HK1190637A

HK1190637A - Method for egfr directed combination treatment of cancer

Info

Publication number: HK1190637A
Application number: HK14103936.5A
Authority: HK
Inventors: Louis Denis; Robert Lorence; Mehdi Shahidi; Flavio Solca
Original assignee: 勃林格殷格翰国际有限公司
Priority date: 2011-05-17
Filing date: 2012-05-16
Publication date: 2014-07-11

Description

Combined method for treating cancer by targeting epidermal growth factor receptor

The present invention relates to methods of treating patients with cancer caused by dysregulation of the human epidermal growth factor receptor (HER/human EGFR), such as, but not limited toNon-small cell lung cancer (NSCLC), Head and Neck Squamous Cell Carcinoma (HNSCC), breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer, glioblastoma, prostate cancer, and colorectal cancer (CRC), comprising administering to a patient in need of such treatment a flexible and effective combination dosing regimen of an irreversible Tyrosine Kinase Inhibitor (TKI) and a human EGFR targeting mAB (mAB), wherein in this method the TKI is administered according to a continuous dosing regimen based on an average daily dose in the range of 10 to 50mg, and the mAB is administered according to an average weekly intravenous dose in the range of 50 to 500mg/m²And is co-administered with a regimen that is repeated three, two or once a week, or once every two weeks, or once every three weeks, or at least once a month. The treatment methods described in the present invention include the treatment of patients who have not been treated with TKI (TKI-nasal Patients) and patients who have been pre-treated with EGFR TKI, particularly those with congenital or acquired resistance to reversible or irreversible TKI treatment, such as gefitinib, erlotinib, 1- (4- (4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one or its salts, EKB-569 (pelitinib), HKI-272 (lenatinib), HKI-357, lapatinib, CI-1033 (canitinib), WZ3146, WZ4002, WZ8040 (structures of the three WZ compounds are disclosed in Wenjun Zhou et al: Nomutatin-selective EGFR kinase inhibitors 790M, in Nature2009, Vol.462, 1070-. In addition the treatment methods of the invention include overcoming congenital or acquired resistance and preventing or delaying acquired resistance to (reversible or irreversible) TKI treatment.

Other aspects of the invention are pharmaceutical compositions and pharmaceutical kits comprising instructions for co-administering the TKI with the mab, indicating that an irreversible TKI is co-administered with a targeted mab to prevent ligand binding to EGFR; also relates to the use of an irreversible TKI in the preparation of a pharmaceutical composition comprising an effective amount of an irreversible TKI, and instructions for co-administration with a monoclonal antibody.

Background

EGFR expression is in a variety of malignant solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma and colorectal cancer, and abnormalities or dysregulation of EGFR activity are known to promote most tumorigenic processes. Lung cancer is a leading cause of cancer death in industrialized countries. Lung-derived cancers are divided into two main types, non-small cell lung cancer and small cell lung cancer, which are determined by cell morphology under a microscope. In general, non-small cell lung cancers (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) spread more slowly to other organs than small cell lung cancer. Approximately 75% of lung cancer cases belong to non-small cell lung cancer (e.g., adenocarcinoma), with the remaining 25% being small cell lung cancer. Chemotherapy offers suitable survival benefits for patients with advanced cancer, but at the cost of significant toxicity, thus emphasizing the need for therapeutic agents with a clear target for critical genetic lesions that lead to tumor growth (Schiller JH et al, N Engl JMed, 346:92-98, 2002).

Mutations that result in overexpression (upregulation) or overactivity of EGFR are associated with a number of cancers, including lung cancer, anal cancer, and glioblastoma multiforme. Mutation, amplification or mismodulation of EGFR or a family member thereof is associated with about 30% of epithelial cancers. Thus, mutations of EGFR have been identified in several types of cancer and anti-cancer treatments have been developed against EGFR, using two approaches: (1) a targeted monoclonal antibody (mAB) that prevents ligand binding to EGFR, and (2) a small molecule Tyrosine Kinase Inhibitor (TKI) that prevents the intracellular catalytic activity of the receptor. Skin toxicity, characterized by rash or acne-like symptoms, and varying degrees of diarrhea are the most common adverse events for EGFR-targeted therapies (Expert opin. investig. drugs (2009)18(3), 293-acetone 300).

Human/mouse chimeric IgG1mAB cetuximab down-regulates EGFR signaling and subsequently inhibits cell proliferation, induces apoptosis and reduces angiogenesis. Cetuximab and chemotherapyThe combination of approaches has been approved by the health authorities for the treatment of metastatic colorectal cancer as well as for the treatment of locally advanced and metastatic head and neck cancer. Cetuximab has also demonstrated little clinical activity as a single drug in advanced non-small cell lung cancer patients previously treated with EGFR TKI (Neal JW, Heist RS, Fidias P, Temel JS, Huberman M, Marcoux JP, Muzikansky A, Lynch TJ, Sequist LV; J thoraconcol.2010Nov; 5(11):1855-8: Cetuximab mongerapy in patents with facilitated non-small cell lung enzyme kinase enzyme therapy). Panitumumab (A)) Is a human IgG2 monoclonal antibody directed against EGFR and is approved for the treatment of metastatic colorectal cancer. Other monoclonal antibodies, zalutumumab, nimotuzumab, matuzumab and Necitumumab, have been developed clinically.

The first generation of small molecule HER TKIs include gefitinib (r) (gefitinib)) And erlotinib () Both reversibly bind to the EGFR. Gefitinib is indicated for the full-line treatment of advanced non-small cell lung cancer carrying EGFR mutations, and erlotinib is indicated for the treatment of advanced non-small cell lung cancer following prior chemotherapy, but full-line treatment of EGFR mutation-positive non-small cell lung cancer is being developed. These new drugs are directed against the EGFR. Patients have been classified as EGFR positive (EGFR) based on whether the detection in tissue shows a mutation⁺) And negative (EGFR)^-) A patient. Tumors of EGFR-positive patients carry EGFR mutations (i.e., G719X, exon 19 deletion, L858R, L861Q) on exons 19 and 21 associated with drug sensitivity, showing response rates of up to 60%, which exceed that of conventional chemotherapy.

Second generation small molecule TKIs have been designed as irreversible EGFR inhibitors that bind irreversibly to EGFR, preferably to cysteine 773 of EGFR. Non-limiting examples include the compounds disclosed in: U.S. Pat. No.6,002,008, US7,019,012, US6,251,912, WO02/50043, WO2004/074263, WO2005/037824, WO2008150118 (especially the compound of example 36, 1- (4- (4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one, or a salt formed with an acidic additive, as disclosed in WO 2011793), EKB-569 (pelitinib), HKI-272 (lenatinib), HKI-357, CI-1033 (canitinib), WZ3146, WZ4002, WZ8040 (structures of the three WZ compounds are disclosed in Wenjun Zhou et al: Novel mutated-selective EGFR enzyme inhitomers EGFR 790 agai, M, nature 992009, Natl 10792, BW-294-29804), or BIPF 29804. BIBW2992 (Arvatinib) and PF-00299804 (dacetinib) are the most advanced second generation small molecule TKIs in the recent clinical progression for the treatment of non-small cell lung cancer.

More particularly BIBW2992, herein denoted by its INN name atorvastatin, which is the compound 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7- ((S) -tetrahydrofuran-3-yloxy) -quinazoline,

preferred for use as maleate salt BIBW2992 maleic acid =1:2:

BIBW2992 is a potent irreversible and selective dual inhibitor of erbB1 receptor (EGFR) with erbB2(Her2/neu) and erbB4(Her4) receptor tyrosine kinases, which can be administered orally. Furthermore, BIBW2992 is designed to covalently bind to EGFR and HER2, thereby irreversibly inactivating the receptor molecules to which it binds. This compound, its salts, e.g. hydrogen maleate, their preparation and pharmaceutical formulations comprising BIBW2992 or its salts, the indications for treatment with BIBW2992 and combinations comprising BIBW2992 are disclosed in WO02/50043, WO2005/037824, WO2007/054550, WO2007/054551, WO2008034776 and WO 2009147238.

PF-00299804 is an oral irreversible pan HER TKI, more specifically a HER1, 2 and 4 tyrosine kinase inhibitor. In preclinical studies, PF-00299804 was shown to inhibit signaling in wild-type and mutant EGFR (including non-small cell lung cancer that is resistant to currently available EGFR inhibitors such as erlotinib and gefitinib). Preclinical findings indicate that PF-00299804 may be clinically effective against non-small cell lung cancer with EGFR or ERB-B2 mutations as well as non-small cell lung cancer carrying the EGFR T790M mutation, which is resistant to gefitinib and erlotinib (Expert opin. investig. drugs (2010)19(12): 1503) 1514).

PF-00299804 (dacomitinib) is the compound N- [4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinazolin-6-yl ] -3-piperidin-1-yl-acrylamide disclosed in WO2005107758 (examples 2 and 3) and has the following structure:

the properties of EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357 and CI-1033 are well known, for example, Expert opin Investig Drugs2009,18(3), 293-. The development of EKB-569 for the treatment of non-small cell lung cancer has been discontinued for several years. Other reports have shown that HKI-272 can overcome T790M-mediated resistance only at suprapharmacological concentrations (N.Godin-Heymann et al, The T790M "gatekeeper" mutation in EGFR differentiation to low concentrations of an irreversible EGFR inhibitor. mol. cancer ther.7,2008: 874-879). Notably, the development of HKI-272 for the treatment of non-small cell lung cancer was discontinued after phase II trials, which indicated that the compound had low activity in patients who had previously been beneficial for TKI and in patients who had not been treated with TKI, possibly due to insufficient bioavailability caused by diarrhea booster dose limitations (l.v. sequist et al, j.clin.onc.28(18),2010, 3076-. These did not translate into clinical benefit, indicating a low level of predictability in this area, compared to encouraging preclinical results and high efficacy of HKI-272.

In addition to generating an initial response in EGFR-mutated non-small cell lung cancer patients, acquired resistance develops after a median time of approximately 12 months. Accepted definitions for acquired resistance include: one or both of the following is met in a patient previously treated with a single agent EGFR-TKI (e.g., gefitinib or erlotinib): objective clinical benefit was obtained when tumors carried EGFR mutations (i.e., G719X, exon 19 deletions, L858R, L861Q) associated with drug sensitivity or were treated with EGFR-TKI; systemic progression of the disease employs RECIST criteria known in the art, whereas treatment with targeted EGFR requires at least 24 weeks of continuous treatment.

Response assessment criteria (RECIST) in solid tumors are disclosed in p.therase et al, J NatlCancer Inst2000,92, 205-; vol24, No.20,2006, pp3245-3251, in J.Clin.Oncol.Vol.24; or Eisenhauer EA, therase P, Bogaerts J, Schwartz LH, Sargent D, Ford R, etc., New response evaluation criterion in solid tumors, reviewed RECISTGulidine (version1.1), Eur J Cancer 2009; 45: 228-. Monitoring of tumor progression may be determined by comparing the tumor status between time points after initiation of treatment or by comparing the tumor status between time points after initiation of treatment and time points before initiation of treatment. During treatment, tumor progression may be monitored visually, for example by radiography, e.g., X-ray, CT scan, or other monitoring methods known to those skilled in the art (including cancer beating) or methods of monitoring tumor biomarker levels.

In addition to primary EGFR mutations (associated with erlotinib and gefitinib sensitivity), nearly half of patients with acquired EGFR-TKI resistance have secondary EGFR mutations in the tyrosine ATP-binding pocket (T790M), which can alter the receptor's affinity for ATP. These secondary mutations allow the cancer cells to continue to signal through the mutated EGFR, indicating that the proportion of patients with acquired resistance to EGFR-TKI, tumor growth and proliferation remains dependent on EGFR.

The presence of MET oncogenes has been reported as a secondary source of resistance (Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA, etc., Clinical definition of acquisition driver to epidemic growth factor inhibitors in small-cell lung cancer 2010; J Clin Oncol 2010; 28: 357-60).

As of 2010, no clinical consensus has been reached on acceptable methods of overcoming or preventing resistance, nor has there been official approval of a particular drug or combination of drugs in this regard.

There is a significant medical need in the art for satisfactory treatment of cancers, particularly epithelial cell cancers such as lung, ovarian, breast, brain, colon and prostate cancers, with the combined benefits of EGFR-targeted therapy and overcoming the non-responsiveness shown by patient cancers. Therefore, the key to the problem of the present invention is to establish an improved treatment for patients suffering from epithelial cell cancer, characterized by an increased efficacy and improved or at least acceptable tolerance, including the following patient populations:

(a) a TKI-untreated cancer patient, wherein the improvement comprises preventing or delaying resistance to TKI treatment,

(b) patients whose tumors express wild-type EGFR (previously described as EGFR)^-)，

(c) Patients whose tumors express a mutant form of EGFR (described hereinbefore as EGFR)⁺)，

(d) A patient that has been previously treated with an EGFR inhibitor, such as gefitinib, erlotinib, afatinib, dacomitinib, or others, wherein the improvement comprises overcoming innate or acquired resistance to the EGFR inhibitor,

(e) a patient having acquired resistance to TKI treatment, such as gefitinib, erlotinib, afatinib, dacomitinib, or others, wherein the improvement comprises overcoming resistance to TKI treatment,

(g) a population of patients having congenital or acquired resistance caused by T790M (T790M +), wherein the improvement comprises preventing/overcoming resistance to TKI treatment, and

(h) a population of patients having innate or acquired resistance not caused by T790M (T790M-), e.g. caused by other mechanisms, e.g. by MET oncogene or by unknown origin, wherein the improvement comprises preventing/overcoming resistance to TKI treatment.

Improvement in treatment selection for patients with non-small cell lung cancer with acquired resistance to gefitinib or erlotinib follows the following concept: the total receptor was blocked by combining TKI and anti-EGFR monoclonal antibodies. This is summarized in S.Ramalingam et al, Journal of clinical Oncology Vol.3, Number3, March2008, 258-265. The hypothesis was that simultaneous vertical inhibition of EGFR and increased blockade of downstream activity was possible by the combination. Residual EGFR activity may leave cancer cells active after exposure to either class of inhibitors alone, but concurrent dual inhibition may lead to apoptosis. The results of the xenograft model support this hypothesis: when cetuximab is administered in combination with erlotinib or gefitinib, a synergistic effect has been observed compared to monotherapy with either drug. Cetuximab has been shown to down-regulate EGFR on the cell surface, potentially increasing sensitivity to TKIs. The conclusion is that: the combination of cetuximab and erlotinib appears to produce a synergistic effect in a way that activates apoptosis in vitro and results in additional tumor growth inhibition in vivo.

However, the question is whether these raw results can translate into clinical benefit. Ramalingam et al report phase I findings,wherein the optimal dose is determined when cetuximab and gefitinib are administered in combination to a patient with advanced/metastatic non-small cell lung cancer (NSCLC) who has previously been treated with platinum-based chemotherapy. Advanced/metastatic non-small cell lung cancer patients who had previously been treated with platinum-based chemotherapy received weekly increasing doses of cetuximab (100, 200, and 250 mg/m)²Intravenous administration) and fixed dose gefitinib (250mg/d, oral administration) until disease progression or unacceptable toxicity occurs. The reported results show that the combination of cetuximab and gefitinib can be administered safely, but only moderately active in advanced/metastatic non-small cell lung cancer.

Y.Y.Janjian et al, Clin Cancer Res2011,17:2521-2527, reported a phase I/II trial on cetuximab and erlotinib that recruited 19 lung adenocarcinoma patients with acquired resistance to erlotinib. Patients with lung adenocarcinoma and clinically defined acquired resistance to erlotinib were treated with 100mg of erlotinib daily in three escalating dose groups (250 mg/m)²、375mg/m²And 500mg/m²) Cetuximab was administered every two weeks. The recommended phase II dose, as well as the initial endpoint of the objective response rate, was then evaluated in a two-stage trial. A determined recommended phase II dose is 500mg/m cetuximab²Every two weeks and erlotinib 100mg daily. At this dose and schedule, no radiographic response was observed. In fact, cetuximab 500mg/m was used²Every two weeks with 100mg erlotinib daily combination inhibits EGFR with no significant activity in patients with acquired resistance to erlotinib. Serious tolerability problems occurred during phase II part of the experiment. Typical grade 2, 3 and 4 toxicities were rash (13 patients, 68%), fatigue (12 patients, 63%) and hypomagnesemia (14 patients, 74%). 31% (6 out of 19 patients) stopped treatment due to intolerable rash.

Both ramalingam et al and y.y.janjigian et al report clinical results from the combination of cetuximab and reversible (first generation) TKI. Conversely, l.regales et al, j.clin.invest.119(10),2009:3000-^L858R(sensitive to erlotinib), EGFR^T790M(resistant to erlotinib) or EGFRL858R + T790M (resistant to erlotinib) in order to evaluate strategies to overcome the most prevalent EGFR TKI resistance mutation (T790M). Other drugs mentioned in the study were HKI-272 (neratinib) and PF-00299804, but no results were reported. The theory behind this is a preclinical study published by others (E.L. KWak, et al, Irreversible inhibitors of the EGF receptor monoclonal antibody resistance to targeting, Proc. Natl. Acad. Sci. U.S. A.2005,102: 7665-. Mice bearing EGFR mutated tumors are treated with a variety of anti-cancer agents, including the irreversible EGFR TKI BIBW2992 and the EGFR-specific antibody cetuximab. It was found that only the combination of these two drugs caused a sharp shrinkage of erlotinib resistant tumors carrying the T790M mutation.

Clinical trials. gov discloses an open-label phase I clinical trial using BIBW2992 in combination with cetuximab for continuous once daily oral treatment, with the main objective of determining the Maximum Tolerated Dose (MTD) and the recommended phase II dose in non-small cell lung cancer patients with acquired resistance to erlotinib or gefitinib, denoted NCT01090011, linked to the clinical trials. gov archive website. The following qualitative information about the dosing regimen is well known:

patients received a medium dose of BIBW2992, once daily, and infused low, medium, and high doses of cetuximab every two weeks

Cetuximab at the medium dose plus three dose levels (low, medium, high) in BIBW 2992.

Results or absolute dosages are not disclosed.

Summary of The Invention

The first object of the invention relates to a method for treating a patient suffering from a cancer caused by deregulated human epidermal growth factor receptor (HER/human EGFR), comprising administering to a patient in need of such treatment a flexible and effective dosing regimen of an irreversible Tyrosine Kinase Inhibitor (TKI) in combination with a human EGFR targeted mAB (mAB), wherein in this method the TKI is administered according to a continuous dosing regimen based on an average daily dose in the range of 10 to 50mg and the mAB is administered according to an average weekly iv dose in the range of 50 to 500mg/m²And is co-administered with a regimen that is repeated three, two or once a week, or once every two weeks, or once every three weeks, or at least once a month.

A second object of the invention is a pharmaceutical kit comprising: a first compartment comprising an effective amount of a human EGFR targeted monoclonal antibody and a second compartment comprising an effective amount of an irreversible TKI.

A third object of the invention is an irreversible TKI for use in a method of treating a patient suffering from a cancer caused by deregulated human epidermal growth factor receptor (HER/human EGFR) by co-administration with a human EGFR targeting mab, wherein the TKI is administered according to a continuous dosing regimen based on an average daily dose in the range of 10 to 50mg and the mab is administered according to an average weekly intravenous dose in the range of 50 to 500mg/m²And a regimen repeated three, two or once weekly, or once every two weeks, or once every three weeks, or at least once monthly is co-administered to patients having such treatment.

A fourth object of the invention is the use of an irreversible TKI for the preparation of a pharmaceutical kit for the treatment of patients suffering from a condition selected from the group consisting of human epidermal growth factor receptor (HER/human EGFR)A cancer patient suffering from dysregulation comprising a first compartment comprising an effective amount of a human EGFR targeted mab and a second compartment comprising an effective amount of an irreversible TKI, wherein the TKI is administered according to a continuous dosing regimen based on an average daily dose in the range of 10 to 50mg and the mab is administered according to an average weekly iv dose in the range of 50 to 500mg/m²And a regimen repeated three, two or once weekly, or once every two weeks, or once every three weeks, or at least once monthly is co-administered to patients having such treatment.

Detailed Description

Clinical results support: it has surprisingly been found that the combination of an irreversible TKI and a monoclonal antibody targeting human EGFR has a more pronounced activity than they would have been expected, this expectation being based on the results reported in the prior art that gefitinib/cetuximab or erlotinib/cetuximab dual targets are not effective in treating patients with lung adenocarcinoma and acquired resistant reversible TKI, and that low tolerance of such combinations are reported or based on preclinical data.

The irreversible TKI and the monoclonal antibody combined at the recommended dose for each drug resulted in good tolerability. This was unexpected in view of the low activity and tolerability of the gefitinib/cetuximab or erlotinib/cetuximab combinations (which are reported in S.Ramalingam et al, Journal of Thoracic Oncology Vol.3, Number3, March2008,258-265 and Y.Y.Janjian et al, Clin Cancer Res2011,17:2521-2527), which was summarized above.

Clinical trial data support: the activity of the combination according to the invention is not limited to T790M mediated resistance to TKI treatment, i.e. not only overcoming T790M mediated (T790M +: tumour carrying T790M) acquired resistance to TKI treatment, but also overcoming non-T790M (T790M-: tumour not carrying T790M) acquired resistance, e.g. by other mechanisms, e.g. MET oncogene or by unknown origin. There is no evidence in the prior art that this occurs.

These findings indicate that treatment with the combination according to the invention has the potential to significantly improve the therapeutic index for EGFR-targeted treatment of cancers (e.g. epithelial cell cancers) caused by deregulation of the human epidermal growth factor receptor (HER/human EGFR). Any of these findings are supported by the clinical results obtained with the combination of BIBW2992 and cetuximab.

Patients with cancers caused by deregulated human epidermal growth factor receptor (HER/human EGFR) include, but are not limited to, patients with non-small cell lung cancer (NSCLC), Head and Neck Squamous Cell Carcinoma (HNSCC), glioblastoma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular carcinoma, and colorectal cancer (CRC), including metastatic forms thereof. Preferred indications are non-small cell lung cancer and head and neck squamous cell carcinoma, especially non-small cell lung cancer.

Furthermore, patients having any of the cancer indications specified above may be conveniently treated by the methods of the invention, including the following patient populations:

(a) a TKI-untreated cancer patient, wherein the treatment prevents or delays resistance to TKI treatment,

(b) a patient whose tumor expresses wild-type EGFR,

(c) a patient whose tumor expresses a mutant form of EGFR,

(d) a patient that has been previously treated with an EGFR inhibitor, such as gefitinib, erlotinib, afatinib, dacomitinib, or others, wherein the treatment overcomes congenital or acquired resistance to the EGFR inhibitor

(e) A patient having acquired resistance to TKI treatment, such as gefitinib or erlotinib, afatinib, dacomitinib or others, wherein the treatment overcomes resistance to TKI treatment,

(g) a population of patients having congenital or acquired resistance caused by T790M (T790M +), wherein the treatment prevents or overcomes resistance to TKI treatment, and

(h) a population of patients having innate or acquired resistance not caused by T790M (T790M-), e.g. caused by other mechanisms, e.g. by MET oncogene or by unknown origin, wherein the treatment prevents or overcomes resistance to TKI treatment.

Preferably, the following patient population having one of the cancer indications specified above is conveniently treated by the method of the invention:

(c) patients whose tumors express a mutant form of EGFR (EGFR)⁺)，

(d) A patient that has been previously treated with an EGFR inhibitor, such as gefitinib, erlotinib, afatinib, dacomitinib, or others, wherein the treatment overcomes the innate or acquired resistance to the EGFR inhibitor,

(h) a population of patients having innate or acquired resistance not caused by T790M (T790M-), e.g. caused by other mechanisms, e.g. by MET oncogene or by unknown origin, wherein the treatment prevents/overcomes resistance to TKI treatment.

More preferably, the following patient population having one of the cancer indications specified above can be conveniently treated by the method of the invention:

(c) tumor patients carrying EGFR mutations at exons 19 and 21 associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q),

Most preferably, the following patient population having one of the cancer indications specified above is conveniently treated by the method of the invention:

It is especially preferred that the following patient population with one of the cancer indications specified above can be conveniently treated by the method of the invention:

(h') a population of patients with acquired resistance not caused by T790M (T790M-), e.g. by other mechanisms, e.g. by MET oncogene or by unknown origin, wherein the treatment overcomes resistance to TKI treatment.

Irreversible TKIs suitable for any aspect of the invention include, but are not limited to, EKB-569 (pelitinib), HKI-272 (lenatinib), HKI-357, CI-1033, BIBW2992 or PF-00299804 and any salt (preferably a pharmaceutically acceptable salt), hydrate or solvate, including polymorphs. Preferred TKIs are BIBW2992 and PF-00299804. Most preferably BIBW 2992.

With respect to suitable irreversible TKIs for any aspect of the invention, 1- (4- (4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one, WZ3146, WZ4002, WZ8040 and any salt (preferably a pharmaceutically acceptable salt), hydrate or solvate, including polymorphs, may be selected.

Monoclonal antibodies suitable for any aspect of the invention include, but are not limited to, cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab. Preferred monoclonal antibodies are cetuximab and panitumumab. Most preferably cetuximab. Another monoclonal antibody suitable for any aspect of the invention is Necitumumab.

In view of the specific aspects of the present invention, any of the irreversible TKIs and any of the monoclonal antibodies mentioned in the context of the present invention may be combined with each other.

Specific combinations suitable for all aspects of the invention are:

EKB-569/cetuximab, EKB-569/panitumumab, EKB-569/zalutumumab, EKB-569/nimotuzumab, EKB-569/matuzumab,

HKI-272/cetuximab, HKI-272/panitumumab, HKI-272/zalutumumab, HKI-272/nimotuzumab, HKI-272/matuzumab, HKI-272/Necitumumab, and combinations thereof,

HKI-357/cetuximab, HKI-357/panitumumab, HKI-357/zalutumumab, HKI-357/nimotuzumab, HKI-357/matuzumab,

CI-1033/cetuximab, CI-1033/panitumumab, CI-1033/zalutumumab, CI-1033/nimotuzumab, CI-1033/matuzumab,

BIBW 2992/cetuximab, BIBW 2992/panitumumab, BIBW 2992/zalutumumab, BIBW 2992/nimotuzumab, BIBW 2992/matuzumab, BIBW2992/Necitumumab, and combinations thereof,

PF-00299804/cetuximab, PF-00299804/panitumumab, PF-00299804/zalutumumab, PF-00299804/nimotuzumab, PF-00299804/Necitumumab, and PF-00299804/matuzumab.

Preferred combinations of the irreversible TKI and the monoclonal antibody suitable for all aspects of the invention are:

HKI-272/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/matuzumab,

PF-00299804/cetuximab, PF-00299804/panitumumab, PF-00299804/zalutumumab, PF-00299804/nimotuzumab and PF-00299804/matuzumab.

More preferred combinations of irreversible TKIs and the monoclonal antibodies suitable for all aspects of the invention are:

HKI-272/cetuximab, HKI-272/panitumumab,

BIBW 2992/cetuximab, BIBW 2992/panitumumab,

PF-00299804/cetuximab and PF-00299804/panitumumab.

The most preferred combination of an irreversible TKI and the monoclonal antibody suitable for all aspects of the invention is:

BIBW 2992/cetuximab, BIBW 2992/panitumumab,

PF-00299804/cetuximab and PF-00299804/panitumumab,

especially preferred is BIBW 2992/cetuximab.

The expressions "preventing", "prevention", "prophylactic treatment" or "prophylactic therapy" as used herein are to be understood as synonyms and mean a reduced risk of developing the symptoms mentioned herein. The expressions "preventing or delaying resistance" or "overcoming resistance" in the context of the present invention refer to avoiding the development of resistance to TKI treatment, or delaying the development of said resistance, or overcoming an existing (congenital or acquired) resistance, by means of the combination treatment according to the dosing regimen of the present invention, which is reflected in a reduced incidence in a first patient population treated by means of the combination according to the dosing regimen of the present invention compared to a second patient population receiving an equivalent parallel treatment, but without the monoclonal antibody component targeting human EGFR.

Resistance to treatment with a TKI or EGFR inhibitor means that the patient does not exhibit a response to treatment. This includes primary resistance, which occurs when TKI untreated patients are first treated with TKI, and acquired resistance, which, although exhibiting a response for a certain period of time during TKI treatment, the disease deteriorates again thereafter.

Furthermore, preventing or delaying resistance to TKI treatment refers to the first patient population, who is undergoing combination therapy (sustained or chronic treatment) according to the dosing regimen of the present invention, exhibiting a response compared to the second patient population. Assessment of treatment response and disease progression was according to revised RECIST guidelines (version 1.1). 45: 228-.

A preferred embodiment of the first object of the invention is a method of treating a patient suffering from non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer or colorectal cancer, including metastatic forms thereof, wherein in this method

The TKI is selected from EKB-569, HKI-272, HKI-357, CI-1033, BIBW2992 and PF-00299804, or a pharmaceutically acceptable salt thereof, which is administered according to a continuous dosing regimen ranging from 10 to 50mg based on the average daily dose, and

the monoclonal antibody is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab in a range of 50 to 500mg/m according to an average weekly intravenous dose²And is co-administered with a regimen repeated three, two or once per week, or once every two weeks, or once every three weeks or at least once per month,

is administered to

(c) A patient having a tumor expressing a mutant form of EGFR, or

(d) A patient that has been previously treated with an EGFR inhibitor, such as gefitinib, erlotinib, afatinib, dacomitinib, or others, wherein the method overcomes innate or acquired resistance to EGFR inhibitors,

(e) a patient having acquired resistance to TKI treatment, such as gefitinib, erlotinib, afatinib, dacomitinib, or others, wherein the method overcomes resistance to TKI treatment,

(g) a patient having congenital or acquired resistance caused by T790M (T790M +), wherein the method prevents or overcomes resistance to TKI treatment, or

(h) A patient having congenital or acquired resistance not caused by T790M (T790M-), e.g. caused by other mechanisms, e.g. by MET oncogene or by unknown origin, wherein the method prevents or overcomes resistance to TKI treatment.

Another preferred embodiment of the first object of the invention is a method of treating a patient suffering from non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer or colorectal cancer, including metastatic forms thereof, wherein in this method

The TKI is selected from HKI-272, BIBW2992 and PF-00299804(BIBW2992 and PF-00299804 are particularly preferred), or a pharmaceutically acceptable salt thereof, which is administered according to a continuous dosing regimen ranging from 10 to 50mg based on the average daily dose, and

the monoclonal antibody is selected from the group consisting of cetuximab and panitumumab, which has an average weekly intravenous dose ranging from 50 to 500mg/m²And co-administered in a regimen repeated twice or once a week, or once every two weeks,

is administered to

(c) Tumor patients carrying EGFR mutations (i.e., G719X, exon 19 deletion, L858R, L861Q) on exons 19 and 21 associated with drug sensitivity, or

(g) a patient having congenital/acquired resistance caused by T790M (T790M +), wherein the method prevents or overcomes resistance to TKI treatment, or

Another preferred embodiment of the first object of the invention is a method of treating a patient suffering from non-small cell lung cancer or head and neck squamous cell carcinoma, including metastatic forms thereof, wherein in this method

The TKI is selected from BIBW2992 and PF-00299804(BIBW2992 is particularly preferred), or a pharmaceutically acceptable salt thereof, which is administered according to a continuous dosing regimen based on an average daily dose in the range of 10 to 50mg, and

the monoclonal antibody is selected from cetuximab and panitumumab (cetuximab)With the most particularly preferred, the present invention) is based on an average weekly intravenous dose ranging from 50 to 500mg/m²And co-administered in a regimen repeated twice or once a week, or once every two weeks,

is administered to

Another preferred embodiment of the first object of the invention is a method of treating a patient suffering from non-small cell lung cancer, including metastatic forms thereof, wherein in this method

BIBW2992, or a pharmaceutically acceptable salt thereof, for administration according to a continuous dosing regimen ranging from 10 to 50mg on average daily dose, and

cetuximab in the range of 50 to 500mg/m according to the mean weekly intravenous dose²And the dosing regimen is repeated twice or once a week for co-administration,

is administered to

(h) Patients having congenital or acquired resistance not caused by T790M (T790M-), e.g. caused by other mechanisms, e.g. by MET oncogene or by unknown origin, wherein the method prevents or overcomes resistance to TKI treatment,

but most preferably is to

(h') a patient having acquired resistance caused by non-T790M (T790M-), e.g., by other mechanisms, e.g., by MET oncogene or by unknown origin, wherein the method overcomes resistance to TKI treatment.

A first preferred embodiment of the second object of the invention is a pharmaceutical kit wherein the second compartment comprises an effective amount of a TKI selected from EKB-569 (pelitinib), HKI-272 (lenatinib), HKI-357, CI-1033, BIBW2992 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 monoclonal antibody selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab.

A third preferred embodiment of the second object of the invention is a pharmaceutical kit comprising a first compartment comprising an effective amount of a monoclonal antibody selected from cetuximab and panitumumab and a second compartment comprising an effective amount of a TKI selected from HKI-272, BIBW2992 and PF-00299804(BIBW2992 and PF-00299804 are particularly preferred), or a pharmaceutically acceptable salt thereof.

A fourth preferred embodiment of the second object of the invention is a pharmaceutical kit comprising a first compartment comprising an effective amount of a monoclonal antibody selected from the group consisting of cetuximab and panitumumab (cetuximab being particularly preferred) and a second compartment comprising an effective amount of a TKI selected from the group consisting of BIBW2992 and PF-00299804(BIBW2992 being particularly preferred), or a pharmaceutically acceptable salt thereof.

A fifth preferred embodiment of the second object of the invention is a pharmaceutical kit comprising a first compartment comprising an effective amount of cetuximab and a second compartment comprising an effective amount of BIBW2992, or a pharmaceutically acceptable salt thereof.

A first preferred embodiment of the third object of the invention is an irreversible TKI for use in a method of treating a patient suffering from non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular carcinoma or colorectal cancer, including metastatic forms thereof, by co-administration with a monoclonal antibody targeting human EGFR,

wherein the TKI is selected from EKB-569, HKI-272, HKI-357, CI-1033, BIBW2992 and PF-00299804, or a pharmaceutically acceptable salt thereof, and is administered according to a continuous dosing regimen ranging from 10 to 50mg based on the average daily dose, and

is administered to

(c) A patient having a tumor expressing a mutant form of EGFR, or

A second preferred embodiment of the third object of the invention is an irreversible TKI for use in a method of treating a patient suffering from non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer or colorectal cancer, including metastatic forms thereof, wherein in this method

The TKI is selected from HKI-272, BIBW2992 and PF-00299804(BIBW2992 and PF-00299804 are particularly preferred), or a pharmaceutically acceptable salt thereof, and is administered according to a continuous dosing regimen ranging from 10 to 50mg based on the average daily dose, and

the monoclonal antibody is selected from the group consisting of cetuximab and panitumumab, and ranges from 50 to 500mg/m according to the average weekly intravenous dose²And co-administered in a regimen repeated twice or once a week, or once every two weeks,

is administered to

A third preferred embodiment of the third object of the invention is an irreversible TKI for use in a method of treating a patient suffering from non-small cell lung cancer or squamous cell carcinoma of the head and neck, including metastatic forms thereof, wherein in this method,

the monoclonal antibody is selected from the group consisting of cetuximab and panitumumab (cetuximab being particularly preferred) and ranges from 50 to 500mg/m according to the average weekly intravenous dose²And co-administered in a regimen repeated twice or once a week, or once every two weeks,

is administered to

A fourth preferred embodiment of the third object of the invention is an irreversible TKI for use in a method of treating a patient suffering from non-small cell lung cancer, including metastatic forms thereof, wherein in this method

The TKI is BIBW2992, or a pharmaceutically acceptable salt thereof, and is administered according to a continuous dosing regimen ranging from 10 to 50mg based on the average daily dose, and

the monoclonal antibody is cetuximab and ranges from 50 to 500mg/m according to the average weekly intravenous dose²And the dosing regimen is repeated twice or once a week for co-administration,

is administered to

but most preferably to

(h') a patient having acquired resistance not caused by T790M (T790M-), e.g., caused by other mechanisms, e.g., by MET oncogene or by unknown origin, wherein the method overcomes resistance to TKI treatment.

A first preferred embodiment of the fourth object of the invention is an irreversible Tyrosine Kinase Inhibitor (TKI) selected from EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357, CI-1033, BIBW2992 and PF-00299804 or a pharmaceutically acceptable salt thereof.

A second preferred embodiment of the fourth object of the invention is a human EGFR targeted monoclonal antibody (mAB) selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab.

In a third preferred embodiment of the fourth object of the invention, the cancer is selected from the group consisting of non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer, and colorectal cancer, including metastatic forms thereof,

the TKI is selected from EKB-569, HKI-272, HKI-357, CI-1033, BIBW2992 and PF-00299804, or a pharmaceutically acceptable salt thereof,

the monoclonal antibody is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and

the patient is

(c) A patient having a tumor expressing a mutant form of EGFR, or

In a fourth preferred embodiment of the fourth object of the invention, the cancer is selected from the group consisting of non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer and colorectal cancer, including metastatic forms thereof,

the TKI is selected from HKI-272, BIBW2992 and PF-00299804(BIBW2992 and PF-00299804 are particularly preferred), or a pharmaceutically acceptable salt thereof,

the monoclonal antibody is selected from western medicine(ii) a cetuximab and panitumumab, and according to an average weekly intravenous dose ranging from 50 to 500mg/m²And co-administered in a regimen repeated twice or once a week, or once every two weeks,

and the patient is

In a fifth preferred embodiment of the fourth object of the invention, said cancer is selected from non-small cell lung cancer or head and neck squamous cell carcinoma, including metastatic forms thereof,

the TKI is selected from BIBW2992 and PF-00299804(BIBW2992 is particularly preferred), or a pharmaceutically acceptable salt thereof,

the monoclonal antibody is selected from the group consisting of cetuximab and panitumumab (cetuximab being particularly preferred), and

the patient is

In a sixth preferred embodiment of the fourth object of the invention said cancer is non-small cell lung cancer, including metastatic forms thereof,

the TKI is BIBW2992, or a pharmaceutically acceptable salt thereof,

is administered to

in a seventh preferred embodiment of the fourth object of the present invention

(h') the patient has acquired resistance not caused by T790M (T790M-), e.g., by other mechanisms, e.g., by MET oncogene or by unknown origin, wherein the method overcomes resistance to TKI treatment.

Dose/irreversible TKI:

formulations of irreversible TKIs are available commercially or described in publications. According to any aspect of the invention, the TKI, e.g. BIBW2992, is administered at an average total daily dose of 10 to 50mg, e.g. at an average total daily dose selected from 10, 15, 20, 25, 30, 35, 40, 45 and 50mg, optionally in divided doses, e.g. 1, 2 or 3 doses per day. Preferably the TKI is administered orally only once a day, but other routes of administration may be used.

Dose/monoclonal antibody:

formulations of the monoclonal antibodies are also commercially available or described in publications. According to any of the aspects of the invention, in the dosage regimen mentioned in the context of the invention, the monoclonal antibody component (e.g. cetuximab or panitumumab) may be 50 to 500mg/m per week on average²E.g., 50, 75, 100, 200, 250, 300, 350, 375, 400, 425, 450, 475, and 500mg/m²。

In the dosage regimen mentioned in the context of the present invention, the single intravenous dose of the monoclonal antibody component (e.g. cetuximab or panitumumab) administered on a body weight basis may be 1 to 15mg/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, 12, 12.5, 13, 13.5, 14, 14.5 or 15 mg/kg. The results are in the range of 70 to 1050mg for a single dose based on a 70kg adult patient.

However, within the limits, it is possible to optionally deviate from the prescribed dosage for the TKI and/or the monoclonal antibody component, depending on the body weight or method of administration, individual response to the drug, nature of the formulation used and time or interval of administration, as necessary. When the dose is administered in the upper position, it may be suitably divided into several administrations during the day.

Instructions for co-administration:

the instructions for co-administration may be in any form suitable for pharmaceutical formulation, for example in the form of a booklet which is added to the secondary packaging of the medicament or printed on the primary or secondary packaging.

The following examples are intended to illustrate the invention without limiting it:

example 1: activity and tolerance 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) (clinical trials. gov identifier: NCT01090011)

Background: despite the initial response to reversible EGFR-TKI such as E or G, all non-small cell lung cancer patients with EGFR-sensitizing mutations develop disease progression. More than half of the cases, "acquired resistance" (AR) was associated with the exon 20EGFR T790M mutation (M) at another position. To date, no therapy has been demonstrated (including those of the anti-EGFR antibody C and E) that is effective in treating AR (Janjigian YY. Clin Cancer Res; Epub Jan 2011). Preclinical data show that a, a potent irreversible ErbB receptor family inhibitor, is active in M cell lines. Combining EGFR targeting a and C has been induced to produce a near complete response in the T790M transgenic mouse model. This is the first clinical study to evaluate the safety and primary efficacy of this combination in non-small cell lung cancer patients.

The method comprises the following steps: non-small cell lung cancer patients clinically defined as AR (Jackman D.J Clin Oncol 2010; 28:357) are orally administered A40mg daily and receive increasing doses (250 and 500 mg/m) every two weeks²) C of (1). Evaluation of objective responses was performed on patients receiving the recommended second phase dose (RP 2D). It is desirable to obtain tumor tissue at or after the occurrence of AR.

As a result: of the 26 patients receiving treatment, 22 patients received the predetermined maximum dose (RP 2D): a40mg + C500mg/m². Median time for E or G in the event of entry into the study was 2.4 years. No dose limiting toxicity was observed. Common Adverse Events (AE) were rash (83%) and diarrhea (62%). 3 (6.4%) patients had grade 3 rash and 2 (4.3%) patients had grade 3 diarrhea. Disease control was observed in all RP2D patients (tumor size reduction up to 76%, treatment duration up to 5 months or more). Confirmation of local response (PR) in 12/32(38%) evaluable patients, 10/17(59%) and 6/55(14%) in T790M + and T790M-non-small cell lung cancer patients, respectively (not yet available)) PR was confirmed.

All results of tolerability (adverse events) and treatment response are summarized in tables 1 and 2.

And (4) conclusion: EGFR targeting a and C in combination is tolerable at RP 2D. Mild to moderate diarrhea and adverse skin events are controllable. Disease control was observed in all patients who took RP 2D. EGFR mutation positive non-small cell lung cancers with AR for erlotinib and gefitinib continue to rely on EGRE signaling. The combination of a and C overcomes the acquired resistance to the previous erlotinib/gefitinib development. Clinical activity is not limited to T790M mediated acquired resistance.

Table 1: summary of rash/acne and diarrhea Adverse Events (AE)

(Afatinib 40+250 cetuximab and Afatinib 40+500 cetuximab, refer to the dosing regimen for Afatinib and cetuximab, see methods section; 4(100.0) represents 4 patients (100%)).

Table 2: treatment response in patients with EGFR mutations at MTD (maximum tolerated dose)

PR local reaction

SD, stabilization of disease

PD disease progression

N number of patients

T790M +: T790M Positive patients

T790M +: T790M negative patients.

Claims

1. Method for treating a patient suffering from a cancer caused by deregulated human epidermal growth factor receptor (HER/human EGFR), comprising administering to a patient in need of such treatment a flexible and effective combination regimen of an irreversible Tyrosine Kinase Inhibitor (TKI) and a human EGFR targeted monoclonal antibody (mAB), wherein in this method the TKI is administered according to a continuous dosing regimen based on an average daily dose in the range of 10 to 50mg and according to an average weekly intravenous dose in the range of 50 to 500mg/m²And is repeated three times, two times or once a week, or once every two weeks,or a dosing regimen that is repeated every three weeks or at least once a month.

2. The method of claim 1, wherein the cancer is selected from non-small cell lung cancer (NSCLC), Head and Neck Squamous Cell Carcinoma (HNSCC), glioblastoma, 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.

3. The method of claim 1 or 2, wherein

(a) The patient is a TKI-naive cancer patient, and the method prevents or delays resistance to TKI treatment, or

(b) The patient has a tumor expressing wild type EGFR, or

(c) The patient has a tumor expressing a mutant form of EGFR, or

(d) The patient has been previously treated with an EGFR inhibitor and the method overcomes congenital or acquired resistance to the EGFR inhibitor, or

(e) The patient has acquired resistance to TKI treatment, wherein the method overcomes resistance to TKI treatment, or

(g) The patient has congenital or acquired resistance caused by T790M (T790M +), wherein the method prevents or overcomes resistance to TKI treatment, or

(h) The patient has congenital or acquired resistance not caused by T790M (T790M-), wherein the method prevents or overcomes resistance to TKI treatment.

4. The method of claim 1, 2 or 3, wherein the irreversible Tyrosine Kinase Inhibitor (TKI) is selected from EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357, CI-1033, BIBW2992 and PF-00299804, or a pharmaceutically acceptable salt thereof.

5. The method of any one of claims 1, 2 or 3, wherein the TKI is selected from 1- (4- (4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one, WZ3146, WZ4002 and WZ8040, or a pharmaceutically acceptable salt thereof.

6. The method of claim 1, 2, 3,4 or 5, wherein the human EGFR targeted monoclonal antibody (mAB) is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab.

7. The method of claim 1, 2, 3,4 or 5, wherein the human EGFR targeted monoclonal antibody (mAB) is Necitumumab.

8. The method of claim 1, wherein the cancer is selected from non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer, or colorectal cancer, including metastatic forms thereof,

the TKI is selected from EKB-569, HKI-272, HKI-357, CI-1033, BIBW2992 and PF-00299804, or a pharmaceutically acceptable salt thereof, and is administered according to a continuous dosing regimen ranging from 10 to 50mg based on an average daily dose,

the monoclonal antibody is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab and ranges from 50 to 500mg/m according to the average weekly intravenous dose²And co-administered with a regimen that is repeated three, two or once a week, or once every two weeks, or once every three weeks or at least once a month,

is administered to

(c) A patient having a tumor expressing a mutant form of EGFR, or

9. The method of claim 1, wherein the cancer is selected from non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer, or colorectal cancer, including metastatic forms thereof,

the TKI is selected from HKI-272, BIBW2992 and PF-00299804, (BIBW2992 and PF-00299804 are particularly preferred), or a pharmaceutically acceptable salt thereof, and is administered according to a continuous dosing regimen ranging from 10 to 50mg based on the average daily dose,

is administered to

10. The method of claim 1, wherein the cancer is selected from non-small cell lung cancer or head and neck squamous cell carcinoma, including metastatic forms thereof,

the TKI is selected from BIBW2992 and PF-00299804, with BIBW2992 being particularly preferred, or a pharmaceutically acceptable salt thereof, and is administered according to a continuous dosing regimen ranging from 10 to 50mg based on an average daily dose,

is administered to

11. The method of claim 1, wherein the cancer is non-small cell lung cancer, including metastatic forms thereof,

the TKI is BIBW2992, or a pharmaceutically acceptable salt thereof, and is administered according to a continuous dosing regimen based on an average daily dose in the range of 10 to 50mg,

is administered to

12. The method of any one of claims 1 to 11, wherein the cancer is non-small cell lung cancer, including metastatic forms thereof, and the patient is a human

13. A pharmaceutical kit comprising a first compartment comprising an effective amount of a human EGFR targeted monoclonal antibody and a second compartment comprising an effective amount of an irreversible TKI.

14. The pharmaceutical kit of claim 13, wherein the irreversible Tyrosine Kinase Inhibitor (TKI) is selected from EKB-569 (pelitinib), HKI-272 (neratinib), HKI-357, CI-1033, BIBW2992, and PF-00299804 or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical kit of claim 13, wherein the TKI is selected from 1- (4- (4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one, WZ3146, WZ4002, and WZ8040, or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical kit of claim 13, 14 or 15, wherein the human EGFR targeted monoclonal antibody (mAB) is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab.

17. The pharmaceutical kit of claim 13, 14 or 15, wherein the human EGFR targeted monoclonal antibody (mAB) is Necitumumab.

18. An irreversible TKI for use in a method of treating a patient with cancer caused by deregulated human epidermal growth factor receptor (HER/human EGFR) by co-administration with a monoclonal antibody targeting human EGFR, wherein the TKI is administered according to a continuous dosing regimen based on an average daily dose in the range of 10 to 50mg and the monoclonal antibody is administered according to an average weekly intravenous dose in the range of 50 to 500mg/m²And a regimen repeated three, two or once weekly, or once every two weeks, or once every three weeks, or at least once monthly is co-administered to a patient in need of such treatment.

19. The irreversible TKI of claim 18, for use in a method of treating a patient suffering from non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer or colorectal cancer, including metastatic forms thereof, by co-administration with a monoclonal antibody targeting human EGFR,

wherein the TKI is selected from the group consisting of 1- (4- (4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one, WZ3146, WZ4002, and WZ8040, or a pharmaceutically acceptable salt thereof, and is administered according to a continuous dosing regimen ranging from 10 to 50mg based on an average daily dose, and

the monoclonal antibody is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab and ranges from 50 to 500mg/m according to the average weekly intravenous dose²And is co-administered with a regimen repeated three, two or once per week, or once every two weeks, or once every three weeks or at least once per month,

is administered to

(c) A patient having a tumor expressing a mutant form of EGFR, or

20. The irreversible TKI of claim 18, for use in a method of treating a patient suffering from non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer or colorectal cancer, including metastatic forms thereof, by co-administration with a monoclonal antibody targeting human EGFR,

wherein the TKI is selected from EKB-569, HKI-272, HKI-357, CI-1033, BIBW2992 and PF-00299804, 1- (4- (4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one, WZ3146, WZ4002 and WZ8040, or a pharmaceutically acceptable salt thereof, and is administered according to a continuous dosing regimen ranging from 10 to 50mg based on an average daily dose, and

the monoclonal antibody is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab and Necitumumab, and ranges from 50 to 500mg/m according to the average weekly intravenous dose²And is co-administered with a regimen repeated three, two or once per week, or once every two weeks, or once every three weeks or at least once per month,

is administered to

(c) A patient having a tumor expressing a mutant form of EGFR, or

21. The irreversible TKI of claim 18, for use in a method of treating a patient suffering from non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular cancer or colorectal cancer, including metastatic forms thereof, by co-administration with a monoclonal antibody targeting human EGFR,

is administered to

(c) A patient having a tumor expressing a mutant form of EGFR, or

22. The irreversible TKI of claim 18 for use in a method of treating a patient having nsclc, squamous cell carcinoma of the head and neck, glioblastoma, breast or colorectal cancer, including metastatic forms thereof, wherein in this method

The TKI is selected from HKI-272, BIBW2992 and PF-00299804, (BIBW2992 and PF-00299804 are particularly preferred), or a pharmaceutically acceptable salt thereof, and is administered according to a continuous dosing regimen ranging from 10 to 50mg based on the average daily dose, and

is administered to

23. The irreversible TKI of claim 18 for use in a method of treating a patient with nsclc or squamous cell carcinoma of the head and neck, including metastatic forms thereof, wherein in this method

the monoclonal antibody is selected from the group consisting of cetuximab and panitumumab (cetuximab being particularly preferred) and ranges from 50 to 500mg/m according to the average weekly intravenous dose²And is repeated twice or once a weekCo-administration is carried out once, or once every two weeks in a repeated dosing regimen,

is administered to

24. The irreversible TKI of claim 18 for use in a method of treating a patient having nsclc, including metastatic forms thereof, wherein in this method

is administered to

25. The irreversible TKI of any of claims 18, 19, 20, 21, 22, 23, and 24, wherein

26. Use of an irreversible TKI for the manufacture of a kit for the treatment of a patient suffering from a cancer caused by deregulated human epidermal growth factor receptor (HER/human EGFR), said kit comprising a first compartment comprising an effective amount of a human EGFR targeted mab and a second compartment comprising an effective amount of an irreversible TKI, wherein the TKI is administered according to a continuous dosing regimen based on an average daily dose in the range of 10 to 50mg, and the mab is administered according to an average weekly iv dose in the range of 50 to 500mg/m²And a regimen repeated three, two or once weekly, or once every two weeks, or once every three weeks, or at least once monthly is co-administered to a patient in need of such treatment.

27. The use according to claim 26, wherein the irreversible TKI is selected from EKB-569 (pelitinib), HKI-272 (lenatinib), HKI-357, CI-1033, BIBW2992 and PF-00299804 or a pharmaceutically acceptable salt thereof.

28. The use according to claim 26, wherein the irreversible TKI is selected from 1- (4- (4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one, WZ3146, WZ4002, and WZ8040, or a pharmaceutically acceptable salt thereof.

29. The use according to claim 26, 27 or 28, wherein the human EGFR targeted monoclonal antibody (mAB) is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab.

30. The use according to claim 26, 27 or 28, wherein the human EGFR targeted monoclonal antibody (mAB) is Necitumumab.

31. The use according to claim 26, wherein the cancer is selected from the group consisting of non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer, esophageal cancer, gastric cancer, renal cancer, cervical cancer, prostate cancer, ovarian cancer, pancreatic cancer, hepatocellular carcinoma, and colorectal cancer, including metastatic forms thereof,

the patient is

(c) A patient having a tumor expressing a mutant form of EGFR, or

32. The use according to claim 26, wherein the cancer is selected from the group consisting of non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, breast cancer and colorectal cancer, including metastatic forms thereof,

the TKI is selected from HKI-272, BIBW2992 and PF-00299804, (BIBW2992 and PF-00299804 are particularly preferred), or a pharmaceutically acceptable salt thereof,

is administered to

33. The use according to claim 26, wherein the cancer is selected from non-small cell lung cancer or head and neck squamous cell carcinoma, including metastatic forms thereof,

the patient is

34. The use according to claim 26, wherein the cancer is non-small cell lung cancer, including metastatic forms thereof,

the TKI is BIBW2992, or a pharmaceutically acceptable salt thereof,

is administered to

35. Use according to any one of claims 26 to 34, wherein