SUMMARY: The Mitogen- Activated Protein kinase pathway (MAP kinase pathway) is an important signaling pathway which enables the cell to respond to external stimuli. There are a number of MAP kinase pathways, which share different proteins at each step. The MAP kinase pathway plays a dual role regulating cytokine production and participating in cytokine dependent signaling cascade. The MAP kinase pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAS family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6%-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E site and is detected in approximately 50% of melanomas. Vemurafenib is a novel oral inhibitor of mutated BRAF. However, Vemurafenib may increase the risk of developing a secondary malignancy (squamous cell carcinoma). Trametinib is a very potent and selective inhibitor of MEK gene and by seeking out this mechanism of action, there is probably a lower risk of another activated event ie. secondary malignancies. This is because MEK is downstream from RAF in the MAP Kinase pathway. In a phase III trial, patients with advanced melanoma with BRAF V600E/K mutations and without brain metastases were randomized to receive Trametinib or chemotherapy (either dacarbazine or paclitaxel). Patients receiving chemotherapy were allowed to crossover to receive Trametinib if they had documented progression. Primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rate (RR) and safety. The outcomes were in favor of Trametinib with a PFS of 4.8 months vs 1.4 months (HR =0.44; P<0.0001), RR of 24% vs 7%, with a 47% reduction in the risk of death compared to chemotherapy. Robert C, Flaherty KT, Hersey P, et al. J Clin Oncol. 2012:30(suppl; abstr LBA8509).
Category: Hem/Onc Updates
Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU) GRID trial
SUMMARY:Regorafenib is an oral multikinase inhibitor. In this randomized trial, patients with advanced GIST who had progressed on both GLEEVEC® (Imatinib) and SUTENT® (Sunitinib) were randomized to receive either Regorafenib or Placebo. The primary endpoint was progression-free survival (PFS). Patients in the Regorafenib group had a statistically significant 3.9 month improvement in progression-free survival (PFS) compared to placebo (4.8 months vs 0.9 months; Hazard Ratio = 0.27; P<.0001). Demetri GD, Reichardt P, Kang YK, et al. J Clin Oncol. 2012; 30 (suppl; abstr LBA10008).
LUX-Lung 3 A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations
SUMMARY: Afatinib is an oral tyrosine kinase inhibitor that irreversibly inhibits EGFR (ErbB1), HER2 (ErbB2), and ErbB4. In this study, chemo naïve patients with advanced stage adenocarcinoma of the lung (stage IIIB/IV) with EGFR mutations, were randomly assigned to receive either Afatinib or a combination of Pemetrexed and Cisplatin. Primary endpoint was progression-free survival (PFS). Treatment with Afatinib resulted in a significantly prolonged PFS compared to combination chemotherapy (median 11.1 vs 6.9 months; HR 0.58; P=0.0004). Further, patients in the Afatinib group had a higher objective response rate ((56% vs 23%; p<0.0001), as well as significant delay in symptom progression, compared to the combination chemotherapy group. Yang JC-H, Schuler MH, Yamamoto N, et al. J Clin Oncol. 2012;30(suppl; abstr LBA7500).
AURELIA A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC)
SUMMARY: AURELIA is a multicenter, randomized, open-label, two-arm Phase III study in which 361 women with platinum-resistant recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer were enrolled. These patients had disease progression within six months of their platinum based chemotherapy. Patients were randomly assigned to receive AVASTIN® (Bevacizumab) in combination with chemotherapy which included weekly paclitaxel, topotecan or pegylated liposomal doxorubicin or chemotherapy alone. The primary end point was Progression Free Survival. There was a 52% reduction in the risk of progression in those who received AVASTIN® plus chemotherapy compared to those who received chemotherapy alone (HR=0.48, P<0.001). Further, there was a significantly higher objective response rate in the AVASTIN® group compared to those who received chemotherapy alone (30.9 percent vs. 12.6 percent, p=0.001). Pujade-Lauraine E, Hilpert F, Weber B, et al. J Clin Oncol 30, 2012 (suppl; abstr LBA5002)
Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer
SUMMARY:Durable tumor responses have been demonstrated in previous clinical studies using high dose interleukin 2 and anti-CTLA 4 antibody YERVOY® (Ipilimumab), for advanced malignancies such as metastatic melanoma. The programmed death 1 (PD-1) receptor is an inhibitory receptor expressed on activated T-cells in the tumor micro environment. It has two known ligands, PD-L1 and PD-L2 which can turn off the immune system when they combine with the PD-1 receptor. BMS-936558 is an anti-PD-1 targeted, fully human, monoclonal antibody which acts similar to the anti CTLA 4 antibody YERVOY®, thereby unleashing the T cell response against cancer cells. Results from a Phase 1 study in which 296 patients were enrolled demonstrated a durable response rate of 18% among patients with advanced non- small cell lung cancer, 28% among patients with advanced melanoma and 27% among patients with advanced renal cell carcinoma. PD-L1 was identified as a potential biomarker for response, with no responses seen in PD-L1 negative tumors. Topalian SL, Hodi S, Brahmer JR, et al. NEJM June 2, 2012.
Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane
SUMMARY:The HER or erbB family of receptors consist of HER 1,HER 2,HER 3 and HER 4. Overexpression of HER 2 in breast cancer has been associated with higher risk for relapse as well as overall survival. Trastuzumab is a humanized monoclonal antibody targeting HER 2. It binds to the extracellular domain of the receptor and blocks the downstream cell signaling pathways. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) comprised of the antibody trastuzumab and the chemotherapy agent DM1 linked together and inhibits HER2 signaling and destroys the HER2-positive tumor cells by delivering the chemotherapy agent DM1 directly inside the tumor cells. The EMILIA trial is a phase III study in which 978 patients with HER2-positive locally advanced or metastatic breast cancer who had previously received treatment with HERCEPTIN® (Trastuzumab) and a taxane chemotherapy, were enrolled. Patient received either trastuzumab emtansine (T-DM1) or XELODA® (Capecitabine) and TYKERB® (Lapatinib) doublet. The primary endpoints were Progression Free Survival (PFS), Overall Survival (OS) and safety. Patients receiving T-DM1 had an improved PFS compared to XELODA® and TYKERB® (9.6 months vs 6.4 months, HR=0.65, P <0.0001). A final OS analysis will be available at a later date. Blackwell KL, Miles D, Gianni L, et al. J Clin Oncol 30, 2012 (suppl; abstr LBA1)
Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia
SUMMARY:In children and adolescents with acute lymphoblastic leukemia (ALL), allogeneic stem cell transplantation is usually considered the treatment option, after failure of remission-induction therapy. In their review of over 44,000 cases of pediatric ALL in three continents, the authors noted that patients with B-cell ALL had better outcomes when treated with a second round of chemotherapy without a transplant. Patients with T-cell ALL however were noted to have a better outcome with transplantation. This review suggests that induction failure in patients with ALL does not automatically warrant transplantation. Schrappe M, Hunger SP, Pui C, et al. N Engl J Med 2012; 366:1371-1381
Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma
SUMMARY: REVLIMID® (Lenalidomide) is an immunomodulatory agent with significant activity in patients with Multiple Myeloma, by virtue of its multiple mechanism of action. In this randomized, double blind, multicenter study, patients 65 years or older with newly diagnosed multiple myeloma, ineligible for transplantation, were randomized and the comparison was MPR followed by R (melphalan, prednisone and REVLIMID® followed by REVLIMID® maintenance) vs MPR or MP followed by placebo. There was a statistically significant prolongation in the progression free survival with a 51% reduction in the risk of progression for those who received REVLIMID® maintenance (MPR followed by R) compared to those who received MPR followed by placebo. This benefit was predominantly observed in patients who were 65-75 years of age. The response rates were also higher in the MPR-R and MPR groups compared to the MP group. There was a slightly higher incidence of second primary malignancies in those exposed to REVLIMID® (MPR-R and MPR) compared to the MP group (7% vs 3%). This study has demonstrated the benefit of adding REVLIMID® for induction therapy as well as maintenance, in patients 65-75 years of age, ineligible for transplant. Palumbo A, Hajek R, Delforge M, et al. N Engl J Med 2012;366:1759-1769
Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma
SUMMARY: REVLIMID® (Lenalidomide) is an immunomodulatory agent with significant activity in patients with Multiple Myeloma, by virtue of its multiple mechanisms of action. In two, double blind, randomized, phase III trials, patients with stable disease following stem cell transplantation, were randomized to receive either REVLIMID® (Lenalidomide) or placebo maintenance, until progression. In both these studies there was a statistically significant improvement in the progression free survival or time to progression in the patient group receiving REVLIMID® maintenance. This benefit was independent of response to initial induction therapy at the time of randomization and other patient characteristics such as B2 microglobulin, cytogenetics or exposure to lenalidomide or thalidomide during induction. There was however a slightly higher incidence of second primary malignancies in the REVLIMID® group compared to the placebo group (8% vs 4%). We have come a long way, controlling this disease and maintenance REVLIMID® has paved the way, changing Multiple Myeloma into a chronic disease. McCarthy PL, Owzar K, Hofmeister CC, et al. N Engl J Med 2012;366:1770-1781 and Attal M, Lauwers-Cances V, Marit G, et al. N Engl J Med 2012;366:1782-1791
Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer
SUMMARY: The mechanism of resistance to hormonal therapy in breast cancer is thought to be related to the activation of mTOR pathway, independent of ER (estrogen receptor) signalling pathway. To test this hypothesis, the authors in this study (BOLERO-2) decided to combine mTOR inhibition with estrogen deprivation. In a phase III trial, patients with ER positive, advanced breast cancer, who had recurred or progressed on prior therapy with nonsteroidal aromatase inhibitors (anastrozole or letrazole), were randomized in a 2:1 ratio to either receive everolimus (mTOR inhibitor) and exemestane (steroidal aromatase inhibitor) or exemestane and placebo. The primary end point of Progression Free Survival was significant with 10.6 months for mTOR inhibitor plus exemestane vs 4.1 months for exemestane plus placebo, according to central review (hazard ratio, 0.36; P<0.001). This new paradigm of adding everolimus to hormonal therapy should change the way we manage patients with advanced breast cancer, who are resistant to hormonal therapy alone. Baselga J, Campone M, Piccart M, et al. N Engl J Med 2012; 366:520-529