Everolimus ("Afinitor")

[Rich66]

(monotherapy, with pac and Traz, with Femara, reverse Traz resistance, mTOR, glucose)

"Discount" source: HERE


Apparently FDA approved in renal and some Pancreatic cancers.
But working towards BC.


Novartis’s Afinitor Curbs Breast Cancer in ‘Game-Changing’ Study
9/25/11

LINK

Among women with breast cancer that had spread after treatment, Afinitor more than doubled the time until their disease worsened compared with those who only got Pfizer Inc.’s Aromasin, according to results presented at a cancer conference in Stockholm today. The trial was stopped early because the primary goal was met earlier than expected.
“This could be game-changing,” said Jose Baselga, a Harvard Medical School professor and chief of hematology and oncology at Massachusetts General Hospital who led the study, in an interview. “I don’t recall a study in this patient population that had this magnitude of an effect. It’s pretty exciting.”
The findings move Novartis closer to marketing Afinitor for a new cancer type. The Basel, Switzerland-based company plans to apply for regulatory approval this year to sell Afinitor as a breast cancer treatment, and expects it to add $1 billion to annual sales

Clinical Oncology
ISSUE: NOVEMBER 2011 | VOLUME: 06:11



Everolimus Touted As Game Changer In Breast Cancer

LINK

“Everolimus is the most important advance in breast cancer since trastuzumab,” Dr. Andre said. A flurry of excitement has certainly been building since the presentation at EMCC, but some oncologists are more cautious in interpreting the data.

Dr. Baselga said comparing BOLERO with the Avastin trial is like comparing apples and oranges. “We are talking about very different disease entities,” he said, and most importantly, the study designs were very different. “The Avastin study was not a registration study and it was not placebo-controlled.

“In all the drugs that we have tested, everolimus is the weakest in inducing cell death in ER-positive cells that were deprived of estrogen,” said Dr. Ellis, referring to a study in Breast Cancer Research (2011;13:R21, PMID: 21362200). “This BOLERO study is a very exciting result in terms of a multitude of agents targeting the PI3 kinase pathway in ER–positive breast cancer.”
If the OS data pans out, researchers say the positive results of the BOLERO-2 trial could be just the tip of the iceberg in terms of using everolimus as a breast cancer therapy. The Phase III BOLERO-1 trial has just finalized accrual. This trial is testing the addition of everolimus to weekly paclitaxel and trastuzumab in patients with HER2-overexpressing MBC who are refractory to trastuzumab. And according to Dr. Baselga, future trials could test mTOR inhibitors in the early adjuvant setting in patients with ER-positive breast cancer.

J Clin Oncol. 2010 Dec 1;28(34):5110-5. Epub 2010 Oct 25.
Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab.

Andre F, Campone M, O'Regan R, Manlius C, Massacesi C, Sahmoud T, Mukhopadhyay P, Soria JC, Naughton M, Hurvitz SA.

LINK

Source

Breast Cancer Unit, Department of Medical Oncology, University Paris XI and Institut Gustave Roussy, Villejuif, France. fandre@igr.fr

Abstract

PURPOSE:

To determine the recommended dose of everolimus, a mammalian target of rapamycin inhibitor, combined with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer pretreated with trastuzumab.
METHODS:

In this phase Ib, multicenter, dose-escalation study, patients were treated with everolimus 5 mg/d, 10 mg/d, or 30 mg/wk in combination with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 4 weeks) and trastuzumab (2 mg/kg weekly). End points included end-of-cycle 1 dose-limiting toxicity (DLT) rate (primary end point), safety, relative dose intensity of study drugs, overall response rate (ORR), and pharmacokinetics.
RESULTS:

Of 33 patients enrolled, 31 were pretreated with taxanes, and 32 were resistant to trastuzumab. Patients received a median of two lines of chemotherapy in the metastatic setting (range, 0 to 17 lines). Three patients experienced cycle 1 DLTs: febrile neutropenia (5 mg/d), stomatitis (10 mg/d), and confusion (30 mg/wk). Grade 3 to 4 neutropenia was the most common toxicity observed (n = 17 patients [52%]). On the basis of observed DLTs and overall safety, 10 mg/d was recommended for additional development. Twenty-seven patients had measurable disease and were evaluable for efficacy. Among these patients, ORR was 44%. Overall disease was controlled for 6 months or more in 74%. Median progression-free survival was 34 weeks (95% CI, 29.1 to 40.7 weeks). Among 11 patients who were resistant to both trastuzumab and taxane, a similar level of antitumor activity was observed (ORR, 55%).
CONCLUSION:

Everolimus combined with weekly paclitaxel and trastuzumab was generally well tolerated and had encouraging antitumor activity in patients with trastuzumab-pretreated and -resistant metastatic HER2-overexpressing breast cancer.

PMID:

20975068

[PubMed - indexed for MEDLINE]

Invest New Drugs. 2011 Aug 2. [Epub ahead of print]
Phase I and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies.

Deenen MJ, Klümpen HJ, Richel DJ, Sparidans RW, Weterman MJ, Beijnen JH, Schellens JH, Wilmink JW.

LINK

Source

Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Abstract

Background
Everolimus is an oral mTOR-inhibitor. Preclinical data show synergistic effects of mTOR inhibition in combination with 5-fluorouracil-based anticancer therapy. The combination of everolimus with capecitabine seems therefore an attractive new, orally available, treatment regimen.



Patients and methods

Safety, preliminary efficacy and pharmacokinetics of everolimus in combination with capecitabine were investigated in patients with advanced solid malignancies. Patients were treated with fixed dose everolimus 10 mg/day continuously, plus capecitabine bid for 14 days in three-weekly cycles. Dose escalation of capecitabine proceeded according to the standard 3 × 3 phase I design in four predefined dose levels (500-1,000 mg/m(2) bid). Results In total, 18 patients were enrolled. Median (range) treatment duration with everolimus was 70 days (21-414). Capecitabine 1,000 mg/m(2) bid combined with 10 mg/day everolimus was declared the maximum tolerated dose, at which level one patient developed dose-limiting toxicity (stomatitis grade 3). Drug-related adverse events were mostly grade ≤2 and included mainly fatigue (56%), stomatitis (50%), and hand-foot syndrome (33%). Partial response was documented in three patients, and four had stable disease. There was no pharmacokinetic interaction between everolimus and capecitabine.


Conclusion

Everolimus 10 mg/day continuously combined with capecitabine 1,000 mg/m(2) bid for 14 days every 3 weeks is a patient-convenient, safe and tolerable oral treatment regimen. This is the first study to demonstrate feasibility of this combination at doses with proven single agent efficacy in a number of tumors. Prolonged clinical benefit was observed in an encouraging 39% of patients with advanced solid malignancies.

PMID:

21809026

[PubMed - as supplied by publisher]

Cancer Chemother Pharmacol. 2011 Sep 13. [Epub ahead of print]
A phase I study of daily everolimus plus low-dose weekly cisplatin for patients with advanced solid tumors.

Fury MG, Sherman E, Haque S, Korte S, Lisa D, Shen R, Wu N, Pfister D.

LINK

Source

Department of Medicine, Head and Neck Medical Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 532, New York, NY, 10021, USA, furym@mskcc.org.

Abstract

PURPOSE:

Preclinical studies demonstrate synergistic anti-tumor activity with the combination of everolimus and cisplatin. We conducted a phase I study to establish the recommended phase II of oral everolimus to be given with low-dose weekly intravenous cisplatin.
METHODS:

Part A used a standard 3 + 3 dose escalation scheme. There were 4 planned dose levels of everolimus: 2.5, 5, 7.5, and 10 mg/day. Subjects received oral everolimus during days 1-21 and cisplatin 20 mg/m(2) intravenously (fixed dose) on days 1, 8, and 15 of a 28-day cycle. Pharmacokinetic (PK) blood samples were collected on day 1 and day 8 of cycle 1 in Part A. After the phase II recommended dose was established (Part A), 6 additional subjects were enrolled in an expansion cohort (Part B). Response was assessed by RECIST q 2 cycles for all subjects.
RESULTS:

Thirty patients were enrolled (18 male, 12 female) and 29 were treated. Median age was 61 years (31-79) and the median number of prior cytotoxic chemotherapy regimens was 2 (0-3). Eighty-three percent of subjects had received prior RT. DLTs occurred at dose level 1 (sudden death of unclear cause in a patient with melanoma metastatic to liver) and dose level 2 (bowel obstruction). No DLTs occurred at dose levels 3 and 4. The most common adverse events (≥grade 3) among 28 patients evaluable for toxicity were lymphopenia (36%), hyperglycemia (11%), fatigue (11%), and venous thrombosis (11%). PK analysis of everolimus demonstrated dose-proportional increases in C (max) (mean 91.9 ng/ml) and AUC(0-INF) (mean 680.5 h*ng/ml) at dose level 4. Three partial responses were seen (metastatic pulmonary carcinoid, n = 2; metastatic sinus carcinoma, n = 1). Prolonged stable disease ≥6 cycles occurred in subjects with pulmonary carcinoid, oropharyngeal squamous cell carcinoma, basal cell carcinoma, papillary thyroid carcinoma, and esthesioneuroblastoma (n = 1 each).

CONCLUSION:
The phase II recommended dose is everolimus 10 mg/day (days 1-21) + cisplatin 20 mg/m(2) (days 1, 8, and 15) of a 28-day cycle. PK data demonstrate dose-proportional increases in exposure, as previously described for everolimus monotherapy. Anti-tumor activity was observed in several tumor types.

PMID:

21913034

[PubMed - as supplied by publisher]

J Hematol Oncol. 2011 Jan 13;4(1):3.
Two-dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors.

Xu B, Wu Y, Shen L, Ye D, Jappe A, Cherfi A, Wang H, Yuan R.

FREE TEXT

Source

Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China.

Abstract

BACKGROUND:

This phase I, randomized, multicenter, open-label study investigated the pharmacokinetics, safety, and efficacy of the oral mammalian target of rapamycin inhibitor everolimus in Chinese patients with advanced solid tumors.
METHODS:

A total of 24 patients with advanced breast cancer (n = 6), gastric cancer (n = 6), non-small cell lung cancer (n = 6), or renal cell carcinoma (n = 6) who were refractory to/unsuitable for standard therapy were randomized 1:1 to oral everolimus 5 or 10 mg/day. Primary end points were pharmacokinetic parameters and safety and tolerability. Pharmacokinetic 24-h profiles were measured on day 15; trough level was measured on days 2, 8, 15, 16, and 22. Tolerability was assessed continuously. This final analysis was performed after all patients had received 6 months of study drug or had discontinued.
RESULTS:

Everolimus was absorbed rapidly; median Tmax was 3 h (range, 1-4) and 2 h (range, 0.9-6) in the 5 and 10 mg/day groups, respectively. Pharmacokinetic parameters increased dose proportionally from the 5 and 10 mg/day doses. Steady-state levels were achieved by day 8 or earlier. The most common adverse events suspected to be related to everolimus therapy were increased blood glucose (16.7% and 41.7%) and fatigue (16.7% and 33.3%) in the everolimus 5 and 10 mg/day dose cohorts, respectively. Best tumor response was stable disease in 10 (83%) and 6 (50%) patients in the 5 and 10 mg/day groups, respectively.
CONCLUSIONS:

Everolimus 5 or 10 mg/day was well tolerated in Chinese patients with advanced solid tumors. The observed safety and pharmacokinetic profile of everolimus from this study were consistent with previous studies.
TRIAL REGISTRATION:

Chinese Health Authorities 2008L09346.

PMID:

21232120

[PubMed - in process]

J Clin Oncol. 2009 Jun 1;27(16):2630-7. Epub 2009 Apr 20.
Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer.

Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G, Steinseifer J, Molloy B, Tokaji E, Gardner H, Phillips P, Stumm M, Lane HA, Dixon JM, Jonat W, Rugo HS.

LINK

Source

Medical Oncology Department, Vall d'Hebron University Hospital, P Vall d'Hebron, Barcelona, Spain. jbaselga@vhebron.net

Abstract

PURPOSE:

Cross-talk between the estrogen receptor (ER) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways is a mechanism of resistance to endocrine therapy, and blockade of both pathways enhances antitumor activity in preclinical models. This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor, everolimus (RAD001).

PATIENTS AND METHODS:

Two hundred seventy postmenopausal women with operable ER-positive breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole (2.5 mg/day) and either everolimus (10 mg/day) or placebo. The primary end point was clinical response by palpation. Mandatory biopsies were obtained at baseline and after 2 weeks of treatment (ie, day 15). Samples were assessed for PI3K mutation status (PIK3CA) and for pharmacodynamic changes of Ki67, phospho-S6, cyclin D1, and progesterone receptor (PgR) by immunohistochemistry.

RESULTS:

Response rate by clinical palpation in the everolimus arm was higher than that with letrozole alone (ie, placebo; 68.1% v 59.1%), which was statistically significant at the preplanned, one-sided, alpha = 0.1 level (P = .062). Marked reductions in progesterone receptor and cyclin D1 expression occurred in both treatment arms, and dramatic downregulation of phospho-S6 occurred only in the everolimus arm. An antiproliferative response, as defined by a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15, occurred in 52 (57%) of 91 patients in the everolimus arm and in 25 (30%) of 82 patients in the placebo arm (P < .01). The safety profile was consistent with historical results of everolimus monotherapy; grades 3 to 4 adverse events occurred in 22.6% of patients who received everolimus and in 3.8% of patients who received placebo.

CONCLUSION:
Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer.

Comment in

• J Clin Oncol. 2009 Jun 1;27(16):2580-2.

Oncologist. 2011 Apr 11. [Epub ahead of print]
Everolimus Induces Rapid Plasma Glucose Normalization in Insulinoma Patients by Effects on Tumor As Well As Normal Tissues.

Fiebrich HB, Siemerink EJ, Brouwers AH, Links TP, Remkes WS, Hospers GA, de Vries EG.

LINK

Abstract

Abstract Background. Mammalian target of rapamycin inhibitor everolimus administered to four insulinoma patients rapidly controlled hypoglycemia (Kulke et al., N Engl J Med 2009;360:195-197). We wanted to identify the kinetics of everolimus effects on controlling hypoglycemia and understand underlying mechanisms. Methods. Three consecutive patients with a metastasized symptomatic insulinoma were started on 100 μg of octreotide subcutaneously three times daily. Because of persisting hypoglycemias, treatment with daily 10 mg of oral everolimus was initiated. Serial plasma glucose levels and serum insulin levels were measured. Computer tomography (CT) scans were performed before and after 2 and 5 months of treatment. [18F]fluoro-2-deoxy-d-glucose positron emission tomography ((18)F-FDG-PET) scans, to visualize glucose metabolism, were made before and after 2 weeks, 5 weeks, and 5 months of treatment. The (18)F-FDG uptake was quantified as the maximum standardized uptake value. Results. All patients achieved control of hypoglycemia on everolimus within 14 days. Insulin levels were 2.5- to 6.3-fold elevated before start of treatment and declined 14%-64% after 4 weeks of treatment. CT scans showed stable disease at 2 months in all patients, with progressive disease after 5 months in one. Before treatment, both the tumor lesions and the muscles and myocardium showed high (18)F-FDG uptake. Everolimus reduced tumor and muscle (18)F-FDG uptake after 2 weeks by 26% ± 14% and 19% ± 41%, and after 5 months by 31% ± 13% and 27% ± 41%. Conclusions. Everolimus normalizes plasma glucose levels in metastatic insulinoma within 14 days, coinciding with a lower glucose uptake in tumor and muscles and declining (pro)insulin levels. This effect on tumor as well as normal tissues explains the rapid controlling of hypoglycemia.

PMID:

21482586

[PubMed - as supplied by publisher]

J Clin Oncol. 2011 Jul 5. [Epub ahead of print]
Targeted Therapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Can There Be Too Many Active Drugs?

Chandarlapaty S, Modi S.
Source

Memorial Sloan-Kettering Cancer Center, New York, NY.

Commentary/TEXT

Some excerpts:

The PI3K/Akt/mTOR cascade has key regulatory functions in normal and oncogenic cellular growth, survival, proliferation, migration, and metabolism.4 Mutational activation of this pathway is observed in the majority of breast cancers and occurs through
amplification of the HER2 receptor, activation of mutations in PIK3CA (PI3K), or loss of the phosphatase and tensin homolog (PTEN) phosphatase. In laboratory models of HER2-positive breast cancer, the PI3K/Akt/mTOR pathway has been shown to have essential roles in tumor maintenance, and it is not surprising that a key mechanism for the antitumor action of trastuzumab is downregulation of this pathway. Several studies have implicated second mutational hits in the pathway in mediating resistance to HER2-targeted therapies and suggested that adding a direct inhibitor of PI3K/Akt/mTOR signaling may overcome trastuzumab resistance.5-7 In their combined studies of the mTOR inhibitor with trastuzumab, Morrow et al3 find an objective response rate of 15% and clinical benefit rate of 34% for the combination in a population of patients who were refractory to trastuzumab. The reported results are at once both meaningful and modest, as they provide some important insights but also leave open the question of the true utility of targeting the PI3K/Akt/mTOR pathway in HER2-positive breast cancer.

To their credit, the authors of the everolimus plus trastuzumab study3 were keenly aware of the need to develop biomarkers to guide therapy and incorporated a detailed analysis of the prevalence of PIK3CA mutation, PTEN expression, and other surrogates for activation of the pathway (p-Akt, p-S6k, p-Src) from patient tumor samples.
However, none of the individual biomarkers of pathway activation correlated with response or improved progression-free survival,

At present, there are at least fourHER2targeting agents in clinical development that have apparently similar or superior efficacy for trastuzumab-refractory HER2-positive breast cancer, including trastuzumab emtansine, neratinib, pertuzumab, and tanespimycin (Table 1). Although all of these have rather unique mechanisms of drug action, their efficacy is impressively similar, and, like everolimus, they cause relatively little toxicity. In addition to these inhibitors that differentially target HER2, there are a number of agents targeting PI3K, Akt, or mTOR that are currently in phase I and II evaluation. Is there a meaningful way to discern which of these agents, all of which may have similar response rates, should be advanced clinically? And how should we choose which therapies should be integrated into combinations for both metastatic and adjuvant disease? For these reasons, a more comprehensive analysis of in vivo mechanisms of resistance and the unique susceptibilities of such tumors is needed. With such a plethora of pharmacologic options in clinical development, perhaps no oncologic disease is more poised to benefit from personalized medicine than HER2-positive breast cancer.

The early understanding of the key role of HER2 in HER2-positive breast cancer has made this disease into a paradigm for advances in translational oncology. Once the community has moved past the excitement of novel target identification and initial therapy,the labor shifts to integrating competing therapies rationally and efficiently.
This article3 presents a challenge and a model. Certainly the efficacy that was reported does push everolimus onto the list of promising therapies for HER2-positive breast cancer and highlights mTOR
as a relevant target, but all the more, it focuses a spotlight on our need for robust biomarkers to rationalize an otherwise uninterpretable menu of options. A successful effort at making headway in this regard will require the sort of collaborative spirit that was modeled by this group of investigators to share their data and resources in a way that accelerates knowledge while minimizing excessive use of scarce resources.
Going forward, such efforts will be bound to include the acquisition (and sharing) of fresh tumor biopsies to allow a molecular interrogation of human tumors, not simply as a snapshot of a fixed and final state, but as the dynamic entities we so often observe them to be.

[Rich66]

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[Rich66]

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[gdpawel]

Don't see why Afinitor can't be used off-label for BC. There are a number of new classes of drugs that target VEGF, at the protein level (Avastin), at the tyrosine kinase level (Nexavar, Sutent) and at the intracellular metabolic pathway mTOR (Afinitor, Torisel). Responses to any individual mechanism occurs in the miniority (subset) of patients. It is unclear why some patients respond to these interventions while others fail. This reinforces the need for cancer therapies to be individualized. It remines us that it is the good outcome of the patient not the therapy applied that constitute successful therapy.

[Rich66]

It's a very pricey drug ..not sure any insurance would help pay for it off label. Of course, if it extends the utility of Tamoxifen or generic Femara and keeps patients out of the hospital...would be a bargain.

[jimzfr]

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Products Type 20：
•Rapamycin derivative series
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[annmask]

Anyone asked their onc about using this off-label? Maybe insurance companies would agree to it. Couldn't be a pricier drug than the ones we are on now I bet...... may be hard to find an onc willing to try without further study. I personally would give it a shot with Tykerb and Herceptin in hopes of a more completed, less toxic effect...

[kykeon22]

the latest news say that novartris is about to ask approval to market afinitor everolimus for breast cancer.

[annmask]

That would be awesome! Lets hope this FDA does better by us than it did with TDM and Avastin!