2015 has certainly got off to an exciting start in oncology! In a unanimous vote, the FDA’s ODAC panel recommended approval of EP2006, Novartis’s biosimilar version of filgrastim (Neupogen), Amgen’s synthetic G-CSF.

The committee backed EP2006 for all five of filgrastim’s indications, which include approvals for chemotherapy-induced febrile neutropenia in patients with nonmyeloid malignancies, for patients with acute myeloid leukemia receiving induction or consolidation chemotherapy, and for cancer patients receiving bone marrow transplants.

The Biosimilars Act of 2010 established an expedited approval pathway for biosimilars. If the FDA follows ODAC’s recommendation and authorizes marketing of EP2006 under this pathway, EP2006 would become the first biosimilar approved in the United States.

And so, as we begin 2015, American healthcare is on the cusp of the biosimilar era, which has the potential to expand patient access and reduce healthcare costs.

Beyond coverage of this critical development, our inaugural issue of 2015 also includes highlights from the two major conferences that closed out 2014, the American Society of Hematology Annual Meeting and the San Antonio Breast Cancer Symposium.

Key areas from ASH highlighted in this issue include anti-CD38 antibodies in multiple myeloma (

), frontline idelalisib monotherapy in older patients with chronic lymphocytic leukemia (

), pembrolizumab in classical Hodgkin lymphoma (

), CAR T-cell therapy in pediatric acute lymphoblastic leukemia (

), brentuximab vedotin in hodgkin lymphoma (

), nivolumab in classical Hodgkin lymphoma (

), and ibrutinib combined with rituximab in mantle cell lymphoma (

Important topics discussed at SABCS featured in this issue include ovarian suppression as a treatment option for younger, premenopausal breast cancer patients (

-paclitaxel versus conventional paclitaxel in high-risk early breast cancer (

); upfront fulvestrant versus anastrozole in HR-positive metastatic breast cancer (

); and immunotherapy with pembrolizumab in heavily pretreated patients with recurrent, metastatic triple-negative breast cancer (

We look forward to continuing to cover groundbreaking developments in oncology for you throughout 2015. For additional coverage, visit our online platform at 

Articles

2015 has certainly got off to an exciting start in oncology! 

Dawn of US Biosimilar Era Arrives

A few weeks ago, physicians and scientists from around the globe gathered in San Francisco for the 2014 American Society of Hematology (ASH) Annual Meeting. While it is well beyond the scope of this column to examine all of the significant data presented at ASH, let’s review some trends, since there were key devel&shy;opments across the board.

The most striking results presented were those involving immune-based therapies, particularly with the definite en&shy;trance of PD-1 inhibitors into hematology (ie, unleashing the immune system by blocking PD-1 T-cell induced exhaustion). Two PD-1 inhibitors showed dramatic activity in heavily pre&shy;treated Hodgkin lymphoma: pembrolizumab (objective re&shy;sponse rate [ORR] = 67%) and nivolumab (ORR = 87%).

Other immune-based therapies were also very impres&shy;sive, with confirmation of the activity of bispecific antibod&shy;ies (linking CD3 and CD19), such as blinatumomab, in acute lymphocyctic leukemia (ALL), and CAR T-cells showing du&shy;rable complete remissions in 92% of pediatric patients with relapsed/refractory ALL.

The second obvious trend at ASH involved small mol&shy;ecules, particularly BCR-targeted agents (ibrutinib, idelal&shy;isib, duvelisib), with more mature data confirming activity in high-risk patients, such as those carrying a del17p, who typically have very poor outcomes with standard chemo&shy;therapy. In a study of 140 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with del 17p, the ORR with ibrutinib was >80% and at 12 months, 79% of patients had not progressed, which is completely unexpected in that population.

Another development reported with small molecules in&shy;volved the BCL2 inhibitor ABT-199 (venetoclax), with data confirming impressive activity across the board in B-cell malignancies. Also, for the first time, a benefit was shown with an IDH2 inhibitor (AG-221) in acute myeloid leukemia.

In another area, a number of new monoclonal antibodies are currently being tested in B-cell non-Hodgkin lymphoma (NHL), particularly naked anti-CD20 (obinutuzumab, ubli&shy;tuximab, and ofatumumab, among others) or antibody-drug conjugates. For example, brentuximab vedotin significantly reduced the risk of relapse and extended progression-free survival (PFS) following autologous stem cell transplant for re&shy;lapsed/refractory Hodgkin lymphoma (AETHERA trial). Bren&shy;tuximab was also used as salvage therapy pre-transplant, ei&shy;ther as a single agent or in combination (with bendamustine, particularly), and showed very impressive results, including a high complete remission rate. This will definitely change the landscape of Hodgkin lymphoma, including emerging data supporting replacement of chemotherapy in elderly patients in the frontline setting.

The momentum seen toward combinations of biological agents continues to expand in multiple myeloma (MM), typi&shy;cally including the proteasome inhibitor bortezomib (and now carfilzomib, or ixazomib [an oral compound]), lenalido&shy;mide (and now also pomalidomide) plus dexamethasone, providing unprecedented responses in the frontline setting.

The true breakthrough in MM, however, is likely the emergence for the first time of Mab candidates in myeloma, particularly those targeting CD38, such as elotuzumab or daratumumab, which have shown activity as single agents in relapsed/refractory MM, offering an option beyond the triplets backbone therapies (as we did with chemoimmu&shy;notherapy in lymphoma).

Beyond this brief highlight of some specific developments from the meeting, a number of themes emerged from ASH that reflect the ongoing changes occurring in oncology.

Logically, combinations of small molecules are being ex&shy;plored to replace chemotherapy with already promising results, including in high-risk patients with CLL, MCL, and indolent NHL.

Though such regimens appear to be potentially less toxic than standard cytotoxic chemotherapy (to some degree debatable), they are associated with extreme costs, par&shy;ticularly for new regimens given for prolonged periods. On the other hand—for example&mdash;6 cycles of chemoim&shy;munotherapy can definitely either cure or give very long remissions to subsets of patients with B-cell lymphomas. This issue is definitely&mdash;and should be&mdash;part of an honest debate moving forward with the development of novel strategies for cancer patients.

effort, which encourages physicians and patients to discuss the necessity of com&shy;mon medical tests and treatments (eg, there is no need for extensive coagulopathy workup in patients who have a deep vein thrombosis or pulmonary embolism in the setting of a transient major risk factor). Without any doubt, this list will continue to grow as we engage physi&shy;cians more toward cost/quality awareness.

Though there is an obvious growing presence of molecu&shy;lar diagnostics in hematologic malignancies, there is still a huge gap with the clinic. Additional efforts are needed for a better molecular stratification of patients including on clinical trials, keeping in mind the need to streamline the exhaustive and lengthy process required through eli&shy;gibility evaluation for such trials.

Finally, several trials continued to highlight the benefit of maintenance approaches (rituximab) in a number of B-cell malignancies. Though there is no doubt that PFS is extended, so far there is no clear benefit in overall surviv&shy;al. In the current era of 

rationale, clinical benefit—based medi&shy;cine

, I believe we should move toward minimal residual disease (MRD)—based endpoints, including for mainte&shy;nance decisions, as I previously detailed in this column.

Overall, ASH confirmed the extraordinary changes hap&shy;pening in the field of hematological malignancies. Though rapidly changing times are often accompanied by some degree of confusion, with hundreds of new options on the horizon, it is a 

problem to have, and a great way to start the New Year.

A few weeks ago, physicians and scientists from around the globe gathered in San Francisco for the 2014 American Society of Hematology (ASH) Annual Meeting. Let's review some trends, since there were key develÂ­opments across the board.

ASH Meeting Highlights a Great Year and Builds Momentum Toward a New Era in Cancer Care

	Director, Breast Care Center, Associate Professor Surgery, Comprehensive Cancer Center at Wake Forest Baptist 

Determination of BRCA1 and 2 mutation carrier status has become increasingly important. Estimates suggest that about 80% of breast cancers and 90% of ovarian cancers are sporadic1; while only 5% to 10% of breast cancers are hereditary. Hereditary mutations of the BRCA1 and BRCA2 genes account for 60% of inherited breast and ovarian cancers.1 According to recent data, the risk of a BRCA2 mutation carrier developing breast cancer by age 70 years is 45%, and her risk of developing ovarian cancer is 11% to 17%; BRCA1 mutation carriers have a slightly higher risk of breast cancer (55%-65%) and a higher risk of ovarian cancer (39%).

In our multidisciplinary breast center, we routinely test women who are at high risk for harboring a BRCA mutation. Genetic counselors play a vital role in identifying and evaluating women who are at high risk for hereditary breast cancer syndromes. For a woman with a known cancer, counseling and testing may help her decide whether to undergo a bilateral mastectomy at the time of her cancer surgery, or whether to opt for careful surveillance of the remaining breast tissue.

The National Comprehensive Cancer Network (NCCN) has well-established criteria for consideration of BRCA 1/2 testing among women with a recent breast cancer diagnosis, including the presence of young age (<45 years), bilateral breast cancers, a family history of male breast cancer, and a significant family history of breast and/ or ovarian cancer.3 The NCCN guidelines have formally included triple-negative breast cancers among women aged <60 years as additional eligibility criteria for consideration of genetic testing.

If a BRCA mutation is discovered, then we recommend bilateral prophylactic mastectomies with bilateral oophorectomies or close observation with breast MRI and transabdominal ultrasound with chemoprevention. Some women who test negative for the mutation still opt for bilateral mastectomies.

The rate of contralateral prophylactic mastectomy (CPM) has more than doubled over the last decade, both in invasive breast cancer and ductal carcinoma in situ.

 It has been suggested that CPM may increase cancer-specific survival. A recent retrospective study showed the CPM was associated with an improved disease-free (P = .0002) and overall survival (P = .03) at 17 years.

 However, the majority of studies over the past decade show inconsistent survival advantage. These studies are retrospective in nature.

There are no prospective studies that have examined survival benefit with CPM and there will likely never be a randomized trial of CPM. From a patient’s prospective, choosing a contralateral prophylactic mastectomy is driven by the fear of recurrent breast cancer.

 CPM substantially reduces the risk of developing contralateral breast cancer. However, the risk of systemic metastases from the incident cancer often outweighs the risk of contralateral breast cancer. Thus, many patients may not have a clear understanding of the actual survival benefit from a CPM.

Prospective Analysis of BRCA Testing and CPM

Given the increasing use of CPM and genetic testing, we performed a prospective study looking at preoperative BRCA testing and the use of CPM. We sought to understand the factors before and after genetic testing that contribute to a breast cancer patient’s decision to have a CPM despite being BRCA negative. We performed a demographic and qualitative questionnaire for stage 0 to III female breast cancer patients.

 Data collection after initial diagnosis of breast cancer was done prior to genetic testing and surgery, and 6 months following surgery. Only women who tested BRCA negative and chose a CPM were given the 6-month survey.

From 2010 to 2014, one hundred women were prospectively enrolled in the study. Women who chose CPM presented at a higher stage (P = .012). A BRCA mutation was found in nine women. Twenty-six women who were BRCA negative chose to undergo a CPM. Compared with women who did not have a CPM, women who underwent a contralateral mastectomy presented at a higher stage (P = .0157) and had invasive ductal carcinoma (P = .05). Twelve women who initially chose a unilateral mastectomy changed their surgery to CPM after genetic testing (P = .0023). We asked them why they chose to have a CPM. The main reason was to be alive for their children.

This is the first prospective study examining genetic testing, surgical choice, and CPM. BRCA-negative women were more likely to have a CPM if they presented at a higher stage and initially chose a unilateral mastectomy. Preoperative genotyping resulted in a significant change in a woman’s surgical choice. We believe that patients need to be educated about the role and perceived survival advantage of CPM and genotyping as part of their surgical decision making.

Genetic testing for cancers is an increasing field. With the inception of new tools such as Myriad myRisk™ Hereditary Cancer 25-gene panel, we can now identify eight primary cancer sites a patient is at risk for inheriting, including breast cancer. The role of the breast surgeon, multidisciplinary team, and genetic counselor will increase in helping women to understand what these genes mean and to accurately evaluate their risk of systemic and contralateral disease.

			Daly MB, Axilbund JE, Buys S, et al. Genetic/familial high-risk assessment: breast and ovarian. J Natl Compr Cancer Netw. 2010;8(5):562—594.

			Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117—1130.

			National Comprehensive Cancer Network, NCCN Guidelines. Version 2.2013. Hereditary Breast and/or Ovarian Cancer Syndrome. NCCN.org.

			Tuttle TM, Habermann EB, Grund EH, et al. Increasing use of contralateral prophylactic mastectomy for breast cancer patients: a trend toward more aggressive surgical treatment. J Clin Oncol. 2007;25(33):5203-5209.

			Boughey JC, Hoskin TL, Degnim AC, et al. Contralateral prophylactic mastectomy is associated with a survival advantage in high-risk women with a personal history of breast cancer. Ann Surg Oncol. 2010;17(10):2702—2709.

			Herrinton LJ, Barlow WE, Yu O, at al. Efficacy of prophylactic mastectomy in women with unilateral breast cancer: a cancer research network project. J Clin Oncol. 2005;23(19):4275- 4286.

			Howard-McNatt M, Isom S, Hurt G, et al. A prospective study of preoperative BRCA status determination and surgical choice. Accepted abstract to be presented at: Society of Surgical Oncology 2015 Annual Cancer Symposium; March 25- 28, 2014; Houston, TX.

Determination of BRCA1 and 2 mutation carrier status has become increasingly important. Estimates suggest that about 80% of breast cancers and 90% of ovarian cancers are sporadic; while only 5% to 10% of breast cancers are hereditary. 

BRCA Testing and Contralateral Prophylactic Mastectomy

Approximately 22,000 women will be diagnosed with epithelial ovarian cancer (EOC) in the United States in 2014, making it the nation’s second most common gynecologic malignancy.

 The cancer, which often presents at an advanced stage, causes more deaths than any other type of gynecologic malignancy.

Current standard treatment for EOC is a combination of surgery and platinum-based chemotherapy. Although most patients initially respond to treatment, the majority of them eventually develop resistance to platinum therapy, and the cancer recurs. Long-term cure rates languish between 20 and 30 percent.

An important and unique characteristic of ovarian cancer is that it tends to recur within, and remain confined to, the abdominal (peritoneal) cavity for most of its natural history, rather than spreading to distant organs. Once a recurrence in the peritoneal cavity is diagnosed, the disease is no longer curable, and median progression-free survival is six to nine months.

Prevention of disease progression and improvement of treatment strategies are therefore of utmost importance.

Because the peritoneal cavity is the predominant site of disease, local intraperitoneal (IP) drug delivery has been evaluated in randomized clinical trials.

These trials compared standard intravenous (IV) chemotherapy to cisplatin-based IP therapy delivered through an IP access device after postoperative recovery (several weeks after surgery).

In a 2006 trial, 2 a statistically significant increase in the median progression-free and overall survival was recorded for the cisplatin/paclitaxel IP treatment compared to the IV group, with a survival benefit of 6 and 16 months, respectively. However, a substantial percentage of patients were unable to complete the planned six cycles of cisplatin/paclitaxel IP chemotherapy, in most cases due to abdominal discomfort following postoperative adhesion barriers and IP catheter-related complications.

Hyperthermic Intraoperative Intraperitoneal Chemotherapy (HIPEC)

HIPEC differs from traditional postoperative IP delivery primarily in terms of timing (it is administered as a one-time dose in the operating room at the time of cytoreductive surgery) and heating of the antineoplastic drug (Figure 1).

The local therapeutic strategy has been explored in the treatment of other solid tumors, including pseudomyxoma peritonei and appendiceal and colorectal cancers,5 both of which have a similar propensity for peritoneal spread as EOC.

Proposed advantages of the intraoperative, single- dose approach include controlled intraoperative drug exposure without the barriers of postoperative adhesions. In addition, hyperthermia has been shown to increase tumor penetration of anticancer drugs and to synergistically enhance cyotoxicity of platinum agents.

Similar to postoperative IP treatment, the approach is most effective in patients with minimal residual disease after cytoreductive surgery. In contrast to established experience with postoperative normothermic IP treatment, prospective studies on HIPEC in EOC are scant.

In short, surgical cytoreduction with HIPEC is a rational but still experimental approach in the management of EOC.

Memorial Sloan Kettering researchers are currently exploring the combination of surgical tumor resection and HIPEC with platinum agents in patients with recurrent ovarian cancer. An initial small pilot study showed HIPEC to be safe.

Pharmacokinetic data confirmed exceedingly high IP drug concentrations. In addition, analysis of tissue confirmed platinum-induced DNA adducts in tumor biopsies, demonstrating penetration and antineoplastic activity in target cells. After 20 months of median follow- up time, the median progression-free survival was 13.6 months. The results were encouraging to further determine the efficacy of HIPEC as a complementary treatment in patients with EOC.

MSK’ s Gynecologic Disease Management Team subsequently initiated a randomized phase II study (Figure 2)¬; the first in-human randomized trial in the United States designed to compare the efficacy and safety of HIPEC with carboplatin at a dose of 800 mg/m2 administered as HIPEC after surgical resection in patients with recurrent ovarian cancer.

In the trial, patients with minimal residual disease of 5 mm or less will be randomized 1:1 to surgery with HIPEC (experimental arm, n = 49) or surgery only (standard therapy arm, n = 49). Both arms will receive standard postoperative IV chemotherapy after recovery (3-4 weeks after surgery).

Our primary objective is to determine the proportion of patients who will have no evidence of disease progression at 24 months after surgical resection, with or without HIPEC. The trial will further explore the safety and efficacy of HIPEC, and the results may have an impact on how patients with advanced ovarian cancer are treated in the future.

			Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9-29.

			Armstrong DK, Bundy B, Wenzel L, et al; GynecologicOncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.

			Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950-1955.

			Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:1001-1007.

			Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versussystemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21:3737-3743.

			Zivanovic O, Abramian A, Kullmann M, et al. HIPEC ROC I: a phase I study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer. Int J Cancer. 2015;136(3):699-708

Approximately 22,000 women will be diagnosed with epithelial ovarian cancer (EOC) in the United States in 2014, making it the nation's second most common gynecologic malignancy.1 The cancer, which often presents at an advanced stage, causes more deaths than any other type of gynecologic malignancy.

January 2015 | Oncology & Biotech News

Dawn of US Biosimilar Era Arrives

ASH Meeting Highlights a Great Year and Builds Momentum Toward a New Era in Cancer Care

BRCA Testing and Contralateral Prophylactic Mastectomy

HIPEC for Ovarian Cancer: An Exciting Locoregional Strategy