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KEYNOTE-689 and the Perioperative Paradigm: A Critical Appraisal of Design-Driven Success
CC BY 4.0 · Indian J Med Paediatr Oncol 2026; 47(05): 418-419
DOI: DOI: 10.1055/s-0046-1816544
The recently presented KEYNOTE-689 trial has reignited interest in perioperative immunotherapy for resectable head and neck squamous cell carcinoma (HNSCC). This study explored the addition of pembrolizumab to definitive surgery and adjuvant radiotherapy with or without chemotherapy, marking a pivotal shift in the management paradigm. KEYNOTE- 689 advances perioperative immunotherapy in resectable HNSCC, but key limitations warrant scrutiny.
Previous trials investigating immune checkpoint blockade (ICB) in the curative-intent setting—namely, KEYNOTE-412 and JAVELIN HN100, failed to demonstrate statistically significant benefit. In KEYNOTE-412, which evaluated concurrent chemoradiotherapy (CRT) with pembrolizumab, the hazard ratio (HR) for event-free survival (EFS) was 0.83 (95%. confidence interval [CI], 0.68–1.03), narrowly missing significance level.[1] Similarly, JAVELIN HN100, which examined avelumab with CRT, reported an HR for progression-free survival of 1.21 (95%. CI, 0.93–1.57), suggesting possible antagonism between ICB and CRT when administered concurrently.[2] This may reflect impaired immune priming due to lymphodepletion during the intensive CRT window.
Furthermore, IMvoke010, an adjuvant trial administering atezolizumab after completion of surgery and CRT, failed to improve EFS (HR 0.94; 95%. CI, 0.70–1.26).[3] [4] Delayed initiation of ICB, after the window of maximal antigen release, may have contributed to suboptimal immune engagement.
KEYNOTE-689 attempted to optimize timing by integrating neoadjuvant and adjuvant pembrolizumab. However, the trial design raises several concerns. As emphasized in the simultaneous editorial by Rosenberg and Vokes, an important unresolved question is which component of immunotherapy, neoadjuvant priming, adjuvant consolidation, or cumulative exposure was primarily responsible for the observed benefit.[5] This distinction is especially relevant in resource-constrained settings, where limited perioperative dosing may be more pragmatic, and parallel observations from lung cancer trials in which short-course nivolumab exposure was associated with meaningful clinical benefit.[6]
Notably, crossover to ICB in the control arm was not permitted, despite robust evidence of benefit in the recurrent/metastatic setting from KEYNOTE-048 (HR for overall survival 0.61 with pembrolizumab vs. EXTREME regimen) and CheckMate-141. This limitation compromises the equipoise of the study and potentially inflates the perceived benefit of perioperative immunotherapy.
Moreover, approximately 10%. of patients in the control arm, around 35 individuals, did not receive the assigned adjuvant treatment but were nonetheless included in the intention-to-treat analysis. The absence of detailed reasons for this omission whether due to disease progression, treatment-related toxicity, or patient withdrawal raises concerns about missed curative opportunities and the potential for analytic bias.
Subgroup analyses are also notably incomplete. Despite human papillomavirus (HPV)-positive oropharyngeal cancer comprising up to 26%. of global HNSCC incidence, efficacy outcomes for this biologically distinct subgroup were not reported. Given the divergent prognosis and treatment responsiveness of HPV-associated disease, omission of this data limits the generalizability of the findings.
Similar underrepresentation of HPV-positive disease and resultant selection bias have been observed in other perioperative and definitive-intent trials, limiting extrapolation to this subgroup.[7] The low representation of HPV-positive patients raises concerns regarding selection bias, a limitation similarly observed in other perioperative and definitive-intent trials, and restricts the generalizability of the findings.
Finally, and perhaps most critically, no health-related quality-of-life (HRQoL) outcomes were reported. A triphasic immunotherapy regimen spanning neoadjuvant, concurrent, and adjuvant phases entails a substantial treatment burden, particularly in a population where functional preservation and long-term survivorship are paramount. The absence of HRQoL data hinders a balanced risk–benefit assessment of this intensive approach.
In conclusion, while KEYNOTE-689 advances the promise of perioperative immunotherapy in resectable HNSCC, its findings must be interpreted in the context of prior trial failures, design limitations, and missing data. A cautious, evidence-based integration into practice awaits further peer-reviewed results and longer-term follow-up.
Publication History
Article published online:
04 May 2026
© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Private Limited
A-13A, Graphix Tower 1, 6th floor, Sector 62, Noida 201309, Uttar Pradesh, India
The recently presented KEYNOTE-689 trial has reignited interest in perioperative immunotherapy for resectable head and neck squamous cell carcinoma (HNSCC). This study explored the addition of pembrolizumab to definitive surgery and adjuvant radiotherapy with or without chemotherapy, marking a pivotal shift in the management paradigm. KEYNOTE- 689 advances perioperative immunotherapy in resectable HNSCC, but key limitations warrant scrutiny.
Previous trials investigating immune checkpoint blockade (ICB) in the curative-intent setting—namely, KEYNOTE-412 and JAVELIN HN100, failed to demonstrate statistically significant benefit. In KEYNOTE-412, which evaluated concurrent chemoradiotherapy (CRT) with pembrolizumab, the hazard ratio (HR) for event-free survival (EFS) was 0.83 (95%. confidence interval [CI], 0.68–1.03), narrowly missing significance level.[1] Similarly, JAVELIN HN100, which examined avelumab with CRT, reported an HR for progression-free survival of 1.21 (95%. CI, 0.93–1.57), suggesting possible antagonism between ICB and CRT when administered concurrently.[2] This may reflect impaired immune priming due to lymphodepletion during the intensive CRT window.
Furthermore, IMvoke010, an adjuvant trial administering atezolizumab after completion of surgery and CRT, failed to improve EFS (HR 0.94; 95%. CI, 0.70–1.26).[3] [4] Delayed initiation of ICB, after the window of maximal antigen release, may have contributed to suboptimal immune engagement.
KEYNOTE-689 attempted to optimize timing by integrating neoadjuvant and adjuvant pembrolizumab. However, the trial design raises several concerns. As emphasized in the simultaneous editorial by Rosenberg and Vokes, an important unresolved question is which component of immunotherapy, neoadjuvant priming, adjuvant consolidation, or cumulative exposure was primarily responsible for the observed benefit.[5] This distinction is especially relevant in resource-constrained settings, where limited perioperative dosing may be more pragmatic, and parallel observations from lung cancer trials in which short-course nivolumab exposure was associated with meaningful clinical benefit.[6]
Notably, crossover to ICB in the control arm was not permitted, despite robust evidence of benefit in the recurrent/metastatic setting from KEYNOTE-048 (HR for overall survival 0.61 with pembrolizumab vs. EXTREME regimen) and CheckMate-141. This limitation compromises the equipoise of the study and potentially inflates the perceived benefit of perioperative immunotherapy.
Moreover, approximately 10%. of patients in the control arm, around 35 individuals, did not receive the assigned adjuvant treatment but were nonetheless included in the intention-to-treat analysis. The absence of detailed reasons for this omission whether due to disease progression, treatment-related toxicity, or patient withdrawal raises concerns about missed curative opportunities and the potential for analytic bias.
Subgroup analyses are also notably incomplete. Despite human papillomavirus (HPV)-positive oropharyngeal cancer comprising up to 26%. of global HNSCC incidence, efficacy outcomes for this biologically distinct subgroup were not reported. Given the divergent prognosis and treatment responsiveness of HPV-associated disease, omission of this data limits the generalizability of the findings.
Similar underrepresentation of HPV-positive disease and resultant selection bias have been observed in other perioperative and definitive-intent trials, limiting extrapolation to this subgroup.[7] The low representation of HPV-positive patients raises concerns regarding selection bias, a limitation similarly observed in other perioperative and definitive-intent trials, and restricts the generalizability of the findings.
Finally, and perhaps most critically, no health-related quality-of-life (HRQoL) outcomes were reported. A triphasic immunotherapy regimen spanning neoadjuvant, concurrent, and adjuvant phases entails a substantial treatment burden, particularly in a population where functional preservation and long-term survivorship are paramount. The absence of HRQoL data hinders a balanced risk–benefit assessment of this intensive approach.
In conclusion, while KEYNOTE-689 advances the promise of perioperative immunotherapy in resectable HNSCC, its findings must be interpreted in the context of prior trial failures, design limitations, and missing data. A cautious, evidence-based integration into practice awaits further peer-reviewed results and longer-term follow-up.
Conflict of Interest
None declared.
References
- World Health Organization. Report on the Burden of Endemic Health Care-Associated Infection Worldwide. Geneva, Switzerland: World Health Organization; 2011: 5 . Accessed March 2020 at: http://apps.who.int/iris/handle/10665/80135
- Odoom A, Tetteh-Quarcoo PB, Donkor ES. Prevalence of hospital-acquired infections in low- and middle-income countries: systematic review and meta-analysis. Asia Pac J Public Health 2025; 37 (05) 448-466
- Ministry of Health and Family Welfare, Government of India. National Guidelines for Infection Prevention and Control in Healthcare Facilities. 2020. National Centre for Disease Control, Directorate General of Health Services; ; January 2020. Accessed July 5, 2026 at: https://www.mohfw.gov.in/sites/default/files/National Guidelines for IPC in HCF - final(1).pdf
- Steyaert S, Peeters C, Wieme AD. et al. Novel Ralstonia species from human infections: improved matrix-assisted laser desorption/ionization time-of-flight mass spectrometry-based identification and analysis of antimicrobial resistance patterns. Microbiol Spectr 2024; 12 (06) e0402123
- Ryan MP, Adley CC. Ralstonia spp.: emerging global opportunistic pathogens. Eur J Clin Microbiol Infect Dis 2014; 33 (03) 291-304
- Bedir Demirdag T, Ozkaya-Parlakay A, Bayrakdar F. et al. An outbreak of Ralstonia pickettii bloodstream infection among pediatric leukemia patients. J Microbiol Immunol Infect 2022; 55 (01) 80-85
- Maroye P, Doermann HP, Rogues AM, Gachie JP, Mégraud F. Investigation of an outbreak of Ralstonia pickettii in a paediatric hospital by RAPD. J Hosp Infect 2000; 44 (04) 267-272
- Rajachandran K, Varghese GS, Kumar JV, Mathew KT. Outbreak of nosocomial infection from an unusual source. Indian J Crit Care Med 2022; 26 (09) 1042-1044
- Boutros N, Gonullu N, Casetta A, Guibert M, Ingrand D, Lebrun L. Ralstonia pickettii traced in blood culture bottles. J Clin Microbiol 2002; 40 (07) 2666-2667
- Stelzmueller I, Biebl M, Wiesmayr S. et al. Ralstonia pickettii-innocent bystander or a potential threat?. Clin Microbiol Infect 2006; 12 (02) 99-101
- Menekşe Ş, Hacıseyitoğlu D, Süzük Yıldız S, Bayrakdar F. An outbreak of Ralstonia pickettii bloodstream infection and clinical outcomes. J Infect Dev Ctries 2022; 16 (04) 705-711
- Krone M, Rauschenberger V, Blaschke V, Claus H, Kurzai O, Kampmeier S. Ralstonia pickettii bloodstream infections with potential genomic link to internationally distributed contaminated saline solution, Germany, October 2023. Euro Surveill 2024; 29 (03) 2400010
- Orme J, Rivera-Bonilla T, Loli A, Blattman NN. Native valve endocarditis due to Ralstonia pickettii: a case report and literature review. Case Rep Infect Dis 2015; 2015: 324675
- Papagrigorakis E, Vavourakis M, Vlachos C. et al. Osteomyelitis caused by Ralstonia mannitolilytica, a rare opportunistic pathogen. Cureus 2022; 14 (04) e24151
- Heagney MA. An unusual case of bacterial meningitis caused by Burkholderia pickettii . Clin Microbiol Newsl 1998; 20 (12) 102-103
- Nasir N, Sayeed MA, Jamil B. Ralstonia pickettii bacteremia: an emerging infection in a tertiary care hospital setting. Cureus 2019; 11 (07) e5084
- Liu CX, Yan C, Zhang P, Li FQ, Yang JH, Li XY. Ralstonia mannitolilytica-induced septicemia and homology analysis in infected patients: 3 case reports. Jundishapur J Microbiol 2016; 9 (07) e34373
Address for correspondence
Publication History
Article published online:
04 May 2026
© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Private Limited
A-13A, Graphix Tower 1, 6th floor, Sector 62, Noida 201309, Uttar Pradesh, India
References
- World Health Organization. Report on the Burden of Endemic Health Care-Associated Infection Worldwide. Geneva, Switzerland: World Health Organization; 2011: 5 . Accessed March 2020 at: http://apps.who.int/iris/handle/10665/80135
- Odoom A, Tetteh-Quarcoo PB, Donkor ES. Prevalence of hospital-acquired infections in low- and middle-income countries: systematic review and meta-analysis. Asia Pac J Public Health 2025; 37 (05) 448-466
- Ministry of Health and Family Welfare, Government of India. National Guidelines for Infection Prevention and Control in Healthcare Facilities. 2020. National Centre for Disease Control, Directorate General of Health Services; ; January 2020. Accessed July 5, 2026 at: https://www.mohfw.gov.in/sites/default/files/National Guidelines for IPC in HCF - final(1).pdf
- Steyaert S, Peeters C, Wieme AD. et al. Novel Ralstonia species from human infections: improved matrix-assisted laser desorption/ionization time-of-flight mass spectrometry-based identification and analysis of antimicrobial resistance patterns. Microbiol Spectr 2024; 12 (06) e0402123
- Ryan MP, Adley CC. Ralstonia spp.: emerging global opportunistic pathogens. Eur J Clin Microbiol Infect Dis 2014; 33 (03) 291-304
- Bedir Demirdag T, Ozkaya-Parlakay A, Bayrakdar F. et al. An outbreak of Ralstonia pickettii bloodstream infection among pediatric leukemia patients. J Microbiol Immunol Infect 2022; 55 (01) 80-85
- Maroye P, Doermann HP, Rogues AM, Gachie JP, Mégraud F. Investigation of an outbreak of Ralstonia pickettii in a paediatric hospital by RAPD. J Hosp Infect 2000; 44 (04) 267-272
- Rajachandran K, Varghese GS, Kumar JV, Mathew KT. Outbreak of nosocomial infection from an unusual source. Indian J Crit Care Med 2022; 26 (09) 1042-1044
- Boutros N, Gonullu N, Casetta A, Guibert M, Ingrand D, Lebrun L. Ralstonia pickettii traced in blood culture bottles. J Clin Microbiol 2002; 40 (07) 2666-2667
- Stelzmueller I, Biebl M, Wiesmayr S. et al. Ralstonia pickettii-innocent bystander or a potential threat?. Clin Microbiol Infect 2006; 12 (02) 99-101
- Menekşe Ş, Hacıseyitoğlu D, Süzük Yıldız S, Bayrakdar F. An outbreak of Ralstonia pickettii bloodstream infection and clinical outcomes. J Infect Dev Ctries 2022; 16 (04) 705-711
- Krone M, Rauschenberger V, Blaschke V, Claus H, Kurzai O, Kampmeier S. Ralstonia pickettii bloodstream infections with potential genomic link to internationally distributed contaminated saline solution, Germany, October 2023. Euro Surveill 2024; 29 (03) 2400010
- Orme J, Rivera-Bonilla T, Loli A, Blattman NN. Native valve endocarditis due to Ralstonia pickettii: a case report and literature review. Case Rep Infect Dis 2015; 2015: 324675
- Papagrigorakis E, Vavourakis M, Vlachos C. et al. Osteomyelitis caused by Ralstonia mannitolilytica, a rare opportunistic pathogen. Cureus 2022; 14 (04) e24151
- Heagney MA. An unusual case of bacterial meningitis caused by Burkholderia pickettii . Clin Microbiol Newsl 1998; 20 (12) 102-103
- Nasir N, Sayeed MA, Jamil B. Ralstonia pickettii bacteremia: an emerging infection in a tertiary care hospital setting. Cureus 2019; 11 (07) e5084
- Liu CX, Yan C, Zhang P, Li FQ, Yang JH, Li XY. Ralstonia mannitolilytica-induced septicemia and homology analysis in infected patients: 3 case reports. Jundishapur J Microbiol 2016; 9 (07) e34373