Recently in Oncology Category

Nilotinib (Tasigna; Novartis) may be poised to become first-line treatment for Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia (CML), like its sister drug imatinib (Gleevec; Novartis). In a company-funded, open-label, randomized head-to-head phase 3 study, nilotinib treatment produced significantly higher major molecular response* (MMR) rates at 1 year than imatinib in patients with newly diagnosed Ph+ CML. Results of the study were presented Tuesday at the annual meeting of the American Hematology Society (ASH) in New Orleans.

In addition, nilotinib treatment was associated with significantly higher rates of a complete cytogenetic response (CCyR)—the absence of Ph+ cells in bone marrow. All-important survival outcomes were apparently not included in the study, which is ongoing. (Long-term [ie, 60-month] data for first-line imatinib in Ph+ CML indicate an overall survival rate of 89%.)

Outcome	Nilotinib 300 mg bid (n = 282)	Nilotinib 400 mg bid (n = 281)	Imatinib 400 mg qd (n = 283)
MMR
3 mo, %	9	5	1
6 mo, %	33	30	12
12 mo, %	44 (P < .0001, vs imatinib)	43 (P < .0001, vs imatinib)	22
Overall, %	57	54	30
12 mo in high-risk pts, %	41	32	17
Complete cytogenic response (CCyR)
By 6 mo, %	67	63	45
By 12 mo, %	80 (P < .0001, vs imatinib)	78 (P = .0005, vs imatinib)	65
Est. rate of progression to accelerated phase/blast crisis at 12 mo, %	<1 (P = .0095, vs imatinib)	<1 (P = .0037, vs imatinib)	4
Discontinuation due to adverse events or lab abnormalities, %	7	11	9

Both nilotinib and imatinib are designed to inhibit the tyrosine-kinase portion (ie, the working end) of the abnormal fusion protein, bcl-abl, which is characteristic of Ph+ CML; but nilotinib is a more selective inhibitor than imatinib.

According to the WSJ, Gleevec, which is currently approved for the first-line treatment of Ph+ CML, generated $3.7 billion in sales last year for Novartis. But the drug's patent will expire in 2015. Nilotinib, 400 mg bid, is currently approved for the treatment of chronic- or accelerated-phase Ph+ CML that is resistant to imatinib. The FDA's Orange Book indicates that the patent on nilotinib will expire in 2023. Treatment with either drug costs more than $40,000 per year.

Last month, Kareem Abdul-Jabbar announced that he was diagnosed with Ph+ CML in December of 2008. It has been inferred here that he is or has been treated with imatinib.

N.B.—Trial name is Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients, abbreviated ENESTnd.

* Defined by the elimination of bone-marrow cells that carry the disease-defining bcr-abl fusion protein. 

NBA legend Kareem Abdul-Jabbar, 62, has Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia (CML), according to numerous news sources. ABC News reports that Abdul-Jabbar was diagnosed with the disorder in December of last year. What treatment Jabbar has received to date is unclear; although the LA Times states that the disease is managed with "daily oral medication" (probably imatinib [Gleevec; Novartis]) and regular "blood analysis."

Here are some facts about CML and its treatment, according to the NCCN Clinical Practice Guidelines:

• CML accounts for 15% of adult leukemias. This year, an estimated 5050 cases will be diagnosed, and 470 will die of the disease.
• The median age of onset is 67 years.
• The disease is characterized by a translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome. The translocation results in a fusion gene, BCR-ABL, which is believed to play an important role in the development of CML. The fusion protein produced by BCR-ABL is an oncogene, with unregulated tyrosine-kinase (TK) activity.
• CML occurs in 3 phases: chronic, accelerated, and blast. CML is usually diagnosed in the chronic phase.
• Untreated CML will progress to advanced disease in 3-5 years.
• First-line treatment for chronic Ph+ CML is imatinib, a selective inhibitor of the TK portion of the bcr-abl fusion protein. 
• Responses to the initial treatment of CML are monitored periodically (eg, every 3 months), by assessing bone marrow cytogenetics (ie, cytogenic response [CyR]) and transcript numbers of the BCR-ABL gene (ie, molecular response).
• Long-term data (median follow-up, 60 months) for first-line imatinib: complete CyR, 87%; overall survival, 89%.
• The most common high-grade toxicities with imatinib: neutropenia and thrombocytopenia. Rare cardiotoxicity has been reported with long-term therapy.
• The most common adverse events with imatinib: GI disturbances, edema, rash, and musculoskeletal complaints.
• Management of disease progression that occurs during imatinib therapy may include increasing the imatinib dosage; the use of an alternative TK inhibitor (dasatinib [Sprycel; BMS] or nilotinib [Tasigna; Novartis]); hematopoietic stem cell transplantation (HSCT), or enrollment in a clinical trial. Traditional chemotherapy regimens may also be considered for blast crisis.

The NCCN guidelines conclude, "The development of imatinib...has revolutionized the treatment of CML." Before the advent of imatinib, CML was treated medically with interferon alpha and low-dose cytarabine. According to ABC, Abdul-Jabbar is a spokesperson for Novartis, the manufacturer of imatinib. 

The FDA approved imatinib for the first-line treatment of CML in December 2002.

NCCN = National Comprehensive Cancer Network.

Image of Abdul-Jabbar in 2007 from Flickr.

And another thing that Avastin (bevacizumab; Genentech) may be good for:

The anti-VEGF monoclonal antibody improved hearing loss and reduced tumor volume in patients with growing vestibular schwannomas. The conclusions are based on data from a small, first-of-its-kind study of patients with neurofibromatosis (NF) type 2—data which are available in an early release article from The NEJM.

Ten consecutive patients with NF type 2 and progressive vestibular schwannomas (who were not candidates for or declined the standard treatment of surgery and radiation therapy*) received at least one dose of bevacizumab (5 mg/kg every 2 weeks). The median annual growth rate of schwannomas before treatment was 62%, and the median duration of treatment was 12 months. (The rationale for assessing bevacizumab in NF-associated schwannomas is based on the expression of VEGF in tumor cells. However, the expression of the VEGF receptor, VEGFR-2, on tumor vessels is not particularly high—which suggests that an anti-VEGF-receptor drug is less likely to be of benefit than bevacizumab.)

In a retrospective analysis, 9/10 tumors shrank (best median response, 26% reduction) after bevacizumab treatment, and 6 demonstrated an imaging response. Only 1 patient experienced an increase in tumor volume (of 32%). Tumor reduction strongly correlated with baseline vasogenic edema on MR images (ie, the mean apparent diffusion coefficent). Improvements in hearing (at <12 weeks) were observed in 5 of 7 eligible patients and were progressive and durable (up to 16 months) in most.

This pilot study was not funded by Genentech; although 1 author (Gregory Sorensen, MD) reported receiving grant support from the company.

NF2 is a dominantly inherited disorder with a prevalence of 1 in 25,000. The most common tumor type associated with the condition is vestibular (or acoustic) schwannomas, benign tumors of the 8th cranial nerve. Growth of tumors causes progressive hearing loss, as does surgical and radiation therapy. Progressive vestibular schwannomas can also produce brainstem compression.

In May, the FDA approved Avastin for the treatment of the uniformly fatal brain tumor, glioblastoma multiforme, after standard therapy.

VEGF = vascular endothelial-cell growth factor.

* Eight patients were at high risk for complete hearing loss with standard therapy.

Delivering chemotherapy to brain tumors is particularly challenging because of the blood-brain barrier (BBB), the collection of tight junctions between endothelial cells in cerebral blood vessels. When intact, these protective junctions prevent the passage of a number of substances—including chemotherapeutic molecules—from the systemic circulation into the brain tumor bed. The key to effective, targeted therapy of brain tumors is to 1) selectively disrupt the BBB to allow the entry of cancer-killing drugs and then 2) reestablish the BBB so that chemotherapeutic agents are retained within the tumor bed.

Biomed engineers at Duke have constructed a prototype of an intravascular catheter, which can deliver BBB-busting hyperthermia* and provide real-time 3D imaging of brain tumors. The thin, flexible catheter is intended to be snaked through the internal jugular vein (which obviates the need for invasive cranial surgery) and manipulated into the dural venous sinuses. The investigators' proof-of-concept experiments, performed in dogs, was published in this month's issue of Ultrasonic Imaging.

The investigators concluded that their next-generation device must be smaller and more flexible than the prototype, to negotiate the curves of the cerebral vasculature. The long-term plan for the catheter is to obtain fluoroscopic-guided access to brain tumors through the venous sinuses, administer BBB-disrupting heat, which would then trigger the release of chemotherapeutic agents to the tumor bed.

* A temperature rise of approximately 5 degrees C.

Depiction of dural sinus system from Gray's Anatomy.

As part of the provisional FDA approval of Avastin (bevacizumab) in metastatic breast cancer, Genentech and Roche continue to supply more data supporting use of the anti-angiogenesis mAb.

In an international, 2-part, placebo-controlled, phase 3 study of 1237 women with advanced HER2-negative breast cancer, the addition of Avastin to either taxane or anthracycline-based chemotherapy (group 1) or capecitabine (group 2) significantly prolonged the primary endpoint of progression-free survival (PFS).* These data complement findings from the E2100 and AVADO phase 3 trials of Avastin in advanced HER2-negative breast cancer.

Currently Avastin is FDA approved for use, in combination with paclitaxel, in chemotherapy-naive patients with advanced HER2-negative breast cancer. The company emphasizes that Avastin has not been shown, as yet, to increase survival or improve disease-related symptoms in breast cancer.

Genentech's chief medical officer, Hal Barron, says that the data from this latest trial, RIBBON-1, and findings from AVADO will be submitted to the FDA by the middle of next year. Data from 3 ongoing or planned trials will be provided to the FDA as well.

Avastin is also FDA approved for the first- or second-line treatment of metastatic colorectal cancer, in combination with IV 5-FU-based chemotherapy, and for the first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous NSCLC, in combination with carboplatin and paclitaxel.

5-FU = 5-fluorouracil; HER2 = human epidermal growth factor receptor 2; mAb = monoclonal antibody; NSCLC = non-small cell lung cancer.

* Time from randomization to disease progression or death.

Genentech announced today that it has submitted a supplemental Biologics License Application (sBLA) to the FDA for the use of its anti-VEGF mAb, bevacizumab (Avastin), in recurrent glioblastoma multiforme (GBM). The application will be considered for accelerated approval, according to Genentech, if accepted by the FDA.

The sBLA is based on data from a recent phase 2 trial, in which bevacizumab (with or without randomized irinotecan chemotherapy) was administered to 167 patients with recurrent, treatment-refractory GBM. Primary endpoints of the study, assessed by MR imaging, were 6-month progression-free survival (PFS) and response rate (≥50% decrease in tumor size). Median durations of treatment were 16 weeks with bevacizumab alone and 22 weeks with bevacizumab plus irinotecan.

Efficacy and safety outcomes were presented, as follows, at the annual meeting of the American Society of Clinical Oncology (ASCO) in June of this year.*

Efficacy Outcome	Bevacizumab (n = 85)	Bevacizumab + Irinotecan (n = 82)
6-month PFS, %	43	50
Overall response rate, %	28	38
Median overall survival, months	9.2	8.7
Median duration of response, months	5.6	4.3

The investigators also reported a substantial decline in the use of corticosteroids with either treatment.

Safety Outcome	Bevacizumab (n = 84)	Bevacizumab + Irinotecan (n = 79)
Grade ≥3 adverse event, %	46	66
Serious AE, %	26	43
AE leading to discontinuation, %    Bevacizumab    Irinotecan	5 0	18 18
AE leading to death, %	2.4	1.3

Two hemorrhages (grade ≥3), one outside of the CNS, were reported with bevacizumab use. The rate of grade ≥3 infection with either treatment was approximately 10%.

The current standard of initial care for GBM is surgical debulking followed by radiation therapy and concurrent temozolomide (which is followed by maintenance temozolomide). There is no standard of care for recurrent disease. Reported response rates with single-agent irinotecan in the recurrent setting are 15% or less.

The rationale for using bevacizumab in GBM is based on the high rate of VEGF expression in the tumor. Genentech reports that it plans to initate a global phase 3 study of Avastin in newly diagnosed GBM next year. 

CNS = central nervous system; mAb = monoclonal antibody; MR = magnetic resonance; VEGF = vascular endothelial-cell growth factor.

* Cloughesy T et al. A phase II, randomized, non-comparative clinnical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM).

HT to the WSJ Health Blog, which reports that the estimated cost for a course of bevacizumab treatment for GBM is nearly $40,000. 

Targeted, combination therapy in cancer sure seems like a good idea. However, the addition of the anti-angiogenesis mAb bevacizumab (Avastin; Genentech) to the EGFR inhibitor erlotinib (Tarceva; Genentech/OSI) did not improve overall survival in patients with platinum-refractory non-small cell lung cancer (NSCLC). The results of the phase 3 trial (BeTa Lung) of the combination were provided by Genentech on Sunday in a press release.

In an international, placebo-controlled, double-blind, phase 3 trial, 636 patients with advanced, platinum-refractory NSCLC received erlotinib with either randomly assigned bevacizumab or placebo. Median survival, the primary endpoint, was 9.2 months in both treatment groups, according to the press release. But progression-free survival and the response rate, secondary endpoints, were higher with the addition of bevacizumab. These data, along with adverse events, will be presented at the upcoming Chicago Multidisciplinary Symposium in Thoracic Oncology in November.

Bevacizumab is approved as first-line treatment (with carboplatin and paclitaxel) in locally advanced, nonsquamous NSCLC, and erlotinib is approved for chemotherapy-refractory NSCLC. Another phase 3 study is evaluating the combination as first-line maintenance therapy for advanced NSCLC after treatment with bevacizumab.

Although the WSJ reported that Genentech and OSI shares fell on the trial news, stock prices—at least in the case of Genentech—appear to be riding along with the very bumpy indexes.

 EGFR = epidermal growth factor receptor; mAb = monoclonal antibody.

A recent article authored by investigators at the University of Utah features an all-time favorite pastime: genealogic digging. The authors examined 2 large kindreds, one in Utah and one in New York, that share an identical autosomal-dominant (AD) deletion mutation, c.426_427delAT, which determines an attenuated form of familial adenomatous polyposis (FAP). FAP and its attenuated forms (AFAP) are associated with substantially increased risks of colonic polyps and colorectal cancer, FAP moreso than AFAP, but phenotypic variance appears to be considerable, particularly in individuals with the attenuated conditions.

 

By using genealogic records at the massively stocked LDS* library and matching surnames between the 2 pedigrees, the investigators identified a common ancestral couple who emigrated from England to America in the early 1600s: George Frye and his nameless wife, aka Mrs. George Frye. The interesting thing about this couple is that the c.426_427delAT mutation appears to have spontaneously originated with one of them, because it has not been identified in England or elsewhere in Europe, according to the authors.

 

The big question the article generates is How many Americans currently alive have inherited the original deletion mutation? The authors indicate that genealogic data are presently not sufficient to identify the full extent of descendants of the founding couple; however, there are at least 11 other American families with the exact allele haplotype who have been identified in Texas, Nebraska, Washington, Vermont, or Michigan and 2 additional families in Wisconsin with a slightly different genotype, mostly likely due to recombination events. Whether this tally is complete is difficult to know, until all progeny lines from Mr. and Mrs. George Frye have been traced, and genetic analyses of living descendants have been performed. The absence of colorectal cancer in a particular lineage is unlikely to preclude the presence of the mutation, because of substantial phenotypic variance. Among the 2 studied kindreds, approximately 37% of mutation-positive members had fewer than 10 colonic adenomatous polyps, and only approximately 7% of these individuals were diagnosed with colorectal cancer.

 

According to records at familysearch.org and ancestry.com, George Sr. and wife produced at least 4 children, 2 of which, George Frye, Jr, and Elizabeth Frye, passed on their acquired mutations to the New York and Utah families, respectively. Now it is certainly possible, despite the 50% probability of passing on the AD mutation, that the 2 other children of the founding couple were also affected and passed on the allele haplotype to their descendents.

 

In any event, it is recorded that George, Jr, had at least 4 children, and that Elizabeth had 9 children. Therefore the minimum probability is that 6 individuals of the third Frye generation (b. circa 1640-1660) carried the mutation, and half of those children passed it onto their children, and so forth (providing that the mutation is not subject to selective pressure, which it does not appear to be). For the sake of further argument, if each couple of each successive generation had 4 children, with 2 of those 4 children acquiring the mutation, then by the thirteenth generation (those individuals b. 1920s-40s), more than 6000 individuals carried the c.426_427delAT mutation. The mutation incidence, in this scenario, is then doubled for the fourteenth generation, at 12,000—which suggests a considerable mountain of genealogic and genetic data to dig through.

 

*Latter-day Saints.