Received: 10 September 2019 | Revised: 5 November 2019 | Accepted: 6 November 2019 DOI: 10.1002/cam4.2722 ORIGINAL RESEARCH VITAL phase 2 study: Upfront 5-fluorouracil, mitomycin-C, panitumumab and radiotherapy treatment in nonmetastatic squamous cell carcinomas of the anal canal (GEMCAD 09-02) Jaime Feliu1 | Rocio Garcia-Carbonero2,3 | Jaume Capdevila4 | Inmaculada Guasch | Vicente Alonso-Orduna | Carlos Lopez | Pilar Garcia-Alfonso8 5 6 7 | Carmen Castanon9 | Isabel Sevilla10 | Laura Cerezo11 | Carles Conill12 | Begona Quintana-Angel13 | Maria E. Sanchez14 | Ismael Ghanem1 | Marta Martin-Richard15 | Miriam Lopez-Gomez16 | Ana Leon17 | Monica Caro18 | Teresa Fernandez19 | Joan Maurel20 1 Department of Medical Oncology, CIBERONC, Catedra UAM-AMGEN, Hospital Universitario La Paz, Madrid, Spain 2 Department of Medical Oncology, Hospital Universitario Virgen del Rocio, Sevilla, Spain 3 Department of Medical Oncology, imas12, UCM, CNIO, CIBERONC, Hospital Universitario 12 de Octubre, Madrid, Spain 4 Department of Medical Oncology, Hospital Universitari Vall d'Hebron, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain 5 Department of Medical Oncology, Hospital Althaia-Manresa, Manresa, Spain 6 Department of Medical Oncology, Instituto de Investigacion Sanitaria de Aragon, Hospital Universitario Miguel Servet, Zaragoza, Spain 7 Department of Medical Oncology, Hospital Universitario Marques de Valdecilla, Santander, Spain 8 Department of Medical Oncology, Hospital General Universitario Gregorio Maranon, Madrid, Spain 9 Department of Medical Oncology, Hospital Virgen Blanca, Leon, Spain 10 Investigacion Clinica y Traslacional en Cancer, Instituto de Investigaciones Biomedicas de Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, Malaga, Spain 11 Department of Radiation Oncology, Hospital Universitario de La Princesa, Madrid, Spain 12 Department of Radiation Oncology, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain 13 Department of Radiation Oncology, Hospital Universitario Virgen del Rocio, Sevilla, Spain 14 Department of Oncology, Hospital Universitario La Paz, Madrid, Spain 15 Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 16 Department of Medical Oncology, Hospital Universitario Infanta Sofia, Madrid, Spain 17 Department of Medical Oncology, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain 18 Department of Radiation Oncology, ICO Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain 19 Department of Medical Oncology, Hospital Son Llatzer, Palma de Mallorca, Spain 20 Department of Medical Oncology, Hospital Clinic, Translational Genomics and Targeted Therapeutics in Solid Tumours Group, IDIBAPS, University of Barcelona, Barcelona, Spain This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. 1008 |  wileyonlinelibrary.com/journal/cam4 Cancer Medicine. 2020;9:1008–1016. | 20457634, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.2722 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. 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 FELIU et al.    1009 Correspondence Jaime Feliu, Servicio de Oncología Abstract Médica, Hospital Universitario La Paz, Aim: VITAL, a phase II single-arm study, aimed to evaluate efficacy and safety Paseo de la Castellana, 261, 28046 Madrid, of panitumumab addition to 5-fluorouracil (5-FU), mitomycin-C (MMC) and radio- Spain. Email: jaime.feliu@salud.madrid.org therapy (RT) in patients with localized squamous cell carcinoma of the anal canal (SCCAC). Funding information This work was supported by Amgen S.A. Methods: Adult, treatment-naïve SCCAC patients (Stage T2-T4, any N, M0) and ECOG-PS ≤2, received panitumumab (6 mg/kg, day 1 and Q2W; 8 weeks), 5-FU (1000 mg/m2/d, days 1-4 and 29-32), MMC (10 mg/m2, days 1 and 29) and RT 45 Gy (1.8 Gy/fraction) to the primary tumor and mesorectal, iliac and inguinal lymph nodes, plus 10-15 Gy boost dose to the primary tumor and affected lymph nodes. The primary objective was disease free survival rate (DFS) at 3-years (expected 3-year DFS rate: 73.7 ± 12%). Results: Fifty-eight patients (31 women; median age: 59 years; ECOG-PS 0-1:98%; TNM II [29%] (T2 or T3/N0/M0)/IIIA (T1-T3/N1/M0 or T4/N0/M0) [21%]/IIIB (T4/ N1/M0 or any T/N2 or N3/M0) [47%]/nonevaluable [4%]) were included. The me- dian follow-up was 45 months. The 3-year DFS rate was 61.1% (95% CI: 47.1, 72.4). The 3-year overall survival rate was 78.4% (95% CI: 65.1, 87.1). Eighteen patients (31.0%) required a colostomy within 2 years posttreatment. Grade 3-4 toxicities were experienced by 53 (91%) patients. Most common grade 3-4 treatment-related events were radiation skin injury (40%) and neutropenia (24%). No toxic deaths occurred. Improved efficacy in colostomy-free survival and complete response rate was ob- served in human papilloma virus positive patients. Conclusions: Panitumumab addition to MMC-5FU regimen in SCCAC patients in- creases toxicity and does not improve patients’ outcomes. RT plus MMC-5FU re- mains the standard of care for localized SCCAC patients. KEYWORDS chemotherapy, radiotherapy, rectal cancer, target therapy 1 | IN TRO D U C T IO N the RT boost dose or replacing MMC with cisplatin during chemoradiotherapy.4,5,7 The substitution of MMC for cis- Anal cancer is a relatively rare cancer which tends to be platin is accepted in the clinic, as similar results have been neglected. However, in 2008 the approximate number observed for both treatments with less myelotoxicity.2,5 of cases was estimated to be 27 000 worldwide.1,2 In the Additionally, capecitabine has been considered as an alterna- United States (US), by 2018, anal cancer or anorectum can- tive to infused 5-FU.2,3 However, 5-FU/MMC + RT remains cer was expected to account for approximately 2.7% of all as the standard of care. digestive cancers.1,2 Squamous cell carcinoma of the anal canal (SCCAC), The combination of 5-fluorouracil (5-FU), mitomycin-C has been associated with many risk factors, most impor- (MMC), and radiotherapy (RT) has been established as the tantly with human papilloma virus (HPV) infection.8-14 The standard of care in Europe and the United States since the HPV-associated E5 protein amplifies the mitogenic sig- 1970s.2,3 This treatment achieves a 5-year overall survival nals through the epidermal growth factor receptor (EGFR) (OS) rate of 70%-80%,4,5 and is particularly effective in cT1/ which is broadly expressed in squamous cell carcinomas T2 tumors achieving long lasting complete tumor regression such as those from anogenital tract and oropharynx.15-17 in 80%-90% of cases. However, in more advanced anal can- Panitumumab and cetuximab are currently the two mono- cers (T3-4 or N+), the 3-year OS rate is 70% and disease-free clonal anti-EGFR antibodies more widely developed in the survival (DFS) rate is around 50%.6 In recent years, several clinic. Both anti-EGFR antibodies are potential treatments strategies have been studied to improve these results, such as for SCCAC patients as not only 80%-90% of SCCAC tu- adding induction or consolidation chemotherapy, increasing mors express EGFR, but also <5% present KRAS mutations, | 20457634, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.2722 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. 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 1010    FELIU et al. which are associated with lack of activity in monoclonal 2.3 | Study outcomes anti-EGFR antibodies.17 In addition, RT can induce EGFR expression in cancer The primary outcome measure in this study was DFS rate cells, resulting in acquired resistance. Anti-EGFR antibod- at 3 years. Secondary outcomes included: complete response ies might help overcome this resistance.18 Though there have (CR) rate, local-regional failure (LRF) free rate, distant fail- been previous studies assessing the addition of cetuximab to ure free rate, cumulative rate of colostomy, colostomy free RT regimens in nonmetastatic SCCAC patients, no studies survival (CFS), recurrence free survival (RFS), OS and have been performed to date evaluating the addition of pa- safety profile of this combination. Safety profile included the nitumumab.19-22 In addition, previous studies have used che- incidence and severity of adverse events (AE) and significant motherapy regimens based on cisplatin-5-FU combinations, changes in analytical parameters. although the combination with MMC-5-FU is still considered standard by many authors.23 This study aimed to evaluate the efficacy and safety of the addition of panitumumab to 5-FU, 2.4 | Statistical considerations MMC and RT standard treatment in patients with SCCAC. A sample size of 58 patients with stage ≥T2N0 was cal- culated in order to have 80% power to detect a relative in- 2 | M AT E R IA L A N D ME T H O DS crement of 3-year DFS rate of 10% compared to the US Gastrointestinal Intergroup Radiation Therapy Oncology Extended methodological details are provided in the Group (RTOG) 98-11 (3-year DFS rate = 68%), and ac- Supplementary material. This phase II, open-label, multicentre, counting for a dropout rate of 10%. Therefore, the expected single-arm trial was conducted in 25 centers in Spain (VITAL 3-year DFS for this study was 73.7 ± 12% in order to obtain Study [GEMCAD-09-02], clini​caltr​ials.gov: NCT01285778, a relative increase of 10% compared to the RTOG 98-11.24 EudraCT Number: 2010-018430-48). The study was conducted Detailed information on efficacy outcomes and their re- in accordance with the ethical principles of the Declaration of porting are provided in the Supplementary material. Helsinki and Good Clinical Practice guidelines. The ethics committee at each participating centre and local authorities approved the study protocol and its amendments. All patients 3 | RESULTS provided written informed consent prior to study entry. 3.1 | Patient characteristics 2.1 | Eligibility criteria A total of 58 patients were enrolled between the January 24, 2011 and the December 2, 2013. All of them were included Patients were required to have histologically or cytologically in the intention-to-treat, per-protocol and safety populations confirmed SCACC with T2-T4 stage and any N stage; age (Figure 1). The overall patient population had a median ≥18 years; Eastern Cooperative Oncology Group perfor- age of 59.2 (range 33.0-83.0) years and 53.5% were female mance status (ECOG-PS) 0-2 and no prior RT or chemother- (Table 1). A high percentage of tumors was HPV positive apy for this malignancy as well as no metastasis. (84.8%), whereas only 9% of the patients were human im- munodeficiency virus (HIV) positive (percentages calculated over assessed values, tumor samples of 13 patients and 12 2.2 | Study treatments patients were not evaluable for HIV and HPV, respectively). Thirty-six patients (62%) had a primary tumor of ≤5 cm in Patients received treatment with panitumumab (Vectibix®; diameter (T1 or T2) versus 20 (34.5%) who had one of >5 cm Amgen) 6 mg/kg intravenously (IV) on day 1 and every (T3 or T4). Thirty-nine (67%) had positive lymph nodes. The 2 weeks for 8 weeks. Panitumumab treatment was followed most common TNM tumor stage was IIIB (T4/N1/M0 or any by 5-FU 1000 mg/m2/d by continuous IV infusion on days T/N2 or N3/M0) (46.6%) (Table 1). 1-4 and 29-32, and MMC 10 mg/m2 IV on days 1 and 29. RT was given on days 1-37 to a total dose of 45 Gy (1.8 Gy/frac- tion, 5 fractions per week) to the primary tumor and meso- 3.2 | Treatment administration rectal, iliac and inguinal lymph nodes, plus a boost dose of 10-15 Gy to the primary tumor and affected lymph nodes. Information regarding panitumumab and chemotherapy rela- Intensity modulated radiation therapy or 3-D conformal RT tive dose intensity, as well as RT administration, are summa- was used depending on the center's availability following rized in Table S1. A total of 56 (97%) patients received the two protocol guidelines (Figure S1). programmed chemotherapy cycles. Most patients received mean | 20457634, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.2722 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. 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 FELIU et al.    1011 Screened patients (n = 65) Excluded (n = 7): Did not meet inclusion criteria (n = 4) Refused to participate (n = 1) Other (n = 2) Enrolled patients (n = 58) End of Study: Per protocol (n = 37) Withdraw of IC (n = 1) Lost to follow up (n = 3) Exitus (n = 12) Other (n = 5) End panitumumab (n = 18) End chemotherapy (n = 11) End radiotherapy (n = 6) Unacceptable toxicity (n = 16) Unacceptable toxicity (n = 9) Unacceptable toxicity (n = 5) Non-related AE (n = 1) Non-related AE (n = 1) Non-related AE (n = 1) Withdraw of IC (n = 1) Withdraw of IC (n = 1) Completed panitumumab Completed chemotherapy Completed radiotherapy treatment (n = 40) treatment (n = 47) treatment (n = 52) FIGURE 1 Patient disposition flow chart ≥90% of the intended dose intensity of panitumumab, MMC and neutropenia in 6.9%, radiation skin injury in 6.9%, diarrhoea 5-FU. Dose modifications were required in 9 patients (15.5%) in 6.9%, neutropenia in 5.2% and proctalgia in 5.2%. Sixty- for panitumumab, in 15 patients (25.9%) for 5-FU and in 11 pa- nine percent of patients presented a hematological toxicity tients (19.0%) for MMC. Regarding panitumumab: 7 patients (53.4% grade 3-4) and 77.6% presented diarrhea or colitis (12.1%) had a dose reduction, 17 patients (29.3%) had a dose (22.4% grade 3-4) throughout the study. Furthermore, 55.1% delay and 16 patients (27.6%) required drug discontinuation. A of patients presented a skin rash (3.4% grade 3-4). AEs of total of 23 patients received a radiation treatment break due to special interest are detailed in Table S2. toxicity with a mean (SD) duration break of 4.9 (4.4) days. 3.4 | Primary outcome: 3-year DFS 3.3 | Overall safety The median follow-up time was 45 months (range 3-67). All patients in the study suffered at least one panitumumab-, Treatment efficacy results are summarized in Table 3. The chemotherapy- and/or RT-related AE (N = 58). A total of DFS rate at 3 years (95% CI) was 61.1% (47.1, 72.4). Hence, 55 patients (94.8%) developed a grade 3-4 treatment-related the expected 3-year DFS rate of 73.7 ± 12% was not achieved AE. The most common, occurring in ≥10% of patients, grade (Figure 2). 3-4 treatment-related AEs are summarized in Table 2. These AEs included: radiation skin injury in 39.7% (31.0% grade 3, 8.6% grade 4), diarrhea in 20.7% (20.7% grade 3, 0% grade 3.5 | Secondary outcome: OS, CR, LRF, 4), neutropenia in 24.1% (19.0% grade 3, 5.2% grade 4), distant metastases, and colostomy leukopenia in 10.3% (10.3% grade 3, 0% grade 4) and lym- phopenia in 15.5% (13.8% grade 3, 1.7% grade 4). A total of The OS at 3 years was 78.4% (95% CI: 65.1, 87.1). The 21 (36.2%) patients reported a serious AE (SAE) related to median OS and DFS were not reached. One patient was co- panitumumab, chemotherapy and/or RT. The most common lostomized prior to his/her study entry. Eighteen patients SAEs, occurring in ≥5% of patients included, were: febrile (31.0%) required a colostomy at some point throughout the | 20457634, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.2722 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. 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 1012    FELIU et al. TABLE 1 Patient characteristics TABLE 3 Main efficacy results Overall popula- Overall popula- tion (N = 58) Percentage (95% CI) tion (N = 58) Median (range) age, year 59.2 (33.0-83.0) DFS rate at 3 y 61.1 (47.1, 72.4) Sex, female, N (%) 31 (53.5) OS rate at 3 y 78.4 (65.1, 87.1) Ethnicity, Caucasian, N (%) 57 (98.3) CFS rate at 3 y 68.1 (54.2, 78.6) ECOG performance status, N (%) Clinical CR rate 81.0 (69.8, 92.2) 0 24 (41.4) LRF-free rate at 3 y 64.8 (50.9, 75.7) 1 33 (56.9) Distant failure free rate, at 3 y 93.0 (82.4, 97.3) 2 1 (1.7) RFS rate at 3 y 75.8 (60.5, 85.8) TNM stage, N (%) Abbreviations: CFS, colostomy-free survival; CI, confidence interval; CR, I 0 (-) complete response; DFS, disease-free survival, LRF, local-regional failure, OS, overall survival; RFS, recurrence-free survival. II 17 (29.3) IIIA 12 (20.7) The CR rate was 81.0% (95% CI: 69.8, 92.2) (N = 47) IIIB 27 (46.6) (Figure S2). Eighteen patients (31.0%) showed only a LRF, NE 2 (3.5) two patients (3.4%) showed a local-regional and distant fail- HIV positivea, N (%) 4 (8.9) ure and two patients (3.4%) showed only distant failure. The a HPV positive , N (%) 39 (84.8) LRF free and the distant failure free rates at 3 years were Abbreviations: ECOG, Eastern Cooperative Oncology Group; HIV, human im- 64.8% (95% CI: 50.9, 75.7) and 93.0% (95% CI: 82.4, 97.3), munodeficiency virus; HPV, human papillomavirus; NE, not evaluable; TNM, respectively. Taking into account only patients with CR (i.e., TNM classification of malignant tumors. 47 patients): 75.8% (95% CI: 60.5, 85.8) of patients were re- a Percentage calculated over observed values (13 patients and 12 patients for the currence-free at 3 years. HIV and HPV results respectively were not evaluated). TABLE 2 Toxicity summary 3.6 | Univariate and multivariable analyses Safety population No significant associations were observed between baseline Treatment related AEsa (N = 58) characteristics (age, sex, ECOG status, primary tumor size, Grade 3-4 related AEs, N (%) 53 (91.4) HPV, HIV, and cancer stage) or rash severity and the DFS b Most common and OS outcomes (Tables S3-S7). Radiation skin injury 23 (39.7) A statistically significant association was observed be- Neutropenia 14 (24.1) tween: (a) CFS in HPV negative (N = 7, mean [SD] = 7.6 Diarrhea 12 (20.7) [0.6]) vs HPV positive (N = 39, 17.3 [0.6]) patients Lymphopenia 9 (15.5) (P = .0277), (b) distant failure free rate in HIV negative (N = 41, mean [SD] = 3.6 [-]) vs HIV positive (N = 4, [-]) pa- Leukopenia 6 (10.3) tients (P = .0240) and (c) CR rate in HPV positive (N = 39, Serious treatment-related AE, N (%) 21 (36.2) 84.6% [95% CI 73.3, 95.9]) vs HPV negative (N = 7, 28.6% Most commonc [95% CI 0.0, 62.1]) patients (P < .05) (Figure S3). However, Febrile neutropenia 4 (6.9) most subpopulations sample sizes were small. Radiation skin injury 4 (6.9) DFS and OS were not associated with any of the prognos- Diarrhoea 4 (6.9) tic factors studied using a multivariable analysis. All patients Neutropenia 3 (5.2) were wild type for RAS and EGFR, so it was not possible Proctalgia 3 (5.2) to evaluate treatment outcomes according to RAS and EFGR mutation status. Abbreviations: AE, adverse events; RT, radiotherapy; SAE, serious AE. a AEs related to panitumumab and/or chemotherapy and/or RT. b Most common (>10%) AE related to any of the three treatments. c Most common (>5%) SAE related to any of the three treatments. 4 | DISCUSSION study because of anal cancer (N = 17, 94.4%) and poor ano- The results of this study show that panitumumab, when added rectal function (N = 1, 5.6%). The CFS rate at 3 years was to MMC-5FU-based chemoradiation, does not improve 68.1% (95% CI: 54.2, 78.6). outcomes for the treatment of patients with nonmetastatic | 20457634, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.2722 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. 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 FELIU et al.    1013 F I G U R E 2 Kaplan-Meier estimates A 100 3-y OS rate = 78.4% (95%CI: 65.1-87.1) of disease free survival (A) and overall survival (B) OS probability (%) 75 50 25 Subjects Event Censored Median (95%CI) 58 22.4% (13) 77.6% (45) NR (NR, NR) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months from first treatment dose No. at risk 58 57 56 53 50 46 40 34 22 14 7 1 0 B 100 3-y DFS rate = 61.1% (95%CI: 47.1 - 72.4) DFS probability (%) 75 50 25 Subjects Event Censored Median (95%CI) 58 37.9% (22) 62.1% (36) NR (16.6, NR) 0 0 6 12 18 24 30 36 42 48 Months from first treatment dose No. at risk 58 52 38 34 33 32 28 24 14 SCCAC stage >T1N0. More specifically, the primary objec- lower than the doses used in this study. Also, Aparicio et al tive of the study, which was to demonstrate an improvement communicated the preliminary results of a phase II study in the 3-year DFS rate, was not achieved. that included 45 patients using this scheme. Despite this At the time of the study design, little data on anti-EGFR dose reduction, 89% and 38% of the patients reported a agents in SCCAC patients was available. However, current grade 3 or grade 4 toxicity, respectively. With a median results have shown that several of the initial studies with follow-up of 18 months, the RFS and CFS were of 72% and cetuximab showed high rates of grade 3-4 radiation-in- 78%, respectively.30 duced dermatitis and diarrhoea. Toxicity was deemed Data from head and neck studies show that toxicity induced unacceptable and led to early discontinuation in two of by RT associated with cetuximab has a marked inflamma- these trials20,25 and also showed poor long-term efficacy tory component, a fact that may have contributed to the poor results.21 Other studies with cetuximab-chemoradiation tolerability of regimens with chemoradiation and cetuximab, did not support further clinical development in phase III associated with unacceptable rates of acute radiation-induced trials of cetuximab in patients with SCCAC, either due to inflammatory grade 3-4 AEs. The results of our study would small numbers,26 excessive toxicity19,22 or incomplete/in- suggest that this tolerability issue is less marked for panitu- conclusive efficacy data.27,28 It should be noted that those mumab, although the non-randomized comparison prevents studies testing cetuximab were conducted mainly with cis- us from drawing any definitive conclusions. In this study, the platin-5FU as a chemotherapy partner.19,20,25 Our study was investigational treatment with panitumumab has resulted in the first to investigate the combination of panitumumab substantial but acceptable and manageable toxicity. Less than with MMC-5FU-RT. After our study commenced, the re- 18% of patients presented grade 3-4 rash. Concerning the sults of a phase I study aiming to determinate the maximum most important toxicities such as radiation-induced epitheli- tolerated dose of panitumumab and 5-FU when combined tis, diarrhea, and neutropenia, no significant increase in grade with MMC-RT was published. The recommended doses 3-4 AEs compared to what was expected from treatment with were 3 mg/kg and 400 mg/m2, respectively,29 considerably MMC-5FU-RT was observed. | 20457634, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.2722 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. 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 1014    FELIU et al. In the multivariable analysis looking for predictive fac- colorectal cancer. Yet they are different. Cetuximab is an immu- tors, none of the variables included was associated with DFS noglobulin G1 isotype mAb, which can elicit immune functions or OS. Although no association was found, to the authors' such as antibody-dependent cell-mediated cytotoxicity involv- knowledge, this is the first time that the association between ing natural killer cells, T-cell recruitment, and T-cell priming. skin rash and efficacy has been addressed in patients with There is evidence that this process can lead to immunosuppres- SCCAC. This result is not consistent with what has been sive feedback loops,39 and some have therefore suggested com- observed in patients with other solid tumors (i.e., colorectal bining checkpoint inhibitors with cetuximab or cobimetinib in adenocarcinoma), in whom skin rash severity is associated microsatellite stable colorectal cancer. Panitumumab, an IgG2 with improved efficacy of anti-EGFR agents.31 In the mul- isotype mAb, is not reported to exert these immune effects. tivariable analysis of CR (81% for the whole population), Therapies targeting PD-1/L1 have produced response no association with skin rash severity was observed either. rates of 15%-20% in patients with HPV associated cancers However, a remarkable result was found concerning the including cervical, anal or head and neck squamous cell car- HPV status. Improved efficacy was observed both in terms cinoma. Another potential target for these diseases is trans- of CFS and CR rate in patients with HPV-positive tumors. forming growth factor-β (TGF-β) as genome wide association Due to the design of the study, it is not possible to determine studies in HPV-positive cancers have shown TGF-β to be sig- whether this was a predictive or prognostic factor of panitu- nificantly overexpressed.40 mumab-MMC-5FU-RT efficacy. However, these results are The nonrandomized design is the main limitation of in line with those observed in patients with squamous cell this study as it can be associated with a selection bias. It is carcinoma of the oropharynx who have a better prognosis if worth mentioning that male sex and advanced stage have they are HPV-positive. In these cases, the possibility of ther- been shown to be poor prognostic markers for LRF and apeutic de-escalation has been suggested.32 The extrapola- OS.3,4 In our study, we included a percentage of men (46%) tion of this concept to patients with HPV-positive SCCAC is higher than those found in previous studies which are close still unknown and could only be confirmed in further larger to 25%-30%,7,19,24-26 and a higher percentage of patients with studies. However, two recent randomized trials have studied positives nodes (67%) and with stage IIIB (47%) than those this strategy in HPV-positive patients with oropharyngeal found in previous studies which are close to 30%-35%.4,5 cancer, concluding that, besides cetuximab resulting in lesser Therefore, our population may be biased toward poor progno- toxicities when administered with RT compared with cispla- sis. However, the phase II design was mandatory as this study tin + RT, it was found to be inferior in OS.33,34 These results is the first conducted and reported, assessing the efficacy and suggest that de-escalation strategy should be carefully used in toxicity of panitumumab associated with MMC-5FU-based clinical practice, and also that anti-EGFR antibodies may not chemoradiation in patients with SCCAC. be the optimal therapies for this strategy. It is necessary to continue investigating with new RT The reason behind the lack of incremental efficacy when techniques and new pharmacological strategies such as im- anti-EGFR is added to chemo-radiotherapy in SCCAC pa- munotherapy with anti-PD-1 mAbs,41 therapeutic vaccines tients remains unknown. Classically, the RAS and EGFR targeting the E6 and E7 oncoproteins,42 PIK3CA mutant mutations have been appointed as factors of resistance to an- targeted therapies (present in 15%-20% SCCAC tumors), or ti-EFGR therapies, but in our study no patient presented with drugs targeting TGF-β.40 these mutations. It could be the case that EGFR downstream mutations (ie, activating in PIK3CA, inactivating in PTEN) might mediate 5 | CONCLUSIONS resistance to EGFR-targeted therapies, being more frequent in HPV-positive oropharyngeal carcinoma.35 Actually, some The addition of panitumumab to the standard chemoradiation retrospective studies in head and neck tumors suggest that regimen with MMC-5FU in patients with SCCAC did not anti-EGFR treatments might be more efficacious in VPH- result in improved outcomes. negative tumors.36 Additionally, it has been described that FBXW7 mutations are associated with anti-EGFR resis- ORCID tance.37 Finally, it is noteworthy that, besides initial studies Jaime Feliu https://orcid.org/0000-0003-4867-1420 suggest an 80%-90% EGFR overexpression rate in SCCAC Jaume Capdevila https://orcid. tumors,16,17 a recent meta-analysis suggests that this may org/0000-0001-8017-9941 occur in only 60%, which may be associated with a lower sensitivity to anti-EGFR therapies.38 DATA AVAILABILIT Y STATEMENT The two monoclonal antibodies (mAb) cetuximab and pa- The data that support the findings of this study are available nitumumab are often considered equally effective and their se- on request from the corresponding author. The data are not lection for clinical use is often a matter of personal choice in publicly available due to privacy or ethical restrictions. | 20457634, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.2722 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. 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 FELIU et al.    1015 R E F E R E NC E S 18. Dent P, Reardon DB, Park JS, et al. Radiation-induced release of 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer transforming growth factor alpha activates the epidermal growth J Clin. 2018;68(1):7-30. factor receptor and mitogen-activated protein kinase pathway in car- 2. 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SUPPORTING INFORMATION Cisplatin and fluorouracil with or without panitumumab in patients Additional supporting information may be found online in with recurrent or metastatic squamous-cell carcinoma of the head the Supporting Information section. and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol. 2013;14:697-710. 37. Lupini L, Bassi C, Mlcochova J, et al. Prediction of response to How to cite this article: Feliu J, Garcia-Carbonero R, anti-EGFR antibody-based therapies by multigene sequencing in Capdevila J, et al. VITAL phase 2 study: Upfront colorectal cancer patients. BMC Cancer. 2015;15:808. 5-fluorouracil, mitomycin-C, panitumumab and 38. Parwaiz I, MacCabe TA, Thomas MG, Messenger DE. A system- radiotherapy treatment in nonmetastatic squamous cell atic review and meta-analysis of prognostic biomarkers in anal carcinomas of the anal canal (GEMCAD 09-02). Cancer squamous cell carcinoma treated with primary chemoradiotherapy. Clin Oncol (R Coll Radiol). 2019;31(12):e1-e13. Med. 2020;9:1008–1016. https​://doi.org/10.1002/ 39. Ferris RL, Lenz H-J, Trotta AM, et al. Rationale for combination of cam4.2722 therapeutic antibodies targeting tumor cells and immune checkpoint