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A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer abh
Lucely Cetina
ah
c
ah
ah
a
Sandra Avila , Jaime Coronel , Eduardo Charco , Rafael Bojalil bf
Blanca Bazán & Alfonso Dueñas-González a
a
c
, Tania Crombet , Roberto Jiménez-Lima , Sergio Zapata , Mayra Ramos , bdh
be
, Horacio Astudillo ,
gh
División de Investigación Clínica, Instituto Nacional de Cancerología, México.
b
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Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana Xochimilco, Ciudad de México. c
Centro de Inmunología Molecular, Habana, Cuba
d
Instituto Nacional de Cardiología Ignacio Chávez.
e
Hospital de Oncología, IMSS Siglo XXI.
f
Instituto Nacional de Enfermedades Respiratorias.
g
Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cancerología, México. h
On behalf of Tumor Study Group A.C. Mexico. Accepted author version posted online: 24 Mar 2015.
To cite this article: Lucely Cetina, Tania Crombet, Roberto Jiménez-Lima, Sergio Zapata, Mayra Ramos, Sandra Avila, Jaime Coronel, Eduardo Charco, Rafael Bojalil, Horacio Astudillo, Blanca Bazán & Alfonso Dueñas-González (2015): A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer, Cancer Biology & Therapy To link to this article: http://dx.doi.org/10.1080/15384047.2015.1026483
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A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer
Lucely Cetinaa,b,h, Tania Crombet c, Roberto Jiménez-Lima a,h, Sergio Zapataa, Mayra Ramosc, Sandra Avilaa,h, Jaime Coronela,h, Eduardo Charcoa, Rafael Bojalilb,d,h, Horacio Astudillob,e, Blanca Bazánb,f, Alfonso Dueñas-Gonzálezg,h.
A. División de Investigación Clínica, Instituto Nacional de Cancerología, México. B. Doctorado en
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Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana -Xochimilco, Ciudad de México. C. Centro de Inmunología Molecular, Habana, Cuba. D. Instituto Nacional de Cardiología Ignacio Chávez. E. Hospital de Oncología, IMSS Siglo XXI F. Instituto Nacional de Enfermedades Respiratorias. G. Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cancerología, México. H. On behalf of Tumor Study Group A.C. Mexico.
RUNNING TITLE: Nimotuzumab in cervical cancer
Correspondence: Dr. Alfonso Dueñas-Gonzalez San Fernando 22, Tlalpan 14080 Mexico City. Mexico e-mail: [email protected]
1
ABSTRACT. Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that has been evaluated in solid tumors as a single agent or in combination with chemotherapy and radiation. Cervical cancer patients who are refractory or progressive to first-line chemotherapy have a dismal prognosis, and no second- or third-line chemotherapy is considered standard. This study aimed to evaluate the efficacy and safety of nimotuzumab. This pilot trial aimed to evaluate the efficacy and safety of nimotuzumab in 17 patients with pre-treated advanced refractory or progressive cervical cancer. Nimotuzumab was administered weekly at 200 mg/m2 as single agent for 4 weeks (induction phase), then concurrent with six 21-day cycles of gemcitabine (800 mg/m2)
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or cisplatin (50mg/m2) for 18 weeks (concurrent phase) and then once every two weeks (maintenance phase). Nimotuzumab could be continued beyond disease progression. Seventeen patients were accrued and evaluated for safety and efficacy. The median number of nimotuzumab applications was 20 (5-96). The median number of chemotherapy cycles administered was 6 (1-6). No toxicity occurred during induction and maintenance phases (single agent nimotuzumab). In the concurrent phase, grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. No complete or partial responses were observed. The stable disease (SD) rate was 35%. The median PFS and OS rates were163 days (95% CI, 104 to 222), and 299 days (95% IC, 177 to 421) respectively. Nimotuzumab is well tolerated and may have a role in the treatment of advanced cervical cancer.
KEY WORDS. Nimotuzumab, monoclonal antibody, EGFR, advanced cervical cancer, pilot study.
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INTRODUCTION. Cervical cancer is the fourth most commonly diagnosed cancer worldwide and the fourth leading cause of cancer death in females, accounting for 9% (528,000) of total new cancer cases and 7.5% (266,000) of total cancer deaths among females in 2008.1 Most patients with very early disease IA and non-bulky IB-IIA1 have recurrence rates below 10%,2,3 however, in locally advanced disease, at least a third of patients have treatment failure either local, or systemic even with the most effective platinum-based doublet chemotherapy with concurrent radiation.4,5 Only a small subset of patients who relapse can be cured with either surgery or radiation, 6,7, however, most are not, hence, systemic
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palliative chemotherapy remains as the sole option for them and for IVB patients.
Currently, cisplatin doublets with paclitaxel, vinorelbine, gemcitabine or topotecan are considered the standard of care, yielding similar response rates, progression-free (PFS), overall survival (OS) rates and quality-of-life outcomes.8,9 Recently, the results of adding bevacizumab to chemotherapy (either a cisplatin-doublet or a non-cisplatin doublet) were reported (GOG-240). At a median follow-up time of 20.8 months, there was a statistically significant difference in favor of the bevacizumab containing arm with a median OS of 13.3 versus 17 months (HR=0.71, 95% CI 0.540.94) p=0.0035, and PFS of 5.9 versus 8.2 months with a (HR=0-67, 95% CI 0.54-0.82) p=0.0002. 10
Nevertheless, these results were not reproduced in a phase II study in which bevacizumab was
added to the cisplatin-topotecan doublet.11 Treatment resulted in excessive toxicity and median survival of 13.4 months, which was similar to the control arm in the GOG-240 study. Whether these poor results were due to the regimen of cisplatin topotecan or due to other reasons originated from differences in study population are unknown, nevertheless these results suggest that additional studies are needed before bevacizumab can be accepted as the standard of care.
Experimental data suggest that the EGFR (Epidermal Growth Factor Receptor) can be a target in cervical cancer as its overexpression ranges from 6% to 90%, and it has been associated with poor 3
prognosis in some studies.12 Despite the exact biological meaning of overexpression of EGFR receptor in cervical cancer is not clearly understood, a number of clinical studies have evaluated its blocking with either inhibitors of the EGFR tyrosine kinase or anti-EGFR monoclonal antibodies. 13 Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that competitively binds to the receptor preventing further ligand binding and EGFR activation.14 Receptor blockade induces an antagonistic effect on tumor cell proliferation, chemosensitation and radiosensitation, in addition, tumor cells decrease their capacity to secrete proangiogenic factors, such as vascular endothelial growth factor, decreasing blood vessel formation and increasing apoptotic cell death in human tumor xenografts that overexpress EGFR.15-17 Nimotuzumab has been
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evaluated in a number of solid tumors as a single agent or in combination with chemotherapy and radiation and its use approved in some countries against glioblastoma, and head & neck cancer.18 In most phase II and randomized studies, nimotuzumab has been administered concurrent with radiation, chemotherapy or chemoradiation followed by maintenance as single agent even beyond progression19 but no results have been published in cervical cancer.
This pilot study was aimed to evaluate the safety and efficacy of nimotuzumab in patients with advanced refractory or progressive cervical cancer. Because patients were pretreated, we decided to use a schedule were initially, four weekly applications of nimotuzumab were administered to assess its tolerability, to then continue nimotuzumab plus single agent chemotherapy for 18 weeks to capitalize on its demonstrated chemosensitation effect17 and then, once every two weeks nimotuzumab, has it has been hypothesized that the prolonged use of nimotuzumab, even beyond progressive disease might be needed to exert its maximal clinical effect, since maintaining a prolonged blockade on the EGFR signaling would be crucial for EGFR-positive cancer cells throughout all the natural history of disease.19
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RESULTS. Patients From July 2008 to January 2012, a total of 17 patients were enrolled. The main clinicopathological characteristics are shown in Table 1. The median age was 52 years (range 28-75), most were squamous cell carcinomas and had an ECOG performance status of 1. Most patients had two or more metastatic sites (47% and 12%) respectively which included supraclavicular and retroperitoneal lymph nodes, lung, liver, brain and bone. All patients had recurrent or persistent disease. Primary treatment comprised concurrent chemoradiation in all but three patients (1 weekly carboplatin, 8 weekly cisplatin and 5 weekly cisplatin-gemcitabine). Two were treated with radical
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hysterectomy and adjuvant radiation (1) or adjuvant carboplatin chemoradiation (1) while 1 patient received neoadjuvant chemotherapy followed by surgery. Ten (59%) patients were refractory or progressed to first-line chemotherapy, four (23%) to second-line, two (12%) to third-line and one (6%) to the fifth-line of treatment. In addition, five (29.4%) of 17 patients also had received concurrent palliative chemoradiation (three with weekly gemcitabine and two with weekly cisplatin), and one patient resection of brain metastases followed by cranial irradiation.
Tolerability All patients were evaluable for safety. The median number of nimotuzumab applications was 20 (596). Most (14 patients) received gemcitabine and 3 received cisplatin. The median number of chemotherapy cycles administered were 6 (1-6). Nimotuzumab was well-tolerated. No toxicity occurred during the induction phase (4 weekly applications of nimotuzumab). The most common toxicity to chemotherapy plus nimotuzumab (concurrent phase) was myelosuppression and gastrointestinal however, no grade 4 events were registered. The grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. In no case treatment with G-CSF was used. (Table 2). No toxicity was observed in the maintenance phase, despite some patients had residual myelosuppression (in no case higher than grade 2) 5
after the concurrent phase. Of note, grade 1 rash was only observed in 5.8% of patients in the whole study.
Efficacy Efficacy was evaluated in all patients. Three had early clinical deterioration and abandoned protocol before assessment, hence were registered as progressive disease (PD). One additional patient had documented PD during induction treatment. Among the 13 patients that underwent evaluation after the third cycle of chemotherapy plus weekly nimotuzumab, there were 7 PD and 6 stable disease (SD) -they met neither PR nor PD-. Overall, in the intention-to-treat population, the SD rate was
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35% (6 patients) and 11 (65%) PD, there were not partial or complete responses. Of note, 3 (17.6%) having PD continued nimotuzumab (the three completed the 6 cycles of nimotuzumab and chemotherapy, and one of these patients continued nimotuzumab alone for one additional month. At the time of the trial closure (December 2013) there were two (11.7%) patients receiving nimotuzumab because of continued disease stabilization. The median PFS and OS rates were 163 days (95% CI, 104 - 222), and 299 days (95% CI, 177 - 421) respectively. (Figure 1).
DISCUSSION. The results of this study demonstrate that nimotuzumab in the schedule tested (induction for 4 weeks, concurrent with chemotherapy for 18 weeks and maintenance until unacceptable toxicity or consent withdrawal in a pre-treated recurrent or persistent cervical cancer patients, is well tolerated and yields disease stabilization in 35% of the patients. This effect translates into PFS and OS rates of 163 and 299 days respectively.
Best palliative care remains as the standard treatment for patients with metastatic, persistent or recurrent disease who show progressive disease to first-line of systemic chemotherapy as no randomized phase III studies have evaluated any second-line treatment (after systemic first-line 6
treatment) against it. There are a number of phase II studies with cytotoxics as second-line therapy but results are difficult to interpret due to the high variability in the population treated, nevertheless, agents such as nab-paclitaxel, pemetrexed and liposomal doxorubicin show encouraging responses from 11 to 28.6 % but median survival rates do not exceed 10 months. 20-22
In this setting, several molecular-targeted agents have been tested, including sunitinib, imatinib and temsirolimus but no evidence of response neither suggestion of increased stabilization of disease were observed.23-25 Lack of activity in advanced disease as monotherapy has also being reported for the small molecule inhibitors of the EGFR erlotinib and gefitinib.26,27 The finding on this study that
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nimotuzumab seems to increase stabilization of disease merits further study, nevertheless, our results should be taken with caution because the design of this study which included administration of chemotherapy for six cycles concurrent with weekly nimotuzumab does not allow us to conclude on the activity of nimotuzumab as single agent. In addition, the paucity of studies with either targeted therapy of cytotoxic chemotherapy in third or more lines of palliative treatment makes difficult to establish valid comparisons, thus, our results can only be considered as hypothesisgenerating.
Nimotuzumab has demonstrated efficacy characterized by the induction of a long-term stable disease with a very low toxicity profile in patients with head and neck squamous cell carcinoma, 28 30
pancreatic cancer, 31 non-small cell lung cancer 32 and glioblastoma.33-35 No studies with
nimotuzumab have been reported in cervical cancer; however, currently nimotuzumab is being studied in different treatment settings of cervical cancer. Among other monoclonal antibodies against the EGFR, only cetuximab has been evaluated in cervical cancer. A small retrospective study of 5 patients with cetuximab monotherapy as a third-to-fifth-line of chemotherapy, reported only one patient with stable disease (20%)36 whereas in a second study, among 31 evaluable
7
patients, no clinical responses were registered and the median PFS and OS times were 1.97 and 6.7 months, respectively.37
We found a low rate of grade 3 and no grade 4 toxicity of nimotuzumab plus chemotherapy and no toxicity with nimotuzumab alone either in the induction or maintenance phases. The skin toxicity of grade 1 in less than 6% of patients was expected as while other anti-EGFR agents are associated with significant skin toxicity -38% of which are grade 3 or 4 reactions- these side effects are rare in cases of nimotuzumab use, and are mostly limited to grade 1 or 2 adverse events.38
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The different toxicity profile could be related to the fact that nimotuzumab is an intermediateaffinity antibody and would have a higher ratio of accumulation in tumors (showing higher EGFR expression levels) than normal tissues, as compared to high-affinity antibodies like cetuximab. 39 According with this statement, two recent reports40,41 show that binding of nimotuzumab and subsequent inhibition of EGFR phosphorylation are detected only in tumor cell lines with medium or high levels of EGFR expression (104 receptors per cell or higher). Furthermore, binding of nimotuzumab Fab fragments was detected only for A431 cells that have the highest EGFR expression level, whereas cetuximab Fab fragments bound also to tumor cells with lower EGFR expression levels.41,34 Thus, these results support that nimotuzumab requires bivalent attachment for binding to tumor cells having a surface density of EGFR molecules above certain threshold. All together, the existing data on nimotuzumab mechanism of action and efficacy in other tumors suggest that it may indeed lead to disease stabilization, nevertheless the limited sample size and the use of chemotherapy make difficult to conclude on this effect upon the course of disease, which also could had resulted just from random. In addition to these study limitations, no expression levels of EGFR were determined in tumors to correlate expression level with clinical outcomes.
In summary, our results suggest that nimotuzumab could have a role in the treatment of advanced 8
cervical cancer and further studies should be done. In this line, currently, a placebo-controlled randomized phase III trial (NCT02083211) is ongoing comparing nimotuzumab against placebo in patients receiving cisplatin vinorelbine as first-line therapy for recurrent and persistent disease.
PATIENTS AND METHODS. Patients This was a pilot conducted at the National Cancer Institute in Mexico. Patients were eligible for the study if they fulfilled the following inclusion criteria: histologically confirmed diagnosis of persistent or recurrent carcinoma of the cervix. In addition, patients had to be not amenable to
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curative surgery, radiation, or both locoregional modalities of treatment. All patients had measurable disease and were required to have an Eastern Cooperative Oncology Group (ECOG) scores 0 to 2, and at least 1 prior systemic chemotherapy regimen for metastatic, persistent or recurrent disease administered at least 3 weeks before starting protocol therapy. Additional eligibility requirements included: absolute neutrophil count ≥1.5 109/L, platelets count ≥100.109/L, total bilirubin, AST and ALT ≤ 1.5 X upper limit of normal, and calculated creatinine clearance (Cockroft) ≥ 50 ml/min. Exclusion criteria included uncontrolled systemic disease or infection, pregnancy or breastfeeding, and previous or concurrent malignancy other than adequately treated non-melanoma skin cancer.
Treatment Treatment protocol consisted on four weekly applications of single agent nimotuzumab administered by intravenous infusion for 30 min. at a dose of 200 mg/m2 (induction) followed by 18 weekly applications of nimotuzumab concurrently with six 21-day cycles of single agent chemotherapy (concurrent). After week 18 (22 weeks since treatment initiation), patients continued with nimotuzumab alone (maintenance) once every two weeks at the same dose until unacceptable toxicity or consent withdrawal. Nimotuzumab could be continued beyond disease 9
progression if the researcher considered patient could benefit from continuing the study drug. No premedication including rash prophylaxis was administered before nimotuzumab infusion. Single agent chemotherapy comprised gemcitabine at 800mg/m2 administered by intravenous infusion for 30 min, or cisplatin at 50mg/m2 administered intravenously in an out-patient setting as follows: 1000 ml of normal saline for 1 h followed by cisplatin diluted in 500 ml of normal saline containing 62.5 ml of 20% mannitol for 1 h, followed by 500 ml of normal saline for 30 min. Antiemetic prophylaxis comprised intravenous ondansetron. No prophylactic G-CSF was allowed.
Dose modification
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Gemcitabine or cisplatin dose had to be reduced 25% for the subsequent cycle in the case of grade 4 neutropenia lasting for ≥7 days, febrile neutropenia, any infection requiring hospitalization and/or antibiotics, grade 4 thrombocytopenia or bleeding requiring platelet transfusion. In case of inadequate blood cell count at day 21, the next cycle had to be delayed until blood count recovery. Nimotuzumab had to be interrupted for up to 2 weeks in the case of any grade ≥3 toxicity. Patients were to be rechallenged with the same dose if toxicity resolved < or equal to grade 2. In case of subsequent grade ≥3 toxicity, nimotuzumab administration was delayed for 2 weeks in induction treatment and for 3 weeks in maintenance treatment and there was not dose reduction.
Pretreatment assessment, response and toxicity evaluations Baseline workup included a complete history and physical examination, complete blood cell count, blood chemistry, and imaging by computed tomography or magnetic resonance imaging (MRI) of target lesions (4 weeks before starting the study). Tumor response was assessed after the first four weekly applications of nimotuzumab, then every 3 cycles according to the RECIST criteria (1.1) by the same imaging modality used for baseline evaluation. Adverse events were recorded according to CTCAE v3.0 at each visit before treatment administration. Follow-up assessments were made 4 weeks after the last dose of study medication and every 3 months thereafter. 10
Disclosure of Potential Conflicts of Interest The study protocol was approved by the Institutional Ethics Committee and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent before entry onto the study. ClinicalTrials.gov Identifier: NCT02095119. Authors state that they have no conflicts of interest.
ACKNOWLEDGEMENTS.
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Study drugs were provided by Laboratorios PiSA S.A. de C.V. México.
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32. Boland W, Bebb G. The emerging role of nimotuzumab in the treatment of non-small cell lung cancer. Biologics 2010; 4:289-98. 33. Massimino M, Bode U, Biassoni V, Fleischhack G. Nimotuzumab for pediatric diffuse intrinsic pontine gliomas. Expert Opin Biol Ther 2011; 11:247-56. 34. Ramos TC, Figueredo J, Catala M, González S, Selva JC, Cruz TM, Toledo C, Silva S, Pestano Y, Ramos M, et al. Treatment of high-grade glioma patients with the humanized anti-epidermal growth factor receptor (EGFR) antibody h-R3: Report from a phase I/II trial. Cancer Biol Ther 2006; 5:375-9. 35. Cabanas R, Saurez G, Alert J, Reyes A, Valdes J, Gonzalez MC, Pedrayes JL, Valle L, Infante
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M, Avila M, et al. Prolonged use of nimotuzumab in children with central nervous system tumors: safety and feasibility. Cancer Biother Radiopharm 2014; 29:173-8. 36. Hertlein L, Lenhard M, Kirschenhofer A, Kahlert S, Mayr D, Burges A, Friese K. Cetuximab monotherapy in advanced cervical cancer: a retrospective study with five patients. Arch Gynecol Obstet 2011; 283:109-13.
37. Santin AD, Sill MW, McMeekin DS, Leitao MM Jr, Brown J, Sutton GP, Van Le L, Griffin P, Boardman CH. Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 2011; 122:495-500. 38. Bebb G, Boland W, Melosky B. Dont´t jump to rash conclusions. Cancer Biol Ther 2011;11:639-41. 39. Crombet T, Osorio M, Cruz T, Roca C, del Castillo R, Mon R, Iznaga-Escobar N, Figueredo R, Koropatnick J, Renginfo E, et al. Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. J Clin Oncol 2004; 22:1646-54. 40. Akashi Y, Okamoto I, Iwasa T, Yoshida T, Suzuki M, Hatashita E, Yamada Y, Satoh T, 16
Fukuoka M, Ono K, et al. Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanized monoclonal antibody to the epidermal growth factor receptor, in nonsmall cell lung cancer cell lines of differing epidermal growth factor receptor status. Br J Cancer 2008; 98:749-55. 41. Garrido G, Tikhomirov IA, Rabasa A, Yang E, Gracia E, Iznaga N, Fernández LE, Crombet T, Kerbel RS, Pérez R. Bivalent binding by intermediate affinity of nimotuzumab: A contribution to
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explain antibody clinical profile. Cancer Biol Ther 2011; 11:373-82.
17
Table 1. Baseline characteristics of patients.
Table 1. Baseline characteristics of patients. Variable
Number (%)
Age, years Median (range)
52 (38-75)
ECOG 1
15 (88)
2
2 (12)
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Histology Squamous
10 (60)
Adenocarcinoma
5 (29)
Adenosquamous
2 ((11)
Metastatic sites 1
7 (41)
2
8 (47)
3
2 (12)
Previous systemic treatment lines 1
10 (59)
2
4 (23)
3
2 (12)
5
1 (5)
18
Table 2. Toxicity during nimotuzumab and chemotherapy (concurrent phase). Table 2. Toxicity during nimotuzumab and chemotherapy (concurrent phase).
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Toxicity N=17
Grade 1(%)
Grade 2 (%)
Grade 3 (%)
Grade 4 (%)
Leucopenia
29.4
23.5
11.7
0.0
Neutropenia
5.8
17.6
0.0
0.0
Anemia
23.5
23.5
5.8
0.0
Thrombocytopenia
23.5
0.0
0.0
0.0
Febrile neutropenia
5.8
0.0
0.0
0.0
Diarrhea
5.8
23.5
11.7
0.0
Nausea
5.8
41
0.0
0.0
Vomiting
5.8
52
0.0
0.0
Fatigue
0.0
82
0.9
0.0
Rash
5.8
0.0
0.0
0.0
Abdominal pain/cramping
17
5.8
0.0
0.0
Anorexia
5.8
0.0
0.0
0.0
Proctitis
0.0
0.0
0.0
0.0
AST
0.0
0.0
0.0
0.0
ALT
0.0
0.0
0.0
0.0
Creatinine
0.4
0.0
0.0
0.0
Percentages are rounded to 100% adding grade 0 toxicity.
19
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Figure 1. The median PFS and OS rates were 163 days (95% CI, 104 - 222), and 299 days (95% CI, 177- 421).
20
Cancer Biology & Therapy Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kcbt20
A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer abh
Lucely Cetina
ah
c
ah
ah
a
Sandra Avila , Jaime Coronel , Eduardo Charco , Rafael Bojalil bf
Blanca Bazán & Alfonso Dueñas-González a
a
c
, Tania Crombet , Roberto Jiménez-Lima , Sergio Zapata , Mayra Ramos , bdh
be
, Horacio Astudillo ,
gh
División de Investigación Clínica, Instituto Nacional de Cancerología, México.
b
Click for updates
Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana Xochimilco, Ciudad de México. c
Centro de Inmunología Molecular, Habana, Cuba
d
Instituto Nacional de Cardiología Ignacio Chávez.
e
Hospital de Oncología, IMSS Siglo XXI.
f
Instituto Nacional de Enfermedades Respiratorias.
g
Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cancerología, México. h
On behalf of Tumor Study Group A.C. Mexico. Accepted author version posted online: 24 Mar 2015.
To cite this article: Lucely Cetina, Tania Crombet, Roberto Jiménez-Lima, Sergio Zapata, Mayra Ramos, Sandra Avila, Jaime Coronel, Eduardo Charco, Rafael Bojalil, Horacio Astudillo, Blanca Bazán & Alfonso Dueñas-González (2015): A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer, Cancer Biology & Therapy To link to this article: http://dx.doi.org/10.1080/15384047.2015.1026483
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A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer
Lucely Cetinaa,b,h, Tania Crombet c, Roberto Jiménez-Lima a,h, Sergio Zapataa, Mayra Ramosc, Sandra Avilaa,h, Jaime Coronela,h, Eduardo Charcoa, Rafael Bojalilb,d,h, Horacio Astudillob,e, Blanca Bazánb,f, Alfonso Dueñas-Gonzálezg,h.
A. División de Investigación Clínica, Instituto Nacional de Cancerología, México. B. Doctorado en
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Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana -Xochimilco, Ciudad de México. C. Centro de Inmunología Molecular, Habana, Cuba. D. Instituto Nacional de Cardiología Ignacio Chávez. E. Hospital de Oncología, IMSS Siglo XXI F. Instituto Nacional de Enfermedades Respiratorias. G. Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cancerología, México. H. On behalf of Tumor Study Group A.C. Mexico.
RUNNING TITLE: Nimotuzumab in cervical cancer
Correspondence: Dr. Alfonso Dueñas-Gonzalez San Fernando 22, Tlalpan 14080 Mexico City. Mexico e-mail: [email protected]
1
ABSTRACT. Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that has been evaluated in solid tumors as a single agent or in combination with chemotherapy and radiation. Cervical cancer patients who are refractory or progressive to first-line chemotherapy have a dismal prognosis, and no second- or third-line chemotherapy is considered standard. This study aimed to evaluate the efficacy and safety of nimotuzumab. This pilot trial aimed to evaluate the efficacy and safety of nimotuzumab in 17 patients with pre-treated advanced refractory or progressive cervical cancer. Nimotuzumab was administered weekly at 200 mg/m2 as single agent for 4 weeks (induction phase), then concurrent with six 21-day cycles of gemcitabine (800 mg/m2)
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or cisplatin (50mg/m2) for 18 weeks (concurrent phase) and then once every two weeks (maintenance phase). Nimotuzumab could be continued beyond disease progression. Seventeen patients were accrued and evaluated for safety and efficacy. The median number of nimotuzumab applications was 20 (5-96). The median number of chemotherapy cycles administered was 6 (1-6). No toxicity occurred during induction and maintenance phases (single agent nimotuzumab). In the concurrent phase, grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. No complete or partial responses were observed. The stable disease (SD) rate was 35%. The median PFS and OS rates were163 days (95% CI, 104 to 222), and 299 days (95% IC, 177 to 421) respectively. Nimotuzumab is well tolerated and may have a role in the treatment of advanced cervical cancer.
KEY WORDS. Nimotuzumab, monoclonal antibody, EGFR, advanced cervical cancer, pilot study.
2
INTRODUCTION. Cervical cancer is the fourth most commonly diagnosed cancer worldwide and the fourth leading cause of cancer death in females, accounting for 9% (528,000) of total new cancer cases and 7.5% (266,000) of total cancer deaths among females in 2008.1 Most patients with very early disease IA and non-bulky IB-IIA1 have recurrence rates below 10%,2,3 however, in locally advanced disease, at least a third of patients have treatment failure either local, or systemic even with the most effective platinum-based doublet chemotherapy with concurrent radiation.4,5 Only a small subset of patients who relapse can be cured with either surgery or radiation, 6,7, however, most are not, hence, systemic
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palliative chemotherapy remains as the sole option for them and for IVB patients.
Currently, cisplatin doublets with paclitaxel, vinorelbine, gemcitabine or topotecan are considered the standard of care, yielding similar response rates, progression-free (PFS), overall survival (OS) rates and quality-of-life outcomes.8,9 Recently, the results of adding bevacizumab to chemotherapy (either a cisplatin-doublet or a non-cisplatin doublet) were reported (GOG-240). At a median follow-up time of 20.8 months, there was a statistically significant difference in favor of the bevacizumab containing arm with a median OS of 13.3 versus 17 months (HR=0.71, 95% CI 0.540.94) p=0.0035, and PFS of 5.9 versus 8.2 months with a (HR=0-67, 95% CI 0.54-0.82) p=0.0002. 10
Nevertheless, these results were not reproduced in a phase II study in which bevacizumab was
added to the cisplatin-topotecan doublet.11 Treatment resulted in excessive toxicity and median survival of 13.4 months, which was similar to the control arm in the GOG-240 study. Whether these poor results were due to the regimen of cisplatin topotecan or due to other reasons originated from differences in study population are unknown, nevertheless these results suggest that additional studies are needed before bevacizumab can be accepted as the standard of care.
Experimental data suggest that the EGFR (Epidermal Growth Factor Receptor) can be a target in cervical cancer as its overexpression ranges from 6% to 90%, and it has been associated with poor 3
prognosis in some studies.12 Despite the exact biological meaning of overexpression of EGFR receptor in cervical cancer is not clearly understood, a number of clinical studies have evaluated its blocking with either inhibitors of the EGFR tyrosine kinase or anti-EGFR monoclonal antibodies. 13 Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that competitively binds to the receptor preventing further ligand binding and EGFR activation.14 Receptor blockade induces an antagonistic effect on tumor cell proliferation, chemosensitation and radiosensitation, in addition, tumor cells decrease their capacity to secrete proangiogenic factors, such as vascular endothelial growth factor, decreasing blood vessel formation and increasing apoptotic cell death in human tumor xenografts that overexpress EGFR.15-17 Nimotuzumab has been
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evaluated in a number of solid tumors as a single agent or in combination with chemotherapy and radiation and its use approved in some countries against glioblastoma, and head & neck cancer.18 In most phase II and randomized studies, nimotuzumab has been administered concurrent with radiation, chemotherapy or chemoradiation followed by maintenance as single agent even beyond progression19 but no results have been published in cervical cancer.
This pilot study was aimed to evaluate the safety and efficacy of nimotuzumab in patients with advanced refractory or progressive cervical cancer. Because patients were pretreated, we decided to use a schedule were initially, four weekly applications of nimotuzumab were administered to assess its tolerability, to then continue nimotuzumab plus single agent chemotherapy for 18 weeks to capitalize on its demonstrated chemosensitation effect17 and then, once every two weeks nimotuzumab, has it has been hypothesized that the prolonged use of nimotuzumab, even beyond progressive disease might be needed to exert its maximal clinical effect, since maintaining a prolonged blockade on the EGFR signaling would be crucial for EGFR-positive cancer cells throughout all the natural history of disease.19
4
RESULTS. Patients From July 2008 to January 2012, a total of 17 patients were enrolled. The main clinicopathological characteristics are shown in Table 1. The median age was 52 years (range 28-75), most were squamous cell carcinomas and had an ECOG performance status of 1. Most patients had two or more metastatic sites (47% and 12%) respectively which included supraclavicular and retroperitoneal lymph nodes, lung, liver, brain and bone. All patients had recurrent or persistent disease. Primary treatment comprised concurrent chemoradiation in all but three patients (1 weekly carboplatin, 8 weekly cisplatin and 5 weekly cisplatin-gemcitabine). Two were treated with radical
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hysterectomy and adjuvant radiation (1) or adjuvant carboplatin chemoradiation (1) while 1 patient received neoadjuvant chemotherapy followed by surgery. Ten (59%) patients were refractory or progressed to first-line chemotherapy, four (23%) to second-line, two (12%) to third-line and one (6%) to the fifth-line of treatment. In addition, five (29.4%) of 17 patients also had received concurrent palliative chemoradiation (three with weekly gemcitabine and two with weekly cisplatin), and one patient resection of brain metastases followed by cranial irradiation.
Tolerability All patients were evaluable for safety. The median number of nimotuzumab applications was 20 (596). Most (14 patients) received gemcitabine and 3 received cisplatin. The median number of chemotherapy cycles administered were 6 (1-6). Nimotuzumab was well-tolerated. No toxicity occurred during the induction phase (4 weekly applications of nimotuzumab). The most common toxicity to chemotherapy plus nimotuzumab (concurrent phase) was myelosuppression and gastrointestinal however, no grade 4 events were registered. The grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. In no case treatment with G-CSF was used. (Table 2). No toxicity was observed in the maintenance phase, despite some patients had residual myelosuppression (in no case higher than grade 2) 5
after the concurrent phase. Of note, grade 1 rash was only observed in 5.8% of patients in the whole study.
Efficacy Efficacy was evaluated in all patients. Three had early clinical deterioration and abandoned protocol before assessment, hence were registered as progressive disease (PD). One additional patient had documented PD during induction treatment. Among the 13 patients that underwent evaluation after the third cycle of chemotherapy plus weekly nimotuzumab, there were 7 PD and 6 stable disease (SD) -they met neither PR nor PD-. Overall, in the intention-to-treat population, the SD rate was
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35% (6 patients) and 11 (65%) PD, there were not partial or complete responses. Of note, 3 (17.6%) having PD continued nimotuzumab (the three completed the 6 cycles of nimotuzumab and chemotherapy, and one of these patients continued nimotuzumab alone for one additional month. At the time of the trial closure (December 2013) there were two (11.7%) patients receiving nimotuzumab because of continued disease stabilization. The median PFS and OS rates were 163 days (95% CI, 104 - 222), and 299 days (95% CI, 177 - 421) respectively. (Figure 1).
DISCUSSION. The results of this study demonstrate that nimotuzumab in the schedule tested (induction for 4 weeks, concurrent with chemotherapy for 18 weeks and maintenance until unacceptable toxicity or consent withdrawal in a pre-treated recurrent or persistent cervical cancer patients, is well tolerated and yields disease stabilization in 35% of the patients. This effect translates into PFS and OS rates of 163 and 299 days respectively.
Best palliative care remains as the standard treatment for patients with metastatic, persistent or recurrent disease who show progressive disease to first-line of systemic chemotherapy as no randomized phase III studies have evaluated any second-line treatment (after systemic first-line 6
treatment) against it. There are a number of phase II studies with cytotoxics as second-line therapy but results are difficult to interpret due to the high variability in the population treated, nevertheless, agents such as nab-paclitaxel, pemetrexed and liposomal doxorubicin show encouraging responses from 11 to 28.6 % but median survival rates do not exceed 10 months. 20-22
In this setting, several molecular-targeted agents have been tested, including sunitinib, imatinib and temsirolimus but no evidence of response neither suggestion of increased stabilization of disease were observed.23-25 Lack of activity in advanced disease as monotherapy has also being reported for the small molecule inhibitors of the EGFR erlotinib and gefitinib.26,27 The finding on this study that
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nimotuzumab seems to increase stabilization of disease merits further study, nevertheless, our results should be taken with caution because the design of this study which included administration of chemotherapy for six cycles concurrent with weekly nimotuzumab does not allow us to conclude on the activity of nimotuzumab as single agent. In addition, the paucity of studies with either targeted therapy of cytotoxic chemotherapy in third or more lines of palliative treatment makes difficult to establish valid comparisons, thus, our results can only be considered as hypothesisgenerating.
Nimotuzumab has demonstrated efficacy characterized by the induction of a long-term stable disease with a very low toxicity profile in patients with head and neck squamous cell carcinoma, 28 30
pancreatic cancer, 31 non-small cell lung cancer 32 and glioblastoma.33-35 No studies with
nimotuzumab have been reported in cervical cancer; however, currently nimotuzumab is being studied in different treatment settings of cervical cancer. Among other monoclonal antibodies against the EGFR, only cetuximab has been evaluated in cervical cancer. A small retrospective study of 5 patients with cetuximab monotherapy as a third-to-fifth-line of chemotherapy, reported only one patient with stable disease (20%)36 whereas in a second study, among 31 evaluable
7
patients, no clinical responses were registered and the median PFS and OS times were 1.97 and 6.7 months, respectively.37
We found a low rate of grade 3 and no grade 4 toxicity of nimotuzumab plus chemotherapy and no toxicity with nimotuzumab alone either in the induction or maintenance phases. The skin toxicity of grade 1 in less than 6% of patients was expected as while other anti-EGFR agents are associated with significant skin toxicity -38% of which are grade 3 or 4 reactions- these side effects are rare in cases of nimotuzumab use, and are mostly limited to grade 1 or 2 adverse events.38
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The different toxicity profile could be related to the fact that nimotuzumab is an intermediateaffinity antibody and would have a higher ratio of accumulation in tumors (showing higher EGFR expression levels) than normal tissues, as compared to high-affinity antibodies like cetuximab. 39 According with this statement, two recent reports40,41 show that binding of nimotuzumab and subsequent inhibition of EGFR phosphorylation are detected only in tumor cell lines with medium or high levels of EGFR expression (104 receptors per cell or higher). Furthermore, binding of nimotuzumab Fab fragments was detected only for A431 cells that have the highest EGFR expression level, whereas cetuximab Fab fragments bound also to tumor cells with lower EGFR expression levels.41,34 Thus, these results support that nimotuzumab requires bivalent attachment for binding to tumor cells having a surface density of EGFR molecules above certain threshold. All together, the existing data on nimotuzumab mechanism of action and efficacy in other tumors suggest that it may indeed lead to disease stabilization, nevertheless the limited sample size and the use of chemotherapy make difficult to conclude on this effect upon the course of disease, which also could had resulted just from random. In addition to these study limitations, no expression levels of EGFR were determined in tumors to correlate expression level with clinical outcomes.
In summary, our results suggest that nimotuzumab could have a role in the treatment of advanced 8
cervical cancer and further studies should be done. In this line, currently, a placebo-controlled randomized phase III trial (NCT02083211) is ongoing comparing nimotuzumab against placebo in patients receiving cisplatin vinorelbine as first-line therapy for recurrent and persistent disease.
PATIENTS AND METHODS. Patients This was a pilot conducted at the National Cancer Institute in Mexico. Patients were eligible for the study if they fulfilled the following inclusion criteria: histologically confirmed diagnosis of persistent or recurrent carcinoma of the cervix. In addition, patients had to be not amenable to
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curative surgery, radiation, or both locoregional modalities of treatment. All patients had measurable disease and were required to have an Eastern Cooperative Oncology Group (ECOG) scores 0 to 2, and at least 1 prior systemic chemotherapy regimen for metastatic, persistent or recurrent disease administered at least 3 weeks before starting protocol therapy. Additional eligibility requirements included: absolute neutrophil count ≥1.5 109/L, platelets count ≥100.109/L, total bilirubin, AST and ALT ≤ 1.5 X upper limit of normal, and calculated creatinine clearance (Cockroft) ≥ 50 ml/min. Exclusion criteria included uncontrolled systemic disease or infection, pregnancy or breastfeeding, and previous or concurrent malignancy other than adequately treated non-melanoma skin cancer.
Treatment Treatment protocol consisted on four weekly applications of single agent nimotuzumab administered by intravenous infusion for 30 min. at a dose of 200 mg/m2 (induction) followed by 18 weekly applications of nimotuzumab concurrently with six 21-day cycles of single agent chemotherapy (concurrent). After week 18 (22 weeks since treatment initiation), patients continued with nimotuzumab alone (maintenance) once every two weeks at the same dose until unacceptable toxicity or consent withdrawal. Nimotuzumab could be continued beyond disease 9
progression if the researcher considered patient could benefit from continuing the study drug. No premedication including rash prophylaxis was administered before nimotuzumab infusion. Single agent chemotherapy comprised gemcitabine at 800mg/m2 administered by intravenous infusion for 30 min, or cisplatin at 50mg/m2 administered intravenously in an out-patient setting as follows: 1000 ml of normal saline for 1 h followed by cisplatin diluted in 500 ml of normal saline containing 62.5 ml of 20% mannitol for 1 h, followed by 500 ml of normal saline for 30 min. Antiemetic prophylaxis comprised intravenous ondansetron. No prophylactic G-CSF was allowed.
Dose modification
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Gemcitabine or cisplatin dose had to be reduced 25% for the subsequent cycle in the case of grade 4 neutropenia lasting for ≥7 days, febrile neutropenia, any infection requiring hospitalization and/or antibiotics, grade 4 thrombocytopenia or bleeding requiring platelet transfusion. In case of inadequate blood cell count at day 21, the next cycle had to be delayed until blood count recovery. Nimotuzumab had to be interrupted for up to 2 weeks in the case of any grade ≥3 toxicity. Patients were to be rechallenged with the same dose if toxicity resolved < or equal to grade 2. In case of subsequent grade ≥3 toxicity, nimotuzumab administration was delayed for 2 weeks in induction treatment and for 3 weeks in maintenance treatment and there was not dose reduction.
Pretreatment assessment, response and toxicity evaluations Baseline workup included a complete history and physical examination, complete blood cell count, blood chemistry, and imaging by computed tomography or magnetic resonance imaging (MRI) of target lesions (4 weeks before starting the study). Tumor response was assessed after the first four weekly applications of nimotuzumab, then every 3 cycles according to the RECIST criteria (1.1) by the same imaging modality used for baseline evaluation. Adverse events were recorded according to CTCAE v3.0 at each visit before treatment administration. Follow-up assessments were made 4 weeks after the last dose of study medication and every 3 months thereafter. 10
Disclosure of Potential Conflicts of Interest The study protocol was approved by the Institutional Ethics Committee and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent before entry onto the study. ClinicalTrials.gov Identifier: NCT02095119. Authors state that they have no conflicts of interest.
ACKNOWLEDGEMENTS.
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Study drugs were provided by Laboratorios PiSA S.A. de C.V. México.
11
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Table 1. Baseline characteristics of patients.
Table 1. Baseline characteristics of patients. Variable
Number (%)
Age, years Median (range)
52 (38-75)
ECOG 1
15 (88)
2
2 (12)
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Histology Squamous
10 (60)
Adenocarcinoma
5 (29)
Adenosquamous
2 ((11)
Metastatic sites 1
7 (41)
2
8 (47)
3
2 (12)
Previous systemic treatment lines 1
10 (59)
2
4 (23)
3
2 (12)
5
1 (5)
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Table 2. Toxicity during nimotuzumab and chemotherapy (concurrent phase). Table 2. Toxicity during nimotuzumab and chemotherapy (concurrent phase).
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Toxicity N=17
Grade 1(%)
Grade 2 (%)
Grade 3 (%)
Grade 4 (%)
Leucopenia
29.4
23.5
11.7
0.0
Neutropenia
5.8
17.6
0.0
0.0
Anemia
23.5
23.5
5.8
0.0
Thrombocytopenia
23.5
0.0
0.0
0.0
Febrile neutropenia
5.8
0.0
0.0
0.0
Diarrhea
5.8
23.5
11.7
0.0
Nausea
5.8
41
0.0
0.0
Vomiting
5.8
52
0.0
0.0
Fatigue
0.0
82
0.9
0.0
Rash
5.8
0.0
0.0
0.0
Abdominal pain/cramping
17
5.8
0.0
0.0
Anorexia
5.8
0.0
0.0
0.0
Proctitis
0.0
0.0
0.0
0.0
AST
0.0
0.0
0.0
0.0
ALT
0.0
0.0
0.0
0.0
Creatinine
0.4
0.0
0.0
0.0
Percentages are rounded to 100% adding grade 0 toxicity.
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Figure 1. The median PFS and OS rates were 163 days (95% CI, 104 - 222), and 299 days (95% CI, 177- 421).
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