Posts Tagged ‘adenocarcinoma’

Author: Tilda Barliya PhD

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Pancreatic cancer has been previously addressed here in our blog (I-IX) but a recent diagnosis of a colleague urged me to go back to the basics and search for more answers and updates hoping it would offer some peace.

Pancreatic cancer is the 4th leading cause of death in the united states with only 3% rate for 5-year survival rate (1). Due to lack of symptoms and limitation in diagnostic methods, patients are mostly diagnosed at mush advanced stages. When reach these stages, patients start to show symptoms of weight loss, abdominal pain, jaundice, by than, the cancer has already spread.

Several treatment options are available in which surgical resection (for the 15%-20% that are eligible for it) increase the 5-year survival rate by up to 20% , and that’s mainly because the cancer comes back about 85 percent of the time (1,2). These statistics are very hard to comprehend, especially with the progress been made in other types of cancer.

So Why pancreatic cancer is so deadly?

Pancreatic cancer biology and genetics

Pancreatic cancer biology and genetics. Nabeel Bardeesy & Ronald A. DePinho. Nature Reviews Cancer 2002: 2, 897-909

The pancreas is a highly vascularized 6 inch dual-function gland that plays a major role in the body. It secretes digestive enzymes and hormones (i.e; insulin, glucagon, somatostatin and pancreatic polypeptide) which assist in the digestion of fats and the absorption of nutrients. These enzymes help further digest carbohydrates, proteins and lipids in the chyme.

It is postulated that a tumor starts to overcome  the functionally of the pancreas;  causing reduction of important hormones (insulin) and enzymes (digestive enzymes) production thus impacting the overall ability of the body to absorb nutrients and get energy coins thus affecting  the overall performance of the body. Several studies were conducted to evaluate the connection between dietary factors and induction of pancreatic cancer, however no direct correlation was observed (11, 12)

More so, the pancreas is located at the junction of several organs; liver, gall bladder and intestines,  thus enabling metastatic cells to harbor multiple vital organ. Most patients die for liver failure due to liver metastases.

These factors; late- diagnosis, reduction in overall body function and failure of vital organs (such as the liver due to metastasis), cause the aggressive and fast death of these panvreatic patients.

A growing number of studies have identified common mutational profiles in simultaneous lesions, providing supportive evidence of the relationship between pancreatic intraepithelial neoplasia (PanINs) and the pathogenesis of pancreatic adenocarcinoma. Nabeel Bardeesy and Ronald A. DePinho summarized this data in Figure and table inserted herein. Intriguingly, there seems to be an ordered series of mutational events in association with specific neoplastic stages (1,4).

Pancreatic cancer biology and genetics. Nabeel Bardeesy & Ronald A. DePinho. Nature Reviews Cancer 2002, 2: 897-909.

The combination of these multiple mutations render pancreatic cancer cells resistant to current chemo and radiotherapy. More so, known pancreatic cancer antigens have generated relatively weak immune responses due to these combined mutagenesis (5, 16). These crucial somatic genetic mutations can generate pancreatic cancer proteins that are essentially altered self proteins

Therefore, in order to design a good  immunotherapeutic approach one must incorporate at least one agent against a pancreatic cancer target as well as one or more agents that will modify both local and systemic mechanisms of pancreatic-cancer-induced.

Another important element that needs to be taken into consideration are the immunological checkpoints. These checkpoints serve two  purposes:

  1. To help generate and maintain self-tolerance, by eliminating T cells that are specific for self-antigens.
  2. To restrain the amplitude of normal T-cell responses so that they do not ‘overshoot’ in their natural response to foreign pathogens

The prototypical immunological checkpoint is mediated by the cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) counter regulatory receptor that is expressed by T cells when they become activated (6).  CTLA4 binds two B7 FAMILY members on the surface APCs — B7.1 (also known as CD80) and B7.2 (also known as CD86): with roughly 20-fold higher affinity than the T-cell surface protein CD28 binds these molecules. CD28 is a co-stimulatory receptor that is constitutively expressed on naive T cells. Because of its higher affinity, CTLA4 out-competes CD28 for B7.1/B7.2 binding, resulting in the downmodulation of T-cell responses (7). Monoclonal antibodies that downregulate B7-H1 and B7-H4 are currently in clinical development. This is just one example of the potential use of targeted therapy for use in clinical trials.

Dan Laheru* and Elizabeth M. Jaffee have summarized the immunotherapy clinical trials  back in 2005:

Immunotherapy for pancreatic cancer |[mdash]| science driving clinical progress

Herein you can read about the latest summary of the NCI portfolio on Pancreatic cancer and research highlights : http://www.cancer.gov/researchandfunding/reports/pancreatic-research-progress.pdf

Here’s their recommendation for future plans for clinical trials:

  • Perform well-designed Phase II studies to help define strategies likely to succeed in a Phase III setting.
  • Adopt consistent entry and evaluation criteria for Phase II trials.
  • Conduct high-priority Phase III trials as intergroup trials and include scientifically appropriate biorepositories.
  • Conduct trials on rational combinations of targeted agents and develop predictive biomarkers to assist in patient selection.
  • Explore use of immune therapies, particularly among those with earlier stage disease.
  • Share trial outcomes, including those of trials with negative results.

According to the NCI clinical trial results from two phase III clinical trials, the targeted therapies sunitinib (Sutent®) and everolimus (Afinitor®) increased the length of time patients with pancreatic neuroendocrine tumors (panNET) survived without the disease progressing. And, in the sunitinib trial, patients who received the drug also had better overall survival. The findings were published February 9, 2011, in the New England Journal of Medicine (NEJM). Although neuroadenoma is rare and presents only 2% of all pancreatic cancer, no effective treatment was available, now these results may offer some hope (9).

More so, a four-drug chemotherapy regimen has produced the longest improvement in survival ever seen in a phase III clinical trial of patients with metastatic pancreatic cancer, one of the deadliest types of cancer (10). Patients who received the regimen, called FOLFIRINOX, lived approximately 4 months longer than patients treated with the current standard of caregemcitabine (11.1 months compared with 6.8 months).

In summary:

Remarkable progress has been made in understanding the  genetics and development biology pancreatic cancer have offered new potential targets for therapy. ” The availability of powerful new technologies and continued contributions of investigators in many related disciplines provides a measure of optimism towards future progress in treating this disease (1)”. Latest results of clinical trials may also shade some hope for patients suffering from this horrible disease.

On a personal note, I hope these new opportunities and clinical trials will offer another avenue to my colleague……


1. Nabeel Bardeesy and Ronald A.DePinho. Pancreatic cancer biology and genetics. Nature Cancer reviews 2002, 2: 897-909. http://www.nature.com/nrc/journal/v2/n12/full/nrc949.html

2. Melinda Wenner. What makes pancreatic cancer so deadly. Scientific American 2008. http://www.scientificamerican.com/article.cfm?id=experts-pancreatic-cancer-gene-upshaw

3. Pancreas. Wikipedia. http://en.wikipedia.org/wiki/Pancreas

4. Jaffee, E. M., Hruban, R. H., Canto, M. & Kern, S.E. Focus on pancreas cancer. Cancer Cell 2, 25–28 (2002). http://www.sciencedirect.com/science/article/pii/S1535610802000934

5.  Dan Laheru* and Elizabeth M. Jaffee. Immunotherapy for pancreatic cancer – science driving clinical progress.  Nature Reviews: Cancer. 2005. 5: 459-467. http://www.nature.com/nrc/journal/v5/n6/full/nrc1630.html

6. Coyle, A. J. & Gutierrez-Ramos, J. C. The expanding B7 superfamily: increasing complexity in co-stimulatory signals regulating T cell function. Nature Immunol 2001. 2, 203–209. http://www.nature.com/ni/journal/v2/n3/full/ni0301_203.html

7.  Walunas, T. L., Bakker, C. Y. & Bluestone, J. A. CTLA-4 ligation blocks CD28-dependent T cell activation. J. Exp. Med 1996. 183, 2541–2550. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192609/


8. Pancreatic Cancer: A summary of NCI’s portfolio and highlights of recent research progress 2010. http://www.cancer.gov/researchandfunding/reports/pancreatic-research-progress.pdf

9. NCI bulletin: Targeted Therapies May Be Effective Against Rare Pancreatic Cancer. http://www.cancer.gov/clinicaltrials/results/summary/2011/panNET-Therapy0411

10. NCI bulletin: Chemotherapy Regimen Extends Survival in Advanced Pancreatic Cancer Patients http://www.cancer.gov/clinicaltrials/results/summary/2011/pancreatic-chemo0611

11. Nilsen TI, Vatten LJ. A prospective study of lifestyle factors and the risk of pancreatic cancer in NordTrondelag, Norway. Cancer Causes Control 2000;11:645-52. http://www.ncbi.nlm.nih.gov/pubmed/10977109

12. Marshall JR, Freudenheim J. Alcohol. In: Schottenfeld D, Fraumeni JF Jr., eds. Cancer Epidemiology and  Prevention, 3rd ed. New York: Oxford University Press, 2006. P. 243-58. http://www.oxfordscholarship.com/view/10.1093/acprof:oso/9780195149616.001.0001/acprof-9780195149616

13. Alison P. Klein. Identifying people at a high risk of developing pancreatic cancer. Nature Reviews Cancer 2012, 13: 66-74. http://www.nature.com/nrc/journal/v13/n1/full/nrc3420.html

14. John P. Morris, Sam C. Wang & Matthias Hebrok. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma.Nature Reviews Cancer 2012. 10:683-695.  http://www.nature.com/nrc/journal/v10/n10/full/nrc2899.html

15. Patrick Goymer. Imaging: Early detection for pancreatic cancer. Nature Reviews Cancer 2008, 8: 408-409. http://www.nature.com/nrc/journal/v8/n6/full/nrc2407.html

16. Koido S, Homma S, Takahara A, Namiki Y, Tsukinaga S, Mitobe J, Odahara S, Yukawa T, Matsudaira H, Nagatsuma K, Uchiyama K, Satoh K, Ito M, Komita H, Arakawa H, Ohkusa T, Gong J, Tajiri H. Current Immunotherapeutic Approaches in Pancreatic Cancer, Clin Dev Immunol. 2011;2011:267539. http://www.hindawi.com/journals/cdi/2011/267539/

Other related articles on this open Access Online Scientific Journal, include the following:

I. Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed.

Aviva Lev-Ari, PhD, RN, 10/24/2012


II. Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University.

Aviva Lev-Ari PhD,RN, 10/24/2012


III. Personalized Pancreatic Cancer Treatment Option.

Aviva Lev-Ari PhD, RN, 10/16/2012


IV. Battle of Steve Jobs and Ralph Steinman with Pancreatic cancer: How we lost.

Ritu Saxena PhD, 5/21/2012


V.  Early Biomarker for Pancreatic Cancer Identified.

Prabodh Kandala, PhD, 5/17/2012


VI. Usp9x: Promising therapeutic target for pancreatic cancer.

Ritu Saxen PhD, 5/14/2012


VII. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing.

Stephen J. Williams, PhD, 10/4/2013


VIII. In Focus: Targeting of Cancer Stem Cells.

Ritu Saxena, PhD, 3/27/2013


IIX. New Ecosystem of Cancer Research: Cross Institutional Team Science.

Aviva Lev-Ari. PhD, RN, 3/24/2013


IX. In Focus: Identity of Cancer Stem Cells.

Ritu Saxena, PhD, 3/22/2013



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Non-small Cell Lung Cancer drugs – where does the Future lie?

In focus: Tarceva, Avastin and Dacomitinib


UPDATED on July 5, 2013

(from reports published in New England Journal of Medicine on drug, crizotinib)


Curator: Ritu Saxena, Ph.D.



Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and usually grows and spreads more slowly than small cell lung cancer.

There are three common forms of NSCLC:

  • Adenocarcinomas are often found in an outer area of the lung.
  • Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
  • Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types.

Lung cancer is by far the leading cause of cancer death among both men and women. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined. The American Cancer Society’s most recent estimates for lung cancer in the United States for 2012 reveal that about 226,160 new cases of lung cancer will be diagnosed (116,470 in men and 109,690 in women), and there will be an estimated 160,340 deaths from lung cancer (87,750 in men and 72,590 among women), accounting for about 28% of all cancer deaths.


Different types of treatments are available for non-small cell lung cancer. Treatment depends on the stage of the cancer. For patients in whom the cancer has not spread to nearby lymph nodes are recommended surgery. Surgeon may remove- one of the lobes (lobectomy), only a small portion of the lung (wedge removal), or the entire lung (pneumonectomy). Some patients require chemotherapy that uses drugs to kill cancer cells and stop new cells from growing.

FDA approved drugs for NSCLC

Abitrexate (Methotrexate)
Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation) 
Alimta (Pemetrexed Disodium)
Avastin (Bevacizumab)
Erlotinib Hydrochloride
Folex (Methotrexate)
Folex PFS (Methotrexate)
Gemcitabine Hydrochloride
Gemzar (Gemcitabine Hydrochloride)
Iressa (Gefitinib)
Methotrexate LPF (Methotrexate)
Mexate (Methotrexate)
Mexate-AQ (Methotrexate)
Paclitaxel Albumin-stabilized Nanoparticle Formulation
Paraplat (Carboplatin)
Paraplatin (Carboplatin)
Pemetrexed Disodium
Platinol (Cisplatin)
Platinol-AQ (Cisplatin)
Tarceva (Erlotinib Hydrochloride)
Taxol (Paclitaxel)
Xalkori (Crizotinib)

On the basis of target, the drugs have been classified as follows:


NSCLC Drug Market Analysis

NSCLC drug market expected to grow from $4.2 billion in 2010 to $5.4 billion in 2020

Although, a whole list of agents is available for the treatment of NSCLC, the market for NSCLC drugs is expected to expand from $4.2 billion in 2010 to $5.4 billion in 2020 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.   

However, drug sales for metastatic/advanced squamous cell non-small-cell lung cancer, which comprises only a small fraction of the market, will decrease from nearly 17 percent in 2010 to approximately 13 percent in 2020. According to surveyed U.S. oncologists and MCO pharmacy directors, increasing overall survival is one of the greatest unmet needs in first-line advanced squamous non-small-cell lung cancer.

In 2009, antimetabolites dominated the NSCLC market, with Eli Lilly’s Alimta (Pemetrexed) accounting for nearly three-quarters of sales within this drug class. Since then, Alimta has faced tough competition from a number of similar drugs and from emerging therapies. It was speculated that the antimetabolites market share would reduce significantly making it the second-largest drug class in NSCLC, while the epidermal growth factor receptor (EGFR) inhibitor class will garner the top market share by 2019.

Genentech/OSI Pharmaceuticals/Roche/Chugai Pharmaceutical’s Tarceva belongs to the EGFR inhibitor class, and has been prescribed principally along with Eli Lilly’s Alimta, to NSCLC patients.Both these drugs have dominated the NSCLC market till 2010, however, their market hold is expected to weaken from 2015-2020, as claimed by Decision Resources Analyst Karen Pomeranz, Ph.D. Decision Resources is a research and advisory firms for pharmaceutical and healthcare issues.

Tarceva (Erlotinib)

Generic Name: Erlotinib, Brand Name: Tarceva

Other Designation: CP 358774, OSI-774, R1415, RG1415, NSC 718781

Mechanism of Action: Tarceva, a small molecule quinazoline, directly and reversibly inhibits the epidermal growth factor receptor (EGFr) tyrosine kinase. Detailed information on how it works could be found at the Macmillian Cancer support website.

Tarceva has been approved for different cancers and several indications have been filed-

  • non-small cell lung cancer (nsclc), locally advanced or metastatic, second line, after failure of at least one prior chemotherapy regimen (2004)
  • pancreatic cancer, locally advanced or metastatic, in combination with gemcitabine, first line (2005)
  • non-small cell lung cancer (nsclc), advanced, maintenance therapy in responders following first line treatment with platinum-based chemotherapy (2010)
  • non-small cell lung cancer (nsclc) harboring epidermal growth factor (EGFr)-activating mutations, first line treatment in advanced disease

Sales of Tarceva 

May, 2012 sales of Tarceva in the US have been reported to be around $564.2 million.

In a recent article published by Vergnenègre et al in the Clinicoeconomic Outcomes Research journal (2012), cross-market cost-effectiveness of Erlotinib was analyzed. The study aimed at estimating the incremental cost-effectiveness of Erlotinib (150 mg/day) versus best supportive care when used as first-line maintenance therapy for patients with locally advanced or metastatic NSCLC and stable disease.

It was determined that treatment with erlotinib in first-line maintenance resulted in a mean life expectancy of 1.39 years in all countries, compared with a mean 1.11 years with best supportive care, which represents 0.28 life-years (3.4 life-months) gained with erlotinib versus best supportive care.

According to the authors analysis, there was a gain in the costs per-life year as $50,882, $60,025, and $35,669 in France, Germany, and Italy, respectively. Hence, on the basis of the study it was concluded that Erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for locally advanced or metastatic NSCLC.

Avastin (Bevacizumab)

Generic Name: Avastin, Brand Name: Bevacizumab

Other Designation: rhuMAb-VEGF, NSC-704865, R435, RG435

Mechanism of Action

Bevacizumab is a recombinant humanized Mab antagonist of vascular endothelial growth factor A (VEGFA) acting as an angiogenesis inhibitor.


Vascular endothelial growth factor (VEGF, VEGF-A, VEGFA)

Avastin is the only currently approved VEGF inhibitor that selectively targets VEGF-A.

Three other approved oral drugs, pazopanib (Votrient; GlaxoSmithKline), sunitinib (Sutent; Pfizer) and sorafenib (Nexavar; Onyx Pharmaceuticals) are orally available multi-targeted receptor tyrosine kinase inhibitors that include VEGF receptors among their tar­gets.

Avastin has been approved for different cancers and several indications have been filed:

  • colorectal cancer, advanced, metastatic, first line, in combination with a 5-FU based chemotherapy regimen
  • colorectal cancer, relapsed, metastatic, second line, in combintion with 5-FU-based chemotherapy (2004)
  • non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with carboplatin and paclitaxel chemotherapy, first line (2006)
  • breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, in combination with taxane chemotherapy (2008, revoked in 2011)
  • non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with platinum-based chemotherapy, first line
  • renal cell carcinoma (RCC), metastatic, in combination with interferon (IFN) alpha, first line (2009)
  • glioblastoma multiforme (GBM), relapsed after first line chemoradiotherapy
  • breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, HEr2 negative, in combination with capecitabine (2009)
  • ovarian cancer, in combination with standard chemotherapy (carboplatin and paclitaxel) as a first line treatment following surgery for women with advanced (Stage IIIb/c or Stage IV) epithelial ovarian, primary peritoneal or fallopian tube cancer
  • ovarian cancer, in combination with carboplatin and gemcitabine as a treatment for women with recurrent, platinum-sensitive ovarian cancer


New medicine Oncology Knowledge Base

Sales of Avastin 

As of May, 2012, sales of Avastin in the US have been reported to be around $2.66 billion.

It attracted a lot of attention over the past few years after its use as a breast cancer treatment. Avastin was approved by the FDA under its fast-track program. However, the data released by the FDA from follow-up studies led to questioning the use of Avastin as a breast cancer drug. Infact, Genentech pulled the indication from Avastin’s label. Henceforth, the FDA did cancel that approval in late 2011. Doctors, however, can still prescribe it off-label. Potential adverse effects of Avastin that came under scrutiny along with unfavorable cost benefit analyses might pose challenges to its growth potential and continued widespread use. However, the sales of Avastin have continued to increase and it has been reported by Fierce Pharma as one of the 15 best-selling cancer drugs list. (Fierce Pharma)

Dacomitinib: New promising drug for NSCLC

Generic Name: Dacomitinib

Other Designation: PF-299804, PF-00299804, PF-299,804, PF00299804

PF-299804 is an orally available irreversible pan-HEr tyrosine kinase inhibitor.

Dacomitinib is a promising new drug on the market. Phase III trials are ongoing for advanced and refractory NSCLC, locally advanced or metastatic NSCLC and the EGFr mutation containing locally advanced or metastatic NSCLC in several countries including those in Europe, Asia, and America.


New medicine Oncology Knowledge base

Dacomitinib bests Erlotinib in advanced NSCLC:  Comparison of its Progression-Free Survival (PFS) with the NSCLC marketed drug, Erlotinib.

In September of 2012, a study was published by Ramalingam et al in the Journal of Clinical Oncology, which was a randomized open-label trial comparing dacomitinib with erlotinib in patients with advanced NSCLC. On the basis of the study it was concluded that dacomitinib demonstrated significantly improved progression-free survival (PFS*) as compared to erlotinib, with a certain degree of toxicity.


Randomized Phase II Study of Dacomitinib Versus Erlotinib in Patients With Advanced Non-Small-Cell Lung Cancer

The results indicated indicated the following:

  • Median PFS was significantly greater with Dacomitinib than Erlotinib, at 2.86 versus 1.91.
  • Mean duration of response was 16.56 months for dacomitinib and 9.23 months for erlotinib.

Patients were divided into groups by tumor type and following results were obtained:

  • Median PFS was 3.71 months with dacomitinib and 1.91 with erlotinib in patients with KRAS wild-type tumors
  • Median PFS was 2.21 months and 1.68 months, in patients with KRAS wild-type/EGFR wild-type tumors.
  • PFS was significantly better in the molecular subgroups harboring a mutant EGFR genotype.

The study also highlighted the side effects which might be more of concern and probably limiting for Dacomitinib.

Although adverse side effects were uncommon in both the groups, certain side effects such as:

  • mouth sores,
  • nailbed infections, and
  • diarrhea

were more common and tended to be more severe with Dacomitinib as compared to Tarceva.

Therefore, for patients for whom side effects of Tarceva seem challenging might face more difficulty with Dacomitinib treatment. Nonetheless, the results of PFS were promising enough and provide a greater efficacy in several clinical and molecular subgroups targeting a larger population than Tarceva. Authors, thus, suggested a larger, randomized phase III trial with the same design.

Current status of Dacomitinib

Based on positive performance of Dacomitinib published in research studies, Pfizer has entered into a collaborative development agreement with the SFJ Pharmaceuticals Group to conduct a phase III clinical trial across multiple sites in Asia and Europe, to evaluate dacomitinib (PF-00299804) as a first line treatment in patients with locally advanced or metastatic non-small cell lung cancer (nsclc) with activating mutations in the epidermal growth factor receptor (EGFr). Under the terms of the agreement, SFJ will provide the funding and clinical development supervision to generate the clinical data necessary to support a registration dossier on Dacomitinib for marketing authorization by regulatory authorities for this indication. If approved for this indication, SFJ will be eligible to receive milestone and earn-out payments.


New medicine Oncology Knowledge base

*PFS or Progression-free survival is defined as the length of time during and after the treatment of as disease, such as cancer, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works.


Recently, another drug PF-02341066 (crizotinib), was tested on patients with non-small cell lung cancer and the results were published in New England Journal of Medicine (2013). Crizotinib is an orally available aminopyridine-based inhibitor of the) and the c-Met/hepatocyte growth factor receptor (HGFR). Crizotinib, in an ATP-competitive manner, binds to and inhibits ALK kinase and ALK fusion proteins. In addition, crizotinib inhibits c-Met kinase, and disrupts the c-Met signaling pathway. Altogether, this agent inhibits tumor cell growth.

  • Shaw and colleagues (2013) investigated whether crizotinib is superior to standard chemotherapy with respect to efficacy. To answer the question, Pfizer launched a phase III clinical trial (NCT00932893; http://clinicaltrials.gov/show/NCT00932893) comparing the safety and anti-tumor activity of PF-02341066 (crizotinib) versus pemetrexed or docetaxel in patients with advanced non-small cell lung cancer harboring a translocation or inversion event involving the ALK gene. Shaw and colleagues (2013) published the results of the clinical trial in a recent issue of New England Journal of Medicine.  A total of 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen were recruited for the trial and patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. According to the results, the median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group. Hazard ratio (HR) for progression or death with crizotinib was 0.49 (95% CI, P<0.001). The response rates were 65% with crizotinib, as compared with 20% with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy.In conclusion, the results from the trial indicate that crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non–small-cell lung cancer with ALK rearrangement. (Shaw AT, et al, Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med 2013; 20 June, 368:2385-2394; http://www.ncbi.nlm.nih.gov/pubmed/23724913).

However, in the same issue of New England Journal of Medicine, Awad and colleagues (2013) reported from a phase I clinical trial (NCT00585195; http://clinicaltrials.gov/show/NCT00585195), that a patient with metastatic lung adenocarcioma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment, showed resistance to crizotinib. Biopsy of the resistant tumor identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. The study was funded by Pfizer (Awad MM, et al, Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013 Jun 20;368(25):2395-401; http://www.ncbi.nlm.nih.gov/pubmed/23724914)


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