared To Previous Year

-7

-6

-2 -2 -3 -3 -3 -3 -3 -4

CR PR OCR

100

Before Treatment

After Treatment

100

10 20 30 40 50 60 70 80 90

ORR

% Patients

Efficacy: HPV-11

Efficacy: HPV-6

CR PR OCR

100

10 20 30 40 50 60 70 80 90

ORR

% Patients

Efficacy: All Patients

Fig. 1 | INO-3107 reduces or eliminates surgical interventions ( N = 32 patients). A Waterfall plot indicating a change in the frequency of clinically indicated surgical interventions during the year of study as compared with the year before. Change in the number of interventions is indicated for each individual patient, and responding patients are color-coded. Complete responders (CR) are labeled dark blue, partial responders (PR) are labeled light blue, and patients who exhibited a decrease in surgical intervention but contributed only to the calculation of overall clinical response (OCR) are green. Non-responders are labeled gray (increase in surgery) or with 0 (no change). B Top left panel: Airway pictures taken before treatment with INO-3107 or after the completion of treatment. The top row is a

complete responder before treatment and at Week 52, the middle and bottom rows are partial responders taken before treatment and Week 26. Top right panel: Bar graphs indicating ef fi cacy breakouts for patients infected with HPV-6, patients infected with HPV-11, and all patients in the study. Complete (dark blue) and partial response (light blue) are separated within the overall response rate (ORR) stack for clarity. OCR (all patients exhibiting a decrease in surgical frequency of any mag nitude in green) is graphed separately to allow for comparison. Bottom panel: Responses are also broken out in tabular fashion. HPV human papillomavirus; % percent.

Nature Communications | (2025)16:1518

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