		Associate Director, Translational Research, Yale Comprehensive Cancer Center

		Smilow Cancer Hospital at Yale-New Haven, Yale School of Medicine

Jay and Lori Eissenberg Professor in Lung Cancer, Director of the Thoracic Molecular Pathology Lab,

		Departments of Pathology and Thoracic/Head & Neck

		The University of Texas MD Anderson Cancer Center, Houston, TX

	What is BATTLE-2 and why is it important?

One of the themes at the 13th International Lung Cancer Congress in Huntington Beach, California, last July was the personalization of therapy based on rapidly increasing knowledge of the molecular profile of individual lung cancers. While the number of known mutations and matching targeted agents is relatively limited at present, clinical trials are being designed to identify effective therapies for specific mutations more efficiently. One such study is BATTLE-2, a biomarker-driven trial for patients with metastatic lung cancer. Roy S. Herbst, MD, PhD, and Ignacio I. Wistuba, MD, two of the principal investigators, discussed the study with OncologyLive.

 The BATTLE-2 trial is a study that is designed to understand how tissue biomarkers predict who will respond to targeted therapy or targeted therapy combinations. The idea behind BATTLE is that every patient gets a biopsy at the time of their treatment so that it reflects the mutational status and biomarker status of their tumor, and then that information is used to put them onto one of four arms of the trial. In this case, the trial has an EGFR inhibitor (erlotinib); an inhibitor of Ras, Raf, and other [signaling molecules] (sorafenib); a combination of erlotinib plus an Akt inhibitor (MK-2206), which is thought to overcome EGFR resistance; and a combination to target 

,âŽ¯a MEK inhibitor (AZD6244) plus an Akt inhibitor (MK-2206).

The way the BATTLE-2 trial works [is that] as soon as the patient has their new biopsy reflecting the tumor at the current time, it goes to Dr Wistuba’s lab. Within a week to 10 days his lab is able to provide a series of markers so we know what the profile is of that patient. Initially, the patients are equally randomized to each of the four arms, but as time goes by, as we learn how the marker profile predicts who does well, we start to adaptively randomize, meaning that they are more likely to get the arm that will benefit. So, this is an approach that the patients like because they’re not just being strictly randomized, but they’re being sorted based on their profile, and we’re learning. Dr Wistuba is also doing discovery work.

 That’s the other important aspect—we use the information to assign the patients to the treatments, but we also use the tissue and the material that we have to potentially discover new things that could benefit future lung cancer patients. We are planning to take all this information and make clinical trials more specific based on what we are learning from these trials. So, it’s not just to assign patients based on the biomarker profile, but to discover new abnormalities in lung cancer that can help the entire field.

 Maybe 20%-30% of patients have a mutation or biomarker that can be used to give them a helpful therapy, but the other 70% don’t, so we’re going to learn by doing this work in a rigorous way with all the techniques that Dr Wistuba and his lab can employ. Dr Wistuba and I are doing this in collaboration with Dr Vassiliki Papadimitrakopoulou [University of Texas MD Anderson Cancer Center], and Dr J. Jack Lee [University of Texas MD Anderson Cancer Center]. We received an RO1 grant from the National Cancer Institute, so this is receiving peer-reviewed support.

 We are also opening this at Yale, where Dr Herbst is now, so we’re going to show that this can be done in a multicenter way, because in the past it has been done at only one institution. By having this biopsy-driven trial in two places, I think this is also a step forward in the field.

	Are clinical trials like this going to be the wave of the future for developing new cancer therapies?

 As we’ve heard at this meeting, some of these mutation and biomarker events are rare, 5%-10% of cases, and even a big center can’t do it by itself. We’ll need to collaborate, and we’re talking about SWOG or other collaborative groups running big studies. We’re piloting that this can be done at two centers. In the future, multicenter efforts such as these (perhaps through the cooperative groups) will be essential as we move forward with personalized medicine. We’re going to do some of the assays at Yale—initially, 

—and then the tissue for discovery is going to be sent to Dr Wistuba. So, a very nice collaboration.

 Absolutely. I think it’s essential. If you don’t let the biology drive the treatment, everything is empiricism and it is going to have a very low chance of hitting the mark. So absolutely, as Dr Wistuba said, treat patients the best you can in real time, but also learn, discover, identify new markers. Patients get a drug and respond, but then they’re resistant; why are they resistant? That is, I believe, the fundamental question. Understanding why patients become resistant, and how we can understand what genes and proteins are involved so we can then target them.

 One of the improvements in our clinical trial based on the BATTLE-1 trial result is that this approach of taking a biopsy from the patient at the time of the treatment has been safe clinically. There are not too many important adverse effects from having a biopsy at that time, and that has actually changed the paradigm of how these biomarker-driven clinical trials are going to be conducted. Instead of relying on a tissue specimen that was taken six months ago or a year ago, before several treatments have happened, this is real time and we’re learning about the genetic makeup of the tumor at that time.

Articles

While the number of known mutations and matching targeted agents is relatively limited at present, clinical trials are being designed to identify effective therapies for specific mutations more efficiently.

BATTLE-2: Next-Generation of Biomarker-Driven Trials

		Cell-Signaling Pathways Explored in Hematologic Malignancies

		ALL indicates acute lymphocyctic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; DLBCL, diffuse large B-cell lymphoma; ET, essential thrombocythemia; FL, follicular lymphoma; MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome; MF, myelofibrosis; NHL, non-Hodgkin lymphoma; PV, polycythemia vera; SLL, small lymphocytic lymphoma.

	Targeted agents have a history of success in the treatment of hematologic malignancies, illustrated by the number of monoclonal antibodies and small-molecule inhibitors currently in clinical use. However, none of these agents are curative, and new treatment options are needed for patients who experience disease relapse.

	Increased understanding of the molecular mechanisms underlying the pathogenesis of these cancers has led to the development of several promising new classes of targeted therapies. The first JAK pathway inhibitor, ruxolitinib (Jakafi; Incyte), gained FDA approval last year, and other drugs in this class are being explored. (

	At the 16th Annual International Congress on Hematologic Malignancies, held February 23-26, 2012, in Utah, a special workshop session was devoted to reviewing recent data regarding emerging signal transduction inhibitors currently in clinical development, which have the potential to impact the treatment of hematologic cancers. Highlights of the presentations are summarized below.

	Signaling through the B-cell receptor (BCR) is necessary for the proliferation and survival of many B-cell malignancies, and Bruton’s tyrosine kinase (BTK) is a key downstream mediator of this signal. In preclinical studies, inhibitors of BTK have been shown to block BCR signaling and induce apoptosis, making this molecule an attractive therapeutic target.

	PCI-32765 (Ibrutinib; Pharmacyclics), a selective and irreversible inhibitor of BTK, is currently in the early stages of clinical investigation. A phase I study was conducted in previously treated, recurrent B-cell malignancies. While grade 1 events were common, there were no grade 4 toxicities, and grade 2/3 events were infrequent. In addition, there were no serious hepatic or renal toxicities, and no evidence of cumulative hematologic toxicity. PCI-32765 was most active in indolent malignancies, with both partial and complete responses seen in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and follicular lymphoma (FL), although partial responses were also observed in more aggressive lymphoma subtypes.

	A phase II trial in relapsed/refractory MCL recently reported an overall response rate (ORR) of 69%, with no difference in outcome between bortezomib-naïve versus bortezomib-treated patients. In addition, a phase II study in relapsed/refractory CLL reported ORRs of 70% (420-mg cohort) and 44% (840-mg cohort), with six-month progression- free survival (PFS) >90%. Transient lymphocytosis peaking at two months after drug initiation was also observed.

	A pilot study is also ongoing in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), based on the observation that NF-κB signaling is constitutively active in this subtype, often as a result of chronically active signaling through the BCR. A number of responses have been observed in the 10 patients enrolled to date. A phase II trial will evaluate PCI-32765 in both ABC and germinal center DLBCL, and will assess whether there is a differential response between these two subtypes.

	PI3 kinases (PI3K) are a family of lipid kinases that play an integral role in regulating intracellular signaling networks involved in cell growth, survival, and metabolism. Dysregulation of this pathway has been implicated in the development and progression of many forms of cancer, as well as resistance to current therapies. There are four different isoforms (alpha, beta, gamma, and delta), each with different biologic roles. The delta isoform in particular is expressed in leukocytes and plays a key role in B-cell signaling, development, and survival, leading to interest in the evaluation of PI3K inhibitors in B-cell malignancies.

	The first PI3K-delta-specific inhibitor to enter clinical trials is CAL-101 (GS-1101; Gilead Sciences). Results were recently reported from a large phase I study that enrolled patients with previously treated hematologic malignancies. Responses were observed in CLL, indolent non-Hodgkin lymphoma (NHL), and MCL, and enrollment was expanded for these malignancies. No responses were seen in DLBCL, acute myeloid leukemia (AML), or multiple myeloma, however, leading to closure of enrollment for these tumor types.

	In general, CAL-101 was well tolerated, although grade 3/4 neutropenia and/or infection were each seen in 24% of patients with CLL, while reversible grade 3/4 transaminitis occurred in 27% of patients with NHL. Responses were seen in 48% of the 21 patients with MCL, and in 63% of 30 patients with indolent NHL, with median durations of response of three cycles and nine cycles, respectively. In the 54 patients with CLL, nodal responses were seen in 80% of patients. This was accompanied by rapid lymphocyte redistribution, for an ORR of 26%. However, CLL-related thrombocytopenia and anemia were improved, and the median duration of response was >11 cycles.

		Selected Signal Transduction Inhibitors in Clinical Development

					Activity has been demonstrated in CLL/SLL, MCL, FL, and DLBCL; ongoing studies are evaluating this agent in combination with other targeted agents and chemotherapy regimens.

					A large phase I study reported single-agent activity in CLL, MCL, and indolent NHL; phase III trials are currently evaluating GS-1101 in combination with rituximab or bendamustine-rituximab in patients with previously treated CLL.

					Several phase I and II trials have been completed and activity has been seen in MCL, FL, DLBCL; combination studies are ongoing.

					Several phase I and II trials have been completed, and activity has been seen in all NHL subtypes; a phase III trial is comparing everolimus versus placebo in patients with DLBCL who have achieved a complete response following a rituximab-containing front-line regimen.

					Phase I single-agent study completed; a phase II trial in MCL, FL and CLL/SLL and a phase Ib combination study are currently recruiting patients.

					Phase IB complete in AML; CALGB 10603 phase III trial completed accrual.

					Phase II in AML recently completed; phase III trial ongoing.

		CLL indicates chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; MCL, mantle cell lymphoma; FL, follicular lymphoma;

		NHL, non-Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; AML, acute myeloid leukemia.

	The serine/threonine kinase mTOR functions downstream of PI3K to regulate several essential cellular functions. In particular, mTOR acts as a sensor of external growth signals and stress conditions, and one of its most important functions involves the regulation of protein translation initiation. Aberrant activation of mTOR has been associated with a wide variety of solid and hematologic tumors, leading to the successful investigation of mTOR inhibition as a therapeutic strategy in several tumor types to date, including renal cell carcinoma and pancreatic neuroendocrine tumors.

	The first-generation mTOR inhibitors temsirolimus (Torisel; Pfizer) and everolimus (Afinitor; Novartis) have both demonstrated preliminary activity in MCL in small studies, with response rates ranging from 6% to 41%. They have also been evaluated in other NHL subtypes, with promising results. As single agents, activity has been observed in FL (ORR approximately 50%), with somewhat lower levels seen in DLBCL (ORR approximately 30%).

	Unfortunately, resistance to these agents inevitably develops. Resistance may be related to the fact that mTOR exists in one of two intracellular complexes, mTORC1 and mTORC2, and first-generation inhibitors only block the formation of the mTORC1 complex. Continued activation of mTORC2 leads to a paradoxical increase in the phosphorylation and activation of the upstream kinase Akt, resulting in continued stimulation of this pathway.

	Several second-generation inhibitors have been developed to block the activity of both mTOR complexes, and these agents are just beginning to enter clinical trials. Another strategy to enhance the efficacy of these agents is through combinations with other targeted agents, and trials are under way combining first-generation inhibitors with rituximab (Rituxan; Genentech), bortezomib (Velcade; Millennium), lenalidomide (Revlimid; Celgene), or histone deacetylase (HDAC) inhibitors in various lymphoma subtypes.

	FLT3 (Fms-like tyrosine kinase 3) is a transmembrane receptor that provides a primarily proliferative signal in myeloblasts and is mutated in approximately 30% to 35% of AML cases. Mutations, either through internal tandem duplications or point mutations in the tyrosine kinase domain, lead to constitutive activation of the receptor. This contributes to proliferative and survival signaling in AML blasts. In addition, 

 mutation has been associated with a higher relapse rate, as well as shorter disease-free and overall survival times, although allelic ratios may have an impact on this effect. These characteristics led researchers to hypothesize that FLT3 inhibition may provide a clinical benefit in AML.

	A number of FLT3 inhibitors are undergoing clinical evaluation in patients with AML. Early studies suggest that as single agents, currently available inhibitors can decrease circulating blasts, but none clear the bone marrow or induce durable responses, leading to studies of these agents in combination with established chemotherapy regimens.

	Results from a phase IB trial of midostaurin (PKC412; Novartis) in combination with chemotherapy in 40 newly diagnosed patients with AML have been reported. Midostaurin was included with both induction and consolidation therapy, and patients with either wild-type or mutant FLT3 were enrolled. The complete response rate was 74% in patients with wild-type AML and 92% in those with mutations. Notably, overall survival was similar between both arms, although only 13 patients had 

-mutated AML. The phase III CALGB 10603 trial is currently evaluating midostaurin in combination with induction/consolidation chemotherapy followed by one year of maintenance therapy with the inhibitor in patients ≤60 years old with newly diagnosed AML with 

 mutations. Accrual was completed in October 2011.

	A second FLT3 inhibitor, lestaurtinib, is also in phase III clinical development. A randomized phase II trial of lestaurtinib in combination with chemotherapy in 224 patients with AML in first relapse, harboring a 

 mutation, found no difference in either response rate or survival. However, unfavorable pharmacokinetics may have played a role, and sustained FLT3 inhibition was difficult to achieve. A correlative study suggested a higher response rate in the 58% of patients who achieved target FLT3 inhibition at day 15. A phase III trial is ongoing, and results are awaited.

	These results suggest that the next generation of targeted therapies has the potential to further improve outcomes in patients with a variety of hematologic malignancies. Additional gains are likely to be achieved through rationally designed combination regimens, which may offer synergistic efficacy or delay the emergence of resistance, and a number of such studies are either under way or in the planning stages. Correlative studies are also being undertaken to identify biomarkers to better select those patients who will, or will not, benefit from a particular therapy.

	In the future, it is likely that therapies for hematologic malignancies will not only contain targeted agents, but will be targeted toward specific subpopulations of patients, in order to maximize benefits. Better outcomes will be achieved by matching the right therapy to the right patients, based on knowledge of the molecular makeup of the individual malignancies.

Presentations at the 16th International Congress on Hematologic Malignancies

	Molecular Lesions in BCR Signaling and BTK Inhibitors

	Staff Clinician, Lymphoma Therapeutics Section

	Director, Hematologic Malignancies Program

Increased understanding of the molecular mechanisms underlying the pathogenesis of hematologic cancers has led to the development of several promising new classes of targeted therapies.

On the Horizon: Novel Inhibitors for Hematologic Malignancies

	At the 16th Annual International Congress on Hematologic Malignancies held in February in Snowbird, Utah, Jeffrey A. Jones, MD, MPH, assistant professor of Hematology at The Ohio State University, summarized results of recent trials investigating novel therapies for chronic lymphocytic leukemia (CLL).

	The first approach discussed involved the immunomodulatory drug lenalidomide. As a single agent, overall response rates (ORRs) of 32% to 58% have been reported in relapsed CLL, but treatment has also been associated with a high rate of tumor-flare response and tumor lysis syndrome (TLS) at higher doses, as well as expected cytopenias. An ORR of 62% was reported in elderly patients who received lenalidomide as first-line therapy.

	In an effort to further improve efficacy and reduce toxicity, lenalidomide was explored in combination with the monoclonal antibody rituximab, reporting an ORR of 66% in relapsed CLL and 75% overall survival (OS) at 36 months. Tumor flare and TLS, but not neutropenia, were reduced with the combination. A more recent phase II study conducted by the CLL Research Consortium examined a shorter course (7 cycles) of the combination in treatment-naïve CLL in two cohorts of patients (<65 years and ≥65 years). Tumor-flare reactions and cytopenias were seen frequently in both cohorts. ORRs of 95% and 78% were observed in younger and older patients, respectively.

	These results suggest that lenalidomide alone or in combination with monoclonal antibody therapy may be a promising strategy in patients for whom aggressive chemoimmunotherapy approaches are not appropriate, such as the elderly or those with comorbid medical illnesses or renal insufficiency.

	Cyclin-dependent kinase inhibitors (CDKIs) are another class of agents currently being evaluated in CLL. Studies of alvocidib (flavopiridol) have reported ORRs of 25% to 50%, but this agent has a narrow therapeutic index and is associated with a significant risk for TLS. Dinaciclib is a secondgeneration CDKI with a broader therapeutic index. A 45% partial response rate has been reported in 33 patients with CLL.

	Finally, the greatest excitement in novel treatments for CLL is in the area of small-molecule signal-transduction inhibitors. “One of the most important insights in CLL biology in the last several decades has been the importance of signaling through the B cell receptor for the maintenance of the disease. And that’s led to a lot of investigation with downstream signal regulation from the B cell receptor and potential inhibitors,” said Jones. Novel inhibitors are at various stages of clinical development, but the two that are most advanced are GS-1101 and PCI-32765.

	Downstream signaling from several cell surface receptors funnels through PI3Kδ, and according to Jones, “seems to drive both the proliferation and survival of the malignant clone as well as cell adhesion and homing.” GS-1101 is a small-molecule inhibitor of PI3Kδ that has been evaluated in phase Ib studies as a single agent, and in combination with either rituximab or bendamustine. Single-agent toxicities are relatively low with this agent, with an 18% rate of grade 3/4 neutropenia, and rates of less than 10% for other cytopenias. Approximately 80% to 90% of patients experience a nodal response with single-agent or combination therapy, but while peripheral blood lymphocytosis limited the ORR to 24% with single-agent GS-1101, the addition of rituximab or bendamustine increased the ORR to the nodal response level.

	PCI-32765 is an oral inhibitor of Bruton’s tyrosine kinase (BTK), a downstream component of the B cell receptor signaling pathway. Sixtyone patients with relapsed/refractory CLL have been treated to date in a phase Ib study. Diarrhea was the most common adverse event, and rates of severe cytopenias were relatively low. As with GS-1101, there was a rapid nodal response in the majority of patients, accompanied by mobilization of lymphocytes from sanctuary sites into the peripheral blood.

	According to Jones, “With continued exposure of the drug, many of these nodal responses will gradually convert to a more overt conventional response.” In addition, he said, “There’s a pretty significant benefit with respect to recovery of cytopenias very early on after initiation of therapy along with resolution of constitutional symptoms.”

Results of recent trials investigating novel therapies for chronic lymphocytic leukemia were discussed at the 16th Annual International Congress on Hematologic Malignancies.

Novel Treatments for Chronic Lymphocytic Leukemia

	The current standard for patients with advanced diffuse large B-cell lymphoma (DLBCL) is R-CHOP-21 (21-day rituximab-cyclophosphamidedoxorubicin- vincristine-prednisone). However, while this regimen cures approximately two-thirds of patients, a significant fraction of patients will still relapse, and the prognosis for these patients is poor.

	At the 16th Annual International Congress on Hematologic Malignancies, John Leonard, MD, professor of Medicine and Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medical College in New York City, discussed several novel therapies currently under investigation for DLBCL.

	One approach being evaluated is the substitution of an alternate chemotherapy regimen for CHOP in combination with rituximab. One such regimen, R-ACVBP (dose-intensive rituximab-doxorubicincyclophosphamide- vindesine-bleomycinprednisone), features increased dose intensity compared with R-CHOP, sequential consolidation using second-line agents, and central nervous system prophylaxis. This regimen has been compared with R-CHOP in patients with DLBCL who are younger than age 60 years with an ageadjusted International Prognostic Index equal to 1. Phase III results showed significant improvements in both progression-free survival (PFS) and overall survival (OS), but with markedly higher hematologic toxicities in the experimental arm, as well as more toxic deaths. Concerns about these high toxicity rates have prevented wide adoption of the R-ACVBP regimen, even in selected patient populations.

	A second regimen under evaluation is R-EPOCH (rituximabetoposide- prednisone-vincristine-doxorubicin-cyclophosphamide), which demonstrated a 5-year PFS of 79% in a phase II trial. A phase III trial, CALGB 50303, is now comparing R-EPOCH with R-CHOP in patients with newly diagnosed DLBCL.

	Another approach being tested by many groups involves adding a new agent to R-CHOP-21. According to Leonard, “It’s hard to break away from R-CHOP-21, given that for two-thirds of the patients, it does the job.” Epratuzumab, bortezomib, lenalidomide, enzastaurin, and radioimmunotherapies are just a few of the novel agents being evaluated in combination with R-CHOP. The challenge is to select combinations that show promise in phase II studies to move forward into phase III trials.

	“Every [phase II] study looks at different patient populations, at diferent time points, using different statistical measures like progression-free or failure-free survival, so at the end of the day it is really hard to know, is this phase II data worthy of pursuing in a phase III trial? That’s why in large-cell lymphoma, many groups are pursuing a randomized phase II strategy or other novel statistical approaches to try to take forward a new regimen,” explained Leonard.

	One such promising regimen is R-CHOP in combination with the proteasome inhibitor bortezomib. This regimen is being evaluated in nongerminal center B-cell (non-GCB)-like tumors, based on the observation that nuclear factor-kappa B (NF-κB) transcriptional activity is upregulated in this subtype. While non-GCB lymphomas generally do poorly with R-CHOP in comparison with GCB-like tumors, when bortezomib was added in a phase II trial, PFS and OS outcomes were similar between the two subtypes. This combination is now being evaluated in non-GCB DLBCL in two phase III trials: PYRAMID (NCT00931918) and LYM2034 (NCT01040871).

	“I think these are important studies. I think ultimately what we will be seeing is novel agents that target molecular subtypes of large cell lymphoma that are defined in more modern ways,” said Leonard. “The message here is that for this [high-risk] group of patients, we really need to continue to look and place a high priority on assessing some of these novel approaches.”

The prognosis for a significant fraction of DLBCL patients that relapse while receiving the current standard treatment of R-CHOP-21 remains poor.

Beyond R-CHOP-21: What's New in Diffuse Large B-Cell Lymphoma

	Patients with hormone receptor-positive metastatic breast cancer (MBC) frequently respond to multiple lines of endocrine therapy but, unfortunately, resistance eventually develops. Research has revealed that signaling through alternate growth factor signaling pathways contributes to resistance, and a number of clinical trials have evaluated combination regimens targeting both estrogen receptor and growth factor signaling pathways.

	At the 2011 School of Breast Oncology, Ruth M. O’Regan, MD, professor and vice-chair for Educational Affairs, Department of Hematology and Medical Oncology, at Emory University, Atlanta, Georgia, reviewed results from key trials investigating the utility of these regimens in patients with hormone receptor-positive MBC. The School of Breast Oncology was held at the university in November.

	Some of the first studies looked at targeting the HER2 receptor in combination with hormonal therapy. The TAnDEM trial compared anastrozole with or without trastuzumab in patients with HER2-positive, hormone receptor-positive MBC. The addition of trastuzumab doubled progression-free survival (PFS) from 2.4 months to 4.8 months (

 = .0016). According to O’Regan, the low PFS observed with anastrozole alone “shows that some of these cancers are resistant to hormonal therapy.”

	A second trial evaluated letrozole with or without lapatinib as firstline therapy for hormone receptor-positive MBC, and included both HER2-positive and HER2-negative patients. “In the intent-to-treat population we see about a month difference in PFS, but it is driven completely by the HER2-positive group. In that group, by adding lapatinib to letrozole, you improved PFS by 5 months,” O’Regan said. (

	Several studies have also looked at adding an mTOR inhibitor to endocrine therapy. The randomized phase II TAMRAD study compared tamoxifen with or without everolimus in patients with hormone receptorpositive MBC who had previously been exposed to aromatase inhibitors. Everolimus increased the clinical benefit rate from 42% to 61%, and time to progression was improved from 4.5 months to 8.6 months.

	“What was very interesting here was that even though this was a small study, the researchers broke it down based on clinical criteria to see whether patients had primary or secondary hormone resistance, and the benefit of adding everolimus was seen predominantly in the patients with secondary hormonal resistance,” O’Regan noted.

	Preliminary results from the BOLERO-2 trial were recently presented at the European Society for Medical Oncology conference in September 2011. This phase III trial randomized postmenopausal patients with estrogen receptor-positive, HER2-negative advanced breast cancer refractory to letrozole or anastrozole to exemestane plus everolimus or placebo. The addition of everolimus increased PFS from 2.8 months to 6.9 months (

 = 1.4 x 10-15). “There is a wide separation of the curves in favor of everolimus,” O’Regan said, and “the 

 value is one of these highly, highly, highly significant 

	Finally, a new area of investigation is the combination of histone deacetylase (HDAC) inhibitors with endocrine therapy. According to O’Regan, “there is a lot of preclinical data suggesting these agents may be important in hormone receptor-positive and hormoneresistant breast cancers.”

	The randomized phase II ENCORE 301 trial evaluated exemestane plus the HDAC inhibitor entinostat or placebo in postmenopausal women with estrogen receptor-positive MBC that had progressed on a nonsteroidal aromatase inhibitor. Preliminary results demonstrated a 2-month improvement in PFS with the addition of entinostat. O’Regan said this combination may be going into a phase III trial, although it was still in the process of being designed.

	These results are promising, and combination regimens will likely add to the treatment armamentarium for hormone receptor-positive MBC in the future. Such approaches may offer patients the hope of delaying resistance and prolonging the time that endocrine therapy is effective.

Patients with hormone receptor-positive metastatic breast cancer (MBC) frequently respond to multiple lines of endocrine therapy but, unfortunately, resistance eventually develops.

Susan R. Peck, PhD

Articles

BATTLE-2: Next-Generation of Biomarker-Driven Trials

On the Horizon: Novel Inhibitors for Hematologic Malignancies

Novel Treatments for Chronic Lymphocytic Leukemia

Beyond R-CHOP-21: What's New in Diffuse Large B-Cell Lymphoma

Overcoming Resistance to Endocrine Therapies