NZ616183B2 - Method for egfr directed combination treatment of cancer - Google Patents
Method for egfr directed combination treatment of cancer Download PDFInfo
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- NZ616183B2 NZ616183B2 NZ616183A NZ61618312A NZ616183B2 NZ 616183 B2 NZ616183 B2 NZ 616183B2 NZ 616183 A NZ616183 A NZ 616183A NZ 61618312 A NZ61618312 A NZ 61618312A NZ 616183 B2 NZ616183 B2 NZ 616183B2
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- cancer
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
Abstract
Discloses use of an irreversible tyrosine kinase inhibitor (TKI) selected from the group consisting of EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357, CI-1033, BIBW 2992, PF-00299804 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one, WZ 3146, WZ 4002, and WZ 8040, or a pharmaceutically acceptable salt thereof, for preparation of a medicament for treating of a human patient suffering from a cancer driven by deregulated Human Epidermal Growth Factor Receptor (HER/Human EGFR) selected from the group consisting of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), malignant glioma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer, and colorectal cancer (CRC), including metastatic forms thereof, wherein the medicament is for use in combination with a Human EGFR targeted monoclonal antibody (mAB) selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab and necitumumab, wherein the treating comprises administering the TKI according to a continuous regimen based on an average daily dose in the range of 10 to 50 mg and co-administering the mAB according to a dosing regimen ranging from an average weekly iv dose of 50 to 500 mg/m2 repeated thrice, twice or once a week, once in two weeks, once in three weeks or at least once monthly. 4002, and WZ 8040, or a pharmaceutically acceptable salt thereof, for preparation of a medicament for treating of a human patient suffering from a cancer driven by deregulated Human Epidermal Growth Factor Receptor (HER/Human EGFR) selected from the group consisting of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), malignant glioma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer, and colorectal cancer (CRC), including metastatic forms thereof, wherein the medicament is for use in combination with a Human EGFR targeted monoclonal antibody (mAB) selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab and necitumumab, wherein the treating comprises administering the TKI according to a continuous regimen based on an average daily dose in the range of 10 to 50 mg and co-administering the mAB according to a dosing regimen ranging from an average weekly iv dose of 50 to 500 mg/m2 repeated thrice, twice or once a week, once in two weeks, once in three weeks or at least once monthly.
Description
METHOD FOR EGFR DIRECTED COMBINATION TREATMENT OF CANCER
The present invention relates to a method of treating patients suffering from cancers driven by
deregulated Human Epidermal Growth Factor or (HENHuman EGFR) such as, but not
limited to, non-small cell lung cancer (NSCLC), head and neck squamous cell oma
(HNSCC), breast cancer, esophageal , gastric cancer, renal cancer, cervical cancer,
ovarian cancer, pancreatic cancer, hepatocellular cancer, malignant glioma, prostate cancer
and colorectal cancer (CRC) comprising a flexible and active regimen for combining an
irreversible tyrosine kinase inhibitor (TKI) and a Human EGFR targeted monoclonal antibody
(mAB), wherein in this method the TKI is administered ing to a continuous regimen
based on an average daily dose in the range of 10 to 50 mg and the mAB is co-administered
according to a dosing regimen ranging from an average weekly intravenous (iV) dose of 50 to
500 mg/m2 repeated , twice or once a week, once in two weeks, once in three weeks or
at least monthly to a patient in need of such treatment. The method of treatment of the
invention includes treatment of TKI naive patients as well as of ts pretreated with
EGFR TKIs, particularly those patients with primary or ed resistance to treatment with
reversible or irreversible TKIs such as gef1tinib, nib, l-(4-(4-(3,4-dichloro
fluorophenylamino)methoxyquinazolinyloxy)piperidin- l -yl)propenone, or salts
thereof, EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357, lapatinib, CI-1033 (canertinib),
WZ 3146, WZ 4002, WZ 8040 (structures of the three WZ compounds sed by Wenjun
Zhou et al.: Novel mutant-selective EGFR kinase tors against EGFR T790M, in Nature
2009, Vol. 462, 1070-1074), Icotinib, BIBW 2992 or PF-00299804 (dacomitinib).
Furthermore the method of treatment of the invention includes to overcome primary or
acquired resistance and prevention or delay of acquired resistance to treatment with
(reversible or irreversible) TKIs.
Additional aspects of the invention are pharmaceutical compositions and ceutical kits
which include instructions for coadministration of the TKI with the mAB, rsible TKIs
for coadministration with a targeted mAB that prevents the binding of ligands to EGFR and
the use of an irreversible TKI for preparation of a pharmaceutical composition sing an
effective amount of the rsible TKI, together with an instruction for coadministration
with the mAB.
ound ofthe invention
EGFR is expressed in several solid malignancies, including NSCLC, HNSCC, malignant
glioma and colorectal cancer, and abnormal or deregulated EGFR activity is known to
contribute to numerous tumorigenic processes. Lung cancer remains the leading cause of
cancer death in industrialized countries. Cancers that begin in the lungs are divided into two
major types, non-small cell lung cancer and small cell lung cancer, depending on how the
cells appear under a microscope. Non-small cell lung cancer (squamous cell oma,
adenocarcinoma, and large cell carcinoma) generally spreads to other organs more slowly
than does small cell lung cancer. About 75 percent of lung cancer cases are categorized as
non-small cell lung cancer (e.g., adenocarcinomas), and the other 25 percent are small cell
lung cancer. For patients with advanced e, chemotherapy provides a modest benefit in
survival, but at the cost of significant toxicity, underscoring the need for therapeutic agents
that are cally targeted to the al genetic lesions that direct tumor growth (Schiller
JH et al., N Engl J Med, 346: 92-98, 2002).
Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have
been associated with a number of s, including lung cancer, anal cancers and
glioblastoma multiforme. Mutations, amplifications or misregulations of EGFR or family
members are implicated in about 30% of all epithelial cancers. uently, mutations of
EGFR have been identified in several types of , and has led to the development of
anticancer therapeutics directed against EGFR, using two approaches: (1) targeted
monoclonal antibodies (mABs) that prevent the binding of ligands to EGFR, and (2) small
molecule tyrosine kinase inhibitors (TKIs) that block the intracellular catalytic activity of the
receptor. Skin toxicity characterized by rash or acne-like symptoms and diarrhea of different
grades are the most common adverse events of EGFR targeted therapies (Expert Opin.
Investig. Drugs (2009) 18(3), 293—300).
The mouse chimeric IgGl mAb cetuximab down-regulates EGFR signaling and
subsequently inhibits cell proliferation, induces apoptosis and reduces angiogenesis.
Cetuximab in ation with herapy has been approved by Health Authorities for
the ent of metastatic colorectal cancer and for the treatment of locally advanced and
metastatic head and neck cancer. Cetuximab has also demonstrated little al activity as a
single agent in patients with advanced NSCLC after prior EGFR TKI therapy (Neal JW, Heist
RS, Fidias P, Temel JS, Huberman M, Marcoux JP, Muzikansky A, Lynch TJ, Sequist LV; J
Thorac Oncol. 2010 Nov; 5(11):1855-8: Cetuximab monotherapy in patients with advanced
non-small cell lung cancer after prior epidermal growth factor receptor tyrosine kinase
inhibitor therapy). Panitumumab (VECTIBIX ®) is a human IgG2 mAB against EGFR and
approved for treatment of metastatic colorectal cancer. Other monoclonals in clinical
development are zalutumumab, nimotuzumab, matuzumab and mumab.
First generation small molecule HER TKIs include gef1tinib (Iressa ®) and erlotinib (Tarceva
®), both binding reversibly to the EGFR. Gefitinib is indicated in all lines of treatment of
advanced NSCLC harbouring EGFR mutations in the tumor and erlotinib is indicated as
treatment of advanced NSCLC after prior chemotherapy, but in development in all lines of
EGFR mutation positive NSCLC These new drugs directly target the EGFR. Patients have
been divided into EGFR positive (EGFR+) and negative ), based upon whether a tissue
test shows a mutation. EGFR positive patients with tumors harboring EGFR mutations in
exons 19 and 21 associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R,
L861Q) have shown an response rate up to 60% which exceeds the response rate for
conventional chemotherapy.
Second generation small molecule TKIs have been designed as rsible EGFR inhibitors
which bind irreversibly to EGFR, preferably to ne 773 of EGFR. iting examples
include compounds disclosed in US. Pat. No. 6,002,008, US 7,019,012, US 6,251,912, WO
02/50043, , , WO 2008150118 fically the compound
of Example 36, 1-(4-(4-(3,4-dichlorofluorophenylamino)methoxyquinazolin
piperidinyl)propenone, or salts thereof formed with acidic additives as
disclosed in WO 5793), EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357, CI-1033
(canertinib), WZ 3146, WZ 4002, WZ 8040 tures ofthe three WZ compounds disclosed
by Wenjun Zhou et al.: Novel mutant-selective EGFR kinase inhibitors against EGFR
T790M, in Nature 2009, Vol. 462, 1070-1074), BIBW 2992 or PF-00299804. BIBW 2992
nib) and PF-00299804 (dacomitinib) are most advanced second generation small
molecule TKIs include, both in ed clinical development for treatment ofNSCLC.
More specifically, BIBW 2992, also referred to herein by it’s INN afatinib, is known as the
compound chlorofluorophenyl)amino] {[4-(N,N-dimethylamino)- l -oxobuten— l -
yl]amino} ((S)-tetrahydrofuranyloxy)-quinazoline,
H CH
N \ WWII 3
l / 0 CH3
N 9
preferably used as a maleate salt BIBW 2992 : maleic acid 1 : 2:
BIBW 2992 is a potent irreversible and selective dual inhibitor of erbbl or (EGFR) and
erbB2 (Her2/neu) and erbB4 (Her4) receptor tyrosine kinases which can be administered
orally. Furthermore, BIBW 2992 was designed to covalently bind to EGFR and HER2 thereby
irreversibly inactivating the receptor molecule it has bound to. This compound, salts thereof
such as the dimaleate salt, their preparation as well as pharmaceutical formulations
comprising BIBW 2992 or a salt f, indications to be treated with BIBW 2992 and
combinations including BIBW 2992 are disclosed in WO 02/50043, , WO
2007/054550, , WO 2008034776 and WO 7238.
99804 is an oral irreversible pan-HER TKI, more specifically an inhibitor of the
HERl, 2, and 4 tyrosine kinases. In preclinical studies, PF-00299804 has been shown to
inhibit the ing in both wild-type and mutant EGFR, including forms ofNSCLC that are
resistant to currently available EGFR inhibitors, such as erlotinib and gef1tinib. Preclinical
findings suggest that PF-00299804 may be clinically effective t NSCLCs with EGFR or
ERB-B2 mutations as well as those harboring the EGFR T790M mutation, which produces
resistance to gefitinib and erlotinib (Expert Opin. Investig. Drugs (2010) 19(12): 1503-1514).
PF-00299804 (dacomitinib) is the compound N-[4-(3-chlorofluoro-phenylamino)
methoxy-quinazolineyl]piperidinyl-acrylamide, disclosed in WO 2005107758 as
Examples 2 and 3 with the following structure:
F:I:::1\NH
OCH3
Characteristics of EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357 and CI-1033 are
hed, e.g. Expert Opin. Investig. Drugs 2009, 18(3), 293-301 provides a .
Development of EKB-569 for treatment ofNSCLC has been discontinued several years ago.
Others report that 2 can me T790M-mediated resistance only at
suprapharmacologic concentrations (N. Godin-Heymann et al., The T790M “gatekeeper”
mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR
inhibitor. Mol. Cancer Ther. 7, 2008:874—879). Remarkably, pment of HKI-272 for
treatment C was discontinued after phase II trial showed that the compound had low
activity in patients with prior t from TKIs and in TKI-naive patients, potentially
because of insufficient ilability from diarrhea-imposed dose limitation (L. V. Sequist et
al., J. Clin . Onc. 28 (18), 2010, 3076-3083). In contrast to encouraging preclinical results and
high potency of HKI-272 these did not translate into clinical t, showing the low level of
predictability in this field.
Despite initial response in NSCLC ts with EGFR mutations, acquired resistance
develops after a median of approximately 12 months. The consensus definition of acquired
resistance includes patients who had previous treatment with a single-agent EGFR-TKI (e. g.,
gefitinib or erlotinib); either or both of the ing: a tumor that harbors an EGFR mutation
known to be ated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L86lQ)
or ive clinical benefit from treatment with an EGFR-TKI; systemic progression of
disease ng RECIST criteria known in the art, while on continuous treatment with EGFR
directed treatment for at least 24 weeks.
Response evaluation criteria in solid tumours (RECIST) are described by P. se et al., J
Natl Cancer Inst 2000, 92, 205-216; in J. Clin. Oncol. Vol 24, No. 20, 2006, pp 3245-3251; or
by Eisenhauer EA, se P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al., New
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J
Cancer 2009;45 :228-247. Monitoring tumor progression may be determined by comparison of
tumor status between time points after treatment has commenced or by comparison of tumor
status between a time point after treatment has commenced to a time point prior to tion
tment. Tumor progression may be monitored during treatment visually, for example, by
means of radiography, for example, X-ray, CT scan, or other ring methods known to
the skilled artisan, including palpitation of the cancer or methods to r tumor biomarker
levels.
In addition to the primary EGFR ons (associated with erlotinib and gef1tinib
sensitivity), approximately half of the patients with acquired EGFR-TKI resistance have a
second EGFR mutation (T790M) in the ATP-binding pocket of the tyrosine kinase that may
alter receptor affinity in favor of ATP. These second mutations enable the cancer cells to
ue signaling via mutant EGFR, suggesting that in a proportion of patients with acquired
resistance to EGFR-TKIs, tumor growth and proliferation remains dependent on EGFR.
The presence ofMET oncogene has been reported as a second sources of resistance (Jackman
D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA et al., Clinical definition of acquired
resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell
lung cancer, J Clin Oncol 2010;28:357—60).
As of 2010 there was no al consensus of an accepted approach to overcome or prevent
resistance nor regulatory al of a specific drug or drug combination in this setting.
There is a significant l need in the art for a actory treatment of cancer, and
cally epithelial cell cancers such as lung, ovarian, breast, brain, colon and prostate
cancers, which incorporates the benefits of EGFR targeted therapy and overcoming the non-
responsiveness ted by patients’ cancers. Thus, the problem underlying the present
invention is to ish an improved treatment of patients suffering from epithelial cell
cancers, characterized by improved cy and ed or at least acceptable tolerability,
including the following patient tions
(a) TKI naive cancer patients, wherein the improvement includes prevention or delay of
resistance to TKI treatment,
(b) patients with tumors expressing the wild-type EGFR (described hereinbefore as
EGFR"),
(c) patients with tumors expressing mutated forms of the EGFR (described hereinbefore
as EGFR+),
(d) patients preViously d with EGFR inhibitors, such as gefitinib or erlotinib
afatinib, dacomitinib or others wherein the improvement es to overcome
primary or acquired resistance to EGFR inhibitors,
(e) patients with acquired ance to treatment with TKIs such as gefitinib or erlotinib,
afatinib, dacomitinib or others wherein the improvement includes to overcome
resistance to TKI treatment,
(g) patient populations with primary or acquired resistance caused by T790M (T790M+),
wherein the improvement includes to prevent/overcome resistance to TKI treatment,
(h) patient tions with primary or acquired resistance not caused by T790M
(T790M-), e. g. by other mechanisms such as MET oncogene or by unknown origin,
wherein the improvement includes to to prevent/overcome resistance to TKI
treatment.
One approach to improve treatment options of NSCLC patients with acquired resistance to
gefitinib or erlotinib followed the concept of total receptor blockade by combining a TKI and
an anti-EGFR mAB. This is summarized by S. Ramalingam et al., Journal of Thoracic
Oncology Vol. 3, Number 3, March 2008, 258-265. The hypothesis was that by the
combination it may be possible to achieve aneous vertical inhibition of EGFR and
enhance abrogation of downstream activity. Residual EGFR activity after exposure to either
class of inhibitor alone may allow cancer cells to remain viable, but simultaneous dual
inhibition may cause apoptosis. Results in xenograft models support this hypothesis: a
synergistic effect has been ed when cetuximab is administered in combination with
erlotinib or gefitinib compared with treatment with either agent alone. Cetuximab has been
shown to down-regulate EGFR on the cellular surface, potentially enhancing the sensitivity to
TKIs. The conclusion was that the combination of cetuximab plus nib seems synergistic
in terms of apoptotic activity in vitro, and results in additive tumor growth inhibition in vivo.
Nevertheless, the question is whether these primary results translate in clinical benefit. S.
Ramalingam et al. report the results of a phase I study carried out to determine the optimal
doses of cetuximab and ib when administered as a combination for patients with
advanced/metastatic non-small cell lung cancer (NSCLC) previously treated with platinum-
based chemotherapy. ts with advanced/metastatic NSCLC treated with prior platinum-
based chemotherapy received escalating doses of weekly cetuximab (100, 200, and 250
mg/mz, iv) and fixed doses of gefitinib (250 mg/d, PO) until disease progression or
unacceptable toxicity. The results ed show that the combination of cetuximab and
ib can be safely administered but has only modest activity in advanced/metastatic
NSCLC.
Y. Y. Janjigian et al., Clin Cancer Res 201 1, 17: 2521-2527, report about a phase I/II trial of
cetuximab and erlotinib enrolling 19 patients with lung adenocarcinoma and acquired
ance to nib. Patients with lung adenocarcinoma and clinically defined acquired
resistance to erlotinib were treated with erlotinib 100 mg daily, along with cetuximab every 2
weeks in three escalating dose cohorts (250 mg/mz, 375 mg/mz, and 500 mg/mz). The
recommended phase II dose was then evaluated in a two-stage trial, with a primary end point
of objective se rate. The recommended phase II dose identified was cetuximab 500
mg/m2 every 2 weeks and erlotinib 100 mg daily. At this dose and schedule, no radiographic
responses were seen. In fact, combined EGFR inhibition, with cetuximab 500 mg/m2 every 2
weeks and erlotinib 100 mg daily, had no significant activity in ts with acquired
ance to erlotinib. During the phase II portion of the trial serious tolerability issues
occured. Common grade 2, 3 and 4 ties were rash (13 patients, 68%), fatigue (12
ts, 63%) and hypomagnesemia (14 ts, 74%). 31 % (6 of 19 patients) discontinued
treatment due to rable rash.
Both, S. Ramalingam et al. and Y. Y. ian et al., report clinical results obtained with the
combination of cetuximab with a reversible (first generation) TKI. In contrast, L. Regales et
al., J. Clin. . 119 (10), 2009: 3000-3010, report results obtained with the irrreversible
(second generation) TKI BIBW 2992 in transgenic mouse lung tumor models that p
lung adenocarcinomas driven by EGFRL858R (sensitive to erlotinib), EGFRT790M (resistant to
erlotinib), or EGFRL858R+T790M (resistant to erlotinib) with a focus to evaluate strategies
to overcome the most common EGFR TKI resistance mutation, T790M. Other agents
mentioned in the investigation were HKI-272 (neratinib) and PF-00299804, but without
reporting results. The rationale behind was that preclinical studies published by others (E. L.
Kwak, et a1., Irreversible inhibitors of the EGF receptor may circumvent acquired resistance
to gefitinib. Proc. Natl. Acad. Sci. U. S. A. 2005, 102:7665—7670; T. A. Carter et a1.,
Inhibition of esistant mutants of ABL, KIT and EGF receptor kinases. Proc. Natl. Acad.
Sci. U. S. A. 2005, 102:11011—11016) suggested that second-generation irreversible EGFR
tors may be able to me T790M-mediated ance, at least in vitro. Mice
bearing tumors ing EGFR mutations were treated with a variety of anticancer ,
including the irreversible EGFR TKI BIBW 2992 and the EGFR-specific antibody cetuximab.
It was found that only the combination of both agents er induced dramatic shrinkage of
erlotinib-resistant tumors harboring the T790M mutation.
An open label phase I clinical trial of continuous once daily oral treatment using BIBW 2992
in combination with cetuximab with the primary objective to determine the maximum
tolerated dose (MTD) and recommended phase 11 doses in patients with NSCLC and acquired
resistance to erlotinib or gefitinib was disclosed in ClinicalTrials.gov at the priority filing date
of the subject patent application, identifier NCT01090011, including the history of changes
available via a link to ClinicalTrials.gov archive site .The following qualitative information
about the administration regimen was publicly available:
0 patients to receive medium BIBW 2992 once daily plus biweekly cetuximab infilsion
at low, median and high dose level
BIBW 2992 medium dose plus three dose levels (low, medium and high) of cetuximab.
Results or absolute dosages were not disclosed.
Summary of the Invention
According to a first aspect of the present ion there is provided use of: an irreversible
tyrosine kinase inhibitor (TKI) selected from the group consisting of EKB-569 (pelitinib),
HKI-272 (neratinib), HKI-357, CI-1033, BIBW 2992, PF-00299804 1-(4-(4-(3,4-dichloro
fluorophenylamino)methoxyquinazolinyloxy)piperidinyl)propenone, WZ 3146,
WZ 4002, and WZ 8040, or a pharmaceutically acceptable salt thereof; for preparation of a
ment for treating of a human patient suffering from a cancer driven by deregulated
Human mal Growth Factor Receptor (HER/Human EGFR) selected from the group
consisting of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma
(HNSCC), malignant glioma, breast cancer, esophageal , gastric cancer, renal cancer,
cervical cancer, prostate , ovarian cancer, pancreatic cancer, hepatocellular cancer, and
colorectal cancer (CRC), including metastatic forms thereof; n the medicament is for
use in combination with a Human EGFR targeted monoclonal antibody (mAB) selected from
the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab
and necitumumab; wherein the treating comprises administering the TKI ing to a
continuous regimen based on an average daily dose in the range of 10 to 50 mg and nistering
the mAB according to a dosing regimen ranging from an average weekly iv
dose of 50 to 500 mg/m2 repeated thrice, twice or once a week, once in two weeks, once in
three weeks or at least once monthly.
According to a second aspect of the present invention there is provided use of: an irreversible
tyrosine kinase inhibitor (TKI) selected from the group consisting of EKB-569 inib),
HKI-272 (neratinib), HKI-357, CI-1033, BIBW 2992, PF-00299804 1-(4-(4-(3,4-dichloro
fluorophenylamino)methoxyquinazolinyloxy)piperidinyl)propenone, WZ 3146,
WZ 4002, and WZ 8040, or a pharmaceutically acceptable salt f; and a Human EGFR
targeted monoclonal antibody (mAB) selected from the group consisting of cetuximab,
panitumumab, zalutumumab, zumab, matuzumab and necitumumab; for preparation of
a medicament for ng of a human patient suffering from a cancer driven by deregulated
Human Epidermal Growth Factor Receptor (HER/Human EGFR) selected from the group
consisting of non-small cell lung cancer (NSCLC), head and neck us cell carcinoma
(HNSCC), malignant glioma, breast cancer, esophageal cancer, gastric cancer, renal ,
(10177874_1):RTK
al cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer, and
colorectal cancer (CRC), ing metastatic forms thereof; wherein the treating comprises
administering the TKI according to a uous regimen based on an average daily dose in
the range of 10 to 50 mg and inistering the mAB according to a dosing regimen
ranging from an average weekly iv dose of 50 to 500 mg/m2 repeated thrice, twice or once a
week, once in two weeks, once in three weeks or at least once monthly.
A first object of the present invention is a method of treating patients suffering from cancers
driven by lated Human Epidermal Growth Factor Receptor (HER/Human EGFR)
sing administering to a patient in need of such ent a flexible and active regimen
for combining an irreversible ne kinase inhibitor (TKI) and a Human EGFR targeted
monoclonal antibody (mAB), wherein in this method the TKI is administered according to a
continuous regimen based on an average daily dose in the range of 10 to 50 mg and the mAB
is co-administered according to a dosing regimen ranging from an average weekly iv dose of
50 to 500 mg/m2 repeated thrice, twice or once a week, once in two weeks, once in three
weeks or at least once monthly.
A second object of the invention is a ceutical kit, comprising a first compartment
which comprises an effective amount of a Human EGFR targeted mAB and a second
compartment which comprises an effective amount of an irreversible TKI.
A third object of the invention is an irreversible TKI for use in a method of treatment of a
patient ing from a cancer driven by deregulated Human Epidermal Growth Factor
Receptor (HER/Human EGFR) by coadministration with a Human EGFR targeted mAB ,
wherein the TKI is administered according to a continuous regimen based on an average daily
dose in the range of 10 to 50 mg and the mAB is co-administered according to a dosing
regimen ranging from an average weekly iv dose of 50 to 500 mg/m2 repeated thrice, twice or
once a week, once in two weeks, once in three weeks or at least once monthly to a patient in
need of such treatment.
A fourth object of the invention is the use of an irreversible TKI for preparation of a
pharmaceutical kit for ent of patients suffering from cancers driven by deregulated
Human Epidermal Growth Factor Receptor (HER/Human EGFR), comprising a first
compartment which comprises an effective amount of a Human EGFR targeted mAB and a
(10410632_1):RTK
second compartment which comprises an ive amount of an irreversible TKI, wherein the
TKI is to be stered according to a continuous regimen based on an average daily dose
in the range of 10 to 50 mg and the mAB is to be co-administered according to a dosing
regimen ranging from an average weekly iv dose of 50 to 500 mg/m2 repeated thrice, twice or
once a week, once in two weeks, once in three weeks or at least once monthly to a patient in
need of such treatment.
Detailed Description of the Invention
Supported by clinical results it has surprisingly been found that the combination of an
irreversible TKI with Human EGFR targeted mAB has significantly more activity than may
have been expected, based on the results reported in the prior art, i.e. that dual targeting of
gef1tinib/cetuximab or erlotinib/cetuximab is not active for treatment of patients with lung
adenocarcinoma and acquired ance to reversible TKIs, as well as in view of the low
tolerability reported for such ations or based on preclinical data.
The irreversible TKI and the mAB can be combined with good tolerability at the
recommended doses of the individual drugs — which was not expected in view of the low
activity and tolerability of the gef1tinib/cetuximab or erlotinib/cetuximab combination
reported by S. Ramalingam et al., l of Thoracic Oncology Vol. 3, Number 3, March
2008, 258-265 and by Y. Y. Janjigian et al., Clin Cancer Res 2011, 17: 2521-2527,
summarized hereinbefore.
al trial data support that the the activity of the combinations according to the invention
is NOT restricted to T790M mediated resistance to TKI treatment, i.e. not only overcomes
T790M mediated +: tumor harboring T790M) acquired resistance to TKI treatment
but also ed resistance not caused by T790M (T790M-: tumor not harboring T790M),
e.g. acquired resistance caused by other mechanisms such as MET oncogene or by n
origin. There is no evidence in the prior art ting that this may be the case.
These findings suggest that the combination treatment according to the invention has the
potential for significant improvement of the therapeutic index for EGFR directed treatments
of s driven by deregulated Human Epidermal Growth Factor Receptor (HENHuman
EGFR), e.g. epithelial cell s. Any of these findings are supported by clinical results
obained with the combination ofBIBW 2992 with cetuximab.
Patients suffering from cancers driven by deregulated Human Epidermal Growth Factor
Receptor man EGFR) include, without limitation, patients suffering from non-small
cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), malignant
glioma, breast cancer, esophageal cancer, gastric cancer, renal , cervical cancer,
prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer, and colorectal
cancer (CRC), including metastatic forms thereof Preferred indications are NSCLC and
HNSCC, especially NSCLC.
rmore, patients having one of cancer indications specified hereinbefore which may
advantageously be treated by the method of the ion include the following patient
populations:
(a) TKI naive cancer patients, wherein the treatment provides prevention or delay of
resistance to TKI treatment,
(b) patients with tumors expressing the wild-type EGFR,
(c) patients with tumors expressing d forms ofthe EGFR,
(d) patients previously treated with EGFR inhibitors, such as gefitinib or erlotinib
afatinib, dacomitinib or others wherein the treatment provides to overcome primary
or acquired resistance to EGFR inhibitors
(e) patients with ed resistance to treatment with TKIs such as gefitinib or erlotinib,
afatinib, tinib or others wherein the treatment provides to overcome resistance
to TKI treatment,
(g) patient populations with primary or acquired ance caused by T790M (T790M+),
wherein the i treatment provides to prevent or overcome resistance to TKI treatment,
(h) patient populations with primary or acquired resistance not caused by T790M
-), e. g. by other mechanisms such as MET oncogene or by unknown origin,
wherein the ent provides to t or overcome resistance to TKI treatment.
2012/059098
Preferably, the following patient populations having one of the cancer indications specified
hereinbefore may advantageously be treated by the method ofthe invention:
(c) ts with tumors expressing mutated forms of the EGFR (EGFRl),
(d) patients preViously treated with EGFR inhibitors, such as gefitinib or erlotinib
afatinib, dacomitinib or others wherein the ent provides to overcome primary
or acquired resistance to EGFR inhibitors,
(e) ts with acquired resistance to treatment with TKIs, such as gefitinib or
erlotinib, afatinib, dacomitinib or others, wherein the treatment provides to overcome
resistance to TKI treatment,
(g) patient populations with primary or acquired resistance caused by T790M (T790M+),
wherein the treatment provides to prevent or overcome resistance to TKI treatment,
(h) patient populations with primary or acquired resistance not caused by T790M
(T790M-), e. g. by other mechanisms such as MET oncogene or by unknown origin,
wherein the treatment provides to t/overcome resistance to TKI treatment.
More preferred, the following patient populations haVing one of the cancer indications
specified hereinbefore may advantageously be treated by the method ofthe invention:
(c) patients with tumors harboring EGFR mutations in exons l9 and 21 associated with
drug sensitivity (i.e., G7l9X, exon 19 deletion, L858R, L861Q),
(e) patients with acquired resistance to treatment with TKIs, such as gefitinib or
erlotinib, afatinib, dacomitinib or , wherein the treatment provides to overcome
resistance to TKI treatment,
(g) patient populations with primary or acquired resistance caused by T790M (T790M+),
n the treatment provides to prevent or overcome ance to TKI treatment,
(h) patient populations with primary or acquired resistance not caused by T790M
(T790M-), e. g. by other mechanisms such as MET oncogene or by unknown origin,
wherein the ent provides to prevent or overcome resistance to TKI treatment.
Most preferred, the following patient population haVing one of the cancer tions
specified before may advantageously be treated by the method ofthe invention:
(h) patient tions with y or acquired resistance not caused by T790M
(T790M-), e. g. by other mechanisms such as MET oncogene or by unknown origin,
wherein the treatment provides to prevent or overcome resistance to TKI treatment.
Particularly preferred, the following patient population having one of the cancer indications
specified hereinbefore may advantageously be treated by the method ofthe invention:
(h') t tions with acquired resistance not caused by T790M
(T790M-), e. g. by other mechanisms such as MET oncogene or by unknown origin,
wherein the treatment provides to overcome resistance to TKI treatment.
Irreversible TKIs suitable with regard to any aspects of the invention include, without
limitation, EKB-569 (pelitinib), HKI-272 inib), HKI-357, CI-1033, BIBW 2992 or PF-
00299804, and any salts, preferably pharmaceutically acceptable salts, hydrates or solvates
thereof, including rphs. Preferred TKIs are BIBW 2992 and PF-00299804. Most
preferred is BIBW 2992.
As a fiarther alternative irreversible TKIs suitable with regard to any aspects of the invention
include l-(4-(4-(3,4-dichlorofluorophenylamino)methoxyquinazolinyloxy)piperidin-
l-yl)propen-l-one, WZ 3146, WZ 4002, WZ 8040, and any salts, preferably
pharmaceutically able salts, hydrates or solvates thereof, including polymorphs.
MABs suitable with regard to any aspects of the invention include, t limitation,
cetuximab, panitumumab, mumab, zumab, and matuzumab. Preferred mABs are
cetuximab and panitumumab. Most preferred is cetuximab. A fiarther mABs suitable with
regard to any aspects of the invention is mumab.
Any of the irreversible TKIs and any of the mABs mentioned in the context of the invention
may be combined with each other with regard to the specified aspects of the invention.
Specific combinations suitable with regard to all aspects of the invention are
EKB-569 / cetuximab, 9 / mumab, EKB-569 / zalutumumab, EKB-569 /
nimotuzumab, EKB-S69 / matuzumab,
2012/059098
HKI-272 / cetuximab, HKI-272 / panitumumab, HKI-272 / zalutumumab, HKI-272 /
zumab, HKI-272 / matuzumab, HKI-272 / necitumumab,
HKI-357 / cetuximab, 7 / panitumumab, HKI-357 / zalutumumab, HKI-357 /
nimotuzumab, HKI-357 / matuzumab,
CI-1033 / cetuximab, CI-1033 / panitumumab, CI-1033 / zalutumumab, CI-1033 /
nimotuzumab, CI- 1 033 / matuzumab,
BIBW 2992 / cetuximab, BIBW 2992 / panitumumab, BIBW 2992 / zalutumumab, BIBW
2992 / nimotuzumab, BIBW 2992 / matuzumab, BIBW 2992 / necitumumab,
PF-00299804 / cetuXimab, PF-00299804 / panitumumab, 99804 / zalutumumab, PF-
00299804 / nimotuzumab, PF-00299804 / mumab,, and PF-00299804 / matuzumab.
red combinations of the irreversible TKIs and the mABs suitable with regard to all
aspects of the invention are
2 / cetuximab, HKI-272 / panitumumab, HKI-272 / zalutumumab, HKI-272 /
nimotuzumab, HKI-272 / matuzumab,
BIBW 2992 / cetuximab, BIBW 2992 / panitumumab, BIBW 2992 / zalutumumab, BIBW
2992 / nimotuzumab, BIBW 2992 / mab,
PF-00299804 / cetuXimab, PF-00299804 / panitumumab, PF-00299804 / zalutumumab, PF-
00299804 / nimotuzumab, and PF-00299804 / matuzumab.
More preferred combinations of the irreversible TKIs and the mABs suitable with regard to
all aspects of the invention are
HKI-272 / cetuximab, HKI-272 / panitumumab,
BIBW 2992 / cetuximab, BIBW 2992 / panitumumab,
PF-00299804 / cetuximab, and 99804 / panitumumab.
Most preferred combinations ofthe irreversible TKIs and the mABs suitable with regard to all
aspects of the invention are
BIBW 2992 / cetuximab, BIBW 2992 / mumab,
PF-00299804 / cetuximab, and PF-00299804 / panitumumab,
specifically preferred is BIBW 2992 / cetuximab.
2012/059098
-l6-
The expressions ntion", "prophylaxis", "prophylactic treatmen " or "preventive
treatment" used herein should be understood synonymous and in the sense that the risk to
develop a condition mentioned herein is reduced. The expression "prevention or delay of
resistance" or "to overcome resistance" in the context of the invention means that
development of ance to TKI treatment is either avoided or onset of resistance is delayed
or already existing (primary or acquired) resistance is me by the combination treatment
regimen of the invention, ed statistically by d nce or later onset of
resistance within a first patient population treated with a combination treatment regimen
according to the invention, in comparison to an equivalent second patient population receiving
parallel treatment but without the Human EGFR targeted monoclonal antibody component.
Resistance to TKI or EGFR inhibitor treatment means that the patient does not show a
response to the treatment. This includes primary resistance of TKI naive patients when treated
for the first time with a TKI, and acquired resistance of patients g response under TKI
treatment for a certain period oftime but then progression of the disease again.
Furthermore, prevention or delay of resistance to TKI treatment means that the patients of the
first patient population show response under the ation treatment regimen according to
the invention either continuously or for a longer period of time, compared to the second
patient population. Treatment response and progression of the disease are evaluated under the
criteria laid down in the revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-
247 mentioned hereinbefore.
A preferred embodiment of the first object of the present invention is a method of treating
patients suffering from NSCLC, HNSCC, malignant glioma, breast cancer, esophageal cancer,
gastric cancer, renal cancer, al , te cancer, ovarian cancer, pancreatic
cancer, hepatocellular cancer or CRC, including metastatic forms thereof, wherein in this
method
a TKI selected from the group consisting of EKB-569, HKI-272, HKI-357, 3,
BIBW 2992 and 99804, or a pharmaceutically able salt thereof, is
stered according to a continuous regimen based on an average daily dose in the
range of 10 to 50 mg and
a mAB selected from the group consisting of cetuximab, panitumumab, zalutumumab,
nimotuzumab and matuzumab is co-administered according to a dosing regimen ranging
from an average weekly iv dose of 50 to 500 mg/m2 repeated thrice, twice or once a
week, once in two weeks, once in three weeks or at least once monthly to
(c) a patient with a tumor expressing mutated forms of the EGFR, or
(d) a patient previously treated with EGFR inhibitors, such as gefitinib or erlotinib
afatinib, tinib or others wherein the method provides to overcome primary or
acquired resistance to EGFR inhibitors,
(e) a patient with acquired resistance to ent with TKIs such as gefitinib or
erlotinib, afatinib, tinib or others wherein the method provides to overcome
resistance to TKI treatment,
(g) a patient with primary or ed resistance caused by T790M (T790M+), wherein
the method provides to prevent or overcome resistance to TKI treatment, or
(h) a patient with primary or acquired resistance not caused by T790M (T790M-), e. g.
by other mechanisms such as MET ne or by unknown origin, n the
method provides to prevent or overcome resistance to TKI treatment.
A fiarther preferred embodiment of the first object of the present invention is a method of
treating patients ing from NSCLC, HNSCC, malignant glioma, breast cancer or CRC,
including metastatic forms thereof, wherein in this method
a TKI selected from the group consisting of HKI-272, BIBW 2992 and 99804,
(BIBW 2992 and PF-00299804 being especially preferred), or a pharmaceutically
able salt thereof, is administered according to a continuous regimen based on an
average daily dose in the range of 10 to 50 mg and
a mAB ed from the group consisting of cetuximab and panitumumab, is co-
administered ing to a dosing n ranging from an average weekly iv dose of
50 to 500 mg/m2 repeated twice or once a week or once in two weeks to
(c) a patient with a tumor harboring EGFR mutations in exons 19 and 21 associated with
drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q), or
(e) a patient with acquired resistance to treatment with TKIs such as gefitinib or
erlotinib, ib, dacomitinib or others n the method provides to overcome
resistance to TKI treatment,
(g) a patient with primary/acquired ance caused by T790M +), wherein the
method provides to prevent or me resistance to TKI treatment, or
(h) a patient with primary or acquired resistance not caused by T790M (T790M-), e. g.
by other mechanisms such as MET oncogene or by unknown origin, wherein the
method provides to prevent or overcome resistance to TKI treatment.
A fiarther preferred embodiment of the first object of the present invention is a method of
treating patients suffering from NSCLC or HNSCC, including metastatic forms thereof,
wherein in this method
a TKI selected from the group consisting of BIBW 2992 and PF-00299804 (BIBW 2992
being especially preferred), or a pharmaceutically acceptable salt thereof, is administered
according to a continuous regimen based on an average daily dose in the range of 10 to
50 mg and
a mAB selected from the group consisting of cetuximab and panitumumab (cetuximab
being especially preferred), is co-administered according to a dosing regimen ranging
from an e weekly iv dose of 50 to 500 mg/m2 ed twice or once a week or
once in two weeks to
(e) a patient with acquired resistance to treatment with TKIs, such as gefitinib or
erlotinib, afatinib, dacomitinib or others, wherein the method provides to overcome
resistance to TKI treatment,
(g) a patient with primary or acquired resistance caused by T790M (T790M+), wherein
the method provides to prevent or overcome resistance to TKI treatment, or
(h) a patient with primary or acquired resistance not caused by T790M -), e. g.
by other isms such as MET oncogene or by unknown origin, wherein the
method provides to tor overcome resistance to TKI ent.
A fiarther preferred embodiment of the first object of the present invention is a method of
treating patients suffering from NSCLC, including metastatic forms f, wherein in this
method
BIBW 2992, or a pharmaceutical acceptable salt thereof, is administered according to a
continuous regimen based on an average daily dose in the range of 10 to 50 mg and
cetuXimab is is inistered according to a dosing regimen ranging from an average
weekly iv dose of 50 to 500 mg/m2 repeated twice or once a week to
(h) a patient with primary or acquired resistance not caused by T790M (T790M-), e. g.
by other mechanisms such as MET oncogene or by n origin, wherein the
method provides to prevent or overcome resistance to TKI treatment,
but most preferably to
(h') a patient with acquired resistance not caused by T790M (T790M-), e.g. by other
mechanisms such as MET oncogene or by unknown origin, wherein the method
es to overcome resistance to TKI treatment.
A first preferred embodiment of the second object of the ion is a pharmaceutical kit,
wherein the second compartment comprises an effective amount of a TKI selected from the
group consisting of EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357, CI-lO33, BIBW
2992 and PF-00299804 or a pharmaceutically acceptable salt thereof
A second preferred embodiment of the second object of the invention is a pharmaceutical kit,
wherein the second compartment comprises an effective amount of a mAB selected from the
group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab.
A second preferred embodiment of the second object of the invention is a pharmaceutical kit,
wherein the second compartment comprises an effective amount of a mAB selected from the
group consisting of cetuximab, mumab, zalutumumab, nimotuzumab and matuzumab.
A third preferred embodiment of the second object of the invention is a pharmaceutical kit,
comprising a first compartment which comprises an ive amount of a mAB selected from
the group consisting of cetuximab and panitumumab, and a second compartment which
comprises an effective amount of a TKI selected from the group consisting of HKI-272,
BIBW 2992 and PF-00299804, (BIBW 2992 and PF-00299804 being especially red), or
a pharmaceutically acceptable salt thereof
A fourth preferred embodiment of the second object of the invention is a pharmaceutical kit,
comprising a first tment which ses an effective amount of a mAB selected from
the group consisting of cetuximab and panitumumab (cetuximab being especially preferred),
and a second compartment which comprises an effective amount of a TKI selected from the
group consisting of BIBW 2992 and PF-00299804 (BIBW 2992 being especially preferred),
or a ceutically acceptable salt thereof
A fivth preferred embodiment of the second object of the invention is a pharmaceutical kit,
comprising a first compartment which comprises an effective amount of cetuximab, and a
second compartment which comprises an effective amount of BIBW 2992, or a
pharmaceutically acceptable salt f
A first preferred ment ofthe third object of the invention is an irreversible TKI for use
in a method of treatment of a t suffering from NSCLC, HNSCC, ant ,
breast , esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer,
ovarian cancer, pancreatic cancer, hepatocellular cancer or CRC, including metastatic forms
thereof, by coadministration with a Human EGFR targeted mAB,
wherein the TKI is selected from the group consisting of EKB-569, HKI-272, HKI-357,
CI-lO33, BIBW 2992 and PF-00299804, or a pharmaceutically acceptable salt thereof,
and is administered according to a continuous regimen based on an average daily dose in
the range of 10 to 50 mg, and
the mAB is selected from the group consisting of cetuximab, panitumumab,
zalutumumab, nimotuzumab and matuzumab and is co-administered according to a
dosing regimen g from an average weekly iv dose of 50 to 500 mg/m2 repeated
thrice, twice or once a week, once in two weeks, once in three weeks or at least once
monthly to
(c) a patient with a tumor expressing d forms of the EGFR, or
(d) a patient previously treated with EGFR inhibitors, such as gefitinib or erlotinib
afatinib, dacomitinib or others wherein the method es to overcome primary or
acquired resistance to EGFR inhibitors,
(e) a patient with acquired resistance to treatment with TKIs such as gefitinib or
erlotinib, ib, dacomitinib or others wherein the method provides to overcome
resistance to TKI ent,
(g) a patient with primary or acquired resistance caused by T790M +), wherein
the method provides to t or overcome resistance to TKI treatment, or
(h) a patient with primary or acquired resistance not caused by T790M (T790M-), e. g.
by other mechanisms such as MET oncogene or by unknown origin, wherein the
method provides to prevent or overcome resistance to TKI treatment.
A second preferred embodiment of the third object of the invention is an irreversible TKI for
use in a method of treatment of a patient suffering from NSCLC, HNSCC, malignant glioma,
breast cancer or CRC, ing atic forms thereof, wherein in this method
the TKI is selected from the group consisting of HKI-272, BIBW 2992 and PF-00299804,
(BIBW 2992 and PF-00299804 being especially red), or a pharmaceutically
acceptable salt thereof, and is administered according to a continuous regimen based on
an average daily dose in the range of 10 to 50 mg, and
the mAB is selected from the group consisting of cetuximab and panitumumab, and is co-
administered according to a dosing regimen g from an average weekly iv dose of
50 to 500 mg/m2 repeated twice or once a week or once in two weeks to
(c) a patient with a tumor harboring EGFR mutations in exons l9 and 21 associated with
drug sensitivity (i.e., G7l9X, exon 19 deletion, L858R, L86lQ), or
(e) a patient with acquired resistance to treatment with TKIs such as gefitinib or
erlotinib, afatinib, dacomitinib or others wherein the method provides to overcome
resistance to TKI treatment,
(g) a t with primary/acquired resistance caused by T790M (T790M+), wherein the
method es to prevent or overcome ance to TKI treatment, or
(h) a patient with primary or acquired resistance not caused by T790M (T790M-), e. g.
by other mechanisms such as MET oncogene or by unknown origin, n the
method provides to prevent or overcome resistance to TKI treatment.
A third preferred embodiment of the third object of the invention is an irreversible TKI for
use in a method of treatment of a patient suffering from NSCLC or HNSCC, including
metastatic forms f, wherein in this method
the TKI is selected from the group consisting of BIBW 2992 and PF-00299804 (BIBW
2992 being especially red), or a pharmaceutically acceptable salt thereof, is
administered according to a continuous regimen based on an average daily dose in the
range of 10 to 50 mg, and
the mAB is selected from the group consisting of cetuximab and panitumumab
(cetuximab being especially preferred), and is co-administered ing to a dosing
n ranging from an average weekly iv dose of 50 to 500 mg/m2 repeated twice or
once a week or once in two weeks to
2012/059098
(e) a patient with acquired resistance to treatment with TKIs, such as gefitinib or
erlotinib, afatinib, dacomitinib or others, wherein the method provides to overcome
resistance to TKI treatment,
(g) a patient with primary or ed resistance caused by T790M (T790M+), wherein
the method provides to prevent or overcome resistance to TKI treatment, or
(h) a patient with primary or acquired resistance not caused by T790M (T790M-), e. g.
by other mechanisms such as MET ne or by n origin, wherein the
method provides to preventor overcome resistance to TKI treatment.
A fourth preferred embodiment of the third object of the invention is an irreversible TKI for
use in a method of treatment of a patient suffering from NSCLC, including metastatic forms
thereof, wherein in this method
the TKI is BIBW 2992, or a pharmaceutical acceptable salt thereof, and is stered
according to a continuous regimen based on an average daily dose in the range of 10 to
50 mg, and
the mAB is cetuximab and is co-administered ing to a dosing regimen ranging
from an average weekly iv dose of 50 to 500 mg/m2 repeated twice or once a week to
(h) a patient with primary or acquired resistance not caused by T790M (T790M-), e. g.
by other mechanisms such as MET oncogene or by unknown origin, wherein the
method provides to prevent or overcome resistance to TKI treatment,
but most preferably to
(h') a t with acquired resistance not caused by T790M (T790M-), e.g. by other
mechanisms such as MET oncogene or by unknown origin, wherein the method
provides to overcome resistance to TKI treatment.
In a first preferred embodiment of the fourth object of the invention the rsible tyrosine
kinase inhibitor (TKI) is selected from the group consisting of EKB-569 (pelitinib), HKI-272
(neratinib), HKI-357, CI-lO33, BIBW 2992 and 99804 or a pharmaceutically
acceptable salt thereof
In a second preferred embodiment of the fourth object of the invention the Human EGFR
targeted monoclonal antibody (mAB) is selected from the group ting of mab,
panitumumab, mumab, nimotuzumab, and matuzumab.
In a third preferred embodiment of the fourth object of the invention the cancer is selected
from the group consisting of NSCLC, HNSCC, malignant glioma, breast cancer, esophageal
cancer, gastric , renal , cervical cancer, prostate cancer, ovarian cancer,
pancreatic , cellular cancer and CRC, including metastatic forms f,
the TKI is selected from the group consisting of EKB-569, HKI-272, HKI-357, CI-lO33,
BIBW 2992 and PF-00299804, or a pharmaceutically acceptable salt thereof,
the mAB is selected from the group consisting of cetuximab, panitumumab,
zalutumumab, zumab and matuzumab , and
the patient is
(c) a patient with a tumor expressing mutated forms of the EGFR, or
(d) a patient previously treated with EGFR inhibitors, such as ib or erlotinib
afatinib, dacomitinib or others wherein the method provides to overcome primary or
acquired resistance to EGFR inhibitors,
(e) a patient with acquired resistance to treatment with TKIs such as gefitinib or
erlotinib, afatinib, dacomitinib or others wherein the method provides to overcome
resistance to TKI treatment,
(g) a patient with primary or ed resistance caused by T790M (T790M+), wherein
the method provides to prevent or overcome resistance to TKI treatment, or
(h) a patient with primary or acquired resistance not caused by T790M (T790M-), e. g.
by other mechanisms such as MET oncogene or by unknown origin, wherein the
method provides to prevent or overcome resistance to TKI treatment.
In a fourth preferred embodiment of the fourth object of the invention the cancer is selected
from the group consisting of NSCLC, HNSCC, malignant glioma, breast cancer and CRC,
including atic forms thereof,
the TKI is ed from the group ting of 2, BIBW 2992 and PF-00299804,
(BIBW 2992 and PF-00299804 being especially preferred), or a pharmaceutically
acceptable salt thereof,
the mAB is ed from the group consisting of cetuximab and panitumumab, and is co-
administered according to a dosing regimen ranging from an average weekly iv dose of
50 to 500 mg/m2 repeated twice or once a week or once in two weeks to, and
the patient is
(c) a patient with a tumor harboring EGFR mutations in exons l9 and 21 associated with
drug sensitivity (i.e., G7l9X, exon 19 deletion, L858R, L86lQ), or
(e) a patient with acquired resistance to treatment with TKIs such as gefitinib or
erlotinib, afatinib, dacomitinib or others wherein the method provides to overcome
ance to TKI treatment,
(g) a patient with primary/acquired resistance caused by T790M (T790M+), wherein the
method provides to prevent or overcome resistance to TKI treatment, or
(h) a patient with primary or acquired resistance not caused by T790M (T790M-), e. g.
by other mechanisms such as MET oncogene or by unknown origin, wherein the
method provides to prevent or overcome resistance to TKI treatment.
In a f1vth preferred embodiment of the fourth object of the ion the cancer is selected
from the group consisting ofNSCLC or HNSCC, including metastatic forms thereof,
the TKI is selected from the group consisting of BIBW 2992 and PF-00299804 (BIBW
2992 being especially red), or a ceutically acceptable salt thereof,
the mAB is selected from the group consisting of mab and panitumumab
(cetuXimab being especially preferred), and
the t is
(e) a patient with acquired resistance to treatment with TKIs, such as gefitinib or
erlotinib, afatinib, dacomitinib or , wherein the method provides to overcome
resistance to TKI treatment,
(g) a t with primary or acquired resistance caused by T790M (T790M+), wherein
the method provides to prevent or overcome resistance to TKI treatment, or
(h) a patient with primary or acquired ance not caused by T790M (T790M-), e. g.
by other mechanisms such as MET oncogene or by unknown origin, wherein the
method provides to preventor overcome resistance to TKI treatment.
In a sixth preferred embodiment of the fourth object of the invention the cancer is NSCLC,
including metastatic forms thereof,
the TKI is BIBW 2992, or a pharmaceutical acceptable salt thereof,
the mAB is cetuximab and is co-administered according to a dosing regimen ranging
from an e weekly iv dose of 50 to 500 mg/m2 repeated twice or once a week to
(h) a patient with primary or acquired resistance not caused by T790M (T790M-), e. g.
by other mechanisms such as MET oncogene or by unknown origin, wherein the
method provides to prevent or overcome resistance to TKI treatment,
In a seventh preferred ment ofthe fourth object of the invention
(h') the patient has acquired resistance not caused by T790M (T790M-), e.g. by other
mechanisms such as MET oncogene or by unknown origin, wherein the method
provides to me resistance to TKI treatment.
Dosages / irreversible TKI:
Dosage forms of the irreversible TKIs are either available on the market or described in
publications. According to any aspect of the invention the TKI, e.g. BIBW 2992, is
administered in a total e daily dose of 10 to 50 mg, e.g. in a total average daily dose
selected from 10, 15, 20, 25, 30, 35, 40, 45 and 50 mg, optionally divided into multiple doses,
e.g. 1, 2 or 3 doses to be administered through the day. Preferably the TKI is administered
orally only once a time per day, but alternative routes of administration may be applied.
Dosages / mABs:
Dosage forms of the mABs also are either available on the market or described in
publications. According to any aspect of the invention e weekly iv doses of 50 to 500
mg/mz, e.g. 50, 75, 100, 200, 250, 300, 350, 375, 400, 425, 450, 475 and 500 mg/m2 ofthe
mAB component, e. g. cetuximab or panitumumab, may be applied in the regimen ned
in the context of the invention.
Based on body weight single iv doses of1 to 15 mg/kg, e.g. 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5,
6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, , 13, 13.5, 14, 14.5 or 15 mg/kg ofthe
mAB component, e. g. cetuximab or mumab, may be applied in the regimen ned
in the context of the invention. Based on a 70 kg adult patient this results in 70 to 1050 mg
range for a single dose.
However, it may optionally be necessary to deviate from the dosage amounts specified for the
TKI and /or the mAB component, within the limitations set, depending on the body weight or
method of administration, the individual response to the medication, the nature of the
formulation used and the time or interval over which it is administered. When dosages at the
high end are stered it may be advisable to spread them over the day in a number of
single doses.
Instructionfor coadmz'nz'stratz'on.‘
Instructions for coadministration may be in any form suitable for pharmaceuticals, e.g. in
form of a leaflet added to the dosage form within secondary ing or an imprint on the
primary or secondary packaging.
The following Example serve to illustrate the invention t restricting it:
e 1: Activity and tolerability of afatinib (BIBW 2992; A) and cetuximab (C) in
patients with non-small cell lung cancer (NSCLC) and acquired resistance to erlotinib
(E) or gefitinib (G) calTrials.gov identifier: NCT01090011)
Background: Despite initial responses to reversible EGFR-TKIs e.g. E or G, all NSCLC
patients with EGFR sensitizing mutations experience e progression. This “acquired
resistance” (AR) is associated with a second site exon 20 EGFR T790M mutation (M) in over
half of cases. So far, no therapy, including the anti-EGFR antibody C plus E, has proven
effective in treating AR (Janjigian YY. Clin Cancer Res; Epub Jan 201 l). Preclinical data
suggest that A, a potent irreversible inhibitor of the ErbB receptor family, is active in M cell
lines. Combined EGFR targeting with A and C has induced near complete responses in
T790M transgenic murine models. This is the first clinical study to assess safety and
preliminary efficacy of this ation in NSCLC patients.
Methods: NSCLC patients with clinically defined AR (Jackman D. J Clin Oncol 2010;
28:357) received oral A 40 mg daily with escalating dose cohorts of biweekly C at 250 and
500 mg/mz. Patients receiving the ended phase 2 dose (RP2D) were evaluated for
objective response. Acquisition oftumor tissue at or after emergence ofAR was mandated.
Results: Of 26 treated patients, 22 received the fined maximum dose = RP2D: A 40 mg
+ C 500 mg/ m2. Median time on E or G at study entry was 2.4 years. No dose-limiting
toxicity was observed.. The common adverse events (AE) were rash (83%) and diarrhea
(62%). 3 (6.4%) ts had grade 3 rash and 2 (4.3%) ts had grade 3 diarrhea. Disease
control was observed in all patients enrolled at RP2D (tumor size reduction up to 76%,
treatment duration up to 5+ ). Confirmed partial responses (PRs) were seen in 12/32
(38%) evaluable patients, ing 10/17 (59%) and 6/55 (14%) not (yet) confirmed PRs in
T790M+ and T790M — NSCLC, respectively.
Overall s regarding tolerability (adverse events) and treatment response are summarized
in tables 1 and 2.
Conclusions: ed EGFR targeting with A and C is tolerable at the RP2D. Mild to
moderate diarrhae and skin adverse events are manageable. Disease control was observed in
all patients enrolled at RP2D. EGFRmut+ NSCLC with AR to nib and gefitinib
continues to depend on EGFR signaling. A in ation with C overcomes acquired
resistance to prior erlotinib / gefitinib. The clinical activity is not restricted to T790M
mediated acquired resistance.
Table l: Rash/Acne and Diarrhae Adverse Events (AE) Summary
Rasfihmcne Ali grade-s
Diarrhea, All grades 29 (61.7)? 311160.83
Rachmcne. Grade 3
Diarrhea, Grade 3
nib 40 + 250 and 40 + 500 CetuX refers to the dosing regimen of Afatinib and
Cetuximab, see Methods; 4(lO0.0) means 4 patients (100%)).
Table 2: Treatment Response by EGFR Mutation for patients at MTD (maximum tolerated
dose)
"rota! Treated 17 11 32
0'“ [(4%)]
FR [N(%)] 10 (59%) 6 (55%) N03) 2 (100%) 18(56%)
FR [M(%)] 6(35%) 4 (36%) (1(0) 2 (100%) 1‘2 (38%)
confirmed
5D [N(‘%_)] 7 (41.2) 4 (36.4) 2 (100.0) 0 (0.0) 13 (40.6)
(”D [WW]
PR: l response
SD: stable disease
PD: progressing disease
N: number ofpatients
T790M--: T790M positive patients
T790M--: T790M negative patients
Claims (8)
1. Use of an irreversible tyrosine kinase tor (TKI) selected from the group ting of EKB-569 inib), HKI-272 (neratinib), HKI-357, CI-1033, BIBW 2992, PF- 00299804 1-(4-(4-(3,4-dichlorofluorophenylamino)methoxyquinazolin yloxy)piperidinyl)propenone, WZ 3146, WZ 4002, and WZ 8040, or a ceutically able salt f, for preparation of a medicament for treating of a human patient suffering from a cancer driven by deregulated Human Epidermal Growth Factor Receptor (HER/Human EGFR) selected from the group consisting of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), malignant glioma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical , prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer, and colorectal cancer (CRC), including metastatic forms thereof, wherein the medicament is for use in combination with a Human EGFR targeted monoclonal antibody (mAB) selected from the group consisting of cetuximab, panitumumab, zalutumumab, zumab, matuzumab and mumab, wherein the treating comprises administering the TKI according to a continuous regimen based on an average daily dose in the range of 10 to 50 mg and co-administering the mAB ing to a dosing regimen ranging from an average weekly iv dose of 50 to 500 mg/m2 repeated thrice, twice or once a week, once in two weeks, once in three weeks or at least once monthly.
2. Use of an irreversible tyrosine kinase inhibitor (TKI) selected from the group consisting of EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357, CI-1033, BIBW 2992, PF-00299804 1- (4-(4-(3,4-dichlorofluorophenylamino)methoxyquinazolinyloxy)piperidinyl)prop- 2-enone, WZ 3146, WZ 4002, and WZ 8040, or a pharmaceutically acceptable salt f, a Human EGFR targeted monoclonal antibody (mAB) selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab and necitumumab, for preparation of a medicament for treating of a human patient suffering from a cancer driven by deregulated Human Epidermal Growth Factor Receptor (HER/Human (10177874_1):RTK [Link] http://en.wikipedia.org/wiki/Zalutumumab [Link] http://en.wikipedia.org/wiki/Nimotuzumab [Link] http://en.wikipedia.org/wiki/Matuzumab EGFR) selected from the group consisting of all cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), malignant glioma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer, and colorectal cancer (CRC), including metastatic forms thereof, wherein the treating comprises administering the TKI according to a continuous regimen based on an average daily dose in the range of 10 to 50 mg and co-administering the mAB according to a dosing regimen ranging from an e weekly iv dose of 50 to 500 mg/m2 repeated thrice, twice or once a week, once in two weeks, once in three weeks or at least once y.
3. The use of claim 1 or claim 2, wherein the TKI is selected from the group consisting of EKB-569, HKI-272, HKI-357, CI- 1033, BIBW 2992 and PF-00299804, or a pharmaceutically acceptable salt thereof, the mAB is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and the patient is (a) a patient with a tumor expressing mutated forms of the EGFR, or (b) a patient usly treated with EGFR inhibitors, or (c) a patient with acquired resistance to treatment with TKIs, or (d) a patient with primary or acquired resistance to treatment with TKIs caused by T790M +), or (e) a patient with primary or acquired ance to treatment with TKIs not caused by T790M (T790M-).
4. The use of claim 1 or claim 2, n the cancer is selected from the group consisting of NSCLC, HNSCC, malignant glioma, breast cancer or CRC, including metastatic forms the TKI is selected from the group consisting of HKI-272, BIBW 2992 and PF- 04, or a pharmaceutically acceptable salt thereof, the mAB is selected from the group consisting of cetuximab and mumab, coadministered according to a dosing regimen ranging from an average weekly iv dose of 50 to 500 mg/m2 ed twice or once a week or once in two weeks, and the patient is (10177874_1):RTK (a) a patient with a tumor harboring EGFR mutations in exons 19 and 21 associated with drug sensitivity, or (b) a patient with acquired ance to treatment with TKIs, or (c) a patient with primary or acquired resistance to treatment with TKIs caused by T790M (T790M+), or (d) a patient with primary or ed resistance to treatment with TKIs not caused by T790M (T790M-).
5. The use of claim 1 or claim 2, wherein the cancer is selected from the group consisting of NSCLC or HNSCC, including metastatic forms thereof, the TKI is selected from the group consisting of BIBW 2992 and PF-00299804 or a pharmaceutically acceptable salt thereof, the mAB is selected from the group consisting of cetuximab and panitumumab, coadministered according to a dosing regimen ranging from an average weekly iv dose of 50 to 500 mg/m2 ed twice or once a week or once in two weeks, and the patient is (a) a patient with acquired resistance to treatment with TKIs, or (b) a patient with primary or acquired resistance to treatment with TKIs caused by T790M (T790M+), or (c) a patient with primary or acquired ance to treatment with TKIs not caused by T790M (T790M-).
6. The use of claim 1 or claim 2, wherein the cancer is NSCLC, including metastatic forms thereof, the TKI is BIBW 2992, or a pharmaceutical acceptable salt thereof, the mAB is cetuximab, inistered according to a dosing regimen ranging from an e weekly iv dose of 50 to 500 mg/m2 repeated twice or once a week, and the patient is a patient with y or acquired resistance to treatment with TKIs not caused by T790M (T790M-).
7. The use of any one of claims 1 to 6, wherein the cancer is NSCLC, including metastatic forms thereof, and the t is a patient with acquired resistance to treatment with TKIs not caused by T790M -). (10177874_1):RTK
8. The use of claim 2, wherein the medicament is in the form of a pharmaceutical kit, said pharmaceutical kit comprising: a first compartment which comprises an ive amount of the Human EGFR targeted monoclonal antibody (mAB), and a second compartment which comprises an effective amount of the irreversible tyrosine kinase inhibitor (TKI).
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11166446.2 | 2011-05-17 | ||
EP11166446 | 2011-05-17 | ||
PCT/EP2012/059098 WO2012156437A1 (en) | 2011-05-17 | 2012-05-16 | Method for egfr directed combination treatment of cancer |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ616183A NZ616183A (en) | 2015-09-25 |
NZ616183B2 true NZ616183B2 (en) | 2016-01-06 |
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