AFINITOR® can overcome endocrine resistance in patients with Metastatic Breast Cancer. This was demonstrated in the BOLERO-2 trial in which patients who had progressed on non-steroidal Aromatase Inhibitors, when treated with a combination of steroidal Aromatase Inhibitor AROMASIN® (Exemestane) and AFINITOR® (Everolimus), had significantly improved Progression Free Survival and Clinical Benefit. AFINITOR® is a mTOR inhibitor and mTOR pathway has been implicated as one of the mechanisms for endocrine resistance in Breast cancer. A recent BOLERO-2 trial update, was published in the Breast Cancer Research and Treatment 2013.
Category: Hem/Onc Updates
Analysis of KRAS/NRAS mutations in phase 3 study 20050181 of panitumumab (pmab) plus FOLFIRI versus FOLFIRI for second-line treatment (tx) of metastatic colorectal cancer (mCRC)
SUMMARY: It is estimated that approximately 97,000 new cases of colon cancer will be diagnosed in 2014 and over 50,000 will die of the disease. The lifetime risk of developing colorectal cancer is about 1 in 20. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. Multi agent chemotherapy in combination with monoclonal antibodies, targeted against Epidermal Growth Factor Receptor (EGFR) such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab), have demonstrated survival benefit, for patients with metastatic colon cancer, whose tumors do not harbor KRAS mutations in exon 2. The authors in this study evaluated the benefit of testing metastatic colorectal cancer tumors for RAS mutations beyond the mutations in the KRAS gene at exon 2.
The most common RAS oncogenes in human cancer are HRAS, KRAS, and NRAS. Mutations in HRAS are not common in colon cancer whereas KRAS and NRAS mutations are seen in colon cancer and tend to be mutually exclusive. Activating mutations in exon 2 of the KRAS gene is seen in about 40% of colon cancer patients and predicts resistance to EGFR therapy. Mutational analysis is therefore usually performed to look for mutations in exon 2 of the KRAS gene. It appears however that a broader assessment of the RAS genes may more accurately predict resistance to EGFR therapy. It is also known that mutations in BRAF gene, which is downstream from RAS, may confer poor prognosis in colon cancer, regardless of therapy. The authors in a previous publication showed that in a phase III study involving 1,186 patients, the addition of VECTIBIX®, a fully human, EGFR targeted, monoclonal antibody, when combined with FOLFIRI (Folinic acid, Fluorouracil and Irinotecan), significantly improved Progression Free Survival, when compared to FOLFIRI alone (HR=0.73; P=0.004), with a trend towards improved Overall Survival (HR=0.85; P=0.12). Evolving data has suggested that testing for additional mutations in the RAS genes may help better understand the efficacy of/resistance to VECTIBIX®. In this present analysis, tumor samples of patients from the authors previous study, that were already known to be Wild Type KRAS – unmutated at KRAS exon 2 (N=597), were assessed for additional RAS mutations, specifically in KRAS exons 3 and 4 and NRAS exons 2, 3 and 4. Eighteen percent (18%) of the Wild Type KRAS exon 2 patients harbored additional RAS mutations. It was noted that patients receiving VECTIBIX® along with FOLFIRI had an improvement in both the median OS and PFS when they had wild-type (unmutated) RAS tumors compared to those, whose tumors harbored RAS mutations (median OS: 16.2 vs 11.8 months; median PFS: 6.4 vs 4.8 months). More importantly, amongst patients with mutated RAS tumors, the addition of VECTIBIX® to FOLFIRI resulted in no significant survival benefit compared to FOLFIRI alone (median OS: 11.8 vs 11.1 months; median PFS: 4.8 vs 4.0 months). The authors concluded that comprehensive RAS mutational analysis rather than KRAS testing alone, gives more relevant information for proper selection of patients with metastatic colorectal cancer, who would benefit from EGFR targeted monoclonal antibodies such as VECTIBIX®. In addition patients with RAS mutations could be spared from the associated cost and toxicites of EGFR targeted monoclonal antibodies that will not improve their outcomes. Peeters M, Oliner KS, Price TJ, et al. J Clin Oncol 32, 2014 (suppl 3; abstr LBA387)
Everolimus plus exemestane as first-line therapy in HR+, HER2− advanced breast cancer in BOLERO-2
SUMMARY:Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 233,000 new cases of invasive breast cancer will be diagnosed in 2014 and 40,000 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive and 15%-20% of breast cancers overexpress HER2/neu oncogene. As such a significant number of breast cancers are Hormone Receptor (HR) positive and HER2 negative. Aromatase Inhibitors (AI’s) are often prescribed, due to their superiority over Tamoxifen, for post menopausal women with HR+ and HER2-negative breast tumors, both in adjuvant as well as metastatic settings. These patients will eventually develop progressive disease on endocrine therapy with AI’s, attributed to endocrine resistance. The average Progression Free Survival for these patients is 4-6 months when treated with other hormonal interventions including higher doses of FASLODEX® (Fulvestrant). Further, FASLODEX® has not been shown to be superior to steroidal or non steroidal AI’s.
The mechanism of endocrine resistance has been attributed to cross talk between Estrogen Receptor signaling and PI3K/AKT/mTOR pathway. The PI3K/AKT/mTOR is a complex pathway, essential for cell proliferation, survival and apoptosis (programmed cell death). This pathway is of interest because of its increased activity in malignant cells as a result of amplification or mutation of the genes associated with PI3-kinase (phosphatidylinositol-3 kinase) and AKT, as well as loss of function of PTEN. PTEN normally prevents activation of AKT and its downstream pathways. Therefore, elevated ER signaling and breast cancer progression has been associated with activation of this mTOR (mammalian Target Of Rapamycin) pathway. Everolimus (AFINITOR®) is a mTOR inhibitor that has been shown to inhibit ER signaling and restore sensitivity to anti-estrogen therapies. With this preclinical knowledge, the Breast cancer trial of OraL EveROlimus-2 (BOLERO-2), which is a randomized, multicenter phase III trial was conducted to evaluate the benefit of combining steroidal AI, AROMASIN® (Exemestane) and an mTOR inhibitor AFINITOR®, for treatment of postmenopausal patients with HR+ and HER2 negative advanced breast cancer, who had either recurrent or progressive disease after non steroidal AI’s. Seven hundred and twenty four (N=724) patients were randomly assigned in a 2:1 ratio to receive either a combination of a steroidal AI, AROMASIN® at 25 mg PO QD and AFINITOR® at 10 mg PO QD (N=485) or AROMASIN® along with a placebo (N=239). Both treatment groups were well balanced and patients were stratified according to sensitivity to previous hormonal therapy and presence of visceral metastases. The primary endpoint for this study was Progression Free Survival (PFS) and secondary endpoints included overall Response Rate (RR), Clinical Benefit Rate (CBR defined as complete response + partial response + stable disease for at least 6 months), Overall Survival, Quality of Life, changes in bone marker levels and patient safety. In this study, close to 60% of the patients had visceral disease and approximately 80% of the patients had prior therapies for metastatic disease, with only 20% receiving the study drugs as their first therapy for metastatic disease. The combination of AFINITOR® and AROMASIN® significantly prolonged PFS compared to AROMASIN® alone (11 vs 4.1 months, HR=0.38, P<0.0001) and the Clinical Benefit Rate was 51% in the combination group and 26% in the AROMASIN® alone group (P<0.0001). The combination of AFINITOR® and AROMASIN® benefitted all subgroups of patients including those who had disease recurrence during or after neoadjuvant/adjuvant non steroidal AI therapy, those with visceral and bone metastases, as well as those who had prior chemotherapy. The most common adverse events in all age groups were rash, stomatitis, fatigue, diarrhea and nausea and these toxicities were manageable. The authors concluded that AFINITOR® given along with AROMASIN® in the study population can decrease the risk of disease progression by 60% and can double the Clinical Benefit Rate, compared to AROMASIN® alone, even in patients 65 years of age or older, thereby delaying the need for chemotherapy. Beck JT, Hortobagyi GN, Campone M, et al. Breast Cancer Res Treat. 2014; 143: 459–467
Yoga Can Improve Sense of Well Being in Breast Cancer Survivors
It appears that Yoga can substantially reduce Inflammation, Fatigue and improve Vitality in breast cancer survivors. This was substantiated in a randomized trial, which enrolled breast cancer patients following local intervention and adjuvant chemotherapy. The authors were also able to measure and demonstrate a drop in the cytokines associated with inflammation, such as Interleukin-6 (IL-6), Interleukin-1beta (IL-1b) and Tumor Necrosis Factor-alfa (TNFa), with Yoga intervention. These interesting and intriguing findings were published in the Journal of Clinical Oncology. A summary of this study is available to review at www.oncoprescribe.com.
Yoga’s Impact on Inflammation, Mood, and Fatigue in Breast Cancer Survivors A Randomized Controlled Trial
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%), will develop invasive breast cancer during their lifetime. Approximately, 233,000 new cases of invasive breast cancer will be diagnosed in 2014 and 40,000 women will die of the disease. According to the SEER database, the 5 year survival of women with early stage breast cancer is well over 90%. This is mainly because of early detection and effective therapies. A third of these cancer survivors however are likely to be physically inactive due to fatigue, general deconditioning and effects of cancer treatment. There is a reduction in their cardiorespiratory fitness. Chronic inflammation has been implicated in decreased physical functioning, disability and mortality, even in those who are in remission. Regular exercise has been shown to reduce inflammation and fatigue. The authors in this study evaluated the impact of Yoga, which provides graded exercise, on inflammation, mood and fatigue. Yoga by definition is a physical, mental, and spiritual practice and hatha Yoga which is practiced in the Western countries, consists of physical and mental strength building exercises and postures. In this randomized controlled study, 200 breast cancer survivors between ages 27 and 76 years, were assigned to either the Yoga group (N=100) or control/no Yoga group (N=100). Both groups were well balanced with no significant difference between the groups in measures of activity, fatigue, body mass index or depressive symptoms. Enrolled patients were stratified by cancer stage and whether radiation therapy was given or not. Participants had Stage 0 – Stage IIIa breast cancer and had completed cancer treatment within the past three years and were at least 2 months post surgery, adjuvant chemotherapy or radiation treatment. Patients in the Yoga group participated in a 90 minute Yoga class, twice a week for 12 weeks (3 months). The protocol included the measurement of cytokines associated with inflammation and they included Interleukin-6 (IL-6), Interleukin-1beta (IL-1b) and Tumor Necrosis Factor-alfa (TNFa). In addition, other validated instruments were utilized to measure Fatigue and Vitality. Immediately following 12 weeks of Yoga intervention, there was a significant improvement in the Vitality score in the Yoga group (P=0.01) and at 3 months post intervention, the Vitality score was even higher (P=0.01). Fatigue was significantly lower 3 months post intervention, in the Yoga group (P=0.002). At 3 months post intervention, all inflammatory cytokines were lower as well, in the Yoga group – IL-6 (P=0.027), TNFa (P=0.027) and IL-1b (P=0.037). More frequent Yoga practice resulted in greater benefits, with improved sleep and decreased inflammation. It should be noted that sleep problems are 2-3 times more common in cancer survivors and close to two thirds of the cancer survivors experience insomnia. The authors concluded that this is the first and largest randomized controlled study that has demonstrated that practice of Yoga or similar such activities, can substantially reduce inflammation and Fatigue and improve Vitality in breast cancer survivors. Kiecolt-Glaser JK, Bennett JM, Andridge R, et al. J Clin Oncol 2014;32:1040-1049
Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab
SUMMARY: It is estimated that in the US, approximately 76,000 new cases of melanoma will be diagnosed and close to 8000 individuals will die of the disease, in 2014. The incidence of melanoma has been on the rise for the past three decades. Unlike other malignancies, the role of chemotherapy for the treatment of melanoma has been limited. Treatment of advanced melanoma with immunotherapy using a cytokine, Interleukin-2 (IL-2), produced by T cells during an immune response, was first explored in the mid 1970’s. Durable responses were noted in a very small percentage of patients but this was associated with significant toxicities. This however opened the doors for the development of various immunotherapies with a better understanding of the Immune checkpoints. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent, related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation . The T cells of the immune system play a very important role in modulating the immune system.
Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. The first immune checkpoint protein to be clinically targeted was CTLA-4. YERVOY® (Ipilimumab), an antibody that blocks Immune checkpoint protein/receptor CTLA- 4, has been shown to prolong overall survival in patients with previously treated, unresectable or metastatic melanoma. In a previous publication, the authors reported the efficacy results of Nivolumab, a PD-1 targeted, fully human, immunoglobulin G4 monoclonal antibody, which demonstrated an objective response in 20% – 25% of patients with advanced Non Small Cell Lung Cancer, Melanoma and Renal Cell Carcinoma, with favorable toxicities. In this article, the authors reported the outcomes in 107 patients with advanced metastatic melanoma, from the pooled cohort of patients, enrolled between 2008 and 2012. Two thirds of these patients had at least 2 prior treatments, for their advanced disease. These patients received Nivolumab IV, once every 2 weeks, given in an outpatient setting, for up to 96 weeks. Patients were evaluated for Overall Survival, long term safety with treatment and response duration after the treatment was discontinued. The median Overall Survival in those treated with Nivolumab was 16.8 months and 1 and 2-year survival rates were 62% and 43%, respectively. This survival benefit is comparable to that seen following treatment with other agents that are presently available for this patient population, such as YERVOY® (Ipilimumab), ZELBORAF® (Vemurafenib) and combination of BRAF and MEK inhibitors. BRAF mutational status did not impact efficacy of Nivolumab. About 30% of the patients had objective responses and the median response duration was 2 years. The authors hypothesize that the ongoing tumor response following Nivolumab discontinuation, and unlike following chemotherapy, may be due to PD-1 blockade, resulting in the establishment of immune memory response, as is seen after antigen exposure against specific infectious organisms. The most common adverse events of any grade were fatigue, rash and diarrhea. These toxicities were not cumulative. The authors concluded that Nivolumab improved Overall Survival in patients with advanced melanoma and the clinical benefit was durable and persisted even after the drug was discontinued. Studies are underway combining Nivolumab with a different checkpoint inhibitor, YERVOY®. The synergy between these two agents may result in even better outcomes. Topalian SL, Sznol M, McDermott DF, et al. J Clin Oncol 2014;32:1020-1030
ARZERRA® combination for Frontline Treatment of CLL
The FDA on April 17, 2014 approved ARZERRA® (Ofatumumab) in combination with LEUKERAN® (Chlorambucil), for the treatment of previously untreated patients with Chronic Lymphocytic Leukemia (CLL), for whom FLUDARA® (Fludarabine) based therapy is considered inappropriate. ARZERRA® is a second generation fully human IgG 1 monoclonal antibody and unlike RITUXAN® (Rituximab) which is a chimeric monoclonal antibody, targets a different region (different epitope) of the CD20 molecule. The combination of ARZERRA® given along with LEUKERAN® significantly improved Progression Free Survival, Response Rates and duration of response, compared to single agent LEUKERAN®. ARZERRA® in combination with LEUKERAN® is a clinically important milestone, in the management of elderly patients with CLL.
Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR) a randomised trial
SUMMARY:It has been well recognized that patients with Breast Cancer with Isolated LocoRegional Recurrences (ILRR), without evidence of distant metastasis, are at a high risk of developing subsequent distant metastasis and may have poor outcomes, in spite of surgical resection of the ILRR. The role of systemic chemotherapy following surgery in this patient population has remained unclear although hormonal intervention in ER positive patients demonstrated disease free survival benefit. To address this question, three cooperative groups, The International Breast Cancer Study Group (IBCSG), Breast International Group (BIG) and NSABP collaborated and conducted this study to find out whether adjuvant chemotherapy improves the outcome of patients with ILRR following surgical resection. In this multicenter trial, 162 patients were randomly assigned to receive chemotherapy (N=85) or no chemotherapy (N=77). Eligible patients had histologically proven first ILRR resected and radiotherapy was recommended for all patients, but was mandated for those with microscopically involved surgical margins. All patients with ER or PR positive recurrent tumors received endocrine therapy and patients randomized to the chemotherapy group received at least two standard cytotoxic drugs (investigators choice) for 3-6 months. Both treatment groups were well balanced, and hormone receptor status was positive in 68% of the patients belonging to each group. The primary endpoint was Disease Free Survival and secondary endpoints included Overall Survival. The five year Disease Free Survival in the adjuvant chemotherapy group was 69% compared with 57% in the no chemotherapy group (HR=0.59, P=0.046). The five year overall survival was also significantly longer in the chemotherapy group compared to the no chemotherapy group (88% vs 76%, HR=0.41, P=0.024). With regards to the chemotherapy benefit based on hormone receptor status, patients with hormone receptor negative ILRR, had a longer Disease Free Survival with adjuvant chemotherapy (P=0.046). The authors concluded that adjuvant chemotherapy significantly improves Disease Free and Overall Survival in Breast Cancer patients with ILRR. This benefit is even more so, in those with ER negative ILRR. Adjuvant chemotherapy should therefore be considered in this patient population. Aebi S, Gelber S, Anderson SJ, et al. The Lancet Oncology 2014;15:156-163
Ofatumumab + Chlorambucil versus Chlorambucil alone in Patients with Untreated Chronic Lymphocytic Leukemia (CLL) Results of the Phase III Study Complement 1 (OMB110911)
SUMMARY: The American Cancer Society's estimates that approximately 15,720 new cases of chronic lymphocytic leukemia (CLL) will be diagnosed in 2014 and approximately 4600 patients will die from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. Majority of these patients have associated comorbidities and would be considered inappropriate for Fludarabine (FLUDARA®) based therapy. COMPLEMENT 1 is a randomized, open-label, multicenter, phase III trial in which Ofatumumab (ARZERRA®) in combination with Chlorambucil (LEUKERAN®) was compared to single agent LEUKERAN®. ARZERRA® is a second generation fully human IgG 1 monoclonal antibody. Unlike Rituximab (RITUXAN®) which is the chimeric monoclonal antibody, ARZERRA® targets a different region (different epitope) of the CD20 molecule. To go back to basics, several antigen molecules are expressed on the surface of normal B cells. Majority of these antigens are involved in cell growth, proliferation, differentiation, immune regulation and complement activation. The various stages of B cell development include hematopoietic stem cell, lymphoid stem cell, Pro B cell, Pre B cell, Immature B cell and Mature B-cell, Activated B cell, Memory B cell and Plasma cell. The CD20 molecule is expressed at specific stages of B cell development (Pre B cell stage to Mature B lymphocyte stage) and on malignant B cells. This molecule however is not expressed on hematopoietic stem cells and plasma cells. As such, targeting CD20 with therapeutic monoclonal antibodies spares the Pro B cell which is a precursor of Pre B cell and this along with intact hematopoietic stem cell facilitates post treatment recovery of B cells. As the plasma cells are spared as well, serum IgG levels are maintained.
Monoclonal antibodies targeting CD20 destroy CD20 positive B cells by 3 different mechanisms. They include Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) and programmed cell death (Apoptosis).
Unlike RITUXAN®, ARZERRA® targets the Small loop epitope of CD20 molecule which is proximal to the B cell membrane and this has been shown to be associated with highly efficient cell lysis through complement dependent cytotoxicity. So, compared to RITUXAN®. ARZERRA® has stronger CDC, similar ADCC and does not appear to induce Apoptosis. In this study, 447 CLL patients for whom FLUDARA® based therapy was considered to be inappropriate due to age and comorbidities, were randomly assigned 1:1 to receive either ARZERRA® in combination with LEUKERAN® or LEUKERAN® alone. ARZERRA® was given as an IV infusion at a dose of 300 mg on Cycle 1, Day 1, 1000 mg on Cycle 1, Day 8 and 1000 mg administered on Day 1 of all subsequent 28 day cycles. LEUKERAN® was given at a dose of 10 mg/m2 orally on Days 1 to 7 every 28 days in both treatment groups. The median age was 69 years and majority of the patients had 2 or more comorbidities. The primary endpoint of this study was Progression Free Survival (PFS) and secondary endpoints included Overall Response Rate (ORR), Overall Survival (OS) and safety. The median number of cycles in both treatment groups was 6. The median PFS was 22.4 months for patients receiving ARZERRA® in combination with LEUKERAN® compared with 13.1 months for those receiving single agent LEUKERAN® (HR=0.57, P< 0.001). The ORR was higher with the combination regimen versus single agent LEUKERAN® (82% vs 69%, P=0.001) and 37% of patients in the combination arm were MRD negative. The median OS for the combination group was not reached. The majority of adverse reactions were Grade 2 or lower, in both of the treatment arms and included infusion reactions, neutropenia, asthenia, headache, herpes simplex, lower respiratory tract infections, arthralgia and upper abdominal pain. The authors concluded that ARZERRA® in combination with LEUKERAN® is a clinically important milestone, in the management of elderly patients with CLL, who are considered inappropriate for FLUDARA® based therapy. Hillmen P, Robak T, Janssens A, et al. Blood 2013;122: Abstract#528
ZYTIGA® improves survival without impacting Quality of Life in CRPC
In a recent article published in The Lancet Oncology, ZYTIGA® (Abiraterone) given along with prednisone delayed patient-reported pain progression and deterioration of Quality of Life in chemotherapy-naive patients with metastatic Castrate Resistant Prostate Cancer (CRPC). This was accomplished without compromising efficacy, which was survival benefit. This is relevant because, patients with Prostate Cancer in general are elderly and it is important that any treatment intervention in this patient population with asymptomatic or mildly symptomatic CRPC improves overall survival without negatively impacting Quality of Life.