HonCode

Go Back   HER2 Support Group Forums > Articles of Interest
Register Gallery FAQ Members List Calendar Search Today's Posts Mark Forums Read

Reply
 
Thread Tools Display Modes
Old 10-11-2009, 07:45 PM   #1
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Lapatinib: A competitor or companion to trastuzumab?

1: Cancer Treat Rev. 2009 Sep 10. [Epub ahead of print] Links
Lapatinib: A competitor or companion to trastuzumab?

Collins D, Hill AD, Young L.
Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
Trastuzumab (Herceptin), a monoclonal antibody against HER2 has established itself as the treatment paradigm of HER2-overexpressing breast cancer. Its success, however, has been tempered by its sequelae. In particular, most tumours become resistant to trastuzumab through a variety of mechanisms. Furthermore, there is both an increased incidence of cardiac dysfunction and a worrying pattern of CNS metastasis associated with trastuzumab. To manage these concerns, many new treatments targeting HER2 have been developed. Of these emerging therapies, the dual tyrosine kinase receptor inhibitor against EGFR and HER2, lapatinib (Tyverb/Tykerb) has shown the most promise to date. Encouraging early results in vitro have now been reproduced in phase II/III clinical trials, both as lapatinib monotherapy and synergistically with other established therapeutic regimes, including trastuzumab itself. Trial results suggest it may be of considerable benefit to patients with trastuzumab-resistant tumours and may play a role in the reduction of CNS relapses. In addition, lapatinib is well-tolerated and unlike trastuzumab, minimal cardiac dysfunction has been documented. A number of trials are underway to assess whether lapatinib will oust trastuzumab from its pole position in the management of HER2-positive breast cancer or whether their combination will prove to be superior to either therapy alone.
PMID: 19748186 [PubMed - as supplied by publisher]
Rich66 is offline   Reply With Quote
Old 10-27-2009, 12:12 AM   #2
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Lapatinib: A competitor or companion to trastuzumab?

J Clin Oncol. 2010 Feb 1. [Epub ahead of print]
Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory Metastatic Breast Cancer.

FREE TEXT

Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J.
Duke University Medical Center, Durham, NC; Dana-Farber Cancer Institute, Boston, MA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Medicine Development Center Oncology, GlaxoSmithKline, Collegeville, PA; Texas Oncology, PA, US Oncology, Tyler; Baylor Sammons Cancer Center, Texas Oncology, PA, US Oncology, Dallas, TX; Otto von Guericke Univeristäte, Madgeburg, Germany; and Vall d'Hebron University Hospital, Barcelona, Spain.
PURPOSE: Preclinical studies in ErbB2-positive cell lines demonstrated a synergistic interaction between lapatinib and trastuzumab, suggesting that dual blockade is more effective than a single agent alone. EGF104900 compared the activity of lapatinib alone or in combination with trastuzumab in patients with ErbB2-positive, trastuzumab-refractory metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients with ErbB2-positive MBC who experienced progression on prior trastuzumab-containing regimens were randomly assigned to receive either lapatinib alone or in combination with trastuzumab. The primary end point was progression-free survival (PFS). Secondary efficacy end points included overall response rate (ORR), clinical benefit rate (CBR; complete response, partial response, and stable disease for >/= 24 weeks), and overall survival (OS). RESULTS: In the intent-to-treat population (N = 296) who received a median of three prior trastuzumab-containing regimens, the combination of lapatinib with trastuzumab was superior to lapatinib alone for PFS (hazard ratio [HR] = 0.73; 95% CI, 0.57 to 0.93; P = .008) and CBR (24.7% in the combination arm v 12.4% in the monotherapy arm; P = .01). A trend for improved OS in the combination arm was observed (HR = 0.75; 95% CI, 0.53 to 1.07; P = .106). There was no difference in ORR (10.3% in the combination arm v 6.9% in the monotherapy arm; P = .46). The most frequent adverse events were diarrhea, rash, nausea, and fatigue; diarrhea was higher in the combination arm (P = .03). The incidence of symptomatic and asymptomatic cardiac events was low (combination therapy = 2% and 3.4%; monotherapy = 0.7% and 1.4%, respectively). CONCLUSION: Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improved PFS and CBR versus lapatinib alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2-positive MBC.

PMID: 20124187 [PubMed - as supplied by publisher]





ASCO: Biologics Work Synergistically Against Metastatic Breast Cancer if Trastuzumab Regimens Fail


2008-06-03T10:36:47-04:00
Crystal Phend
What breastcancer.org says about this article…

ASCO: Biologics Work Synergistically Against Metastatic Breast Cancer if Trastuzumab Regimens Fail

The study reviewed here found that women diagnosed with HER2-positive metastatic breast cancer that either came back or progressed while getting Herceptin (chemical name: tastuzumab) benefited from adding Tykerb (chemical name: lapatanib) to the treatment plan instead of switching from Herceptin to Tykerb.
Both Herceptin and Tykerb are targeted therapy medicines.
There were almost 300 women in the study. After the HER2-positive metastatic breast cancer came back during Herceptin treatment, about half the women continued to get Herceptin AND had Tykerb added to their treatment plans. The other half stopped getting Herceptin and switched to Tykerb.
Six months later:
  • 28% of the cancers treated with both Herceptin and Tykerb didn't grow, compared to 13% of the cancers treated with only Tykerb.
  • Nearly 25% of the women who got both Herceptin and Tykerb benefited in some way from the treatment, compared to about 12% of the women who switched to Tykerb. The women were considered to benefit if the cancer didn't grow or went into complete or partial remission.
  • 80% of the women who got both Herceptin and Tykerb were alive, compared to 70% of the women who switched to Tykerb.
A year after the change in their treatment plans, 45% of the women treated with both Herceptin and Tykerb were alive, compared to 36% of the women who switched to Tykerb.
Both Herceptin and Tykerb work by blocking the ability of the HER-2/neu protein to make HER2-positive breast cancer cells grow. Herceptin and Tykerb do this in different ways. Herceptin blocks the protein on the cancer cell's surface. Tykerb blocks the protein inside the cell.
Tykerb, in combination with the chemotherapy medicine Xeloda (chemical name: capecitabine), is approved by the U.S. Food and Drug Administration to treat HER2-positive, metastatic breast cancer that has stopped responding to Herceptin. But rather than stopping Herceptin and switching to Tykerb when metastatic breast cancer comes back or progresses, many doctors have been adding Tykerb to the treatment plan while continuing Herceptin.
Even though Tykerb isn't approved to be used in combination with Herceptin, the results of this study suggest that this approach might be better than stopping Herceptin and switching to Tykerb.
The researchers think that blocking the effect of the HER2/neu protein both outside and inside the cancer cell at the same time might be better than blocking the protein in only one place. This approach is known as "total HER2 blockade."
Herceptin is given intravenously. Herceptin can cause flu-like side effects such as fever, chills, muscle aches, or nausea. These side effects generally become less severe after the first treatment. Herceptin can sometimes cause heart damage and in some cases the heart damage can be life-threatening.
Tykerb is a pill taken by mouth. Tykerb doesn't seem to cause the serious heart problems associated with Herceptin. The most common side effects from Tykerb when given in combination with Xeloda are diarrhea, redness and tingling in the hands and feet, and a rash. These side effects usually aren't severe. Other side effects can include stomach upset, vomiting, and fatigue.
In this study, the most common side effect was diarrhea. About 48% of the women treated with Tykerb alone had diarrhea; 60% of the women treated with Herceptin and Tykerb had diarrhea. One woman did die from a heart problem, but the heart problem wasn't directly related to the Herceptin or Tykerb treatment.
If you're being treated with Herceptin for HER2-positive metastatic breast cancer, you might want to talk to your doctor about the results of this research. Together you and your doctor can decide whether adding Tykerb to your treatment plan might make sense for you if the cancer stops responding to Herceptin alone.
Visit the Breastcancer.org Targeted Therapies section to learn more about Herceptin and Tykerb.


Research News on Targeted Therapies




J Cancer Res Clin Oncol. 2009 Apr;135(4):643-7. Epub 2008 Oct 21.
Monitoring circulating epithelial tumour cells (CETC) to gauge therapy: in patients with disease progression after trastuzumab persisting CETC can be eliminated by combined lapatinib treatment.

Camara O, Jörke C, Hammer U, Egbe A, Rabenstein C, Runnebaum IB, Hoeffken K, Pachmann K.
Women's Hospital, Friedrich Schiller University, Bachstr. 18, 07740, Jena, Germany.
BACKGROUND: In breast cancers, the gene for the growth factor receptor HER2 can be amplified leading to increased aggressiveness and metastasis formation. The monoclonal antibody trastuzumab prolongs relapse-free survival highly significantly but eventually many patients relapse. METHOD: In this study, CETC were monitored using the Maintrac method during adjuvant trastuzumab treatment and during subsequent treatment with capecitabine/lapatinib. RESULTS: In one patient, trastuzumab led to marginal reduction in CETC with disease progress. The combination of capecitabine/lapatinib was preliminarily capable to eliminate all CETC, however, CETC reappeared. The CONCLUSIONS:second patient received adjuvant taxane together with trastuzumab and 1 year of further trastuzumab during which CETC increased. After stopping trastuzumab skin metastases occurred. Capecitabine/lapatinib led to complete CETC elimination with stable disease. In patients with lack of CETC reduction in spite of trastuzumab treatment correlated with disease progression the combination of capecitabine/lapatinib highly efficiently led to rapid elimination of CETC warranting further monitoring during such studies.

PMID: 18936973 [PubMed - indexed for MEDLINE]




J Clin Oncol. 2009 Mar 10;27(8):1191-6. Epub 2009 Feb 2.
Effects of food on the relative bioavailability of lapatinib in cancer patients.

Koch KM, Reddy NJ, Cohen RB, Lewis NL, Whitehead B, Mackay K, Stead A, Beelen AP, Lewis LD.
GlaxoSmithKline, Clinical Pharmacology, Research Triangle Park, NC, USA.
Comment in:
PURPOSE: This study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. PATIENTS AND METHODS: A single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. RESULTS: The low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (C(max)) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and C(max) of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. CONCLUSION: These large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.

PMID: 19188677 [PubMed - indexed for MEDLINE]



1: Clin Transl Oncol. 2009 Jul;11(7):455-9.Links
mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb(R)).

Vázquez-MartÃ*n A, Oliveras-Ferraros C, Del Barco S, MartÃ*n-Castillo B, Menéndez JA.
The small molecule HER2 tyrosine kinase inhibitor (TKI) lapatinib (Tykerb(R)) is approved for the therapy of patients with HER2-positive breast carcinomas who have progressed on trastuzumab (Herceptin(R)). Unfortunately, the efficacy of this HER2 TKI is limited by both primary (inherent) and acquired resistance, the latter typically occurring within 12 months of starting therapy. One of the key factors limiting our understanding of the mechanisms involved in lapatinib resistance is the lack of published preclinical models. We herein review lapatinib-refractory models recently developed at the bench and the survival pathways discovered. As hyperactivation of the pharmacologically targetable PI3K/mTOR/p70S6K1 axis appears to be central to the occurrence of lapatinib resistance, preclinical data showing enhanced antitumour effects when combining lapatinib with mTOR inhibitors (e.g., rapamycin analogues and NVP-BEZ235) highlight the importance of translational work to yield clinically useful regimens capable of delaying or treating lapatinib resistance. The unexpected ability of the anti-type II diabetes drug metformin to inactivate mTOR and decrease p70S6K1 activity further reveals that this biguanide, generally considered non-toxic and remarkably inexpensive, might be considered for new combinatorial lapatinib-based protocols in HER2-overexpressing breast cancer patients.
Rich66 is offline   Reply With Quote
Old 10-27-2009, 03:58 AM   #3
Ellie F
Senior Member
 
Join Date: Feb 2009
Posts: 1,526
Re: Lapatinib: A competitor or companion to trastuzumab?

Thanks for info Rich
I noticed a number of sisters on the board are using this combo so this is very promising.It will be interesting how this performs in trials against T-DM1
Ellie
Ellie F is offline   Reply With Quote
Old 10-27-2009, 08:59 AM   #4
schoolteacher
Senior Member
 
Join Date: Feb 2008
Location: Georgia
Posts: 1,486
Re: Lapatinib: A competitor or companion to trastuzumab?

Rich,

Thanks for posting this article. I will keep it in my folder in case I need it.

Amelia
schoolteacher is offline   Reply With Quote
Old 10-28-2009, 01:01 PM   #5
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Lapatinib: A competitor or companion to trastuzumab?

Oncogene. 2009 Feb 12;28(6):803-14. Epub 2008 Dec 8.
Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity.

Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, Smith DJ, Landolfi S, Ramon y Cajal S, Arribas J, Baselga J.
Medical Oncology Department, Vall d'Hebron Research Institute, Vall d'Hebron University Hospital, Barcelona, Spain.
Lapatinib is a human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially non-overlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo- (HER2/HER2) and hetero- (HER2/EGFR and HER2/HER3) dimers. Lapatinib-induced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo, where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.

PMID: 19060928 [PubMed - indexed for MEDLINE]
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 11-05-2009, 06:48 PM   #6
Rich66
Senior Member
 
Rich66's Avatar
 
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
Re: Lapatinib: A competitor or companion to trastuzumab?

A Phase I Study of a 2-Day Lapatinib Chemosensitization Pulse Preceding Nanoparticle Albumin-Bound Paclitaxel for Advanced Solid Malignancies

Amy J. Chien1,6, Julie A. Illi6, Andrew H. Ko1,6, Wolfgang M. Korn1,6, Lawrence Fong1,6, Lee-may Chen2,6, Mohammed Kashani-Sabet3,6, Charles J. Ryan1,6, Jonathan E. Rosenberg1,6, Sarita Dubey1,6, Eric J. Small1,6, Thierry M. Jahan1,6, Nola M. Hylton4,6, Benjamin M. Yeh4,6, Yong Huang5, Kevin M. Koch7 and Mark M. Moasser1,6 Authors' Affiliations: Departments of 1 Medicine, 2 Obstetrics, Gynecology, and Reproductive Sciences, 3 Dermatology, 4 Radiology, 5 Biopharmaceutical Sciences, and 6 Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, California and 7 Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina
Requests for reprints: Mark M. Moasser, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, Box 0875, San Francisco, CA 94143-0875. Phone: 415-476-0158; Fax; 415-353-7692; E-mail: mmoasser@medicine.ucsf.edu.
Purpose: Systemic chemotherapy fails to access much of the tumor burden in patients with advanced cancer, significantly limiting its efficacy. In preclinical studies, brief high doses of tyrosine kinase inhibitors (TKI) targeting the human epidermal growth factor receptor (HER) family can prime tumor vasculature for optimal chemotherapeutic delivery and efficacy. This study investigates the clinical relevance of this approach.
Experimental Design: A phase I clinical study of escalating doses of the HER TKI lapatinib given as a 2-day pulse before a weekly infusion of nab-paclitaxel (100 mg/m2) was conducted in patients with advanced solid tumors.
Results: Twenty-five patients were treated. Treatment was associated with grade 1 to 2 toxicities including diarrhea, nausea, rash, neutropenia, neuropathy, fatigue, alopecia, and anemia. The two dose-limiting toxicities were grade 3 vomiting and grade 4 neutropenia, and the maximum tolerated dose of lapatinib was defined as 5250 mg/day in divided doses. Lapatinib concentrations increased with increasing dose. Dynamic Contrast Enhanced Magnetic Resonance Imaging studies in a subset of patients confirmed a decrease in tumor vascular permeability immediately following a lapatinib pulse. Sixty-five percent of evaluable patients experienced a partial or stable response on this therapy, 72% of whom were previously taxane-refractory.
Conclusion: A 2-day pulse of high-dose lapatinib given before weekly nab-paclitaxel is a feasible and tolerable clinical regimen, suitable for testing this novel vascular-priming chemosensitization hypothesis developed in preclinical models. (Clin Cancer Res 2009;15(17):5569–75)



Anticancer Drugs. 2009 Nov;20(10):918-25.
Role of efflux pump activity in lapatinib/caelyx combination in breast cancer cell lines.

Vannini I, Zoli W, Fabbri F, Ulivi P, Tesei A, Carloni S, Brigliadori G, Amadori D.
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (FC), Italy.
The aim of this study was to investigate, at preclinical level, efflux pump modulation induced by lapatinib, a small-molecule dual inhibitor of the epidermal growth factor receptor (EGFR), in HER2-negative or HER2-positive breast cancer cell lines (SkBr3 and BRC230). We also evaluated the cytotoxic activity and modulation of biomolecular cellular pathways regulated by caelyx and lapatinib, used singly or in combination, at concentrations corresponding to peak plasma level in the two cell lines. Lapatinib was active in the HER2-overexpressing cell line, SkBr3, but not in BRC230 cell line, which does not express HER2. Conversely, caelyx exerted a cytotoxic effect on both the cell lines. Simultaneous exposure to lapatinib and caelyx in SkBr3 cell line produced an additive cytotoxic effect with dephosphorylation of HER2 and EGFR, an upregulation of p21, and an induction of apoptosis through dephosphorylation of BAD and caspase cleavage. In BRC230, simultaneous treatment induced a synergistic effect that was because of, at least in part, an upregulation of p21. Lapatinib also blocked efflux pumps, such as the breast cancer resistance protein I by increasing the length of time in which caelyx was present in tumor cell cytoplasm, which led to caspase cleavage, BAD dephosphorylation, and apoptosis. Our data indicate that lapatinib used in combination with caelyx is active in HER2-expressing cells, probably because of lapatinib-induced dephosphorylation of the HER2-EGFR pathway, and also in non-HER2-expressing cells, possibly because lapatinib blocks efflux pump activity, increasing the length of time of intracellular exposure to caelyx and thereby increasing its cytotoxic effect.

PMID: 19752719 [PubMed - indexed for MEDLINE]





Cancer Res. 2008 Oct 1;68(19):7905-14.
Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2.

Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby CR Jr, Huang Y, Robey RW, Liang YJ, Chen LM, Shi CJ, Ambudkar SV, Chen ZS, Fu LW.
State Key Laboratory for Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
Erratum in:
  • Cancer Res. 2008 Dec 15;68(24):10387.
Lapatinib is active at the ATP-binding site of tyrosine kinases that are associated with the human epidermal growth factor receptor (Her-1 or ErbB1) and Her-2. It is conceivable that lapatinib may inhibit the function of ATP-binding cassette (ABC) transporters by binding to their ATP-binding sites. The aim of this study was to investigate the ability of lapatinib to reverse tumor multidrug resistance (MDR) due to overexpression of ABC subfamily B member 1 (ABCB1) and ABC subfamily G member 2 (ABCG2) transporters. Our results showed that lapatinib significantly enhanced the sensitivity to ABCB1 or ABCG2 substrates in cells expressing these transporters, although a small synergetic effect was observed in combining lapatinib and conventional chemotherapeutic agents in parental sensitive MCF-7 or S1 cells. Lapatinib alone, however, did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in sensitive and resistant cells. Additionally, lapatinib significantly increased the accumulation of doxorubicin or mitoxantrone in ABCB1- or ABCG2-overexpressing cells and inhibited the transport of methotrexate and E(2)17betaG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. However, lapatinib did not affect the expression of these transporters at mRNA or protein levels. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, we conclude that lapatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function. These findings may be useful for cancer combinational therapy with lapatinib in the clinic.

PMID: 18829547 [PubMed - indexed for MEDLINE]



Int J Cancer. 2009 Oct 23. [Epub ahead of print]
Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo.

Morse MA, Wei J, Hartman Z, Xia W, Ren XR, Lei G, Barry WT, Osada T, Hobeika AC, Peplinski S, Jiang H, Devi GR, Chen W, Spector N, Amalfitano A, Lyerly HK, Clay TM.
Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710.
The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific anti-serum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific anti-serum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2-vaccine induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels, and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior anti-tumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted. (c) 2009 UICC.




Cancer Res. 2008 Sep 1;68(17):7083-9.
Synergistic inhibition with a dual epidermal growth factor receptor/HER-2/neu tyrosine kinase inhibitor and a disintegrin and metalloprotease inhibitor.

Witters L, Scherle P, Friedman S, Fridman J, Caulder E, Newton R, Lipton A.
Department of Medicine, The Milton S. Hershey Medical Center/Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
The ErbB family of receptors is overexpressed in numerous human tumors. Overexpression correlates with poor prognosis and resistance to therapy. Use of ErbB-specific antibodies to the receptors (Herceptin or Erbitux) or ErbB-specific small-molecule inhibitors of the receptor tyrosine kinase activity (Iressa or Tarceva) has shown clinical efficacy in several solid tumors. An alternative method of affecting ErbB-initiated tumor growth and survival is to block sheddase activity. Sheddase activity is responsible for cleavage of multiple ErbB ligands and receptors, a necessary step in availability of the soluble, active form of the ligand and a constitutively activated ligand-independent receptor. This sheddase activity is attributed to the ADAM (a disintegrin and metalloprotease) family of proteins. ADAM 10 is the main sheddase of epidermal growth factor (EGF) and HER-2/neu cleavage, whereas ADAM17 is required for cleavage of additional EGF receptor (EGFR) ligands (transforming growth factor-alpha, amphiregulin, heregulin, heparin binding EGF-like ligand). This study has shown that addition of INCB3619, a potent inhibitor of ADAM10 and ADAM17, reduces in vitro HER-2/neu and amphiregulin shedding, confirming that it interferes with both HER-2/neu and EGFR ligand cleavage. Combining INCB3619 with a lapatinib-like dual inhibitor of EGFR and HER-2/neu kinases resulted in synergistic growth inhibition in MCF-7 and HER-2/neu-transfected MCF-7 human breast cancer cells.Combining the INCB7839 second-generation sheddase inhibitor with lapatinib prevented the growth of HER-2/neu-positive BT474-SC1 human breast cancer xenografts in vivo. These results suggest that there may be an additional clinical benefit of combining agents that target the ErbB pathways at multiple points.

PMID: 18757423 [PubMed - indexed for MEDLINE]

J Clin Oncol. 2009 Aug 20;27(24):3908-15. Epub 2009 Jul 20.
Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer.

Finn RS, Press MF, Dering J, Arbushites M, Koehler M, Oliva C, Williams LS, Di Leo A.
Geffen School of Medicine at University of California, Los Angeles, CA, USA. Rfinn@mednet.ucla.edu
PURPOSE: Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) with activity in HER2-amplified metastatic breast cancer (MBC). Its role in non-HER2-amplified MBC remains unclear. EGF30001, a phase III trial of lapatinib and paclitaxel versus paclitaxel and placebo, demonstrated lapatinib does not significantly benefit HER2-negative or HER2-unselected patients with MBC. Published data support interactions between steroid hormone and peptide growth factor signaling. We hypothesized that molecular subgroups may exist within EGF30001 that would benefit from lapatinib. METHODS: A blinded, retrospective biomarker evaluation was performed using immunohistochemistry to semiquantitate estrogen (ER), progesterone (PR), and EGFR expression. HER2 amplification was determined by fluorescent in situ hybridization. Effects of these biomarkers on event-free survival (EFS) were examined in patients with available tissue (n = 493). RESULTS: Lapatinib improved median EFS in HER2-amplified, ER- or PR-positive MBC (n = 36; 5.7 v 4.5 months; P = .351); benefit was greater and statistically significant in HER2-amplified, ER-negative, PR-negative MBC (n = 42; 8.3 v 5.0 months; P = .007). In HER2-negative, ER-positive MBC, median EFS improvement varied by degree of PR expression (H-score): no benefit if PR-strong (n = 133; 9.3 v 7.3 months; P = .373), benefit if PR-weak (n = 50; 7.3 v 2.4 months; P = .026), and potential antagonism if PR-negative (n = 40; 3.7 v 7.2 months; P = .004). No benefit was seen in triple-negative MBC (n = 131; median EFS, 4.6 v 4.8 months; P = .255). EGFR expression was not correlated with benefit from lapatinib. CONCLUSION: Although subgroups are small, these analyses support the hypothesis that semiquantitative determination of hormone receptor status may be a surrogate for EGFR and/or HER2 dependency.

PMID: 19620495 [PubMed - indexed for MEDLINE]
__________________

Mom's treatment history (link)
Rich66 is offline   Reply With Quote
Old 11-05-2009, 10:06 PM   #7
vlcarr
Senior Member
 
vlcarr's Avatar
 
Join Date: Jun 2009
Posts: 343
Re: Lapatinib: A competitor or companion to trastuzumab?

This is combo I did but mine was for newly diagnosed Stage II or III, cancer could not have spread to get in the trial. As you can see below, my results were amazing. It totally did away with my tumor.

I hope this will make it easier for all to get this combo.
__________________
Vicky
Age 47, TN, Diagnosed 05/09
Her2+, ER/PR-, Stage III, 2 tumors = 1 8cm tumor
Grade 3
Sentinel Node Biopsy-speck present in 1 node
Completed 3 month clinical trial of weekly Herceptin and 1000mg Tykerb daily
Tumor no longer present
Right mastectomy and lymph node removal 09/25/09
No cancer present at time of surgery, none in lymph nodes
Start TCH 10/15, every 3 weeks for 4 months followed by radiation
Finished chemo 01/28/10-YEAH!
Herceptin every 3 wks until end of June
Radiation begins 03/01, 6 1/2 weeks
Radiation complete--Yeah!!
Developed lymphedema after radiation
In hospital for 4 days with pneumonia:(
Herceptin done! 06/24/10
Port Removed 07/08/10
Still in PT for lymphedema and mobility issues
DIEP Reconstruction 05/11
I can be changed by what happens to me, but I refuse to be reduced by it~~Maya Angelou
vlcarr is offline   Reply With Quote
Old 01-27-2010, 07:28 AM   #8
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Is Tykerb better than Herceptin?

Maybe, for these reasons.

Cells are the most basic structure of the body. Cells make up tissues, and tissues make up organs, such as the lungs or liver. Each cell is surrounded by a membrane, a thin layer that separates the outside of the cell from the inside.

For a cell to perform necessary functions for the body and respond to its surroundings, it needs to communicate with other cells in the body. Communication occurs through chemical messages in a process called signal transduction. The purpose of these signals is to tell the cell what to do, such as when to grow, divide into two new cells, and die.

Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than current treatments and less harmful to normal cells.

However, the monoclonal antibodies like Herceptin and Erbitux are "large" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside, which are protected from the drug. The cells may pass small molecules back and forth.

Exciting results have come from studies of multitargeted tyrosine kinase inhibitors, "small" molecules that act on multiple receptors in the cancerous cells, like Tykerb and Sutent. Targeted "small-molecule" therapies ruled at the recent annual ASCO meeting of oncologists. The trend is away from the monoclonals to the small molecules, a trend in which a new predictive test may be able to hasten.

The functional tumor cell profiling assay is able to test molecularly-targeted anti-cancer drug therapies like Iressa, Tarceva, Tykerb, Sutent and Nexavar, because of being small molecules. The cell-based assay relies upon a technique known as Functional Tumor Cell Profiling, in which living tumor cells are removed from an individual cancer patient and exposed in the laboratory to the new drugs.

Basically, Functional Tumor Cell Profiling measures the response of the tumor cells to drug exposure. Following this exposure, it measures both cell metabolism and cell morphology. The effect of drugs on the whole cell, resulting in a cellular response to the drug, measures the interaction of the entire genome.

A variety of metabolic and apoptotic measurements are then used to determine if a specific drug was successful at killing the patient's cancer cells. The whole cell profiling method differs from other tests in that it assesses the activity of a drug upon combined effect of all cellular processes, using several metabolic (cell metabolism) and morphologic (structure) endpoints, at the cell "population" level (rather than at the "single cell" level).

Other tests, such as those which identify DNA or RNA sequences or expression of individual proteins often examine only one component of a much larger, interactive process. Functional Tumor Cell Profiling measures genes before and after drug exposure. Gene expression profiles measures the gene expression only in the "resting" state, prior to drug exposure.

The Functional Tumor Cell Profiling Assay is the only assay that involves direct "visualization" of the cancer cells at endpoint. This allows for accurate assessment of drug activity, discriminates tumor from non-tumor cells, and provides a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro.

Source:

Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007

Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)

Tykerb (lapatinib) is one of the first oral agents with the potential to compete directly with the IV drugs which is both a high-volume and high-revenue part of office-based practices.

Although oral tyrosine kinase inhibitors, like Tykerb, offer patients a well-tolerated, conveniently administered alternative to intravenous (IV) therapy, Decisions Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, found that oncologists are not yet ready to use Tykerb as a replacement for Herceptin.

Ninety-one percent of surveyed oncologists stated that intravenous (IV) cancer therapies are more remunerative than oral therapies. And fifty-eight percent of oncologists say they would favor IV Herceptin over oral Tykerb because administration of IV drugs remains an important source of income for their practices.
gdpawel is offline   Reply With Quote
Reply

Thread Tools
Display Modes

Posting Rules
You may not post new threads
You may not post replies
You may not post attachments
You may not edit your posts

BB code is On
Smilies are On
[IMG] code is On
HTML code is On

Forum Jump


All times are GMT -7. The time now is 08:35 AM.


Powered by vBulletin® Version 3.8.7
Copyright ©2000 - 2024, vBulletin Solutions, Inc.
Copyright HER2 Support Group 2007 - 2021
free webpage hit counter