New cancer treatment targets cancer cells images

As cancer research continues to learn more about how gene changes in cells can cause cancer, this research is helping to introduce new types of cancer drugs. Until fairly recently, only a few types of cancers could be treated with targeted therapy, but now these drugs are used to treat many different types of cancer, such as breast cancer, colorectal cancer, lung cancer, pancreatic, lymphoma, leukemia and melanoma.
While targeted therapy drugs used in cancer treatment are generally considered as chemotherapy, these drugs do not work the same as standard chemotherapy drugs, which often attack a patient’s healthy cells along with the cancer cells. Unlike traditional chemotherapy, targeted therapy will go after cancer cells, while doing less damage to the patient’s normal, healthy cells. Currently there are a number of targeted therapies now approved by the FDA to treat many types of cancers. Recent studies show that not all tumors have the same targets, which explains why a targeted therapy treatment may not work for every patient.
For instance, some patients may have an appropriate target for a particular targeted therapy, allowing them to be treated with that therapy.
In some instances, patients may be candidates for targeted therapy if they meet specific criteria, such as their cancer did not respond to other types of therapies, the cancer has spread, or if the cancer is inoperable. While it is currently an exciting time for cancer research in regards to targeted therapy, as more are being approved to treat different types of cancer, these targeted therapies will still not benefit patients whose tumor does not contain a proper target. Research shows that roughly 20% to 25% of all breast cancers have too much of a protein called human epidermal growth factor receptor 2 (HER2). More cancer research is confirming that drugs which block the epidermal growth factor receptor (EGFR), often overproduced in this type of cancer, may be effective for stopping or slowing the growth of colon or rectal cancer.
Cancer drugs that block the epidermal growth factor receptor (EGFR) may also be effective in stopping or slowing the growth of certain types of lung cancer, especially if the EGFR gene contains certain mutations. Lynparza (olaparib) is recently FDA approved targeted therapy for various types of advanced ovarian cancer that are related to defective BRCA genes.
Currently there are a number of clinical trials underway on many different types of cancer to investigate new targets and drugs aimed at them. Even though targeted therapy does not generally attack a patient’s healthy cells the way standard chemo drugs may, a patient may still experience some side effects with this treatment.
High Blood Pressure Some targeted therapies may cause a patient’s blood pressure to rise.
Blood Clotting Other targeted cancer drugs may interfere with the formation of new blood vessels. Throughout a patient’s treatment with targeted therapy drugs, their health care team will closely monitor them for any possible side effects. While the idea of targeting a drug to a tumor seems straight forward, this therapy is complex and not always effective. While the development of these targeted therapies are a breakthrough in treating cancer, only a few cancers can still be eliminated with just these drugs alone. Oncology Associates provides world class cancer care to patients in Omaha and throughout Nebraska, with clinics in Blair and Norfolk. Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. Presentation by Jim Lechner, MD, for Providence Cancer Survivor Celebration on June 2, 2012 in Olympia, Wash. With the advent of the importance of histology in non–small-cell lung cancer (NSCLC) and the development of targeted agents that work on newly found mutations, the field of lung cancer therapy has greatly changed. Lung cancer is the second most common form of cancer and the most common cause of cancer-related deaths in men and women, yet cure rates are significantly lower than those of other less prevalent cancers, such as cancers of the breast and colon. Especially in the last several years, significant advances have been made in personalized chemotherapy choices, based on histology and on the availability of targeted agents that are effective and less-toxic options for lung cancer patients. Gefitinib and erlotinib (Tarceva) bind in a reversible fashion to the adenosine triphosphate (ATP) binding site of EGFR tyrosine kinase, inhibiting initiation of signaling cascades. With this evolving knowledge, gefitinib and erlotinib were brought to the front-line treatment of patients with advanced NSCLC harboring EGFR mutations, and by December 2010, results of multiple randomized phase III trials comparing front-line erlotinib or gefitinib against platinum-based chemotherapy in patients with advanced NSCLC were reported. Afatinib is an irreversible ErbB family blocker that covalently binds to the cysteine residue of EGFR, providing longer inhibition of EGFR. Cetuximab (Erbitux), a chimeric monoclonal IgG1 antibody that blocks EGFR signaling, has been investigated in the front line in combination with platinum-based chemotherapy in advanced NSCLC through two multicenter, randomized phase III trials.
However, cetuximab is being investigated further in combination with other targeted therapies. Dacomitinib (PF-00299804) is a pan-HER inhibitor that binds irreversibly to the ATP domain of EGFR, HER2, and HER4 and has demonstrated EGFR inhibition in cell lines harboring L858R and T790M mutations.[18,19] In a global phase II study, 188 patients were randomized to dacomitinib or erlotinib after progression on chemotherapy. A number of agents targeting parallel and downstream signaling of the EGFR pathway are under development for the treatment of NSCLC, including MET inhibitors.
Tivantinib (ARQ 197) is an oral, selective, non–ATP-competitive inhibitor of MET receptor tyrosine kinase. In conclusion, targeting the EGFR pathway for treatment of NSCLC continues to expand from the reversible EGFR TKIs to the irreversible EGFR TKIs and other monoclonal antibodies that, used as single agents and in combination with other novel therapies, remain a backbone of management for those who harbor EGFR mutations. Crizotinib is an oral, small-molecule competitive ATP inhibitor, primarily of MET, and it also has selective ALK inhibition.[35,36,39] It was first studied in humans in 2006 in the PROFILE 1001 study, using an initial standard dose-escalation pharmacokinetic schema followed by a clinical efficacy evaluation. Response to crizotinib is independent of age, sex, performance status, and prior treatment.[43] Upon the initial results of PROFILE 1001, a multicenter open-label phase II study (PROFILE 1005) was initiated. Crizotinib gained FDA approval in August 2011 for locally advanced or metastatic NSCLC that is ALK-positive, based on the previously described studies reporting response rates alone.
Currently, the National Comprehensive Cancer Network (NCCN) guidelines give a category 2A recommendation for the ALK inhibitor crizotinib in the first-line setting in patients with locally advanced or metastatic NSCLC who have the ALK gene rearrangement.[46] The NCCN also recommends FISH as the standard diagnostic test until further evidence regarding use of RT-PCR and IHC for assessing ALK status becomes available. Several other ALK inhibitors are in the development pipeline, with investigative goals aiming for more selective ALK inhibition and the overcoming of crizotinib resistance.
Researchers have identified a potential alternative approach to blocking the activity of a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.
Initial treatment of prostate cancer that has spread beyond the prostate mostly focuses on blocking androgens’ effect on tumors, typically by interfering with androgen production or blocking the action of androgens.
Eventually, however, most advanced prostate cancer becomes castration-resistant, continuing to progress and spread even when androgen levels are very low or undetectable, possibly because of changes to the AR protein or to its expression level, or due to mutations in the AR gene. To date, though, there has been little progress in directly targeting variant forms of AR or alterations in the AR gene that can promote treatment resistance. By analyzing data from publicly available sources of tumor genomic data, the team homed in on a nuclear receptor protein called ROR-γ as a possible regulator of the AR gene.
Several lines of evidence pointed to the possibility that ROR-γ is involved in prostate cancer.
Further work in prostate cancer cell lines that overexpress AR suggested a direct relationship between ROR-γ and the receptor.
The researchers saw similar results when they treated cell lines with different ROR-γ inhibitors, including two drug-like molecules that are being developed to treat autoimmune disorders. Additional experiments in cell lines showed that targeting ROR-γ affected the expression of cancer-related genes that are regulated by AR, including IGF1 and PTEN. Finally, the research team tested the ROR-γ inhibitors in different prostate cancer mouse models, including models of prostate cancer that have resistance-related variants of the AR protein.
In a mouse model of castration-resistant prostate cancer, the ROR-γ inhibitor SR2211 markedly reduced tumor size, but enzalutamide treatment did not. Targeted therapy is one way in cancer treatment aimed at the specific process of cancer cell growth, cycle life (in some cases also on the blood vessels that feed tumors).
The importance of KRAS mutations in NSCLC may change with further exploration of downstream pathways. Squamous cell carcinoma is consistently related to smoking, and compared with adenocarcinoma there are no specific molecular targets identified, limiting therapeutic options. As immunotherapy has become an exciting area in oncology, with new therapies directed at tumors such as melanoma, more research is being conducted in NSCLC.
A significant amount of research is studying immune modulation with compounds targeting CTLA-4 or PD-1 (see Figures 2 and 3). Recently in the New England Journal of Medicine (NEJM), Topalian et al reported responses in patients with multiple tumor types (including NSCLC) using an anti-PD1 antibody (MDX-1106) in a phase I trial while, in the same NEJM issue, Brahmer et al showed equally positive results using an anti–PD-L1 antibody (MDX-1105) in a similar phase I trial.[70,71] Programmed death protein 1 (PD1) is an immune checkpoint receptor that can mitigate immunosuppression of cytotoxic T cells. With the initial positive results described above in both the phase I trial of anti-PD1 and the phase I trial of anti–PD-L1 antibodies, ongoing phase II and III trials are being undertaken in NSCLC. Even with the advances in targeted therapy and the prospect of immunotherapy, cytotoxic chemotherapy is still the backbone of therapy for patients with lung cancer. As the rapid evolution of genome technology coupled with a fall in sequencing costs has increased the technical and economic feasibility of complete molecular profiling of a patient’s tumor, molecular diagnostic kits are being developed to guide the use of an increasing number of therapies.
In conclusion, multiple advances have been made in the number and types of therapy available for treatment of patients with lung cancer.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. One form of cancer treatment that involves the use of these drugs is referred to as targeted therapy. In addition, clinical trials are continuing to look for additional drugs aimed at new targets that have recently been discovered.
Targeted therapies work by going straight to the genes and proteins in cancer cells to halt their ability to grow and spread.
And each of these genes produces a different protein, which also performs a different task for the cell. A patient’s tumor tissue must be first tested to determine if they have an appropriate target. And in some instances, even if there is a proper target, this still does not guarantee that the treatment will work.
Gilotrif (Afatinib) is a recent FDA approved targeted therapy for the treatment of non-small cell lung cancer.
In fact, more than half of patients taking a certain targeted therapy drug have experienced some type of skin related side effect. Unfortunately, there is not much that can be done to prevent this, but your health team will routinely monitor blood pressure closely for patients taking a drug with this type of side effect.
Sometimes the target in the cancer cell may wind up not being as important as was originally thought, so the drug will not provide much of a benefit to the patient.
With a few exceptions, patients with cancer generally receive targeted therapy as part of a combination with surgery, chemotherapy, radiation or hormonal therapy.
In addition to new uses of chemotherapeutics and targeted agents, the possibilities of immunotherapy are also being explored. More than two decades ago, very few treatments were available for lung cancer; over time, however, we have made modest strides in finding new forms of chemotherapy and new treatment targets.

The first of these targeted agents was bevacizumab (Avastin), a humanized monoclonal antibody directed at vascular endothelial growth factor (VEGF), which was associated with an improvement in overall survival (OS) in non–small-cell lung cancer (NSCLC) when added to carboplatin and paclitaxel.[1] With the success of bevacizumab as a model, newer therapies are constantly being investigated, and this review aims to provide an overview of current practice, with insights into future management. Two classes of agents targeting EGFR have been investigated extensively in patients with NSCLC: the tyrosine kinase inhibitors (TKIs) and the monoclonal antibodies (mAbs). Through numerous studies, it became clear that responses to these targeted agents did not emerge from unselected populations. The mechanisms of resistance and means of overcoming them have become active areas of research. Bevacizumab and cetuximab have shown promising results in the Southwest Oncology Group (SWOG) 0536 trial.[16] In this safety-and-efficacy phase II single-arm study, approximately 100 patients with advanced NSCLC were treated front-line with carboplatin, paclitaxel, bevacizumab, and cetuximab. In a trial with combination afatinib-cetuximab in patients with EGFR mutations and disease progression on erlotinib, disease control was observed in all 22 patients treated with the 40-mg dose of afatinib, with tumor size reduction of up to 76%.[17] This is under further investigation with an ongoing expanded cohort.
In a phase II study evaluating two dosing regimens, the RR was 20% and the PFS was 5.3 months. A global randomized, double-blind, placebo-controlled phase II trial compared erlotinib plus ARQ 197 vs erlotinib plus placebo in EGFR inhibitor–naive patients with advanced NSCLC. There are three methods of detecting ALK rearrangement: a fluorescence in situ hybridization (FISH) break apart assay, immunohistochemistry (IHC), and reverse-transcriptase polymerase chain reaction (RT-PCR). After two patients in this phase I study had a dramatic response (coinciding with the discovery of ALK gene rearrangements in patients with NSCLC), an expanded prospective cohort was enrolled, with testing for ALK rearrangement.[42] Updated results from September 2012 showed a 60% RR (3 complete responses, 84 partial responses), a median time to first documented objective response of 8 weeks, and a median duration of response of 49 weeks. Preliminary results of the prospective randomized phase III trial (PROFILE 1007) comparing crizotinib and either pemetrexed (Alimta) or docetaxel in the second-line setting were recently presented in Vienna at the 2012 meeting of the European Society for Medical Oncology (ESMO). Nuclear receptors (which also include AR itself) are proteins that, when activated, bind DNA directly to regulate gene activity. The drugs had no effect on normal prostate cells or prostate cancer cell lines that don’t overexpress AR.
The drugs halted tumor growth in all of the mouse models, except for a model of prostate cancer that did not overexpress AR.
Sowalsky cautioned that there is still important work to do before drugs that target ROR-γ can be tested in men with castration-resistant prostate cancer. Other types of treatments, such as hormonal therapy, biological therapy or stem cell transplant, may also be used in certain cases for some types of cancer. Future studies are being designed to investigate the response to various specific ALK inhibitors and to identify other homologous molecular targets.
The data reported from a published trial of the mitogen-activated protein kinase–1 (MEK1) inhibitor selumetinib have drawn interest for patients with KRAS mutations. They contribute to cancer development by stimulating proliferation of various cell types, inhibiting differentiation of some precursor cells, and playing a crucial role in cell differentiation and growth.[61,62] Mutations in these receptors have been seen in 20% of lung squamous cell carcinomas and rarely in adenocarcinoma.
Initially vaccine therapy was centered on small-cell lung cancer, with investigations of nonspecific vaccines such as Bacille Calmette-Gurin (BCG), but initial trials were negative.[63] Currently in NSCLC, several vaccines are in phase III trials based on benefits seen in early-phase studies, and we recently received results from a trial using the vaccine L-BLP25 (Stimuvax). Currently, ipilimumab (Yervoy, a monoclonal antibody that improves antitumor immunity via blockade of the cytotoxic T-cell lymphocyte antigen 4 [CTLA-4], impeding immune downregulation) is approved for use in advanced-stage melanoma. An active form of immune evasion used by tumor cells involves the joining of PD1 to its ligand (PD-L1), found on many tumor cells or in the tumor microenvironment.
Two other compounds, in addition to the medications described above, are also being studied in phase I trials (AMP-224, a Fc fusion protein targeting PD-L2) and phase II trials (MK-3475, a PD-1 inhibitor).[72] Although response rates initially seem small, the rates are comparable to reported responses with chemotherapy. After determining that clinical outcomes were improved with weekly rather than every-3-week administration of nab-paclitaxel in phase II trials, a phase III randomized trial was conducted in patients with advanced NSCLC to evaluate carboplatin with nab-paclitaxel vs carboplatin-paclitaxel in the front-line setting. The International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) are examples of large-scale integrative programs whose goal is to harness the full potential of the cancer genome to deliver personalized cancer medicine through multidisciplinary programs.
One overriding theme that is present with all our new therapies is the importance of identifying specific characteristics in our patients that will guide or even change our therapeutic options. The use of a targeted therapy may be restricted to patients whose tumor has a specific gene mutation that codes for the target, where as patients who do not have this mutation would not be good candidates, as the therapy would have nothing to target. Patients are encouraged to follow up with their health care team to gain more information about possible therapies and treatment options. If a patient’s test results show the cancer is HER2 positive, there are several FDA approved drugs that may be recommended as as targeted therapy options. While the FDA has approved several BRAF inhibitors, these drugs should not be used by patients whose tumors do not have these mutations. For instance, some drugs will target substances that are more common on cancer cells, but may also be found on healthy cells. These problems usually develop slowly over days to weeks and are not signs of a drug allergy. Some patients may require medicine to help bring their blood pressure back down to a safe level while they are using a targeted therapy. These drugs may also cause blood clotting in the patient’s legs and lungs, as well as heart attacks and strokes. And patient’s experiencing any side effects should inform their health care team about any new or unusual changes. As physicians learn more about the specific changes in cancer cells, more targeted treatments will be developed. Significant results were not seen just with specific patient characteristics or even EGFR amplification but instead noted in patients with specific EGFR mutations. Amplification of MET and T790M mutations account for 20% and 50%, respectively, of these cases.[11] Irreversible EGFR inhibitors, targeted therapies against MET, and dual-pathway blockades have activity in this resistant population. In this open-label, randomized phase III study, patients with EGFR-mutated, advanced lung adenocarcinoma received front-line treatment with either afatinib or cisplatin-pemetrexed.
Despite the positive results from FLEX, cetuximab has not been approved for treatment of NSCLC. The feasibility endpoint was met, and secondary endpoints revealed an RR of 53%, PFS of 7 months, and OS of 14 months. The primary endpoint of PFS was 7.7 months in the crizotinib arm and 3 months in the chemotherapy arm. Chen and his colleagues looked for another approach, searching for proteins that regulate the AR gene and, thus, affect AR synthesis. Please note that blog posts that are written by individuals from outside the government may be owned by the writer, and graphics may be owned by their creator. These are mainly seen in nonsquamous lung cancer with clinical pathologic features similar to ALK rearrangement. The published subset data from both the FLEX and BMS 099 trials demonstrate response correlations with mutational status similar to those seen in colorectal adenocarcinomas. In a randomized discontinuation trial reviewed in poster form at the ASCO meeting in 2012, the mTOR inhibitor ridaforolimus was provided as a single agent in a subset of pretreated patients with advanced NSCLC.
FGFR1 amplification seems to be directly correlated with smoking dose and does not differ by ethnicity. The anti-PD1 antibody showed an objective response in 14 of the 122 NSCLC patients, with a PFS of 26% at 24 weeks, while the anti–PD-L1 antibody showed an objective response in 5 of 49 patients treated, with a PFS of 31% at 24 weeks. We eagerly await final results of these new studies, as immune-modulation therapy may become a new modality for the treatment of NSCLC. The RR (primary endpoint) was higher in those treated with nab-paclitaxel (33% vs 25%, P = .005), and this was even more pronounced in those with squamous cell carcinoma (41% vs 24%).
To get closer to our goal of personalized medicine, we suggest a potential approach to patient care (Figure 4). This requires an even more careful selection of patients based on information gathered from their tumors. When certain proteins are blocked, or stop working altogether, the cancer cells stop growing and die.
For example Herceptin (trastuzumab) was developed to target cancers that over produce the HER2 protein. Zelboraf (Vemurafenib) is an example of targeted drug therapy used for metastatic melanoma.
When the drug from therapy treatment attacks more than one target, side effects are more likely to occur. However, allergic reactions to these drugs generally start suddenly, usually within minutes to hours from when the drug was given.
Inform your health team if you experience any problems with sudden swelling, pain or tenderness in the arms or legs.
The sooner health providers are informed, the sooner they can treat any possible side effects and keep them from getting worse. The results of these trials demonstrate that testing for EGFR mutations should be a standard, to identify those who would benefit from front-line EGFR-TKI treatment. These results have led to the ongoing phase III SWOG 0819 trial of carboplatin-paclitaxel and bevacizumab (in eligible patients), with or without cetuximab, in patients with advanced NSCLC. Recently, the FDA granted “breakthrough therapy” designation to LDK378, allowing expedited development of the drug (of note, this designation is distinct from that of priority review or that of accelerated approval.)[48] Two heat shock protein 90 (HSP90) inhibitors, retaspimycin and ganetespib, have demonstrated clinical activity in patients with ALK-rearranged NSCLC. In such cases, it is necessary to contact the writer, artist, or publisher to obtain permission for reuse.
Differences of targeted therapies with standard therapy (surgery, Chemotherapy, Radiation) is that they are only on targeted therapies focus on a specific molecule led to the development and spread of cancer cells.
ROS1 rearrangements are very rare and seen in 1% to 2% of patients with NSCLC, and there is no difference in prevalence between Asian and non-Asian patients. FGFR1 amplification develops early and hence is seen in biopsy specimens of primary and metastatic lesions.[61,62] FISH and IHC testing are well correlated.
With these preliminary phase II results, a phase III trial (Stimulating Targeted Antigenic Responses To NSCLC [START]) was initiated to investigate vaccine vs placebo in unresectable stage III patients who were stable or responding after combined-modality therapy with chemotherapy and radiation. Interestingly, subset analysis showed a benefit in patients with squamous histology, compared with no observed benefit in those with nonsquamous histology.
Of note, both studies showed an increase in immune-related adverse events but more importantly, there were three deaths in the anti-PD1 study, due to pneumonitis. Standard front-line chemotherapy for squamous cell carcinoma has remained a platinum-based doublet; new treatment options are needed. The aim will be to establish a consistent and robust validation workflow of the discovered genomic abnormalities with next-generation sequencing analysis, to enable real-time predictive targeted patient therapy by analyzing tissue specimens and circulating tumor cells (CTCs) for molecular markers in a Clinical Laboratory Improvement Amendments (CLIA)-certifiable manner.
To provide the best therapy for our patients, we must accept that their tumor characteristics can change over time, especially after chemotherapy, and that truly personalized treatment of the patient, in real time, is only possible with the most up-to-date information about their tumor status. Kadcyla, or T-DM1, is yet another targeted drug therapy for treating women with stage 2 or stage 4 metastatic breast cancer that is also HER2-positive. Patients experiencing chest pain, sudden shortness of breath, vision problems, weakness, seizures or difficulty talking, must seek immediate emergency help.

Overall, side effects from targeted therapy are manageable and are generally less severe than with traditional chemotherapy treatment.
While on the standard therapy, healthy tissue is also affected by the administration of the drug. After the initial in vitro discovery of ROS1 inhibition by an ALK inhibitor in the HCC78 cell line, the expanded cohort of ROS1 in PROFILE 1001 (18 patients) was treated with crizotinib.
Other MEK inhibitors currently in development include XL518, which is under investigation in a phase I dose-escalation trial for patients with solid tumors, and MEK162, which will be investigated in a phase II trial targeting melanoma that is now enrolling patients. Nab-paclitaxel–carboplatin should be considered a preferred front-line regimen for patients with advanced squamous cell carcinoma of the lung. A number of different platforms include high-throughput mutation analysis and quantitative-PCR methodologies.
Other targeted therapies are being evaluated in clinical trials to see how well they work in treating breast cancer.
Other allergic reactions may include serious side effects like difficulty breathing, a tightness in the throat, dizziness, or swelling of the tongue or lips. There were also improvements in the 1-year disease-control rate, cancer-related symptoms, and QoL with afatinib. Targeted therapy can be used alone or in combination with chemotherapy drugs to obtain effective results in the signal blocks the growth of cancer cells. The overall RR was 57%, and 8 of 12 patients achieved a complete response.[49] FISH is the standard diagnostic test, although RT-PCR and IHC are being developed to detect ROS1. Tramenitib and dabrafenib are MEK inhibitors in multiple phases of development, primarily for melanoma, but investigations will include patients with additional solid tumors as well as hematologic malignancies. Final data are pending from a European study comparing cisplatin and gemcitabine with or without BIBF 1120, and a phase III trial combining docetaxel with BIBF 1120. While the results with L-BLP25 did not meet their primary endpoint, we must await results of phase III trials involving other vaccine therapies (eg, MAGRIT: MAGE-A3 as Adjuvant Non–small-cell Lung Cancer Immunotherapy Lung Cancer Vaccine Trial, using the MAGE-A3 vaccine) before we can make definitive conclusions. Interestingly, nab-paclitaxel provides a novel treatment approach by increasing intratumoral concentrations of drug through a receptor-mediated transport process that involves binding to a gp60 receptor, activation of a caveolin-1 protein, and formation of caveolae transporters.[75] SPARC (secreted protein, acidic, cysteine-rich [osteonectin]) is a protein secreted by tumor that binds to albumin and thus may be affected by this biologically interactive albumin-bound paclitaxel. Studies such as the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial have highlighted the feasibility and value of obtaining more patient specimens and subsequently planning for discovery of new markers correlated with clinical outcome.[76] The schema not only underscores the obvious importance of initial tissue acquisition leading to biomarker testing, but it also shows the importance of considering rebiopsy at the time of progression.
The most frequent adverse events were diarrhea and rash, although no patients discontinued afatinib because of rash.
The SPARC pathway may be a new target in NSCLC and is being evaluated further through biomarker assays in patients treated with nab-paclitaxel. Although rebiopsy is not currently a standard practice in patients with lung cancer, we propose that this should be considered more frequently, as it is clear that lung cancer is not a homogenous entity and that any histologic change, or any change in mutational status, could lead to the gains or losses of new therapies for our patients. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new born animal.
As more targets are identified and new therapies are developed, patients will be eligible for treatments that work best for their type of breast cancer.
LUX-Lung 3 is the first randomized study to demonstrate benefit of an oral targeted therapy vs chemotherapy in a molecularly selected population.
Afatinib has also demonstrated benefit in those previously treated with EGFR TKIs.[13] Based on these results, afatinib is currently available to those who are both TKI-naive and TKI-resistant, through an open-label expanded-access program. On the formation of cancer cells, too many new cells are formed, whereas the old cells do not die as they should. Targeted therapy for breast cancer focus on proteins that signal cancer cells to grow and divide uncontrollably. A randomized phase III study of gefitinib (IRESSA) versus standard chemotherapy (gemcitabine plus cisplatin) as a first-line treatment for never-smokers with advanced or metastatic adenocarcinoma of the lung. First-SIGNAL: first-line single-agent Iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicenter, open-label-randomised phase 3 trial. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicenter, open-label, randomized, phase 3 study. LUX-Lung 3: a randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. A phase II trial of afatinib (BIBW 2992) in patients (pts) with advanced non-small cell lung cancer previously treated with erlotinib (E) or gefitinib (G). Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. SWOG 0536: phase II trial of carboplatin, paclitaxel, cetuximab and bevacizumab followed by cetuximab and bevacizumab in advanced non-small cell lung cancer. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyroside kinase inhibitor. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small cell lung cancer. Phase II study of the multitargeted tyroside kinase inhibitor XL647 in patients with non-small-cell lung cancer. Combination efficacy with MetMAb and erlotinib in a NSCLC tumor model highlight therapeutic opportunities for c-Met inhibitors in combination with EGFR inhibitors. Targeting MET with XL184 to reverse EGFR tyrosine kinase inhibitor (TKI) resistance in NSCLC: impact of preclinical studies on clinical trial design. Results from ARQ 197-209: A global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Rationale and Design of MARQUEE: a phase III, randomized, double-blind study of tivantinib plus erlotinib versus placebo plus erlotinib in previously treated patients with locally advanced or metastatic, nonsquamous, non-small-cell lung cancer. Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. The MetLUNG study: a randomized, double-blind, phase III study of onartuzumab (MetMAb) plus erlotinib versus placebo plus erlotinib in patients with advanced, MET-positive non-small cell lung cancer (NSCLC). Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond.
Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. Distinct clinical features and outcomes in never-smokers with non-small cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase I study.
Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC). Phase 3 randomized study of crizotinib versus pemetrexed or docetaxel chemotherapy in advanced, ALK-positive NSCLC (PROFILE 1007).
Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.
Novartis compound LDK378 receives FDA Breakthrough Therapy designation for ALK+ non-small cell lung cancer [press release].
Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement.
Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib.
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Impact of AKT inhibitor MK-2206 on erlotinib resistance in non-small cell lung cancer (NSCLC).
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Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer.
Merck: Phase III trial of L-BLP25 (Stimuvax) in patients with non-small cell lung cancer did not meet primary endpoint [press release]. Improving survival for stage IV non-small cell lung cancer: a surveillance, epidemiology, and end results survey from 1990 to 2005. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.
William WN Jr, Erickson H, Wei C, et al: Differences in mutation patterns of diagnostic versus post-chemotherapy samples in patients with metastatic non-small cell lung cancer (NSCLC) [poster]. Accepted for presentation at the 2013 meeting of the American Society of Clinial Oncology (ASCO).

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