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Posts Tagged ‘progression-free survival’


Prognostic algorithm for retroperitoneal sarcoma

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Prognostic Nomogram for Retroperitoneal Sarcoma Validated in Large Cohort

Cancer Network  By

 

A new study validated a prognostic nomogram for retroperitoneal sarcoma (RPS) using a large, external cohort. The nomogram incorporates six variables, and provided strong concordance with observed disease-free survival (DFS) and overall survival (OS).
RPS account for about 15% of all soft-tissue sarcomas, and their unique characteristics make traditional staging difficult, according to study authors led by Chandrajit P. Raut, MD, of Brigham and Women’s Hospital in Boston. A multi-institutional nomogram was developed previously based on a 523-patient cohort who underwent surgical resection for RPS between 1999 and 2009.

The nomogram included six clinical characteristics and variables: age at the time of diagnosis; tumor size; FNCLCC tumor grade; histologic subtype; multifocality at the time of initial presentation; and extent of surgical resection. Because the American Joint Committee on Cancer (AJCC) is considering including this tool in its forthcoming revised staging system, the study authors decided to validate it in an external cohort of 631 RPS patients who underwent surgery at one of six centers. The results were published online ahead of print in Cancer.

The 7-year DFS rate in the validation cohort was 38.4%, and the 7-year OS rate was 58%. This was similar to the development cohort’s outcomes, at 35.7% and 50.5%, respectively. All six of the nomogram’s included variables were found to be independently prognostic.

The researchers used a Harrell C-statistic to measure the nomogram’s discriminative ability. For DFS, the result was 0.69, while for OS it was 0.73. These were very similar to the concordance rates found in the development cohort (0.71 and 0.74, respectively).

“Correlation between observed and nomogram-predicted DFS and OS rates suggest good calibration of the multi-institutional RPS nomogram in a larger, independent validation cohort,” the authors wrote. “External validation of the…nomogram established its broad applicability in predicting outcomes in patients with primary RPS who were treated at experienced centers, and supports its inclusion in the 8th edition of the AJCC classification.”

Study Details
The median age in the validation cohort was 59 years, and the median tumor size was 21 cm. There were similar numbers of patients with FNCLCC grade 1 (32.7%), 2 (39.8%), and 3 (27.5%) tumors.

The most common histologic subtype was dedifferentiated liposarcoma (36.6%), followed by well-differentiated liposarcoma (25%), leiomyosarcoma (21.7%), and other subtypes. Almost all patients (94.8%) had a complete resection. Most patients (91%) did not receive chemotherapy or radiotherapy (68.3%).

 

 

Panobinostat Shows Promise in Phase I Sarcoma Trial

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http://www.cancernetwork.com/sarcoma/panobinostat-shows-promise-phase-i-sarcoma-trial

Ball-and-stick model of panobinostat; image © molekuul.be / Shuttersto…

 

A phase I trial found that panobinostat combined with epirubicin is well tolerated and could offer benefit in patients with refractory sarcoma.
“More than half of patients treated for localized soft tissue sarcoma will experience relapse,” wrote study authors led by Pamela N. Munster, MD, of the University of California, San Francisco. Histone deacetylase (HDAC) inhibitors have shown some promise in other early phase I studies with anthracyclines. “Furthermore, HDAC inhibition was shown to promote differentiation and apoptosis in sarcoma.”

The new phase I trial combined the HDAC inhibitor panobinostat—which was approved in February 2015 for the treatment of multiple myeloma—with epirubicin. It began as a 3 + 3 dose escalation trial in patients with advanced solid tumors, followed by an expansion cohort at the maximum tolerated dose in 20 sarcoma patients. The results were published in Annals of Oncology.

In total, 40 patients received 20- to 60-mg panobinostat; 17 patients had previous exposure to topoisomerase II inhibitors. The study drug was administered on days 1, 3, and 5, followed by 75-mg/m2 epirubicin on day 5, in 21-day cycles. Dose-limiting toxicities were seen at 50 mg (one patient) and 60 mg (two patients); these included atrial fibrillation, grade 4 thrombocytopenia and febrile neutropenia, and grade 3 fatigue. The recommended phase II dose was set at 50 mg, and the 20 sarcoma patients in the expansion cohort received this dose.

Of 37 total evaluable patients, a partial response was seen in four of them (11%), and 17 patients (46%) had stable disease.

In only the 20-patient sarcoma expansion cohort, 12 patients were deemed to have received benefit from panobinostat. There was one response in those patients, and 11 patients had stable disease for longer than 3 months. The median progression-free survival in these patients was 3.4 months, and the median overall survival was 8.3 months. The authors noted that acquired topoisomerase resistance was reversed in 8 of 14 patients.

“A major challenge in HDAC inhibitor therapy is the absence of biomarkers,” wrote the authors. In this study, they showed that patients with a “pronounced degree” of peripheral blood mononucleocyte histone acetylation were more likely to derive benefit from the therapy. A decrease in neutrophil count over the first 5 days of the first cycle of therapy also was correlated with clinical benefit.

“This study suggests that further investigation of HDAC inhibition in combination with DNA-damaging agents in defined advanced sarcoma subtypes to validate these preliminary findings is warranted,” concluded the authors.

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Author/Curator: Ritu Saxena, PhD

For several decades, research efforts have focused on targeting progression of cancer cells in primary tumors. Primary tumor cell targeting strategies include standard chemotherapy and immunotherapy and modulation of host microenvironment including tumor vasculature. However, cancer progression is comprised of both primary tumor growth and secondary metastasis (Langley RR and Fidler IJ. Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev. 2007 May;28(3):297-321; http://www.ncbi.nlm.nih.gov/pubmed/17409287). Owing to the property of unilimited cell division, cells in primary tumor increase rapidly in number and density and are able to favorably influence their microenvironment. Metastasis, on the other hand, depends on the ability of cancer cells to disseminate, circulate, adapt to the harsh environment and seed in different organs to establish secondary tumors. Although tumor cells are shed into the circulation in large numbers since early stages of tumor formation, few tumor cells can survive and proceed to overt metastasis. (Husemann Y et al. Systemic spread is an early step in breast cancer. Cancer Cell. 2008 Jan;13(1):58-68; http://www.ncbi.nlm.nih.gov/pubmed/18167340). Tight vascular wall barriers, unfavorable conditions for survival in distant organs, and a rate-limiting acquisition of organ colonization functions are just some of the impediments to the formation of distant metastasis (Chiang AC and Massagué J. Molecular basis of metastasis. N Engl J Med. 2008 Dec 25;359(26):2814-23; http://www.ncbi.nlm.nih.gov/pubmed/19109576).

It has been hypothesized that metastasis is initiated by a subpopulation of circulating tumor cells (CTC) found in the blood of patients. Therefore, understanding the function of CTC and targeting the CTC is gaining attention as a possible therapeutic avenue in carcinoma treatment.

CTCs

Figure: Circulating tumor cells in the metastatic cascade

(Image source: Chaffer CL and Weinberg RA. Science 2011,331, pp. 1559-1564; http://www.ncbi.nlm.nih.gov/pubmed/21436443)

Isolation of CTC

Initial methods relied on the difference in physical properties of cells. When spun in a centrifuge, different cells in the blood sample settle in separate layers based on their byoyancy, and CTC are found in the white blood cell fraction. Because CTC are generally larger than white blood cells, a size-based filter could be used to separate the cell types (Vona G, et al, Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulating tumor cells. Am J Pathol, 2000 Jan;156(1):57-63; http://www.ncbi.nlm.nih.gov/pubmed/10623654).

Herbert A Fritsche, PhD, Professor and Chief, Clinical Chemistry, Department of Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, demonstrated that the CTC can be captured using antibody labeled magnetic beads, either in positive or negative selection schema. After the circulating tumor cells are isolated, they may be characterized by immunohistochemistry and counted.  Alternatively, these cells may be characterized by gene expression analysis using RT-PCR. One of the CTC detection methods, Veridex Inc, Cell Search Assay, has been cleared by the US FDA for use as a prognostic test in patients with metastatic cancers of the breast, prostate and colon. This technology relies on the expression of epithelial cellular adhesion molecular (EpCAM) by epithelial cells and the isolation of these cells by immunomagnetic capture using anti-EpCAM antibodies.  Enriched CTC are identified by immunofluorescence. Martin Fleisher, PhD, Chair, Department of Clinical Laboratories, Memorial Sloan-Kettering Cancer Center discussed in a webinar at the biomarker symposia, Cambridge Healthtech Institute, that every new technology has shortcomings, and the reliance on cancer cells to express sufficient EpCAM to enable capture may affect the role of this technology in future clinical use. Heterogeneous downregulation of epithelial surface antigen in invasive tumor cells has been reported. Thus, alternative methods to detect CTC are being developed. These new methods include-

  1. Flow cytometry that sorts cells by size and surface antigen expression.
  2. CTC microchips that are designed to capture CTC as whole blood flows past EpCAM-coated mirco-posts.
  3. Enrichment by filtration using filters with a pore size of 7-8 µm, that permits smaller red blood cell, leukocytes, and platelets to pass, but captures CTC that have diameters of about 12-15 µm.

Better identification of CTC

Baccelli et al (2013) developed a xenograft assay and demonstrated that the primary human luminal breast cancer CTC contain metastasis-initiated cells (MICs) that give rise to bone, lung and liver metastases in mice. These MIC-containing CTC populations expressed EPCAM, CD44, CD47 and MET. It was observed that in a small cohort of patients with metastases, the number of CTC expressing markers EPCAM,CD44, CD47 and MET, but not of bulk EPCAM+ CTC, correlated with lower overall survival and increased number of metastasic sites. These data describe functional circulating MICs and associated markers, which may aid the design of better tools to diagnose and treat metastatic breast cancer. The findings were published in the Nature Biotechnology journal recently (Baccelli I, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nature Biotechnology 2013 31, 539–544; http://www.ncbi.nlm.nih.gov/pubmed/23609047).

CTC as prognostic and predictive factor for cancer progression

Martin Fleisher, PhD states “detecting CTC in peripheral blood of patients with cancer has become a clinically relevant and important prognostic biomarker and has been shown to be a predictive biomarker post-therapy. But, key to the use of CTC as a biomarker is the technology designed to enrich cancer cells from peripheral blood.”

Since CTC isolation methods started being established, correlation studies between the cells and a patient’s disease emerged. In 2004, investigators at the Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center (Houston, TX) discovered that the CTC were associated with disease progression and survival in metastatic breast cancer. The clinical trial recruited 177 patients with measurable metastatic breast cancer for levels of CTC both before the patients were to start a new line of treatment and at the first follow-up visit. The progression of the disease or the response to treatment was determined with the use of standard imaging studies at the participating centers. Patients in a training set with levels of CTC equal to or higher than 5 per 7.5 ml of whole blood, as compared with the group with fewer than 5 CTC per 7.5 ml, had a shorter median progression-free survival (2.7 months vs. 7.0 months, P<0.001) and shorter overall survival (10.1 months vs. >18 months, P<0.001). At the first follow-up visit after the initiation of therapy, this difference between the groups persisted (progression-free survival, 2.1 months vs. 7.0 months; P<0.001; overall survival, 8.2 months vs. >18 months; P<0.001), and the reduced proportion of patients (from 49 percent to 30 percent) in the group with an unfavorable prognosis suggested that there was a benefit from therapy.  Thus, the number of CTC was found to be an independent predictor of progression-free survival and overall survival in patients with metastatic breast cancer (Cristofanilli M, et al, Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004 Aug 19;351(8):781-91; http://www.ncbi.nlm.nih.gov/pubmed/15317891).

Similar results have been observed in other cancer types, including prostate and colorectal cancer. The Cell Search System developed by Veridex LLC (Huntingdon Valley, PA) enumerated CTC from 7.5 mL of venous blood and was used to compare the outcomes from three prospective multicenter studies investigating the use of CTC to monitor patients undergoing treatment for metastatic breast, colorectal, or prostate cancer. Evaluation of CTC at anytime during the course of disease allowed assessment of patient prognosis and is predictive of overall survival (Miller MC, et al. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer. J Oncol. 2010; http://www.ncbi.nlm.nih.gov/pubmed/20016752). In addition, the CTC test may permit the oncologist to make an early decision to discontinue first line therapy for metastatic breast cancer and pursue more aggressive alternative treatments.

Genetic analysis of CTC

Additional studies have analyzed the genetic mutations that the cells carry, comparing the mutations to those in a primary tumor or correlating the findings to a patient’s disease severity or spread. In one study, lung cancer patients whose CTC carried a mutation known to cause drug resistance had faster disease progression than those whose CTC lacked the mutation. The investigators analyzed the evolutionary aspect of cancer progression and studied the precursor cells of metastases directly for the identification of prognostic and therapeutic markers. Single disseminated cancer cells isolated from lymph nodes and bone marrow of 107 consecutive esophageal cancer patients were analyzed by whole-genome screening which revealed that primary tumors and lymphatically and hematogenously disseminated cancer cells diverged for most genetic aberrations. Chromosome 17q12-21, the region comprising HER2, was identified as the most frequent gain in disseminated tumor cells that were isolated from both ectopic sites. Furthermore, survival analysis demonstrated that HER2 gain in a single disseminated tumor cell but not in primary tumors conferred high risk for early death (Stoecklein NH, et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell. 2008 May;13(5):441-53; http://www.ncbi.nlm.nih.gov/pubmed/18455127).

The abovementioned studies indicate that CTC blood tests have been successfully used to track the severity of a cancer or efficacy of a treatment. In conclusion, the evolution of the CTC technology will be critical in the emerging area of targeted therapy.  With the development and use of new technologies, the links between the genomic information and CTC could be explored and established for targeted therapy.

Challenges in CTC research

  1. Potential clinical significance of CTC has been demonstrated as early detection, diagnostic, prognostic, predictive, surrogate, stratification, and pharmacodynamic biomarkers. Hong B and Zu Y (2013) discuss that “the role of CTC as a disease marker may be unique in different clinical conditions and should be carefully interpreted. A good example is the comparison between the prognostic and predictive biomarkers. Both biomarkers employ progression-free survival and overall survival for data interpretation; however, the prognostic biomarker is independent of specific drug treatment or therapy, and used for the determination of outcomes before treatment, while the predictive biomarker is related to a particular treatment to predict the response. Furthermore, inconsistent results are increasingly reported among the various CTC assay methods, specifically pertaining to results for the CTC detection rate, patient positivity rate, and the correlation between the presence of CTC and survival rate (Hong B and Zu Y. Detecting circulating tumor cells: current challenges and new trends. Source. Theranostics. 2013 Apr 23;3(6):377-94; http://www.ncbi.nlm.nih.gov/pubmed/23781285).
  2. Heterogeneity in CTC along with several other technical factors contribute to discordance, including the changes in methodology, lack of reference standard, spectrum and selection bias, operator variability and bias, sample size, blurred clinical impact with known clinical/pathologic data, use of diverse capture antibodies from different sources, lack of awareness of the pre-analytical phase, oversimplification of the cytopathology process, use of dichotomous decision criteria, etc (Sturgeon C. Limitations of assay techniques for tumor markers. In: (ed.) Diamandis EP, Fritsche HA, Lilja H, Chan DW, Schwartz MK. Tumor markers: physiology, pathobiology, technology, and clinical applications. Washington, DC: AACC Press. 2002:65-82; Gion M and Daidone MG. Circulating biomarkers from tumour bulk to tumour machinery: promises and pitfalls. Eur J Cancer. 2004;40(17):2613-2622; http://www.ncbi.nlm.nih.gov/pubmed/15541962). Therefore, employing a standard protocol is essential in order to minimize a lot of inconsistencies and technical errors.
  3. CTC in a small amount of blood sample might not represent the actual CTC count in the whole blood. In fact, it has been reported that the Cell Search system might undercount the number of CTC. Nagrath et al (2007) have demonstrated that the average CTC number per mL of whole blood is approximately 79-155 in various cancers (Nagrath S, et al. Isolation of rare circulating tumous cells in cancer patients by microchip technology. Nature. 2007;450(7173):1235-1239; http://www.ncbi.nlm.nih.gov/pubmed/18097410). In addition, an investigative CellSearch Profile approach (for research use only) detected an approximately 30-fold higher number of the median CTC in the same paired blood samples (Flores LM, et al. Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer. Br J Cancer. 2010;102(10):1495-502; http://www.ncbi.nlm.nih.gov/pubmed/20461092). Such measurement discrepancies indicate that the actual CTC numbers in the blood of patients could be at least 30-100 fold higher than that currently reported by the only FDA-cleared CellSearch system.

Thus, although promising, the CTC technology faces several challenges both in detection and interpretation, which has resulted in its limited clinical acceptance and use. In order to prepare the CTC technology for future widespread clinical acceptance, a comprehensive guideline for all phases of CTC technology development was published by the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium. The guidelines describe methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the FDA and the National Cancer Institute (NCI) (Parkinson DR, et al. Considerations in the development of circulating tumor cell technology for clinical use. J Transl Med. 2012;10(1):138; http://www.ncbi.nlm.nih.gov/pubmed/22747748).

Reference:

  1. Langley RR and Fidler IJ. Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev. 2007 May;28(3):297-321; http://www.ncbi.nlm.nih.gov/pubmed/17409287
  2. Husemann Y et al. Systemic spread is an early step in breast cancer. Cancer Cell. 2008 Jan;13(1):58-68; http://www.ncbi.nlm.nih.gov/pubmed/18167340
  3. Chiang AC and Massagué J. Molecular basis of metastasis. N Engl J Med. 2008 Dec 25;359(26):2814-23; http://www.ncbi.nlm.nih.gov/pubmed/19109576
  4. Vona G, et al, Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulating tumor cells. Am J Pathol, 2000 Jan;156(1):57-63; http://www.ncbi.nlm.nih.gov/pubmed/10623654
  5. Baccelli I, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nature Biotechnology 2013 31, 539–544; http://www.ncbi.nlm.nih.gov/pubmed/23609047
  6. Cristofanilli M, et al, Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004 Aug 19;351(8):781-91; http://www.ncbi.nlm.nih.gov/pubmed/15317891
  7. Miller MC, et al. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer. J Oncol. 2010; http://www.ncbi.nlm.nih.gov/pubmed/20016752
  8. Stoecklein NH, et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell. 2008 May;13(5):441-53; http://www.ncbi.nlm.nih.gov/pubmed/18455127
  9. Hong B and Zu Y. Detecting circulating tumor cells: current challenges and new trends. Source. Theranostics. 2013 Apr 23;3(6):377-94; http://www.ncbi.nlm.nih.gov/pubmed/23781285
  10. 10. Sturgeon C. Limitations of assay techniques for tumor markers. In: (ed.) Diamandis EP, Fritsche HA, Lilja H, Chan DW, Schwartz MK. Tumor markers: physiology, pathobiology, technology, and clinical applications. Washington, DC: AACC Press. 2002:65-82
  11. Gion M and Daidone MG. Circulating biomarkers from tumour bulk to tumour machinery: promises and pitfalls. Eur J Cancer. 2004;40(17):2613-2622; http://www.ncbi.nlm.nih.gov/pubmed/15541962
  12. Nagrath S, et al. Isolation of rare circulating tumous cells in cancer patients by microchip technology. Nature. 2007;450(7173):1235-1239; http://www.ncbi.nlm.nih.gov/pubmed/18097410
  13. Flores LM, et al. Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer. Br J Cancer. 2010;102(10):1495-502; http://www.ncbi.nlm.nih.gov/pubmed/20461092
  14. Chaffer CL and Weinberg RA. Science 2011,331, pp. 1559-1564; http://www.ncbi.nlm.nih.gov/pubmed/21436443

Other related articles on circulation cells as biomarkers published on this Open Access Scientific Journal, include the following:

Blood-vessels-generating stem cells discovered

Ritu Saxena, PhD

https://pharmaceuticalintelligence.com/2012/10/22/blood-vessel-generating-stem-cells-discovered/

Cardiovascular and circulating endothelial cells as BIOMARKERS for prediction of Disease progression risks

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation Curator, Author,Writer, Reporter: Larry Bernstein, MD, FCAP

Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs Author and Curator: Aviva Lev-Ari, PhD, RN

Vascular Medicine and Biology: Macrovascular Disease – Therapeutic Potential of cEPCs Curator and Author: Aviva Lev-Ari, PhD, RN

Repair damaged blood vessels in heart disease, stroke, diabetes and trauma: Cellular Reprogramming amniotic fluid-derived cells into Endothelial Cells

Reporter: Aviva Lev-Ari, PhD, RN

Stem cells in therapy

A possible light by Stem cell therapy in painful dark of Osteoarthritis” – Kartogenin, a small molecule, differentiates stem cells to chondrocyte, healthy cartilage cells Author and Reporter: Anamika Sarkar, Ph.D and Ritu Saxena, Ph.D.

Human embryonic pluripotent stem cells and healing post-myocardial infarctionAuthor: Larry H. Bernstein, MD

Stem cells create new heart cells in baby mice, but not in adults, study showsReporter: Aviva Lev-Ari, PhD, RN

Stem cells for the rescue of mitochondrial dysfunction in Parkinson’s diseaseReporter: Ritu Saxena, Ph.D.

Stem Cell Research — The Frontier is at the Technion in Israel Reporter: Aviva Lev-Ari, PhD, RN

Research articles by MA Gaballa, PhD

Harris DT, Badowski M, Nafees A, Gaballa MAThe potential of Cord Blood Stem Cells for Use in Regenerative Medicine. Expert Opinion in Biological Therapy 2007. Sept 7(9): 1131-22.

Furfaro E, Gaballa MADo adult stem cells ameliorate the damaged myocardium?. Human cord blood as a potential source of stem cells. Current Vascular Pharmacology 2007, 5; 27-44.

 

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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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Personalized Medicine in NSCLC

Reviewer: Larry H Bernstein, MD, FCAP

Introduction

Early in the 21st century, gefitinib, an epi­dermal growth factor receptor (EGFRtyrosine kinase inhibitor became available  for the treatment of non-small cell lung can­cer (NSCLC). Over 80% of selected patients

  • EGFR mutation-positive patients, respond to gefitinib treatment;
  • most patients develop acquired resistance to gefitinib within a few years.
Recently, many studies have been performed to determine precisely how to select patients who will respond to gefitinib, the best timing for its administration, and how to avoid the development of acquired resistance as well as adverse drug effects.
Lung cancers are classified according to their his­tological type. Because each variant has different bio­logical and clinical properties, including response to treatment, a precise classification is essential to pro­vide appropriate therapy for individual patients. Lung cancer consists of two broad categories—non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

NSCLC  – 20%–40% RR to chemotherapy

  • ade­nocarcinoma (AC),  40%–50% ( most common form)
    • higher sensitivity to chemotherapy than SCC or LC
  • squamous cell carcinoma (SCC),  ∼30%
  •  large cell carcinoma (LCC). 10%
The majority of patients with SCLC are diagnosed with
  • advanced cancer with distant metastasis
  • high sensitivity to chemotherapy.
  • response rate (RR) for SCLC is reportedly 60%–80%
  • complete remission is observed in only 15%–20% of patients
The Potential of Personalized Medicine in Advanced NSCLC
Personalized medicine—
  • matching a patient’s unique molecular profile with an appropriate targeted therapy—
  • is transforming the diagnosis and treatment of non–small-cell lung cancer (NSCLC).

Through molecular diagnostics, tumor cells may be differentiated based on the presence or absence of

  • receptor proteins,
  • driver mutations, or
  • oncogenic fusion/rearrangements.

The convergence of advancing research in drug development and genetic sequencing has permitted the development of therapies specifically targeted to certain biomarkers, which may offer a differential clinical benefit.

Putting personalized medicine in NSCLC into practice
With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC.1,2
Biomarker Testing in Advanced NSCLC: Evolution in Pathology Clinical Practice
http://www.medscape.com/infosite/letstest/article-3
Multidisciplinary Approaches in the Changing Landscape of Advanced NSCLC
http://www.medscape.com/infosite/letstest/article-4
Oncology Perspectives on Biomarker Testing
http://www.medscape.com/infosite/letstest/article-1

References
1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer. Version 2.2012.
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf.                   August 6, 2012.
2. Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010;29(1):37-48.

Over the last decade, a growing number of biomarkers have been identified in NSCLC.3,4 To date, 2 of these molecular markers have been shown to have both prognostic and predictive value in patients with advanced NSCLC: epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements.5-8 Testing for these biomarkers may provide physicians with more information on which to base treatment decisions, and reflex testing may permit consideration of appropriate therapy from the outset of treatment.2,9,10

References:
Lovly CM, Carbone DP. Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol. 2011;8(2):68-70.
Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380.
Quest Diagnostics. Lung Cancer Mutation Panel (EGFR, KRAS, ALK).                       Sept 17, 2012
http://questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=Lung/TS_LungCancerMutation_Panel.htm.

Rosell R, Gervais R, Vergnenegre A, et al. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. Presented at: 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, J Clin Oncol. 2011;29(suppl). Abstract 7503.                        Aug 6, 2012.                    http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=78285.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer. Version 2.2012.
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf.                        Aug 6, 2012
College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) expert panel. Lung cancer biomarkers guideline draft recommendations. http://capstaging.cap.org/apps/docs/membership/transformation/new/lung_public_comment_supporting_materials.pdf.      Aug 6, 2012.
Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010;29(1):37-48.

 Background Studies
In 2002, gefitinib (ZD1839; AstraZeneca) , the first epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, became available as an innovative molecular-targeted drug for the treatment of unresectable NSCLC. Initially, many NSCLC patients were expected to respond to gefitinib because many solid tumors, including NSCLC, are known to overexpress EGFR, which has a role in tumor pro­liferation and is used as a biomarker to predict poor prognosis. Gefitinib was shown to have a dra­matic effect on a limited number of patients; but  it was ineffective in 70%–80% of patients with NSCLC. There have been reports of death caused by interstitial pneumonia (IP), one of the critical adverse drug reactions (ADRs) associated with gefitinib use. Therefore, there is a need for  predicting the effects of gefitinib, and criteria for select­ing patients who could be treated with gefitinib.
 In 2004, Lynch et al. and Paez et al. each pub­lished, on the same day, sensational reports in the New England Journal of Medicine and Science, identifying somatic mutations in the tyrosine kinase domain of the EGFR gene in patients with gefitinib-sensitive lung cancer, as compared with none of the patients who had no response. Therefore, screening for EGFR mutations in lung cancer showed potential for identifying patients who would respond to gefi­tinib therapy. It then was found that patients with EGFR mutations in the area of the gene cod­ing for the ATP-binding pocket of the tyrosine kinase domain responded to gefitinib. Consequently, the EGFR genotyping has been used to select patients who will respond to gefitinib. Other genetic mutations have also been reported as indicators of the response or resistance to gefitinib; for example, mutations of the KRAS gene are associated with primary resistance to gefitinib. Thus, screening of EGFR and KRAS is used to
  • predict the effects of gefi­tinib and
  • to select patients who will respond to gefitinib in the clinical setting.
Until now, the effects of gefitinib have been predicted only by genotyping factors, such as EGFR and KRAS mutations. However, Nakamura et al showed a relationship between the blood concentration of gefitinib and its clinical effects. In their study of 23 NSCLC patients with EGFR mutations, the ratio of the gefitinib concentration on day 8 to that on day 3 after the first administration of gefitinib (C8/C3) correlated with the progression-free survival (PFS) period. Patients with a higher C8/C3 ratio had a significantly lon­ger PFS (P = 0.0158, 95% confidence interval [CI]: 0.237–0.862), which  suggests the importance of the PK of gefitinib on its clinical outcome.   Chmielecki et al. concurrently reported that maintain­ing a high concentration of erlotinib, another EGFR tyrosine kinase inhibitor (EGFR-TKIs) with the same mechanism of action as gefitinib, could
  1. delay the establishment of drug-resistant tumor cells and
  2. decrease the proliferation rate of drug-resistant cells compared to
    • treatment using a lower concentration of erlotinib.
Pharmacogenetic profile
Initially, gefitinib was expected to induce a response in patients with tumors that overexpressed EGFR because it exerts its antineoplastic effects by com­petitively inhibiting the binding of ATP to the ATP-binding site of EGFR.  A number of studies contradict this hypothesis:
(1) while approxi­mately 40%–80% of NSCLC overexpress EGFR, only 10%–20% of NSCLC patients respond to gefi­tinib;5,6 and
(2) while EGFR overexpression is known to be more common in SCC than AC, gefitinib shows a higher antineoplastic effect on AC than on SCC, while other reports indicated no correlation between the expression levels of EGFR and clinical outcomes.
In 2004, somatic mutations were identified in the EGFR tyrosine kinase domain of patients with gefitinib-responsive lung cancer, as compared with no mutations in patients exhibiting no response, and the presence of an EGFR mutation was highly correlated with a good response to gefitinib.The conformational change of the EGFR ATP-binding site caused by genetic mutations constitutively acti­vates the EGFR downstream signaling pathway and increases the malignancy of cancer. Conversely, the conformational change of the ATP-binding site can also increase its affinity for gefitinib; therefore, gefi­tinib can inhibit the downstream signaling pathway more easily, strongly induces apoptosis, and reduces the proliferation of cancer cells.
Mutations in exons 18–21 of EGFR are predictive factors for the clinical efficacy of gefitinib;
  • deletions in exon 19 and missense mutations in exon 21 account for ∼90% of these mutations.

The detection of EGFR muta­tions in exons 19 and 21 is considered to be essential to predict the clinical efficacy of gefitinib.
Acquired resistance
All responders eventually develop resistance to gefitinib but in 2005, an EGFR mutation in exon 20, which substitutes methionine for threonine at amino acid position 790 (T790M), was reported to be one of the main causes of acquired resistance to gefitinib. The EGFR T790M vari­ant

  1. changes the structural conformation of the ATP-binding site, thereby
  2. increasing the affinity of ATP to EGFR, while
  3. the affinity of gefitinib to ATP is unchanged.

Screening methods for EGFR and KRAS mutations
The detection of EGFR and KRAS mutations has been usually achieved by sequencing DNA amplified from tumor tissues; however, sequencing techniques are too complex, time-consuming, and expensive.  The selection of an appropri­ate method to detect EGFR and KRAS mutations is essential to make an exact prediction of the efficacy of gefitinib in individual patients. Advances in diagnostics and treatments for NSCLC have led to better outcomes and higher standards of what outcomes are expected. These new understandings and treatments have raised multiple new questions and issues with regard to the decisions on the appropriate treatment of NSCLC patients.

  • Biomarkers are increasingly recognized and applied for guidance in diagnosis, prognosis and treatment decisions and evaluation.
  • Biologics and newer cancer treatments are enabling the possibility for new combined treatment modalities in earlier stage disease
  • Maintenance therapy has been shown to be useful, but optimal therapy choices before and after maintenance therapy need clarification
  • The importance of performance status on treatment decisions
  • Comparative effectiveness is becoming an expectation across all treatments and diseases, and will prove difficult to accomplish within the complexity of cancer diseases
NCCN Molecular Testing White Paper: Effectiveness, Efficiency, and Reimbursement
PF Engstrom, MG Bloom,GD Demetri, PG Febbo, et al.
Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decisionmaking is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory-developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility. The NCCN Molecular Testing Work Group identified
challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence. (JNCCN 2011;9[Suppl 6]:S1–S16)
Executive Summary
The FDA recently announced plans for oversight of laboratory-developed tests (LDTs) and released draft guidance regarding the development of companion diagnostics concurrently with therapeutics, both areas over which the FDA has regulatory authority. As recognized by the FDA, these types of diagnostic tests are used increasingly to directly inform treatment decisions, and this especially impacts patients with cancer and their oncologists. However, because of the increasing complexity of some LDTs and increasing commercial interest in oncology-related LDTs in general, the FDA is considering whether its policy of exercising “enforcement discretion”

for LDTs is still appropriate. To provide guidance regarding challenges of molecular testing to health care providers and other stakeholders, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations external to NCCN.  The NCCN Molecular Testing Work Group agreed to define molecular testing in oncology as

  • procedures designed to detect somatic or germline mutations in DNA and
  • changes in gene or protein expression that could impact the
    • diagnosis,
    • prognosis,
    • prediction, and
    • evaluation of therapy of patients with cancer.
Therefore, the discussion focused on molecular tests that predict outcomes for therapy.
Realizing the importance of personalized medicine in advanced NSCLC
E Topol, B Buehler, GS Ginsburg.       Medscape Molec Medicine
With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf/
Lung Cancer in the Never Smoker Population: An Expert Interview With Dr. Nasser Hanna

Lung cancer in the never smoker population is a distinct disease entity with specific molecular changes, offering the potential for targeted therapy.
Experts And Viewpoint, Medscape Hematology-Oncology, December 2007

An Update on New and Emerging Therapies for NSCLC
Simon L. Ekman, MD, PhD; Fred R. Hirsch, MD, PhD
On completion of these readings participants will be thoroughly familiar with these issues:
  1. The influence of histologic types and genetic and molecular markers on choosing and personalizing therapy in patients with advanced NSCLC
  2. The role of the pathologist in properly classifying subtypes of NSCLC and reporting the presence of molecular markers in tumor samples
  3. Familiarize themselves with effective methods of obtaining adequate tissue samples from patients and recognize the importance of accurate pathologic assessment of NSCLC
The rapid developments in molecular biology have opened up new possibilities for individualized treatment of non-small cell lung cancer (NSCLC), and, in recent years, has mainly focused on the epidermal growth factor receptor (EGFR). A greater understanding of the molecular mechanisms behind
  • tumorigenesis and
  • the identification of new therapeutic targets
    • have sparked the development of novel agents
    • intended to improve the standard chemotherapy regimens for NSCLC.
Along with the advent of targeted therapy, identifying biomarkers to predict the subset of patients more likely to benefit from a specific targeted intervention has become increasingly important.
EGFR TYROSINE KINASE INHIBITORS 
tumor-associated mutations in the tyrosine kinase domain of EGFR have been associated with response to EGFR TKIs
The most common EGFR-sensitizing mutations encompass deletions in exon 19 and a point mutation at L858R in exon 21; together,
  • they account for approximately 85% of EGFR mutations in NSCLC.
  • Other EGFR mutations have been detected, particularly in exon 20.
    •  mutations identified in exon 20 have been linked to resistance to EGFR TKIsNon-Small Cell Lung Cancer: Biologic and Therapeutic Considerations for Personalized Management
      Taofeek K. Owonikoko, MD, PhD
What is the role and application of molecular profiling in the management of NSCLC?
It is essential to:
  1. Identify advances in the understanding of molecular biology and histologic profiling in the treatment of NSCLC
  2. Summarize clinical data supporting the use of tumor biomarkers as predictors of therapeutic efficacy of targeted agents in NSCLC
  3. Devise an individualized treatment plan for patients with advanced NSCLC based on a tumor’s molecular profile
  4. Identify methods for overcoming barriers to effective incorporation of molecular profiling for the management of NSCLC into clinical practice
Non-small cell lung cancer (NSCLC),the most common type of lung cancer, usually grows and spreads more slowly than small cell lung cancer.
The three common forms of NSCLC are:
  1. Adenocarcinomas are often found in an outer area of the lung.
  2. Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
  3. Large cell carcinomas occur in any part of the lung and tend to grow and spread faster than the other two types
Smoking causes most cases of lung cancer. The risk depends on the number of cigarettes you smoke every day and for how long you have smoked. Some people who do not smoke and have never smoked develop lung cancer.
Working with or near the following cancer-causing chemicals or materials can also increase your risk:
  • Asbestos
  • Chemicals such as uranium, beryllium, vinyl chloride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, and diesel exhaust
  • Certain alloys, paints, pigments, and preservatives
  • Products using chloride and formaldehyde
Non-small cell lung c

ancer
(NSCLC) accounts for
  • approximately 85% of all lung cancers.
Lung cancer  may produce no symptoms until the disease is well advanced, so early recognition of symptoms may be beneficial to outcome.
At initial diagnosis,
  • 20% of patients have localized disease,
  • 25% of patients have regional metastasis, and
  • 55% of patients have distant spread of disease.
Revisiting Doublet Maintenance Chemo in Advanced NSCLC 
H. Jack West, MD
  • Pemetrexed Versus Pemetrexed and Carboplatin as Second-Line Chemotherapy In Advanced Non-Small-Cell Lung Cancer
Ardizzoni A, Tiseo M, Boni L, et al
J Clin Oncol. 2102;30:4501-4507
Historically, our second-line therapy has evolved into a strategy of pursuing single-agent therapies for patients with advanced non-small cell lung cancer (NSCLC) who have received prior chemotherapy. This approach was developed on the basis of benefits conferred by such established treatments as docetaxel, pemetrexed, and erlotinib — each well-tested as single agents — and evidence indicating a survival benefit in previously treated patients.
A study out of Italy by Ardizzoni and colleagues published in the Journal of Clinical Oncology directly compares carboplatin/pemetrexed with pemetrexed alone, and
  • it provides more evidence that our current approach of sequential singlet therapy remains appropriate.
This randomized phase 2 trial enrolled 239 patients with advanced NSCLC, initially of any histology, then later amended (September 2008) to enroll
  • only patients with non-squamous NSCLC because of mounting evidence that pemetrexed is not active in patients with the squamous subtype of advanced NSCLC.
Patients must have received prior chemotherapy (without restriction on regimen except that it could not include pemetrexed). Participants were randomly assigned 1:1 to receive pemetrexed at the standard dose of 500 mg/m2 IV every 21 days or the same chemotherapy with carboplatin at an area under the curve of 5, also IV every 21 days.
The primary endpoint for the trial was progression-free survival (PFS), and the trial was intended to have results pooled with a nearly identically designed trial that was done in The Netherlands. The Dutch trial compared pemetrexed with carboplatin/pemetrexed at the same dose and schedule. The vast majority of patients (97.5%) had a performance status of 0 or 1, and the median age was 64 years.
The Italian study found no evidence to support a benefit in efficacy from the more aggressive doublet regimen. Specifically,
  • median PFS was 3.6 months with pemetrexed alone vs 3.5 months with carboplatin/pemetrexed.
  • Response rate (RR) and median overall survival (OS) were also no better with the doublet regimen
      • RR 12.6% vs 12.5%, median OS 9.2 vs 8.8 months, for pemetrexed and carboplatin/pemetrexed.

Moreover, pooling the data from the Italian trial with the Dutch trial demonstrated no significant differences between the 2 strategies. Subgroup analysis showed that

  • the patients with squamous NSCLC had a superior median PFS of 3.2 months with the carboplatin doublet vs 2.0 months with pemetrexed alone.

Unfortunately, this only confirms that adding a second agent is beneficial for patients receiving an agent previously shown to be ineffective in that population.

Viewpoint
Putting it in the context of previous data, these results only provide further confirmation that more is not better.
  • combinations are associated with more toxicity than single-agent therapy, and
  • this is likely to be especially relevant in previously treated patients whose ability to tolerate ongoing therapy over time may be reduced.

It is critical to balance efficacy with tolerability to enable us to deliver the treatment over a prolonged period. We need to recognize the importance of pacing ourselves if our goal is to administer treatments in a palliative setting for an increasingly longer duration.

Epidermal growth factor receptor (EGFR) signal...

Epidermal growth factor receptor (EGFR) signaling pathway. (Photo credit: Wikipedia)

EGFR structure

EGFR structure (Photo credit: Wikipedia)

ATP synthase

ATP synthase (Photo credit: Ethan Hein)

Non-small cell carcinoma - FNA

Non-small cell carcinoma – FNA (Photo credit: Pulmonary Pathology)

Articles on NSCLC in Pharmaceutical Intelligence:
Key Sources:
  1. Realizing the importance of personalized medicine in advanced NSCLC
    E Topol, B Buehler, GS Ginsburg. 

    Medscape Molec Medicine The Potential of Personalized Medicine in Advanced NSCLC

    With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC
  2. Revisiting Doublet Maintenance Chemo in Advanced NSCLC
    H. Jack West, MD     http://www.medscape.com/viewarticle/777367
    Pemetrexed Versus Pemetrexed and Carboplatin as Second-Line Chemotherapy In Advanced Non-Small-Cell Lung Cancer
    Ardizzoni A, Tiseo M, Boni L, et al
    J Clin Oncol. 2102;30:4501-4507
  3. Lung Cancer in the Never Smoker Population: An Expert Interview With Dr. Nasser Hanna
    Experts And Viewpoint, Medscape Hematology-Oncology, December 2007
  4. Non-Small Cell Lung Cancer: Biologic and Therapeutic Considerations for Personalized Management
    Taofeek K. Owonikoko, MD, PhD   August 24, 2011.   Medscape
  5. An Update on New and Emerging Therapies for NSCLC
    Simon L. Ekman, MD, PhD; Fred R. Hirsch, MD, PhD     Medscape
  6. Lovly CM, Carbone DP. Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol. 2011;8(2):68-70.
  7. Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629.

  8. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380.
  9. Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy.

    Cancer Metastasis Rev. 2010;29:37-48.

  10. NCCN Oncology Insights Report on Non-Small Cell Lung Cancer 1.2010
  11.   Review of the Treatment of Non-Small Cell Lung Cancer with Gefitinib
    T Araki, H Yashima, K Shimizu, T Aomori
    Clinical Medicine Insights: Oncology 2012:6 407–421  http://dx.doi.org/10.4137/CMO.S7340

 

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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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Sunitinib brings Adult Acute Lymphoblastic Leukemia (ALL) to Remission – RNA Sequencing – FLT3 Receptor Blockade

Curator: Aviva Lev-Ari, PhD, RN

Updated 11/13/2013

Pazopanib versus Sunitinib in Renal Cancer

N Engl J Med 2013; 369:1968-1970November 14, 2013DOI: 10.1056/NEJMc1311795

Article

To the Editor:

Cancer treatments are expensive. The estimation of the total cost can be challenging because of several factors such as efficacy, toxicity, and the costs and duration of supportive care and end-of-life care. Motzer et al. (Aug. 22 issue)1 report similar efficacy but a favorable safety and quality-of-life profile and less medical resource utilization with pazopanib as compared with sunitinib in first-line therapy for metastatic renal cancer. Since oncology is becoming an increasingly value-based specialty, we wanted to highlight another important aspect of this trial. Pazopanib appears to be favorable not only in terms of safety and quality of life, but also in terms of overall cost. A 30-day supply of pazopanib (at a dose of 800 mg daily) ranges from $3,500 to $8,556, whereas a 30-day supply of sunitinib (at a dose of 50 mg daily) ranges from $4,500 to $13,559.2 The total cost of pazopanib during the median progression-free survival of 8.4 months is $29,400 to $71,870, and the total cost of sunitinib during the median progression-free survival of 9.5 months is $42,750 to $127,454. Less toxicity and less medical resource utilization with pazopanib will most likely further lower the overall costs of treatment with this agent. Comparative-effectiveness trials hold great promise for maximizing patient safety, improving treatment outcomes, and reducing costs.

Ryan Ramaekers, M.D.
Mark Tharnish, Pharm.D.
M. Sitki Copur, M.D.
Saint Francis Cancer Treatment Center, Grand Island, NE
mcopur@sfmc-gi.org

No potential conflict of interest relevant to this letter was reported.

2 References

To the Editor:

Motzer et al. report a combined analysis of two open-label noninferiority trials (927 patients in the original trial and 183 patients in a second trial), each of which compared pazopanib with sunitinib with respect to progression-free survival in renal-cell carcinoma. Quality-of-life outcomes were subjective.

Analysis of noninferiority trials is notoriously difficult.1,2 The authors’ analysis of the trials, which was open-label because of the different administration schedules of the drugs, presents problems in interpreting progression-free survival and quality of life. The studies define disease progression differently. The larger study defined progression-free survival according to independent review. The protocol for the smaller study states that progression-free survival “will be summarized . . . based on the investigator assessment.” Inference from subjective outcomes in unmasked trials (e.g., quality of life in both studies and progression-free survival in the smaller study and therefore in the combined analysis) is subject to well-known bias. Moreover, the article does not state how many of the 379 participants (34%) who discontinued the intervention before death or disease progression (see Fig. S2 in the Supplementary Appendix, available with the full text of the article at NEJM.org) were assessed for progression-free survival. A fair comparison must use rigorous methods to handle missing data.3 Since the article did not deal appropriately with missing data, its conclusions regarding noninferiority are uninterpretable.

Janet Wittes, Ph.D.
Statistics Collaborative, Washington, DC
janet@statcollab.com

Dr. Wittes reports that her company, Statistics Collaborative, has consulting agreements with both GlaxoSmithKline and Pfizer, the manufacturers of the drugs discussed in the article by Motzer et al. In addition, Statistics Collaborative has contracts with several other companies that produce drugs for patients with cancer. No other potential conflict of interest relevant to this letter was reported.

3 References

To the Editor:

Motzer et al. state that “the results of the progression-free survival analysis in the per-protocol population were consistent with the results of the primary analysis.” However, the predefined margin of noninferiority (<1.25) was not met. The upper limit of the confidence interval (1.255) was clearly above the defined threshold.1 In a noninferiority trial, the use of the intention-to-treat population is generally nonconservative,2 the full analysis set and the per-protocol analysis set are considered to have equal importance, and the use of the intention-to-treat population should lead to similar conclusions for a robust interpretation.3 Thus, it is surprising that the authors did not come to or discuss the same conclusions as that of the French National Authority for Health4: “serious doubt exists about the noninferiority result of pazopanib compared to sunitinib” and “the clinical significance of the noninferiority threshold defined in the protocol was an efficacy loss of 2.2 months in the median progression-free survival. This is too large for patients.”

Jochen Casper, M.D.
Silke Schumann-Binarsch, M.D.
Claus-Henning Köhne, M.D.
Klinikum Oldenburg, Oldenburg, Germany
casper.jochen@klinikum-oldenburg.de

Dr. Casper reports receiving consulting fees from Bayer, Novartis, and Pfizer and speaking fees from Novartis and Pfizer. No other potential conflict of interest relevant to this letter was reported.

4 References

The authors reply: In reply to Ramaekers et al.: we agree that decisions regarding the provision of health care include economic evaluations to identify treatments that provide the best clinical benefit at an acceptable cost.

To clarify a point in the letter by Wittes: the primary end point of this phase 3 trial was progression-free survival evaluated by an independent review committee; these data were assessed for all 1110 patients from both trials. This is specified in the protocol. The consistency of the quality-of-life results with the observed differences in the safety profiles for the two drugs speaks to the absence of bias in the quality-of-life outcome. The number of patients in whom follow-up ended before progression was assessed by the independent review committee was balanced between the two groups: 156 patients in the pazopanib group (28%) and 168 patients in the sunitinib group (30%). To Wittes’s final point regarding rigorous methods to handle missing data: the algorithm for assigning disease-progression and censoring dates followed the Guidance for Industry of the Food and Drug Administration1 and is included in the protocol of our article.

In reply to Casper et al.: there is no consensus regarding whether the per-protocol population is more conservative than the intention-to-treat population for the noninferiority analysis.2,3Reviews of noninferiority trials indicate that the per-protocol population is not generally more conservative than the intention-to-treat population, and there are scenarios in which the per-protocol analysis itself could introduce bias.3 A systematic review indicated that more than 70% of published findings from noninferiority trials in oncology show results in only the intention-to-treat population and not in the per-protocol population.4 Our phase 3 trial had a single primary analysis in the intention-to-treat population, with the per-protocol population included as a key sensitivity analysis, as supported by Fleming et al.5 No formal hypothesis testing was planned for the per-protocol population, nor was the trial powered for this. Consistency of the point estimates was desired to show an absence of bias due to the analysis population. This absence of bias was shown by the consistency of the hazard ratios (1.07 in the per-protocol analysis vs. 1.05 in the primary analysis). For an underpowered per-protocol comparison, it is inappropriate for Casper et al. to interpret that the upper bound that barely exceeded 1.25 in our per-protocol analysis is an indication of inconsistency of results across the two populations. The noninferiority margin was selected in consultation with oncology experts, and justification of the margin is in the protocol.

Robert J. Motzer, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY
motzerr@mskcc.org

Lauren McCann, Ph.D.
Keith Deen, M.S.
GlaxoSmithKline, Collegeville, PA

Since publication of their article, the authors report no further potential conflict of interest.

REFERENCES

Food and Drug Administration. Guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. May 2007 (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf).
Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the importance of rigorous methods. BMJ 1996;313:36-39[Erratum, BMJ 1996;313:550.]
CrossRef | Web of Science | Medline
Brittain E, Lin D. A comparison of intent-to-treat and per-protocol results in antibiotic non-inferiority trials. Stat Med 2005;24:1-10
CrossRef | Web of Science | Medline
Tanaka S, Kinjo Y, Kataoka Y, Yoshimura K, Termukai S. Statistical issues and recommendations for noninferiority trials in oncology: a systematic review. Clin Cancer Res 2012;18:1837-1847
CrossRef | Web of Science | Medline
Fleming TR, Odem-Davis K, Rothmann MD, Li Shen Y. Some essential considerations in the design and conduct of non-inferiority trials. Clin Trials2011;8:432-439
CrossRef | Web of Science | Medline
SOURCE

Original Article Published on 7/9/2012

July 6, 2012 NY Times reports on a new approach based on DNA and RNA sequencing and a cancer drug for kidney cancer to bring REMISSION to Adult acute lymphoblastic leukemia (ALL).

On the lower left corner of this page – Watch the VIDEO

second-chance.html

Dr. Lukas Wartman, is a Cancer Researcher specializing in Leukemia. He suspected he had Leukemia, the very disease he had devoted his medical career to studying.

After years of treatment and two relapses of ALL, he has exhaused all conventional approaches to his disease. At Washington University in St. Louis, his colleagues in the lab, decoded Dr. Wartman’s genetic information by genome sequencing techniques t determine the genetic cause of his ALL. The team found an overactive gne, FLT3 on Chromosome 13. The gene was treated with pfizer’s Suntinib drug for advanced kidney cancer.

Blood samples free of ALL found in days after using the drug. As results were very promising, Pfizer, the drug’s maker who has turned down Dr. Wartman’s request for the drug under their compassionate use program, though he explained that his entire salary was only enough to pay for 7 1/2 months of Sutent (Suntinib). While he does not know why Pfizer gave him the drug finally, he suspects it was the plea of his Nurse Practitioner, Stephanie Bauer, NP.

Identification of the genetic cause for his ALL, thus discovering a breakthough in understanding and treatment for ALL in other patients, involved the following steps:

SAMPLE

two tissue samples taken from Dr. Wartman’s Bone marrow and skin cells

SEQUENCE

Extracts of DNA and RNA from Dr. Wartman’s cells, two types of genetic material tested

COMPARISON

DNA sequesnces showed genetic mutations possibly related to his ALL, none seemed treatable. However, RNA sequencing revealed that a normal Gene, FLT3, on cheomozome 13, was overactive in his leukemia cells

TARGETING

The FLT3 gene helps create new white blod cells in the bone marrow. Dr. Wartman’s marrow bone cells were covered with an extreme number of FLT3 receptors which possibly caused the growth of his leukemia.

TREATMENT – Receptor Blockade 

Drug known to block FLT3 receptor, Sunitinib, used for kedney cancer treatment, was given to Dr. Wartman. Two weeks after Dr, Wartman began taking the drug, tests revealed that his leukenia was in remission.

NEW MARKETS FOR FLT3  GENE BLOCKADE DRUG  – KIDNEY CANCER AND LEUKEMIA

Pfizer has NOW a NEW market for Sunitinib — All CANCER PATIENTS DIAGNOSED WITH Adult acute lymphoblastic leukemia (ALL) where an overactive FLT3 gene on chomosome 13 is found.

NEW TREATMENT OPTIONS FOR Adult acute lymphoblastic leukemia (ALL)

Thus, any (ALL) diagnosed patient needs to be tested for Chromosome 13, ONLY rather then the entire genome sequencing of the Patient. If FLT3 is not found overactive, THEN proceed with entire genome sequencing of the Patient. IF another gene is overactive FIND DRUG FOR RECEPTOR BLOCKADE.

SIZING THE MARKET FOR FLT3 BLOCKADE DRUGS: KIDNEY CANCER vs LEUKEMIA

The Market for Adult ALL is much bigger than the market for kidney cancer. Thus, this discovery regarding the remission of Dr. Wartman’s remission following two relapses is so significant for Pfizer and for any patient with the diagnosis of Adult ALL.

I recommend the reader to click on the links and follow the reactions of the public to this article in The New York Times.

http://www.nytimes.com/2012/07/08/health/in-gene-sequencing-treatment-for-leukemia-glimpses-of-the-future.html?pagewanted=all

Read HUNDREDS of Comments by Cancer Patients and the readers of The New York Times Health Section

http://www.nytimes.com/2012/07/08/health/in-gene-sequencing-treatment-for-leukemia-glimpses-of-the-future.html?pagewanted=all#commentsContainer

 

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