First results of a multicenter, non-randomized, prospective phase II study of the efficacy and safety of induction therapy with pembrolizumab, cisplatin, and 5-fluorouracil in patients with unresectable squamous cell carcinoma of the oropharynx, hypopharynx and larynx

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Abstract

Background. The approved regimen of induction chemotherapy with docetaxel + cisplatin + 5-fluorouracil has high risk of unacceptable toxicity for many patients with advanced head and neck cancer (HNSCC). Toxicity can also compromise the delivery of the following chemoradiation. In order to improve the results of these pts treatment we conducted a prospective multicenter non-randomized phase II study of induction immunochemotherapy followed by (chemo)radiation and here we report first results of objective response rate (ORR), the safety profile of induction therapy and risk of further radiation therapy omission (NCT05551767).

Materials and methods. The inclusion criteria were: unresectable stage III–IVA cancer of larynx, oropharynx, hypopharynx, PD-L1-positive (CPS≥1) squamous cell cancer, ECOG 0-2. Included pts received 3 cycles of pembrolizumab 200 mg d1+ cisplatin 100 mg/m2 d1 + 5-fluorouracil 1000 mg/m2/day 1-4 d followed by (chemo-) radiation.

Results. Since January 2022 a total of 120 pts were included. Median age was 60 (35–75), the majority were male (105; 87.5%). Objective responses were assessed in 116 of 120 pts. ORR on induction phase was 62.9% (n=73), including 16.4% (n=19) of complete responses. Median change of target lesions was -55% (from -100% to 65%). To date, only 7 pts did not start (chemo)radiation in time due to disease progression (4 pts) or refuse of consent (3 pts). Among 95 pts who completed radiation therapy 94.7% received radiation dose ≥66Gy. The incidence of grade 3-4 adverse events was 30,8%, in 6 (5%) pts it required hospitalization. No grade 5 adverse events were observed. The most common toxicity was hematological with neutropenia grade 3-4 in 28 (23.3%) pts. There was mild immune-related toxicity: 2 (1.7%) pts had skin rash and 1 (0.8%) – hypothyroidism. The use of high dose of cisplatin resulted in a trend to decline glomerular filtration rate (median decrease was 10.5% from baseline) although none of pts required hemodialysis.

Conclusion. Induction therapy with pembrolizumab plus cisplatin and 5-fluorouracil provided meaningful ORR and acceptable safety profile in locally advanced HNSCC. It almost did not influence the following radiation therapy omission rate. Further follow-up is needed to assess long-term efficacy.

About the authors

Olesia A. Stativko

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department

Author for correspondence.
Email: olesya_stativko@mail.ru
ORCID iD: 0009-0002-1084-1551
SPIN-code: 3627-0262

Department Head, Moscow State Budgetary Healthcare Institution "Oncological Center No. 1"

Russian Federation, Moscow

Ilya A. Pokataev

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department

Email: olesya_stativko@mail.ru
ORCID iD: 0000-0001-9864-3837
SPIN-code: 7338-9428

D. Sci. (Med.), Moscow State Budgetary Healthcare Institution "Oncological Center No. 1"

Russian Federation, Moscow

Sergey A. Kravtsov

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department

Email: olesya_stativko@mail.ru
ORCID iD: 0000-0002-0681-8976

D. Sci. (Med.), Moscow State Budgetary Healthcare Institution "Oncological Center No. 1"

Russian Federation, Moscow

Liudmila G. Zhukova

Loginov Moscow Clinical Scientific Center

Email: olesya_stativko@mail.ru
ORCID iD: 0000-0003-4848-6938

D. Sci. (Med.)

Russian Federation, Moscow

Daniil L. Stroyakovskiy

Moscow City Oncology Hospital №62

Email: olesya_stativko@mail.ru
ORCID iD: 0000-0003-1973-1092

Cand. Sci. (Med.)

Russian Federation, Moscow

Emil R. Sabitov

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department

Email: olesya_stativko@mail.ru
ORCID iD: 0009-0009-5110-2457

Department Head, Moscow State Budgetary Healthcare Institution "Oncological Center No. 1"

Russian Federation, Moscow

Evgeniya S. Kuzmina

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department

Email: olesya_stativko@mail.ru
ORCID iD: 0009-0007-2856-5176
SPIN-code: 9668-5733

Department Head, Moscow State Budgetary Healthcare Institution "Oncological Center No. 1"

Russian Federation, Moscow

Polina S. Feoktistova

Loginov Moscow Clinical Scientific Center

Email: olesya_stativko@mail.ru
ORCID iD: 0000-0002-0340-7119
SPIN-code: 9638-4788

Cand. Sci. (Med.)

Russian Federation, Moscow

Tatiana G. Antonova

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department

Email: olesya_stativko@mail.ru
ORCID iD: 0009-0007-6646-7454

Department Head, Moscow State Budgetary Healthcare Institution "Oncological Center No. 1"

Russian Federation, Moscow

Marina A. Lyadova

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department; Russian Medical Academy of Continuous Professional Education

Email: olesya_stativko@mail.ru
ORCID iD: 0000-0002-9558-5579
SPIN-code: 8220-2854

Cand. Sci. (Med.), Novokuznetsk State Institute for Further Training of Physicians, Moscow State Budgetary Healthcare Institution "Oncological Center No. 1"

Russian Federation, Moscow; Novokuznetsk

Margarita V. Nosova

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department

Email: olesya_stativko@mail.ru
ORCID iD: 0009-0003-0622-2528

oncologist, Moscow State Budgetary Healthcare Institution «Oncological Center No. 1"

Russian Federation, Moscow

Rozana S. Sydykova

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department

Email: olesya_stativko@mail.ru
ORCID iD: 0000-0002-5569-3655

oncologist, Moscow State Budgetary Healthcare Institution"Oncological Center No. 1"

Russian Federation, Moscow

Kristina N. Lisitsyna

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department

Email: olesya_stativko@mail.ru
ORCID iD: 0009-0002-6817-4907

oncologist, Moscow State Budgetary Healthcare Institution "Oncological Center No. 1"

Russian Federation, Moscow

Tatiana B. Strelnikova

Moscow City Oncology Hospital №62

Email: olesya_stativko@mail.ru

oncologist

Russian Federation, Moscow

Gulnara R. Alizade

Loginov Moscow Clinical Scientific Center

Email: olesya_stativko@mail.ru

oncologist

Russian Federation, Moscow

Sergey A. Parts

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department

Email: olesya_stativko@mail.ru
ORCID iD: 0009-0003-9954-4584
SPIN-code: 1350-6713

Cand. Sci. (Med.), Moscow State Budgetary Healthcare Institution "Oncological Center No. 1"

Russian Federation, Moscow

Magomed M. Dolov

Moscow International Cancer Center

Email: olesya_stativko@mail.ru
ORCID iD: 0009-0004-5039-7875

radiotherapist

Russian Federation, Moscow

Anna Kh. Tedeeva

Moscow International Cancer Center

Email: olesya_stativko@mail.ru

Department Head

Russian Federation, Moscow

Vsevolod N. Galkin

Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department; Sechenov First Moscow State Medical University (Sechenov University)

Email: olesya_stativko@mail.ru
ORCID iD: 0000-0002-6619-6179

D. Sci. (Med.), Prof.

Russian Federation, Moscow; Moscow

References

  1. Каприн А.Д. Злокачественные новообразования в России в 2021 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена − филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2022 [Kaprin AD. Zlokachestvennyie novoobrazovaniia v Rossii v 2021 godu (zabolevaiemost' i smertnost'). Moscow: MNIOI im. P.A. Gertsena − filial FGBU “NMITS radiologii” Minzdrava Rossii, 2022 (in Russian)].
  2. Болотина Л.В., Владимирова Л.Ю., Деньгина Н.В. Практические рекомендации по лекарственному лечению опухолей головы и шеи. Злокачественные опухоли. 2022;12(3s2-1):94-112 [Bolotina LV, Vladimirova LIu, Dengina NV. Prakticheskiie rekomendatsii po lekarstvennomu lecheniiu opukholei golovy i shei. Zlokachestvennyie Opukholi. 2022;12(3s2-1):94-112 (in Russian)].
  3. Ho KF, Swindell R, Brammer CV. Dose intensity comparison between weekly and 3-weekly Cisplatin delivered concurrently with radical radiotherapy for head and neck cancer: A retrospective comparison from New Cross Hospital, Wolverhampton, UK. Acta Oncologica. 2008;47(8):1513-8.
  4. Strojan P, Vermorken JB, Beitler JJ, et al. Cumulative cisplatin dose in concurrent chemoradiotherapy for head and neck cancer: A systematic review. Head Neck. 2016;38(Suppl. 1):E2151-8. doi: 10.1002/hed.24026
  5. Machiels JP, René Leemans C, Golusinski W, et al.; EHNS Executive Board; ESMO Guidelines Committee; ESTRO Executive Board. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS–ESMO–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(11):1462-75. doi: 10.1016/j.annonc.2020.07.011
  6. Ghi MG, Paccagnella A, Ferrari D, et al. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II–III trial. Ann Oncol. 2017;28(9):2206-12.
  7. Kramer HJ, Jaar BJ, Choi MJ, et al. An Endorsement of the Removal of Race From GFR Estimation Equations: A Position Statement From the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Am J Kidney Dis. 2022;80(6):691-6.
  8. Domenge C, Hill C, Lefebvre JL, et al. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. Br J Cancer. 2000;83(12):1594-8.
  9. Hitt R, López-Pousa A, Martínez-Trufero J, et al. Phase III Study Comparing Cisplatin Plus Fluorouracil to Paclitaxel, Cisplatin, and Fluorouracil Induction Chemotherapy Followed by Chemoradiotherapy in Locally Advanced Head and Neck Cancer. J Clin Oncol. 2005;23(34):8636-45.
  10. Iocca O, Farcomeni A, Di Rocco A, et al. Locally advanced squamous cell carcinoma of the head and neck: A systematic review and Bayesian network meta-analysis of the currently available treatment options. Oral Oncol. 2018;80:40-51.
  11. Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol. 2011;12(2):153-9.
  12. Paccagnella A, Orlando A, Marchiori C, et al. Phase III Trial of Initial Chemotherapy in Stage III or IV Head and Neck Cancers: a Study by the Gruppo di Studio sui Tumori della Testa e del Collo. JNCI J Nat Cancer Inst. 1994;86(4):265-72.
  13. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and Fluorouracil Alone or with Docetaxel in Head and Neck Cancer. New Engl J Med. 2007;357(17):1705-15.
  14. Ferrari D, Ghi MG, Franzese C, et al. The Slippery Role of Induction Chemotherapy in Head and Neck Cancer: Myth and Reality. Front Oncol. 2020;10:7. doi: 10.3389/fonc.2020.00007
  15. Bernadach M, Lapeyre M, Dillies AF, et al. Predictive factors of toxicity of TPF induction chemotherapy for locally advanced head and neck cancers. BMC Cancer. 2021;21(1):360.
  16. Ko EC, Genden EM, Misiukiewicz K, et al. Toxicity profile and clinical outcomes in locally advanced head and neck cancer patients treated with induction chemotherapy prior to concurrent chemoradiation. Oncol Rep. 2012;27(2):467-74. doi: 10.3892/or.2011.1512
  17. Fayette J, Fontaine-Delaruelle C, Ambrun A, et al. Neoadjuvant modified TPF (docetaxel, cisplatin, fluorouracil) for patients unfit to standard TPF in locally advanced head and neck squamous cell carcinoma: a study of 48 patients. Oncotarget. 2016;7(24):37297-304.
  18. Inhestern J, Schmalenberg H, Dietz A, et al. A two-arm multicenter phase II trial of one cycle chemoselection split-dose docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy before two cycles of split TPF followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1). Ann Oncol. 2017;28(8):1917-22. doi: 10.1093/annonc/mdx20
  19. Lee KW, Koh Y, Kim SB, et al. A Randomized, Multicenter, Phase II Study of Cetuximab With Docetaxel and Cisplatin as Induction Chemotherapy in Unresectable, Locally Advanced Head and Neck Cancer. Oncologist. 2015;20(10):1119-20.
  20. Dietz A, Wichmann G, Flentje M, et al. Final results of the randomized phase II DeLOS-II trial: Induction chemotherapy (IC) followed by radiotherapy (R) vs. cetuximab (E) plus IC and R for functional larynx preservation in resectable laryngeal and hypopharyngeal cancer (LHSCC). J Clin Oncol. 2016;34(Suppl. 15):6025. doi: 10.1200/JCO.2016.34.15_suppl.6025
  21. Vermorken JB, Remenar E, van Herpen C, et al.; EORTC 24971/TAX 323 Study Group. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695-704. doi: 10.1056/NEJMoa071028
  22. Harrington KJ, Burtness D, Greil R, et al. Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol. 2023;41(4):790-802.
  23. Machiels JP, Tao Y, Licitra L, et al. Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2024;25(5):572-87.
  24. Spicer JD, Garassino MC, Wakelee H, et al. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;404(10459):1240-52.
  25. Wu D, Li Y, Xu P, et al. Neoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial. Nat Communicat. 2024;15(1):2177.

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2. Fig. 1. CONSORT standard chart of the distribution of patients included in the study.

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3. Fig. 2. Histogram of the depth of effects during induction CT (the percentage change in the sum of the measured foci in comparison with the initial radiological assessment is provided).

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