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Posts Tagged ‘PFS’


In focus: Melanoma therapeutics

 

Author and Curator: Ritu Saxena, Ph.D.

In the last post of Melanoma titled “In focus: Melanoma Genetics”, I discussed the clinical characteristics and the genetics involved in Melanoma.  This post would discuss melanoma therapeutics, both current and novel.

According to the American Cancer Society, more than 76,000 new cases and more than 9100 deaths from melanoma were reported in the United States in 2012[1] Melanoma develops from the malignant transformation of melanocytes, the pigment-producing cells that reside in the basal epidermal layer in human skin. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate.

Melanoma therapeutics

Surgical treatment of cutaneous melanoma employs specific surgical margins depending on the depth of invasion of the tumor and there are specific surgical treatment guidelines of primary, nodal, and metastatic melanoma that surgeons adhere to while treatment. Melanoma researchers have been focusing on developing adjuvant therapies for that would increase the survival post-surgery.

Chemotherapy

Among traditional chemotherapeutic agents, only dacarbazine is FDA approved for the treatment of advanced melanoma (Eggermont AM and Kirkwood JM, Eur J Cancer, Aug 2004;40(12):1825-36). Dacarbazine is a triazene derivative and alkylates and cross-links DNA during all phases of the cell cycle, resulting in disruption of DNA function, cell cycle arrest, and apoptosis. Currently, 17 clinical trials are underway to test the efficacy and effectiveness of dacarbazine against melanoma as either a single agent or in combination chemotherapy regimens with other anti-cancer chemotherapeutic agents such as cisplatin, paclitaxel. Temozolomide is a triazene analog of dacarbazine and is approved for the treatment of malignant gliomas. At physiologic pH, it is converted to a short-lived active cytotoxic compound, monomethyl triazeno imidazole carboxamide (MTIC). MTIC methylates DNA at the O6 and N7 positions of guanine, resulting in inhibition of DNA replication. Unlike dacarbazine, which is metabolized to MITC only in the liver, temozolomide is metabolized to MITC at all sites. Temozolomide is administered orally and penetrates well into the central nervous system. Temozolomide is being tested in many combination regimens for patients with melanoma metastatic to the brain (Douglas JG and Margolin K, Semin Oncol, Oct 2002;29(5):518-24).

Immunotherapy

Melanoma and the immune system are closely related. Hence, immunotherapy has been explored in the treatment of the disease. The two most widely investigated immunotherapy drugs for melanoma are Interferon (IFN)-alpha and Interleukin-2 (IL-2).

The role of IFNalpha-2b in the adjuvant therapy of patients with localized melanoma at high risk for relapse was established by the results of three large randomized trials conducted by the US Intergroup; all three trials demonstrated an improvement in relapse-free survival and two in overall survival. One of these trials, a large randomized multicenter trial performed by the Eastern Cooperative Oncology Group (ECOG), in high-risk melanoma patients showed significant improvements in relapse-free and overall survival with adjuvant IFN-α-2b therapy, compared with standard observation (ECOG 1684). The results of the study led to FDA approval of IFN-α-2b for treatment of melanoma. This study was performed on patients with deep primary tumors without lymph node involvement and node-positive melanomas. In other studies, little antitumor activity has been demonstrated in IFN-α-2b–treated metastatic stage IV melanoma.

Recombinant IL-2 showed an overall response rate of 15-20% in metastatic melanoma and was capable of producing complete and durable remissions in about 6% of patients treated. Based upon these data, the US FDA has approved the use of high-dose IL-2 for the therapy of patients with metastatic melanoma. Aldesleukin (Brand name: Proleukin) is a recombinant analog of the endogenous cytokine interleukin-2 (IL-2). It binds to and activates the IL-2 receptor (IL-2R), followed by heterodimerization of the IL-2R beta and gamma(c) cytoplasmic chains; activation of Jak3; and phosphorylation of tyrosine residues on the IL-2R beta chain, resulting in an activated receptor complex (NCI). The activated complex recruits several signaling molecules that act as substrates for regulatory enzymes associated with the complex. It is administered intravenously and stimulates lymphokine-activating killer (LAK) cells, natural killer (NK) cells and the production of cytokines such as gamma interferon (nm|OK). Several clinical trials are currently underway using Aldesleukin to determine the efficacy of combination treatment in melanoma patients.

Another anti-cancer immunotherapeuty-based mechanism involved inhibition of inhibitory signal of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a molecule on T-cells that plays a critical role in regulating natural immune responses. Ipilimumab (Brand name: Yervoy) was by FDA for melanoma treatment.  It is a human monoclonal antibody (MAb) T-cell potentiator that specifically blocks CTLA-4. It is approved for inoperable advanced (Stage III) or metastatic (Stage IV) melanoma in newly diagnosed or previously treated patients (nm|OK). The approval, March 25, 2011, was based on a randomized (3:1:1) double-blind double-dummy clinical trial (MDX010-20) in patients with unresectable or metastatic melanoma who had received at least one prior systemic treatment for melanoma. Patients were randomly assigned to receive either ipilimumab, 3 mg/kg intravenously, in combination with the tumor vaccine (n=403); ipilimumab plus vaccine placebo (n=137); or tumor vaccine with placebo (n=136). Patients treated with ipilimumab alone had a median overall survival (OS) of 10 months while those treated with tumor vaccine had a median OS of 6 months. The trial also demonstrated a statistically significant improvement in OS for patients treated with the combination of ipilimumab plus tumor vaccine compared with patients treated with tumor vaccine alone. For more information on the trial, check the clinical trials website, www.clinicaltrials.gov

Signaling pathway inhibitors

Approximately 90% of BRAF gene mutations involve valine (V) to glutamic acid (E) mutation at number 600 residue (V600E). The resulting oncogene product, BRAF (V600E) kinase is highly active and exhibits elevated MAPK pathway. The BRAF(V600E) gene mutation occurs in approximately 60% of melanomas indicating that it could be therapeutically relevant. Vemurafenib (Brand name: Zelboraf) is a novel small-molecule inhibitor of BRAF (V600E) kinase. It selectively binds to the ATP-binding site and inhibits the activity of BRAF (V600E) kinase. Vemurafebib inhibits over active MAPK pathway by inhibiting the mutated BRAF kinase, thereby reducing tumor cell proliferation (NCI). Encouraging results of phase III randomized, open-label, multicenter trial were reported recently at the 2011 ASCO meeting (Chapman PB, et al, ASCO 2011, Abstract LBA4).  The trial compared the novel BRAF inhibitor vemurafenib with dacarbazine in patients with BRAF-mutated melanoma. Previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for BRAF mutation were randomized (1:1) to vemurafenib or dacarbazine. The response rate (RR) was significantly high (48.4%) in vemurafenib treated patients as compared to 5.5% in dacarbazine among the 65% of patients evaluable for RR to date. In addition, vemurafenib was associated with significantly improved OS and PFS compared to dacarbazine in patients with previously untreated BRAF (V600E) mutation bearing patients with metastatic melanoma.

Biochemotherapy

Biochemothreapy combine traditional chemotherapy with immunotherapies, such as IL-2 and IFN-α-2b. These combination therapies seemed promising in phase II trials, however, seven large studies failed to show statistically significant increased overall survival rates for various biochemotherapy regimens in patients with stage IV metastasis (Margolin KA, et al, Cancer, 1 Aug 2004;101(3):435-8). Owing to inconsistent results of the available studies with regard to benefit including RR, OS and progression time, and consistently high toxicity rates, clinical practice guideline do not recommend biochemotherapy for the treatment of metastatic melanoma (Verma S, et al, Curr Oncol, April 2008; 15(2): 85–89).

Vaccines

The use of therapeutic vaccines is an ongoing area of research, and clinical trials of several types of vaccines (whole cell, carbohydrate, peptide) are being conducted in patients with intermediate and late-stage melanoma. Vaccines are also being tested in patients with metastatic melanoma to determine their immune effects and to define their activity in combination with other immunotherapeutic agents such as IL-2 or IFNalpha (Agarwala S, Am J Clin Dermatol, 2003;4(5):333-46). In fact, recently investigators at the Indiana University Health Goshen Center for Cancer Care (Goshen, IN) conducted a randomized, multicenter phase III trial involving 185 patients with stage IV or locally advanced stage III cutaneous melanoma. The patients were assigned into treatment groups with IL-2 alone or with vaccine (gp100) followed by IL-2. The vaccine-IL-2 group had a significantly improved OR as compared to the IL-2-only group (16% Vs. 6%) and longer progression free survival (2.2 months Vs. 1.6 months). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months Vs. 11.1 months). Thus, a combination of vaccine and immunotherapy showed a better response rate and longer progression-free survival than with interleukin-2 alone in patients with advanced melanoma (Schwartzentruber DJ, et al, N Engl J Med, 2 Jun 2011;364(22):2119-27).

Which Treatment When?

Earlier, there were essentially two main options for patients suffering from advanced melanoma, dacarbazine and IL-2. Dacarbazine, a chemotherapeutic agent produces modest improvements in survival or symptomatic benefits in most patients. Interleukin-2 -based drugs, on the other hand, induce long-term remissions in a small group of patients but are highly toxic. Recently, FDA approved ipilimumab and vemurafenib for patients with metastatic melanoma. Apart from these, therapies are also aiming at starving the tumor by inhibiting angiogenesis or depleting nutrients essential for cancer growth. Of the antiangiogenic compounds, VEGFR inhibitors SU5416 and AG-013736 demonstrated broad-spectrum antitumor activity in mice bearing xenografts of human cancer cell lines originating from various tissues, including melanoma. In addition, several trials are currently underway to test the efficacy of the drugs in combination. In the future, personalized medicine-based recommendations of novel and existing drugs for melanoma patients might be the way to go.

Reference:

  1. Eggermont AM and Kirkwood JM, Eur J Cancer, Aug 2004;40(12):1825-36
  2. Douglas JG and Margolin K, Semin Oncol, Oct 2002;29(5):518-24
  3. Chapman PB, et al, ASCO 2011, Abstract LBA4
  4. Margolin KA, et al, Cancer, 1 Aug 2004;101(3):435-8
  5. Verma S, et al, Curr Oncol, April 2008; 15(2): 85–89
  6. Agarwala S, Am J Clin Dermatol, 2003;4(5):333-46
  7. Schwartzentruber DJ, et al, N Engl J Med, 2 Jun 2011;364(22):2119-27
  8. Chudnovsky Y, et al, J Clin Invest, Apr 2005;115(4):813-24.
  9. National Cancer Institute (National Institute of Health)
  10. Clinical Trials reported on the U.S. Institute of Health
  11. New Medicine Oncology KnowledgeBase (nm|OK)

Related articles on Melanoma on this Open Access Online Scientific Journal: 

  1. In focus: Melanoma Genetics Curator- Ritu Saxena, Ph.D.
  2. Thymosin alpha1 and melanoma Author/Editor- Tilda Barliya, Ph.D.
  3. A New Therapy for Melanoma  Reporter- Larry H Bernstein, M.D.
  4. Melanoma: Molecule in Immune System Could Help Treat Dangerous Skin Cancer Reporter: Prabodh Kandala, Ph.D.
  5. Why Braf inhibitors fail to treat melanoma. Reporter: Prabodh Kandala, Ph.D.

 

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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.

 

Introduction

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.

Treatment

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)
Bevacizumab
Carboplatin
Cisplatin
Crizotinib
Erlotinib Hydrochloride
Folex (Methotrexate)
Folex PFS (Methotrexate)
Gefitinib
Gemcitabine Hydrochloride
Gemzar (Gemcitabine Hydrochloride)
Iressa (Gefitinib)
Methotrexate
Methotrexate LPF (Methotrexate)
Mexate (Methotrexate)
Mexate-AQ (Methotrexate)
Paclitaxel
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:

Image

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.

Targets

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

SOURCE:

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.

SOURCE:

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.

SOURCE:

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.

SOURCE:

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.

REFERENCES

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)

Reference: 

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