Closing in on Anal Cancer: Has the Era of Immune Checkpoint Inhibitors Truly Arrived?
Main Article Content
Abstract
Squamous cell carcinoma of the anus (SCCA) is a rare malignancy, with rising incidence and mortality largely attributed to human papillomavirus (HPV) infection. While chemoradiotherapy remains the standard treatment for locoregional disease, the management of recurrent or metastatic SCCA has long been a challenge due to limited therapeutic options and poor prognosis. Recent advancements, particularly the use of immune checkpoint inhibitors (ICIs), have revolutionized the treatment landscape. It has been demonstrated that combining carboplatin-paclitaxel with immunotherapy improves progression-free survival (PFS) and overall survival (OS) in metastatic SCCA, representing a practice-changing development. HPV-positive tumors, with their distinct immunogenic profile, have shown promise in responding to ICIs, although the risk of increased toxicity remains. Current research continues to explore novel treatment combinations, including ICIs, targeted therapies, and chemoradiotherapy, to enhance treatment outcomes and overcome resistance mechanisms. As ICIs gain a more central role in the treatment of SCCA, ongoing trials and future studies will define the optimal strategies for improving patient outcomes in both early and advanced disease.
Keywords:
Squamous cell carcinoma of the anus, immunotherapy, , immune checkpoint inhibitors, HPV, metastatic anal cancer
Article Details
How to Cite
PEIXOTO, Renata D'Alpino; FERREIRA, Artur Rodrigues; DONADIO, Mauro Daniel Spina.
Closing in on Anal Cancer: Has the Era of Immune Checkpoint Inhibitors Truly Arrived?.
Medical Research Archives, [S.l.], v. 12, n. 12, dec. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5999>. Date accessed: 06 jan. 2025.
doi: https://doi.org/10.18103/mra.v12i12.5999.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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21. Gilbert D, Serup-Hansen E, Linnemann D, et al. Tumour-Infiltrating Lymphocyte Scores Effectively Stratify Outcomes over and above P16 Post Chemo-Radiotherapy in Anal Cancer. Br J Cancer. 2016, 114, 134–7. doi: 10.1038/bjc.2015.448.
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23. NCT04719988. Anti-PD-1 and mDCF Followed by Chemoradiotherapy in Patients With Stage III Squamous Cell Anal Carcinoma. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
24. NCT03233711. Nivolumab After Combined Modality Therapy in Treating Patients With High Risk Stage II-IIIB Anal Cancer. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
25. NCT04929028. Therapy Adapted for High Risk and Low Risk HIV-Associated Anal Cancer. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
26. NCT04230759. Radiochemotherapy +/- Durvalumab for Locally-advanced Anal Carcinoma. a Multicenter, Randomized, Phase II Trial of the German Anal Cancer Study Group. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
27. NCT05060471. PD-1 Blockade Combined With Chemotherapy Followed by Concurrent Immunoradiotherapy for Locally Advanced SCCA Patients. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
28. NCT05661188. Tiraglolumab Atezolizumab and Chemoradiotherapy in Localized Anal Carcinoma (TIRANUS). Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
29. Rao et al. LBA2 - POD1UM-303/InterAACT 2: Phase III study of retifanlimab with carboplatin-paclitaxel (c-p) in patients (Pts) with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) not previously treated with systemic chemotherapy (Chemo). ESMO 2024; Abstract #5348. Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623
30. Kim S, Ghiringhelli F, de la Fouchardière C, et al. Atezolizumab plus modified docetaxel, cisplatin, and fluorouracil as first-line treatment for advanced anal cancer (SCARCE C17-02 PRODIGE 60): a randomised, non-comparative, phase 2 study. Lancet Oncol. 2024 Apr;25(4):518-28. doi: 10.1016/S1470-2045(24)00081-0.
31. Morris V, Salem M, Nimeiri H, et al. Nivolumab for Previously Treated Unresectable Metastatic Anal Cancer (NCI9673): A Multicentre, Single-Arm, Phase 2 Study. Lancet Oncol. 2017, 18, 446–53. doi: 10.1016/S1470-2045(17)30104-3.
32. Marabelle A, Cassier P, Fakih M, et al. Pembrolizumab for Previously Treated Advanced Anal Squamous Cell Carcinoma: Results from the Non-Randomised, Multicohort, Multicentre, Phase 2 KEYNOTE-158 Study. Lancet Gastroenterol Hepatol. 2022, 7, 446–54. doi: 10.1016/S2468-1253(21)00382-4.
33. Rao S, Anandappa G, Capdevila J, et al. A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202). ESMO Open. 2022 Aug;7(4):100529. doi: 10.1016/j.esmoop.2022.100529.
34. Lonardi S, Prete A, Morano F, et al. Randomized phase II trial of avelumab alone or in combination with cetuximab for patients with previously treated, locally advanced, or metastatic squamous cell anal carcinoma: the CARACAS study. J Immunother Cancer. 2021 Nov;9(11):e002996. doi: 10.1136/jitc-2021-002996.
35. © National Comprehensive Cancer; Network, Inc. All Rights Reserved; National Comprehensive Cancer Network® (NCCN®) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Anal Carcinoma Version 2. 2023. Available online: https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf (accessed on 22 August 2023)
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38. Morris V, Liu S, Johnson B, et al. 403MO Atezolizumab in Combination with Bevacizumab for Patients with Unresectable/Metastatic Anal Cancer. Ann Oncol. 2020, 31, S412. doi: 10.1016/j.annonc.2020.08.514.
39. Morris V, Ciombor K, Polite B, et al. O-12 NCI9673 (Part B): A Multi-Institutional ETCTN Randomized Phase II Study of Nivolumab with or without Ipilimumab in Refractory, Metastatic Squamous Cell Carcinoma of the Anal Canal. Ann Oncol. 2023, 34, S185–S186. doi: 10.1016/j.annonc.2023.04.027.
40. NCT04444921. EA2176: Phase 3 Clinical Trial of Carboplatin and Paclitaxel +/- Nivolumab in Metastatic Anal Cancer Patients. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
41. NCT04894370. Combination of Spartalizumab, mDCF and Radiotherapy in Patients With Metastatic Squamous Cell Anal Carcinoma. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
42. NCT05544929. A Study of Safety and Efficacy of KFA115 Alone and in Combo With Pembrolizumab in Patients With Select Advanced Cancers. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
43. NCT04287868. Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
44. NCT03946358. Combination of UCPVax Vaccine and Atezolizumab for the Treatment of Human Papillomavirus Positive Cancers (VolATIL). Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
45. NCT05941507. A Study to Evaluate TROP2 ADC LCB84 Single Agent and in Combination With an Anti-PD-1 Ab in Advanced Solid Tumors. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
46. NCT04708470. A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
47. NCT05858736. Safety, PK and Efficacy of AI-061 in Advanced Solid Tumors. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
48. NCT04429542. Study of Safety and Tolerability of BCA101 Monotherapy and in Combination Therapy in Patients with EGFR-driven Advanced Solid Tumors. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
49. NCT02628067. Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-158/KEYNOTE-158). Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
50. Rahnea-Nita RA, Toma RV, Grigorean V, et al. Reinitiating Chemotherapy beyond Progression after Maintenance Immunotherapy in Extensive-Stage Small-Cell Lung Cancer. Medicina (Kaunas). 2024 Jul 28;60(8):1225. doi: 10.3390/medicina60081225.
2. Deshmukh A, Suk R, Shiels M, et al. Recent Trends in Squamous Cell Carcinoma of the Anus Incidence and Mortality in the United States, 2001-2015. J Natl Cancer Inst. 2020;112:829–838. doi:10.1093/jnci/djz219
3. Mignozzi S, Santucci C and Malvezzi M. Global trends in anal cancer incidence and mortality. Eur J Cancer Prev. 2024 Mar 1;33(2):77-86. doi: 10.1097/CEJ.0000000000000842. Epub 2023 Nov 27.
4. Rao S, Guren M, Khan K, et al. Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(9):1087-1100. doi: 10.1016/j.annonc.2021.06.015.
5. Rao S, Sclafani F, Eng C, et al. International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct. J Clin Oncol. 2020 Aug 1;38(22):2510-2518. doi: 10.1200/JCO.19.03266.
6. Hainsworth J, Burris H, Meluch A, et al. Paclitaxel, carboplatin, and long-term continuous infusion of 5-fluorouracil in the treatment of advanced squamous and other selected carcinomas: results of a phase II trial. Cancer. 2001;92:642–9. doi: 10.1002/1097-0142(20010801)92:3<642::aid-cncr1365>3.0.co;2-z.
7. Kim S, François E, André T, et al. Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2018 Aug;19(8):1094-106. doi: 10.1016/S1470-2045(18)30321-8.
8. Rao S, Sclafani F, Eng C, et al. International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct. J Clin Oncol. 2020 Aug 1;38(22):2510-2518. doi: 10.1200/JCO.19.03266. Epub 2020 Jun 12.
9. Lee M and Allen C. Immunotherapy for HPV Malignancies. Semin Radiat Oncol. 2021 Oct;31(4):361-370. doi:10.1016/j.semradonc.2021.02.008.
10. Powell SF, Gitau M, Reynolds J, et al. Pembrolizumab in combination with chemoradiotherapy in human papillomavirus-associated head and neck squamous cell carcinoma. SITC Annual Meeting. 2018 Abstract O50.
11. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016 Nov 10;375(19):1856-1867. doi: 10.1056/NEJMoa1602252.
12. Ryan D, Compton C and Mayer R. Carcinoma of the anal canal. N Engl J Med. 2000;342:792–800. doi: 10.1056/NEJM200003163421107
13. Scheffner M, Werness B, Huibregtse J, et al. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990;63:1129–36. doi: 10.1016/0092-8674(90)90409-8.
14. Balsitis S, Sage J, Duensing S, et al. Recapitulation of the effects of the human papillomavirus type 16 E7 oncogene on mouse epithelium by somatic Rb deletion and detection of pRb-independent effects of E7 in vivo. Mol Cell Biol. 2003;23:9094–9103. doi:10.1128/MCB.23.24.9094-9103.2003.
15. Martin D, Rödel F, Balermpas P, et al. The immune microenvironment and HPV in anal cancer: Rationale to complement chemoradiation with immunotherapy. Biochim Biophys Acta Rev Cancer. 2017 Aug;1868(1):221-30. doi:10.1016/j.bbcan.2017.05.001.
16. Shamseddine A, Burman B, Lee N, et al. Tumor Immunity and Immunotherapy for HPV-Related Cancers. Cancer Discov. 2021 Aug;11(8):1896-1912. doi: 10.1158/2159-8290.CD-20-1760.
17. Armstrong S, Malley R, Wang H, et al. Molecular Characterization of Squamous Cell Carcinoma of the Anal Canal. J Gastrointest Oncol. 2021, 12, 2423. doi: 10.21037/jgo-20-610.
18. Wessely A, Heppt M, Kammerbauer C, et al. Evaluation of PD-L1 Expression and HPV Genotyping in Anal Squamous Cell Carcinoma. Cancers. 2020, 12, 2516. doi: 10.3390/cancers12092516.
19. Iseas S, Golubicki M, Robbio J, et al. A Clinical and Molecular Portrait of Non-Metastatic Anal Squamous Cell Carcinoma. Transl Oncol. 2021, 14, 101084. doi: 10.1016/j.tranon.2021.101084.
20. Balermpas P, Martin D, Wieland U, et al. Human Papilloma Virus Load and PD-1/PD-L1, CD8+ and FOXP3 in Anal Cancer Patients Treated with Chemoradiotherapy: Rationale for Immunotherapy. Oncoimmunology. 2017, 6, e1288331. doi: 10.1080/2162402X.2017.1288331.
21. Gilbert D, Serup-Hansen E, Linnemann D, et al. Tumour-Infiltrating Lymphocyte Scores Effectively Stratify Outcomes over and above P16 Post Chemo-Radiotherapy in Anal Cancer. Br J Cancer. 2016, 114, 134–7. doi: 10.1038/bjc.2015.448.
22. NCT04046133. Phase 1b/II Trial of Pembrolizumab Plus IMRT in Stage III/IV Carcinoma of Anus. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
23. NCT04719988. Anti-PD-1 and mDCF Followed by Chemoradiotherapy in Patients With Stage III Squamous Cell Anal Carcinoma. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
24. NCT03233711. Nivolumab After Combined Modality Therapy in Treating Patients With High Risk Stage II-IIIB Anal Cancer. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
25. NCT04929028. Therapy Adapted for High Risk and Low Risk HIV-Associated Anal Cancer. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
26. NCT04230759. Radiochemotherapy +/- Durvalumab for Locally-advanced Anal Carcinoma. a Multicenter, Randomized, Phase II Trial of the German Anal Cancer Study Group. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
27. NCT05060471. PD-1 Blockade Combined With Chemotherapy Followed by Concurrent Immunoradiotherapy for Locally Advanced SCCA Patients. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
28. NCT05661188. Tiraglolumab Atezolizumab and Chemoradiotherapy in Localized Anal Carcinoma (TIRANUS). Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
29. Rao et al. LBA2 - POD1UM-303/InterAACT 2: Phase III study of retifanlimab with carboplatin-paclitaxel (c-p) in patients (Pts) with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) not previously treated with systemic chemotherapy (Chemo). ESMO 2024; Abstract #5348. Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623
30. Kim S, Ghiringhelli F, de la Fouchardière C, et al. Atezolizumab plus modified docetaxel, cisplatin, and fluorouracil as first-line treatment for advanced anal cancer (SCARCE C17-02 PRODIGE 60): a randomised, non-comparative, phase 2 study. Lancet Oncol. 2024 Apr;25(4):518-28. doi: 10.1016/S1470-2045(24)00081-0.
31. Morris V, Salem M, Nimeiri H, et al. Nivolumab for Previously Treated Unresectable Metastatic Anal Cancer (NCI9673): A Multicentre, Single-Arm, Phase 2 Study. Lancet Oncol. 2017, 18, 446–53. doi: 10.1016/S1470-2045(17)30104-3.
32. Marabelle A, Cassier P, Fakih M, et al. Pembrolizumab for Previously Treated Advanced Anal Squamous Cell Carcinoma: Results from the Non-Randomised, Multicohort, Multicentre, Phase 2 KEYNOTE-158 Study. Lancet Gastroenterol Hepatol. 2022, 7, 446–54. doi: 10.1016/S2468-1253(21)00382-4.
33. Rao S, Anandappa G, Capdevila J, et al. A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202). ESMO Open. 2022 Aug;7(4):100529. doi: 10.1016/j.esmoop.2022.100529.
34. Lonardi S, Prete A, Morano F, et al. Randomized phase II trial of avelumab alone or in combination with cetuximab for patients with previously treated, locally advanced, or metastatic squamous cell anal carcinoma: the CARACAS study. J Immunother Cancer. 2021 Nov;9(11):e002996. doi: 10.1136/jitc-2021-002996.
35. © National Comprehensive Cancer; Network, Inc. All Rights Reserved; National Comprehensive Cancer Network® (NCCN®) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Anal Carcinoma Version 2. 2023. Available online: https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf (accessed on 22 August 2023)
36. Rogers J, Ohinata A, Silva N, et al. Epidermal Growth Factor Receptor Inhibition in Metastatic Anal Cancer. Anticancer Drugs. 2016, 27, 804–8. doi: 10.1097/CAD.0000000000000383.
37. Rogers J, Jácome A, Ohinata A, et al. Outcomes with Anti-EGFR Monoclonal Antibodies in Metastatic and Recurrent Anal Squamous Cell Carcinoma. Expert Rev Anticancer Ther. 2020, 20, 901–8. doi: 10.1080/14737140.2020.1810573.
38. Morris V, Liu S, Johnson B, et al. 403MO Atezolizumab in Combination with Bevacizumab for Patients with Unresectable/Metastatic Anal Cancer. Ann Oncol. 2020, 31, S412. doi: 10.1016/j.annonc.2020.08.514.
39. Morris V, Ciombor K, Polite B, et al. O-12 NCI9673 (Part B): A Multi-Institutional ETCTN Randomized Phase II Study of Nivolumab with or without Ipilimumab in Refractory, Metastatic Squamous Cell Carcinoma of the Anal Canal. Ann Oncol. 2023, 34, S185–S186. doi: 10.1016/j.annonc.2023.04.027.
40. NCT04444921. EA2176: Phase 3 Clinical Trial of Carboplatin and Paclitaxel +/- Nivolumab in Metastatic Anal Cancer Patients. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
41. NCT04894370. Combination of Spartalizumab, mDCF and Radiotherapy in Patients With Metastatic Squamous Cell Anal Carcinoma. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
42. NCT05544929. A Study of Safety and Efficacy of KFA115 Alone and in Combo With Pembrolizumab in Patients With Select Advanced Cancers. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
43. NCT04287868. Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
44. NCT03946358. Combination of UCPVax Vaccine and Atezolizumab for the Treatment of Human Papillomavirus Positive Cancers (VolATIL). Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
45. NCT05941507. A Study to Evaluate TROP2 ADC LCB84 Single Agent and in Combination With an Anti-PD-1 Ab in Advanced Solid Tumors. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
46. NCT04708470. A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
47. NCT05858736. Safety, PK and Efficacy of AI-061 in Advanced Solid Tumors. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
48. NCT04429542. Study of Safety and Tolerability of BCA101 Monotherapy and in Combination Therapy in Patients with EGFR-driven Advanced Solid Tumors. Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
49. NCT02628067. Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-158/KEYNOTE-158). Available at: https://clinicaltrials.gov/ Accessed September 26, 2024.
50. Rahnea-Nita RA, Toma RV, Grigorean V, et al. Reinitiating Chemotherapy beyond Progression after Maintenance Immunotherapy in Extensive-Stage Small-Cell Lung Cancer. Medicina (Kaunas). 2024 Jul 28;60(8):1225. doi: 10.3390/medicina60081225.