Novartis drug Afinitor® significantly extended time without disease progression in women with HER2 positive advanced breast cancer.

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• Everolimus plus trastuzumab and vinorelbine met primary endpoint of extending PFS compared to placebo plus trastuzumab and vinorelbine after prior therapy[1]
• Results of Phase III trial, BOLERO-3, first to show potential benefit of everolimus in HER2 positive advanced breast cancer, an aggressive form of the disease[1]
• Detailed data will be presented at the upcoming ASCO Annual Meeting and shared with regulatory authorities worldwide

Results of a pivotal Phase III trial in women with HER2 positive (HER2+) advanced breast cancer showed that Afinitor^® (everolimus) tablets in combination with trastuzumab (Herceptin^®*) and vinorelbine significantly extended progression-free survival (PFS) after prior therapy when compared to treatment with placebo plus trastuzumab and vinorelbine,meeting the study’s primary endpoint[1].

Efficacy and safety data from the BOLERO-3 (Breast cancer trials of OraL EveROlimus-3) trial were assessed as part of a prospectively planned analysis. These results will be presented on June 2 at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois[2], as well as at future medical congresses, and shared with regulatory authorities worldwide.

“We are encouraged by the BOLERO-3 results and are committed to helping improve treatment options for the HER2 positive patient population where there remains an unmet need,” said Alessandro Riva, Global Head, Oncology Development & Medical Affairs, Novartis Oncology. “Everolimus works differently than any currently available treatment for HER2 positive breast cancer, and these results support its potential expanded role in advanced breast cancer.”

Everolimus targets the PI3K/AKT/mTOR pathway, which is hyperactivated in many types of cancers[3]. mTOR is a protein that acts as an important regulator of cell division, blood vessel growth and cell metabolism[4]. Data confirm that blocking mTOR is a proven approach to maximize the benefit of existing advanced breast cancer treatments[4].

Everolimus is approved as Afinitor in more than 65 countries including the United States and the countries of the European Union to treat postmenopausal women with hormone receptor-positive, HER2 negative (HR+/HER2 negative) advanced breast cancer in combination with exemestane, after recurrence or progression following a non-steroidal aromatase inhibitor[1]. The specific indications vary by country[1]. HR+/HER2 negative advanced breast cancer is the most common form of the disease[5]. Approximately 70% of all invasive breast cancers are positive for HR expression at the time of diagnosis[6].

*Herceptin^® is a registered trademark of Genentech, Inc.

Study design

BOLERO-3 is a Phase III, randomized, double-blind study of everolimus plus trastuzumab and vinorelbine conducted at 159 clinical trial sites globally[1]. The trial included 569 women with HER2 positive locally advanced or metastatic breast cancer who were previously treated with a taxane and were resistant to trastuzumab[1]. Participants were randomized 1:1 to receive either everolimus 5 mg/day orally or placebo, plus weekly vinorelbine 25 mg/m² IV and weekly trastuzumab 2 mg/kg IV following loading dose of 4 mg/kg[1].

The primary endpoint of the trial is PFS[1]. Secondary endpoints include overall survival, objective response rate, time to deterioration of performance status, changes in quality-of-life scores over time, clinical benefit rate, duration of response, time to response, safety and pharmacokinetics[1].

About advanced breast cancer

Advanced breast cancer comprises metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III)[7]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the brain, bones or liver[7]. Locally advanced breast cancer occurs when the cancer has spread to lymph nodes and/or other tissue in the area of the breast, but not to distant sites in the body[7].

Overactivation of the PI3K/AKT/mTOR pathway has been associated with disease progression in women with advanced breast cancer[4]. Eighty percent of advanced breast cancer is either hormone receptor-positive (HR+) and/or human epidermal growth factor receptor-2 positive (HER2 positive)[1],[8].

HR+ advanced breast cancer is the most common type of advanced breast cancer, with an estimated 220,000 women diagnosed globally each year[1]. HR+ advanced breast cancer is characterized by hormone receptor-positive tumors, a group of cancers that express receptors for certain hormones such as estrogen and progesterone. Cancer cell growth can be driven by these hormones[9].

In HER2 positive advanced breast cancer, overexpression of the HER2 gene activates signaling pathways, such as the mTOR pathway, leading to the uncontrolled growth and division of cancer cells[1],[10]. Globally, an estimated 140,000 women are living with HER2 positive advanced breast cancer[1].

About Afinitor^® (everolimus)

Everolimus is approved as Afinitor^® in the European Union for the treatment of hormone receptor-positive,HER2 negative (HR+/HER2 negative) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative breast cancer (advanced HR+/HER2 negative breast cancer) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Afinitor (everolimus) tablets is approved in more than 95 countries, including the United States and throughout the European Union, in the oncology settings of advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy, and in the United States and European Union for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin.

Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor^® or Votubia^®, Certican^® and Zortress^® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets

Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.

The most common adverse drug reactions (incidence >=10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, nausea, decreased appetite, infections (including upper respiratory tract infection), low level of red blood cells, abnormal taste, inflammation of lung tissue, weight loss, swelling of extremities or other parts of the body, nose bleeds, itching, vomiting, high level of blood cholesterol, headache, high level of blood sugar, cough, spontaneous bleeding or bruising, and breathlessness. The most common Grade 3-4 adverse drug reactions (incidence >=2 percent) are mouth ulcers, feeling tired or weak, infections, inflammation of lung tissue, diarrhea, spontaneous bleeding or bruising, low white blood cells (a type of blood cell that fights infection), and breathlessness. Cases of hepatitis B reactivation, blood clots in the lung or legs, and menstruation disorders such as absence of periods have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Source: Novartis newsletter

What is Radioimmunotherapy (RIT) Treatment of NHL?

Radioimmunotherapy (RIT) is a type of targeted therapy that delivers radiation directly to cancer cells. It combines a monoclonal antibody—a type of protein that recognizes and binds to certain parts of cancer cells—with radioactive material. When the monoclonal antibody binds to the cancer cell, the radiation kills the cell.

Currently, RIT is used for the treatment of B-cell non-Hodgkin lymphomas (see examples below). RIT is also being evaluated for the treatment of other types of cancer, including prostate cancer and glioblastoma.

RIT is given on an outpatient basis, is generally completed in 10 days (as opposed to the longer duration of conventional chemotherapy), and avoids many of the side effects of chemotherapy. Because RIT may result in a temporary reduction in blood cell counts, patients typically need to have their blood cell levels monitored after treatment.

Examples of RIT

Zevalin® (ibritumomab tiuxetan): Zevalin therapy combines the monoclonal antibody Rituxan® (rituximab) with Zevalin, which is comprised of an anti-CD20 monoclonal antibody and Yttrium-90, a radioisotope that delivers the radiation. When injected into the body, Zevalin attaches to a protein (CD20) found only on the surface of B-lymphocytes, such as cancerous B-cells found in many forms of non-Hodgkin’s lymphoma. The radioactivity that is spontaneously emitted targets the B-cell and destroys it. This approach protects healthy tissue.  To learn more about Zevalin and view stories from other patients living with follicular lymphoma go to www.Zevalin.com. To locate a Zevalin-experienced oncologist click here.

Bexxar® (tositumomab and iodine I 131 tositumomab): Bexxar also targets B lymphocytes, and is comprised of an anti-CD20 monoclonal antibody and radioactive iodine 131. Bexxar is used for the treatment of certain patients with CD20-positive relapsed or refractory non-Hodgkin lymphoma.

Zevalin and Advanced Follicular Lymphoma

Researchers conducted a study that included 414 patients with CD20-positive stage III or IV follicular lymphoma who achieved a complete or partial response after first-line induction treatment. Patients were randomly assigned to receive Zevalin or no further treatment.

After a median follow-up of 3.5 years, the results indicated that Zevalin significantly prolonged median progression-free survival (PFS) in all patients, regardless of whether they had achieved a partial or complete response. Median PFS in patients treated with Zevalin was 36.5 months, compared to 13.3 months for patients in the control group. For patients who achieved a partial response after induction treatment, those who received Zevalin had a median PFS of 29.3 months compared to 6.2 months for those in the control group. Among patients who achieved complete response after induction, those who received Zevalin had a median PFS of 53.9 months compared to 29.5 months in the control group. What’s more, 77 percent of patients who experienced a partial response after induction converted to a complete response, which resulted in a final complete response rate of 87 percent.

The researchers concluded that Zevalin significantly prolonged PFS and resulted in a high conversion rate from partial to complete response, regardless of the type of first-line induction treatment.

Reference:

Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. Journal of Clinical Oncology. 2008; 26: 5156-5164.

 

Source: cancerconnect.com

Novartis drug Ilaris® approved by FDA to treat active systemic juvenile idiopathic arthritis, a serious form of childhood arthritis.

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  Ilaris® (canakinumab) is the first interleukin-1 beta inhibitor for the treatment of SJIA and the only treatment approved specifically for SJIA that is given as a monthly subcutaneous injection[1]

 

• In Phase III studies, 84% of Ilaris-treated SJIA patients achieved significant improvement of systemic and arthritic symptoms (pediatric ACR30) after a single subcutaneous dose[1]

 

• SJIA is a rare, disabling autoinflammatory disease with limited treatment options[2]; Ilaris is being investigated in other inflammatory conditions, including several rare diseases for which approved treatment options do not exist

 

 Novartis announced today that the US Food and Drug Administration (FDA) has approved Ilaris^® (canakinumab) for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients aged 2 years and older. Ilaris is the first interleukin-1 beta (IL-1 beta) inhibitor approved for SJIAand the only treatment approved specifically for SJIA that is given as a once-monthly subcutaneous injection[1]. SJIA is a rare and disabling form of childhood arthritis characterized by spiking fever, rash and arthritis that can affect children as young as 2 years old and can continue into adulthood[2],[3].

 

This approval was based on two Phase III trials in SJIA patients, aged 2-19, showing significant improvement in the majority of Ilaris-treated patients[1]. Study 1 showed that 84% of patients treated with one subcutaneous dose of Ilaris achieved the primary endpoint of the adapted pediatric American College of Rheumatology 30 (ACR30), compared to 10% achievement of ACR30 for placebo at Day 15[1]. In the open-label part of Study 2, 92 of 128 patients attempted “corticosteroid tapering”. Of those 92 patients, 62% were able to substantially reduce their use of corticosteroids, and 46% completely discontinued corticosteroids[1]. In the controlled portion of Study 2, there was a 64% relative reduction in the risk of flare for patients in the Ilaris group as compared to those in the placebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75).

 

“In the US, this approval marks the second Ilaris indication for patients living with rare, autoinflammatory conditions,” said Timothy Wright, MD, Global Head of Development, Novartis Pharmaceuticals. “We are committed to studying Ilaris in other IL-1 beta mediated inflammatory diseases, including several rare diseases for which treatment options do not currently exist.”

 

SJIA affects 5-15 children per 100,000 in the United States,and is the most severe subtype of juvenile idiopathic arthritis[3]-[5]. Although the disease can be life-threatening, treatment options are limited. Corticosteroids are often used to treat symptoms and pain despite their long term use being associated with potentially serious adverse effects, including Cushing syndrome, growth suppression and osteoporosis[1],[6],[7].

 

Ilaris is being investigated in a number of rare autoinflammatory conditions, including Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), colchicine-resistant Familial Mediterranean Fever (FMF) and Hyper IgD Syndrome (HIDS). Ilaris is considered an investigational agent for these conditions at this point in time. As such, the role that Ilaris could play in treating these conditions and potential benefit to patients is still being determined.

 

About the Pivotal Phase III Studies

Study 1, a 4-week, randomized, double-blind, placebo-controlled study, involved 84 patients between the ages of 2 and 19 years with active SJIA[1],[2]. Patients were treated with either a single subcutaneous dose of Ilaris (4 mg/kg, up to 300 mg) (n=43) or placebo (n=41)[1]. The primary endpoint was the proportion of patients achieving the adapted pediatric American College of Rheumatology (ACR) 30 response criteria and resolution of fever from baseline at Day 15[1]. This means that patients had at least a 30% improvement in systemic and arthritic symptoms versus baseline. The study met its primary endpoint.

 

Study 2, a two-part study, had an open-label, single-arm active treatment in Part I followed by a randomized, double-blind, placebo-controlled, event-driven withdrawal design in Part II[1]. A total of 177 patients between the ages of 2 and 19 years with active SJIA were enrolled in the study[1]. Some of these patients had previously participated in the Study 1. In Part I, patients received a subcutaneous dose of Ilaris (4 mg/kg, up to 300 mg) every 4 weeks[1]. The primary endpoint of Part I was to assess whether treatment with Ilaris allowed successful tapering of corticosteroids in at least 25% of SJIA patients who entered the study using a corticosteroid.

 

In Part II of the study, patients were randomized to either continue receiving Ilaris, or to receive placebo every 4 weeks (“placebo-after-Ilaris group”), until a pre-specified number (37) of flare-events (“flares”) had occurred[1]. The primary endpoint of Part II was to demonstrate that the time to flare was longer with Ilaris than with placebo.

 

The primary endpoints for Study 1 and Study 2 were all met.

 

About Ilaris

Ilaris is a selective, fully human, monoclonal antibody that inhibits IL-1 beta, which is an important part of the body’s immune system defenses[1]. Excessive production of IL-1 beta plays a prominent role in certain inflammatory diseases[8]. Ilaris works by neutralizing IL-1 beta for a sustained period of time, therefore inhibiting inflammation[1].

 

In addition to its approval for SJIA in the US, Ilaris is approved in the EU for the treatment of refractory gouty arthritis, and in more than 60 countries, including in the EU, US, Switzerland and Japan for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), a rare, lifelong, genetic disorder with debilitating symptoms[1]. The approved indication may vary depending upon the individual country.

 

References:

1. Ilaris [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2013.
2. Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome. Nat Clin Pract Rheumatol 2006; 2(1):28-34.
3. Ramanan AV, Grom AA. Does systemic-onset juvenile idiopathic arthritis belong under juvenile idiopathic arthritis? Rheumatology (Oxford) 2005; 44(11):1350-3.
4. Beukelman T, Patkar NM, Saag KG, et al. 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis: Initiation and Safety Monitoring of Therapeutic Agents for the Treatment of Arthritis and Systemic Features. Arthritis Care & Research 2011; 63(4):465-482.
5. Dewitt EM, Kimura Y, Beukelman T, et al. Consensus Treatment Plans for New-Onset Systemic Juvenile Idiopathic Arthritis. Arthritis Care & Research 2012; 64(7):1001-1010.
6. U.S. National Library of Medicine (NLM), National Institutes of Health (NIH). Cushing Syndrome. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/000389.htm. Last accessed: 12/12/12.
7. Teitelbaum SL,Seton MP, Saag KG. Should Bisphosphonates be Used for Long-Term Treatment of Glucocorticoid-Induced Osteoporosis? Arthritis Rheum. 2011 February 63(2): 325-328. doi:10.1002/art.30135.
8. Martinon F, Petrilli V.  Gout-associated uric acid crystals activate the NALP3 inflammasome.Nature 2006; 440(9): 237-241.

 

Source: Novartis newsletter

Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.

Background

EGFR overexpression occurs in 27—55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma.

Methods

In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1—21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1—21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785.

Findings

Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6—13·0) compared with 8·8 months (7·7—9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07—1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3—4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 [13%] vs 74 [28%]).

Interpretation

Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma.

Discussion

The REAL3 trial is one of two concurrent randomised phase 3 trials (the other being the EXPAND trial15) assessing the addition of anti-EGFR monoclonal antibodies to chemotherapy in first-line oesophagogastric cancer. Based on the findings of REAL3, use of panitumumab in combination with EOC cannot be recommended in an unselected population with advanced oesophagogastric adenocarcinoma, and was associated with inferior overall survival and PFS. Notably, this detrimental outcome in the experimental group was not predicted by the phase 2 endpoint of response rate (overall response rate 52% with mEOC+P). This trial does, however, confirm the efficacy of the EOC control group in this setting, with median overall survival and PFS results that are consistent with those previously reported in REAL2 (11·2 months for overall survival and 7·0 months for PFS).3

The poor outcome associated with mEOC+P in this trial did not seem to be attributable to increased treatment-related deaths, and therefore other potential explanations for our findings need to be considered. First, as reported previously,12combination of panitumumab with full-dose EOC in the initial stages of the trial was associated with unacceptably high rates of grade 3 diarrhoea (four of the first five patients by cycle four). Therefore, we had to reduce the starting doses of oxaliplatin (by 23%) and capecitabine (by 20%) in the experimental group. Although these changes undoubtedly reduced the frequency of grade 3—4 diarrhoea with mEOC+P (17% in phase 3 population), they also served to reduce the dose intensity of chemotherapy, which is reflected in the reduced incidence of grade 3—4 neutropenia and peripheral neuropathy noted in the mEOC+P group. Additionally, the dose intensity data show a reduced proportion of patients achieving at least 80% of the planned capecitabine dose in the experimental group, suggesting that mEOC+P was still slightly more difficult to deliver than standard EOC.

Second, a negative interaction might have occurred between panitumumab and one or more of the EOC components. Evidence in the setting of colorectal cancer suggests that the chemotherapy partner for anti-EGFR therapy might be an important determinant of treatment efficacy, with oxaliplatin-containing regimens yielding inconsistent results. The OPUS16and PRIME11 studies provide evidence of improved outcomes with the addition of cetuximab and panitumumab respectively, whereas no benefit was associated with the addition of cetuximab in the COIN17 and NORDIC VII18 studies in the same setting. Recent cell-line data also suggest that greater synergy might exist between anti-EGFR therapy and irinotecan than with oxaliplatin.19 Additionally, the COIN trial17 results suggest that there might be a differential benefit from cetuximab dependent on the fluoropyrimidine partner, with patients receiving oxaliplatin plus fluorouracil seemingly deriving increased benefit compared with those treated with oxaliplatin plus capecitabine. At present, the significance of these potential interactions is unknown, and has not been assessed in the setting of oesophagogastric cancer.

Third, our findings might have been affected because we assessed panitumumab therapy in a molecularly unselected population. During the years since the inception of the REAL3 trial, several studies have advanced our understanding of the EGFR signalling pathway and its role in oesophagogastric adenocarcinoma. Hot-spot mutations in key oncogenic drivers such as KRAS (common in colorectal cancer) and BRAF (common in malignant melanoma) are now known to be infrequent molecular events in oesophagogastric adenocarcinoma. Indeed, the 5·7% frequency of KRAS mutation in our population is in keeping with the 3—10% reported in other studies,20—22 and we did not note any BRAF mutations in 167 tumour samples tested. By contrast, gene copy number alterations (amplifications and deletions) seem to be a relatively frequent finding in oesophagogastric adenocarcinoma and are more likely to represent the key molecular alterations driving carcinogenesis. Two recent series23, 24 of detailed genomic analyses in oesophagogastric adenocarcinoma reported that about 37% of tumours harbour copy number aberrations in genes that are deemed to be targetable, including KRAS, EGFR, HER2, and MET. Randomised clinical trials are therefore needed to establish whether targeting of these oncogenic signal transduction pathways can meaningfully improve outcomes for patients.

In preclinical studies, cetuximab can decrease EGFR pathway signalling via reduced phosphorylation of EGFR and AKT in oesophagogastric cancer cell lines.25 In combination with chemotherapy, cetuximab results in synergistic inhibition of cell proliferation and enhanced apoptosis.25—27 In hypoxic gastric cancer cell lines the addition of anti-EGFR therapy reversed oxaliplatin resistance.26 Additionally, a synergistic antitumour effect of combined cetuximab and S-1 was apparent in gastric cancer cell lines overexpressing EGFR.25, 27 In colorectal cancer, somatic mutations in codon 12, 13, or 61 of the KRASoncogene confer resistance to panitumumab therapy.11, 28 MET amplification with or without KRAS mutations might be associated with resistance to cetuximab therapy in gastric cancer cell lines;29 however, no validated predictive biomarkers for this setting exist.

Unfortunately, despite preclinical data suggesting a role for anti-EGFR therapy in the treatment of oesophagogastric adenocarcinoma, the REAL3 trial findings are supported by two other phase 3 trials assessing anti-EGFR therapy in this disease setting. The EXPAND trial15 assessed the addition of cetuximab to a cisplatin-capecitabine doublet in 904 patients with previously untreated adenocarcinoma of the stomach and gastro-oesophageal junction, and did not meet its primary endpoint of improved PFS (HR 1·09, 95% CI 0·92—1·29, p=0·32).15 EXPAND also noted no improvement with the addition of cetuximab in either overall survival (HR 1·00, 95% CI 0·87—1·17, p=0·95) or overall response rate (30% in the experimental group vs 29% for controls). The COG trial30 assessed the anti-EGFR tyrosine-kinase inhibitor gefitinib compared with placebo in the second-line treatment of 450 patients with oesophageal and type I—II gastro-oesophageal junction cancers. This trial also did not meet its primary endpoint, with no improvement in overall survival (HR 0·90, p=0·285). However, improvements in PFS (HR 0·795, p=0·017) and disease control at 8 weeks (25·5% in the experimental group vs 16·0% in controls, p=0·014) were noted, suggesting some activity of gefitinib in a small undefined subset of patients.

Taken together, these relatively consistent findings suggest that the EGFR pathway is unlikely to represent an important therapeutic target in most patients with oesophagogastric cancer (panel). The presented biomarker analyses accompanying the REAL3 trial are restricted by small patient numbers and low rates of tested mutations. However, this work is ongoing in the full trial dataset and these translational analyses represent a unique opportunity to further assess the molecular biology of advanced oesophagogastric adenocarcinoma within a randomised trial setting. Techniques such as gene-expression profiling and next-generation sequencing might help to provide further information regarding the driver genetic events in this complex disease. Furthermore, the evaluation of genetic aberrations in pathways linked to EGFR signalling could still offer the prospect of identification of a low-frequency biomarker that identifies a subpopulation of patients benefiting from anti-EGFR targeted therapy in this setting.

Source: lancet

New options for second-line therapy of advanced renal cancer.

Several drugs targeting VEGF or mTOR pathways have been approved for treatment of advanced renal-cell carcinoma because of improvements noted in progression-free survival (PFS) in phase 3 trials.1 Validation of prognostic models showed that treatment with such drugs can lead to a median overall survival of around 43 months for patients in favourable risk categories and 23 months for patients in intermediate risk categories.2 With few exceptions, patients on first-line therapy progress and proceed to need one or more subsequent lines of targeted therapy. In a population-based study,3 patients in a favourable risk group had progression on first-line VEGF-targeted therapy after a median of 16·6 months (compared with 15 months for patients in an intermediate risk group) and progression after 6·2 months on second-line targeted therapy (5·5 months for intermediate risk). Two phase 3 trials4, 5 assessed outcomes after failure of a previous VEGF-targeted therapy to establish evidence for the mTOR-inhibitor everolimus and the selective inhibitor of VEGF receptors 1—3, axitinib. The AXIS trial5 is the only study that directly compared two active compounds (axitinib vs sorafenib) after failure of an approved first-line regimen. In AXIS, more than a third of patients had received cytokines and over half had received sunitinib as first-line therapy. Axitinib led to an improvement in median PFS compared with sorafenib in the intention-to-treat analysis. However, the difference in PFS for patients after sunitinib treatment based on investigator and independent review committee assessments was only slight. Data for overall survival, a secondary endpoint, were immature before the first report was published in 2011. Because guidelines and clinical practice favour targeted therapy in preference to cytokines as first-line treatment,1 axitinib is regarded as a treatment option for second-line therapy of advanced renal-cell carcinoma.5

In The Lancet Oncology, Robert Motzer and colleagues6 now report mature overall survival data for the AXIS trial. Such an analysis is important because crossover between the two study arms was not allowed. No significant differences in overall survival were noted between patients in both treatment arms who received the same first-line regimen (median overall survival 20·1 months [95% CI 16·7—23·4] with axitinib vs 19·2 months [17·5—22·3] with sorafenib; hazard ratio 0·969, 95% CI 0·800—1·174, p=0·3744). More than half the patients in each arm continued with a third-line treatment after progression on study drug and treatment after progression was allowed. This design confounded overall survival results and raises questions as to whether PFS is meaningful in this setting.7 Third-line therapy partly explains the long time interval noted between progression on second-line treatment and overall survival. However, inclusion of patients with a less aggressive tumour biology might have contributed to this outcome. Only a third of patients in the AXIS trial were Memorial Sloan Kettering Cancer Center (MSKCC) poor risk at entry,5 suggesting that individuals with rapid deterioration of performance or accelerated progression during first-line therapy are less likely to enter trials than are patients with more favourable risk profiles.

For patients previously treated with sunitinib in Motzer and colleagues’ study,6 median time on first-line therapy was about 10 months, with a median overall survival for all risk groups of 15·2 months (95% CI 12·8—18·3) for axitinib and 16·5 months (13·7—19·2) for sorafenib. Patients who received cytokines had first-line therapy for about 6 months and a median overall survival of 29·4 months (24·5—not assessable) for axitinib and 27·8 months (23·1—34·5) for sorafenib. After correction for the different length of first-line therapies, overall survival seemed to be increased by about 7—9 months in patients who had cytokines before VEGF-targeted therapy. Resistance to previous VEGF-targeted therapy, which might not be apparent in patients previously untreated with such an approach, cannot fully explain this difference. Motzer and colleagues noted a putative association of overall survival with length of previous sunitinib treatment for both axitinib and sorafenib, although there was substantial overlap in the 95% CIs.6 A retrospective Database Consortium analysis of 464 patients who had received two lines of VEGF-targeted therapies reported no correlation between first-line PFS and second-line PFS.8 Rather, a significant difference in multivariate analysis of baseline prognostic factors in favour of cytokine versus sunitinib pretreatment (HR 0·503, 95% CI 0·395—0·641; p<0·0001) suggested that patients with less advanced disease were most likely to start treatment with cytokines.6 However, information about the distribution of prognostic factors between patients who were pretreated with cytokines and sunitinib, which could have important implications for treatment sequences, is not provided in Motzer and colleagues’ study.

Data from trials and population-based analyses suggest that a ceiling has almost been reached in terms of outcome with present targeted therapies and prognosis that relies on models based on clinical factors.2 The mature AXIS data add axitinib to the choices for second-line treatment with similar outcome and different toxicity profiles.4—6 Despite prognostic factors assessed in the updated analysis and a correlation of development of hypertension during axitinib and sorafenib treatment with overall survival, the choice for a second-line drug or even treatment beyond progression at failure of first-line treatment remains an educated guess. The outcome of this study proves once again that renal-cell carcinoma is a heterogenous cancer9 that needs further research into predictive biomarkers to tailor treatment choices.

Source: Lancet

 

Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study.

CLEOPATRA is a phase 3 study to compare the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive first-line metastatic breast cancer. The results of the primary analysis showed significantly longer median progression-free survival in the pertuzumab group than in the placebo group. Interim analysis of overall survival favoured the pertuzumab group but was not significant. Here, we report results for overall survival after an additional year of follow-up.

Methods

The study was a double-blind randomised trial undertaken at 204 centres in 25 countries. Patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy or biological treatment for their metastatic disease were randomly assigned to receive either pertuzumab, trastuzumab, and docetaxel (n=402) or the same regimen with a matching placebo replacing pertuzumab (n=406). Randomisation was in a 1:1 ratio, stratified by geographical region and previous treatment status. The primary endpoint was progression-free survival (assessed independently), which has been reported previously; no follow-up data were gathered for the primary endpoint. Secondary endpoints included overall survival, progression-free survival (assessed by investigator), objective response rate, and safety. Median follow-up was 30 months in both groups. Efficacy endpoints were analysed in the intention-to-treat population and safety was analysed by treatment received. The study is completed but safety and survival data continue to be followed up. This trial is registered with ClinicalTrials.gov, number NCT00567190.

Findings

In the intention-to-treat population, 267 patients died by data cutoff (May 14, 2012), 154 (38%) of 406 in the placebo group and 113 (28%) of 402 in the pertuzumab group. Median overall survival was 37·6 months (95% CI 34·3—NE [not estimable]) in the placebo group but had not been reached (95% CI 42·4—NE) in the pertuzumab group (hazard ratio 0·66, 95% CI 0·52—0·84; p=0·0008). Investigator-assessed median progression-free survival was 12·4 months (95% CI 10·4—13·5) in the placebo group and 18·7 months (16·6—21·6) in the pertuzumab group (hazard ratio 0·69, 95% CI 0·58—0·81). Serious adverse events were reported in 115 (29%) of 396 patients who received placebo, trastuzumab, and docetaxel and 148 (36%) of 408 who received pertuzumab, trastuzumab, and docetaxel, and included febrile neutropenia, neutropenia, diarrhoea, pneumonia, and cellulitis. Overall, adverse events were similar to those reported at the primary analysis with respect to frequency, severity, and specificity.

Interpretation

Our analysis shows a significant improvement in overall survival with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer, compared with placebo, trastuzumab, and docetaxel. Since this effect was not achieved at the expense of adverse events, this regimen represents a substantial improvement on the standard of care for this population of patients.

Source: Lancet

 

Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial.

Summary

Background

Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1—3 HCV infection.

Methods

In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1—3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18—70 years, had an HCV RNA concentration of 50 000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 μg per week) and ribavirin (1000—1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772.

Findings

In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events—fatigue, headache, nausea, and chills—were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77—97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80—98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37—77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12.

Interpretation

Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1.

Source: Lancet

Phase 3 study: Canagliflozin improved beta cell function.

An SGLT2 inhibitor recently approved by the FDA may improve measures of beta cell function in addition to glycemic control in patients already taking metformin plus sulfonylurea, according to phase 3 study results presented here at the AACE Annual Scientific and Clinical Congress.

“Despite the fact it doesn’t act directly on the beta cells, there is a lot of evidence from previous studies that SGLT2 inhibitors can improve beta-cell function,” David Polidori, PhD, of Janssen Research & Development, LLC, said here during a presentation.

Polidori and colleagues conducted a 26-week, randomized, double blind, placebo controlled study to evaluate canagliflozin (Invokana, Janssen) 100-mg and 300-mg compared with placebo as an add on to metformin plus sulfonylurea in patients with type 2 diabetes (n=469; mean age, 57 years). The mean baseline HbA1c level was 8.1%, BMI was 33 kg/m², and duration of diabetes was 9.6 years, according to data.

Of the 469 patients, 168 were administered a meal tolerance test at baseline and week 26. Their plasma glucose and serum C-peptide levels were measured seven times over a 3-hour period.

Polidori reported that at week 26, canagliflozin 100 mg significantly reduced HbA1c by –0.71% and 300 mg  by –0.92% compared with placebo (P<.001).

Further data indicate that the insulin secretion rates (ISR) vs. glucose relationship did not change with placebo. However, the relationship shifted upwards in both canagliflozin doses, Polidori said. This indicated an increase in ISR at each plasma glucose concentration, according to data.

Measures of beta cell function, including the ratio of C-peptide to glucose, were approximately 20% higher than baseline levels in both canagliflozin groups (P=.051 for 100 mg and P=.056 for 300 mg) but remained relatively unchanged in the placebo group. Mean beta cell glucose sensitivity was also increased by about 20% in both canagliflozin groups (P=.14 for 100 mg andP=.22 for 300 mg).

Additionally, mean ISR at 9 mM of glucose increased by about 50% to 60% in both canagliflozin groups (P=.02 for 100 mg and P=.007 for 300 mg), but remained relatively unchanged in the placebo group.

“Consistent with what we’ve seen in patients at earlier stages of diabetes and in some of the animal studies, both doses of canagliflozin improved the measures of beta cell function that we looked at in the meal tolerance test in these more advanced patients who were already inadequately controlled on dual therapy. This is promising,” Polidori said. “This is 26-week data and we’re certainly interested to see longer term data to see if this type of treatment can better prolong beta cell function and hopefully slow the rate of progression of type 2 diabetes.” – by Samantha Costa

Source: Endocrine Today

 

 

Maintenance Chemotherapy for Advanced Non–Small-Cell Lung Cancer: New Life for an Old Idea.

Abstract

Although well established for the treatment of certain hematologic malignancies, maintenance therapy has only recently become a treatment paradigm for advanced non–small-cell lung cancer. Maintenance therapy, which is designed to prolong a clinically favorable state after completion of a predefined number of induction chemotherapy cycles, has two principal paradigms. Continuation maintenance therapy entails the ongoing administration of a component of the initial chemotherapy regimen, generally the nonplatinum cytotoxic drug or a molecular targeted agent. With switch maintenance (also known as sequential therapy), a new and potentially non–cross-resistant agent is introduced immediately on completion of first-line chemotherapy. Potential rationales for maintenance therapy include increased exposure to effective therapies, decreasing chemotherapy resistance, optimizing efficacy of chemotherapeutic agents, antiangiogenic effects, and altering antitumor immunity. To date, switch maintenance therapy strategies with pemetrexed and erlotinib have demonstrated improved overall survival, resulting in US Food and Drug Administration approval for this indication. Recently, continuation maintenance with pemetrexed was found to prolong overall survival as well. Factors predicting benefit from maintenance chemotherapy include the degree of response to first-line therapy, performance status, the likelihood of receiving further therapy at the time of progression, and tumor histology and molecular characteristics. Several aspects of maintenance therapy have raised considerable debate in the thoracic oncology community, including clinical trial end points, the prevalence of second-line chemotherapy administration, the role of treatment-free intervals, quality of life, economic considerations, and whether progression-free survival is a worthy therapeutic goal in this disease setting.

Source: JCO

 

Sequential Phase I and II Trials of Stereotactic Body Radiotherapy for Locally Advanced Hepatocellular Carcinoma.

Abstract

Purpose To describe outcomes of prospective trials of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC).

Patients and Methods Two trials of SBRT for patients with active HCC unsuitable for standard locoregional therapies were conducted from 2004 to 2010. All patients had Child-Turcotte-Pugh class A disease, with at least 700 mL of non-HCC liver. The SBRT dose range was 24 to 54 Gy in six fractions. Primary end points were toxicity and local control at 1 year (LC1y), defined as no progressive disease (PD) of irradiated HCC by RECIST (Response Evaluation Criteria in Solid Tumors).

Results A total of 102 patients were evaluable (Trial 1, 2004 to 2007: n = 50; Trial 2, 2007 to 2010: n = 52). Underlying liver disease was hepatitis B in 38% of patients, hepatitis C in 38%, alcohol related in 25%, other in 14%, and none in 7%. Fifty-two percent received prior therapies (no prior sorafenib). TNM stage was III in 66%, and 61% had multiple lesions. Median gross tumor volume was 117.0 mL (range, 1.3 to 1,913.4 mL). Tumor vascular thrombosis (TVT) was present in 55%, and extrahepatic disease was present in 12%. LC1y was 87% (95% CI, 78% to 93%). SBRT dose (hazard ratio [HR] = 0.96; P = .02) and being in Trial 2 (HR = 0.38; P = .03) were associated with LC1y on univariate analysis. Toxicity ≥ grade 3 was seen in 30% of patients. In seven patients (two with TVT PD), death was possibly related to treatment (1.1 to 7.7 months after SBRT). Median overall survival was 17.0 months (95% CI, 10.4 to 21.3 months), for which only TVT (HR = 2.47; P = .01) and being in Trial 2 (HR = 0.49; P = .01) were significant on multivariate analysis.

Conclusion These results provide strong rationale for studying SBRT for HCC in a randomized trial.

Source: JCO