Squamous Non-Small Cell Lung Cancer (NSCLC):
Necitumumab is a monoclonal antibody that blocks activity of epidermal growth
factor receptor (EGFR), a protein commonly found on squamous non-small cell lung
cancer (NSCLC).
Takeda and Nakagawa (2015) stated that dysregulation of EGFR signaling due to
receptor over-expression or activating mutation is associated with cancer cell
proliferation, metastasis, and survival. They noted that EGFR has become an
important therapeutic target for NSCLC, and several EGFR-targeted agents, such
as tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs), have been
developed. The EGFR-TKIs afatinib, Erlotinib, and Gefitinib have been approved
by the Food and Drug Administration (FDA) for the treatment of advanced NSCLC,
and sensitivity to these drugs has been shown to be associated with the presence
of EGFR mutations. Various mAbs to EGFR have also been evaluated in
pre-clinical and clinical studies. In particular, phase III clinical trials
have shown a clinically significant survival benefit for addition of the
anti-EGFR mAbs Cetuximab or necitumumab to a platinum doublet in
chemotherapy-naive patients with advanced NSCLC.
Sacco
et al (2015) noted that over the past 2 decades, progress in the treatment of
patients with metastatic squamous NSCLC has been limited. The EGFR is involved
in tumor progression and invasion and therefore it has become the target of
several studies in lung cancer. Strategies to block this pathway are focused on
the development of small molecule (TKI) and mAbs. Some mAbs have been studied
in patients with advanced NSCLC. For the first time, a fully human
immunoglobulin G (IMC-11F8), subclass 1 (IgG1) mAb targeting the EGFR, in
combination with standard chemotherapy (cisplatin + gemcitabine), has been shown
to increase overall survival (OS) in chemo-naive patients with confirmed
metastatic squamous cell histology.
In an
open-label, phase III, multi-center, randomized controlled trial (RCT), Thatcher
et al (2015) compared treatment with necitumumab plus gemcitabine and cisplatin
versus gemcitabine and cisplatin alone in patients with previously untreated
stage IV squamous NSCLC. This study was carried out at 184 sites in 26
countries. Patients aged 18 years or older with histologically or cytologically
confirmed stage IV squamous NSCLC, with an Eastern Cooperative Oncology Group
(ECOG) performance status of 0 to 2 and adequate organ function and who had not
received previous chemotherapy for their disease were eligible for inclusion.
Enrolled patients were randomly assigned 1:1 to a maximum of six 3-week cycles
of gemcitabine and cisplastin chemotherapy with or without necitumumab according
to a block randomization scheme (block size of 4) by a telephone-based
interactive voice response system or interactive web response system.
Chemotherapy was gemcitabine 1,250 mg/m (2) administered intravenously over 30
mins on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m (2) administered
intravenously over 120 mins on day 1 of a 3-week cycle. Necitumumab (800 mg),
administered intravenously over a minimum of 50 mins on days 1 and 8, was
continued after the end of chemotherapy until disease progression or intolerable
toxic side effects occurred. Randomization was stratified by ECOG performance
status and geographical region. Neither physicians nor patients were masked to
group assignment because of the expected occurrence of acne-like rash -- a class
effect of EGFR antibodies -- that would have unmasked most patients and
investigators to treatment. The primary end-point was OS, analyzed by
intention-to-treat.
Between January 7, 2010, and February 22, 2012, these researchers enrolled 1,093
patients and randomly assigned them to receive necitumumab plus gemcitabine and
cisplatin (n = 545) or gemcitabine and cisplatin (n = 548). Overall survival
was significantly longer in the necitumumab plus gemcitabine and cisplatin group
than in the gemcitabine and cisplatin alone group (median of 11.5 months [95 %
confidence intervals [CI] 10.4 to 12.6]) versus 9.9 months [8.9 to 11.1];
stratified hazard ratio (HR) 0.84 [95 % CI: 0.74 to 0. 96; p = 0.01]). In the
necitumumab plus gemcitabine and cisplatin group, the number of patients with at
least 1 grade-3 or worse adverse event was higher (388 [72 %] of 538 patients)
than in the gemcitabine and cisplatin group (333 [62 %] of 541), as was the
incidence of serious adverse events (257 [48 %] of 538 patients versus 203 [38
%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin
group had grade 3 to 4 hypomagnesaemia (47 [9 %] of 538 patients in the
necitumumab plus gemcitabine and cisplatin group versus 6 [1 %] of 541 in the
gemcitabine and cisplatin group) and grade 3 rash (20 [4 %] versus 1 [less than
1 %]). Including events related to disease progression, adverse events with an
outcome of death were reported for 66 (12 %) of 538 patients in the necitumumab
plus gemcitabine and cisplatin group and 57 (11 %) of 541 patients in the
gemcitabine and cisplatin group; these were deemed to be related to study drugs
in 15 (3 %) and 10 (2 %) patients, respectively. Overall, these researchers
found that the safety profile of necitumumab plus gemcitabine and cisplatin was
acceptable and in line with expectations. The authors concluded that these
findings showed that the addition of necitumumab to gemcitabine and cisplatin
chemotherapy improved OS in patients with advanced squamous NSCLC and
represented a new first-line treatment option for this disease.
On
November 24, 2015, the FDA approved necitumumab (Portrazza) in combination with
2 forms of chemotherapy to treat patients with metastatic squamous NSCLC who
have not previously received medication specifically for treating their advanced
lung cancer based on the findings of the phase III clinical trial by Thatcher et
al (2015). However, necitumumab was not found to be an effective treatment in
patients with non-squamous NSCLC. The most common side effects of necitumumab
are skin rash and hypomagnesemia, which can cause muscular weakness, seizure,
irregular heartbeats and can be fatal. Portrazza includes a boxed warning to
alert health care providers of serious risks of treatment with necitumumab,
including cardiac arrest and sudden death, as well as hypomagnesemia.
Experimental Indications:
Necitumumab is also being investigated in the treatment of other solid tumors;
however, its effectiveness for these indications has not been established.
Colorectal Cancer
Dienstmann and Tabernero (2010) stated that necitumumab (IMC-11F8) is a fully
human IgG1 mAb targeting the EGFR for the potential treatment of cancer, in
particular NSCLC. Pre-clinical studies indicated that the anti-tumor activity
of necitumumab is either comparable with or superior to that of Cetuximab (a
chimeric anti-EGFR mAb). In a phase I clinical trial in patients with advanced
solid malignancies, necitumumab displayed non-linear pharmacokinetic behavior.
The toxicity profile of necitumumab is acceptable, with skin toxicity being the
most frequently reported adverse event in the phase I and II clinical trials
conducted to date. The authors stated that preliminary data from a phase II
clinical trial of necitumumab in combination with chemotherapy for the
first-line treatment of advanced colon cancer are promising.
Furthermore, a phase II clinical trial on the use of IMC-11F8 in combination
with chemotherapy in the treatment of colorectal cancer has been completed (Last
updated:
January 22, 2014.
https://www.clinicaltrials.gov/ct2/show/NCT00835185?term=Necitumumab&rank=11.
Head and Neck Squamous Cell Carcinoma
Cohen
(2014) stated that over-expression of the EGFR is a common characteristic of
head
and neck squamous cell carcinomas (HNSCC). Cetuximab is a chimeric anti-EGFR
mAb with multiple approved indications in HNSCC, including with radiation
therapy (RT) for loco regionally advanced disease, as monotherapy after platinum
progression, and with platinum/5-fluorouracil for recurrent or metastatic
disease. There remain, however, numerous unanswered questions regarding the
optimal use of Cetuximab in HNSCC, including patient selection, its mechanisms
of action and resistance, the effect of human papillomavirus status on outcomes,
its role when combined with induction chemotherapy or adjuvant radiation, and
optimal management of skin toxicity and hypersensitivity reactions. In
addition, a variety of other anti-EGFR agents (the multi-targeted small molecule
TKIs lapatinib, dacomitinib, and afatinib and the anti-EGFR mAbs zalutumumab,
nimotuzumab, and Panitumumab) are currently under investigation in phase II and
III clinical trials in different HNSCC therapeutic settings. The anti-EGFR TKI
Erlotinib is currently in phase III development for oral cancer prevention.
Numerous other drugs are in earlier stages of development for HNSCC treatment,
including novel anti-EGFR mAbs (MEHD7945A, necitumumab, and RO5083945),
small-molecule TKIs (vandetanib, icotinib, and CUDC-101), EGFR anti-sense,
various add-on therapies to radiation and chemotherapy (bevacizumab,
interleukin-12, lenalidomide, alisertib, and VTX-2337), and drugs (temsirolimus,
everolimus, OSI-906, dasatinib, and PX-866) intended to overcome resistance to
anti-EGFR agents. Overall, a wealth of clinical trial data is expected in the
coming years, with the potential to modify significantly the approach to
anti-EGFR therapy for HNSCC.