OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Although there is much work to be done on the research front, the 

 story is shaping up as an important development in oncology with the potential to generate novel therapies for notable subsets of patients with cancer as well as new strategies for preventing disease in at-risk populations.

Yet there are many considerations in translating the growing body of scientific knowledge about 

 mutations into clinical use, and some of these elements are tackled on 

. Given the higher risk of breast and ovarian cancer in 

 mutation carriers, should broader screening for the abnormality be implemented?

This question moved to the front burner recently when Mary-Claire King, PhD, whose research linked the 

 gene to hereditary breast cancer, suggested all women should be screened routinely at about age 30.

Mark E. Robson, MD, discussed the challenges in implementing screening beyond familial and ethnic risk factors at the 

 Miami Breast Cancer Conference in Miami Beach earlier this year.

His thoughts are captured in our cover story, “

 Screening Is Becoming a Thorny Public Health Issue

There also is the matter of which patients might be eligible for therapy directed at 

-mutated cancers. One impetus moving this discussion forward is the FDA’s approval in December of the PARP inhibitor olaparib—the first in a new class of drugs that is proving to be effective in patients with platinum-resistant ovarian cancer who carry the mutation.

Maurie Markman, MD, our editor-in-chief, discusses some of the intriguing therapeutic implications for 

 mutation carriers with pancreas and prostate cancers in his column, “

BRCA Experience Is Pointing the Way to a New Diagnostic Paradigm

As we move forward in this new era of precision medicine in oncology, the themes presented in these discussions surely will be raised in many forms. We consider molecular diagnostics vitally important in cancer care and thus one of our foremost editorial priorities. Please let us know what you would like to learn about these topics and, as always, thank you for reading.

Articles

Given the higher risk of breast and ovarian cancer in BRCA mutation carriers, should broader screening for the abnormality be implemented?

BRCA Questions Resound

Population-based cancer screening using genetic sequencing technology is an idea worthy of careful consideration, but there are many challenges to implementing such a program, according to Mark E. Robson, MD, a Miami Breast Cancer Conference faculty member who specializes in the identification and management of people who have inherited an increased risk for cancer.

 that predisposes a woman to breast or ovarian cancer, for example, “may not manifest itself until it causes cancer in a young person,” Robson said in an interview. “So, the argument is that if we test everybody and find those who have mutations, we will potentially be able to intervene early. This now becomes a potential public health benefit.”

Yet Robson, who serves as director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, sees many challenges in population-based testing for 

mutations. He explored these considerations in a presentation at the 32nd Annual Miami Breast Cancer Conference, held February 26-March 1 in Miami Beach, Florida.

“There is a conversation that’s taking place right now about whether there should be broader 

 testing offered to people who don’t necessarily meet any particular criteria, family, or personal history, and the rationale for that is that there are a number of people who have 

 mutations inherited from their father or who come from families where there is limited information,” Robson said in the interview.

 genetic screening entered the popular imagination in May 2013 when actress and director Angelina Jolie announced that she had undergone a double mastectomy based on the discovery that she had a 

 mutation that significantly increased her likelihood of developing breast and ovarian cancer. Jolie has a family history of ovarian cancer, but many other women with mutations do not have a history that would prompt testing.

Whereas the average woman in the United States has a 12% lifetime risk of breast cancer, 

 carriers have at least a 50% to 60% lifetime risk.

 mutations have an even higher risk of developing ovarian cancer—over 40% among 

 carriers, up from a 1.4% chance in women without the mutations.

 Prophylactic mastectomy reduces the chances of developing breast cancer by over 90%, and preventive salpingo-oophorectomy substantially reduces the risk of ovarian cancer, which is hard to detect by screening.

Large-scale population-based genetic test screening may not be practical because of issues of cost and complexities of interpretation. But it may be feasible for groups that have an increased chance of carrying a more limited range of mutations, said Robson, noting the Ashkenazi Jewish population (Jewish individuals of Eastern/Central European origin), of whom 1 in 40 carry one of three specific 

A study performed in Israel found that population-based testing had merit not merely because of the prevalence of 

 mutations among Ashkenazi individuals but also because the cancer risk among female carriers in that group increases dramatically with age.

For Jewish Ashkenazi women, the cumulative risks of developing either breast or ovarian cancer by age 60 and 80 years, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for 

 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for 

 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the (Ashkenazi) population,” the report said. “General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria.”

The study also suggested that an Ashkenazi population screening could serve as an investigative model for evaluating the genetic predisposition to cancer in other populations.

“It is an interesting step in the evolution of a genetic susceptibility testing from an almost boutique type of analysis with nothing but a personal utility, which was what it was back in the 1990s, now to something that is potentially so clearly clinically useful that it should be offered to everyone,” Robson said.

A strong advocate for more general screening is Mary-Claire King, PhD, who won the 2014 Lasker- Koshland Special Achievement Award in Medical Science for linking the 

 gene to hereditary breast cancer. “To identify a woman as a carrier only after she develops cancer is a failure of cancer prevention,” King and colleagues wrote in a 

Journal of the American Medical Association

 “It is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care.”

The World Health Organization has supported the use of population-based genetic screening where the disease risk through identifiable genetic mutations is demonstrably high and effective treatments exist.

 The US Preventive Services Task Force has recommended that primary care providers screen women via questionnaire to determine whether they have a family history of breast, ovarian, tubal, or peritoneal cancer, and then recommend those with positive results for 

Although they endorsed broad screening, King and her fellow researchers said testing for 

 mutations should be carefully defined, since there are numerous 

mutations that may or may not threaten an individual’s health. “The challenge is not identification, but interpretation, of making sense of what is identified. Thus far, cancer genetic testing has responded poorly to this challenge,” they wrote.

Includes fallopian tube and primary peritoneal cancers.

		BC indicates breast cancer; NCCN, National Comprehensive Cancer Network; TNBC, triple-negative breast cancer; USPSTF, US Preventive Services Task Force.

		1. US Preventive Services Task Force. BRCA-related cancer: risk assessment, genetic counseling, and genetic testing. http://goo.gl/q5PKTU.

		Published December 2013. Accessed April 6, 2015. 2. NCCN Clinical Practice Guidelines. Version 1.2015. Published March 30, 2015.

	A number of challenges require consideration when proposing a broad public health genetic screening for an adult onset disorder, Robson said.

	“There are some difficult questions that come up, centered around who is the right target, what is the right test, to whom should it be delivered, should it be full sequencing or should it just be looking for mutations in target populations, and what information do people need to be able to decide whether or not they want to participate?

	“Although we do have effective treatments for 

-related predispositions, the demonstrably effective treatments are surgical, and can have significant negative impact upon the women who undergo the procedure. Women considering testing need to understand the decisions that will follow if they are found to carry a mutation.

	“So, do we as a society want to have this be something that follows the traditional path of informed decision making by an individual after nondirective counseling, or is this something that we should recommend the same way we recommend vaccination? Is this an opt-in or is this an opt-out kind of question?” Robson asked.

			McCarthy AM, Armstrong K. The role of testing for 

			Gabai-Kapara E, Lahad A, Kaufman B, et al. Population-based screening for breast and ovarian cancer risk due to 

			King MC, Levy-Lahad E, Lahad A. Population-based screening for 

: 2014 Lasker Award [published online September 8, 2014]. 2014;312(11):1091-1092.

			Moyer VA, U.S. Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for 

-related cancer in women: U.S. Preventive Services Task Force recommendation statement. 

Population-based cancer screening using genetic sequencing technology is an idea worthy of careful consideration, but there are many challenges to implementing such a program.

Broad BRCA Screening is Becoming a Thorny Public Health Issue

 The FDA has approved nearly two dozen monoclonal antibodies (mAbs) that have revolutionized the treatment of a variety of different cancers. Until recently, however, mAbs seemed to have limited capacity to improve survival in multiple myeloma, a common hematologic cancer that remains incurable despite substantial improvements in treatment options.

Now, the prospects for mAbs to change the treatment paradigm for the malignancy have grown considerably brighter as early-phase clinical trial results suggest that emerging agents with novel mechanisms of action are capable of delivering significant efficacy. Two of these agents, elotuzumab and daratumumab, have garnered the FDA’s coveted breakthrough therapy status as part of combination regimens. And, the success of immune checkpoint blockade strategies in other malignances has spurred researchers to consider agents targeting the programmed cell death 1 (PD-1) pathway in multiple myeloma therapy.

Indeed, the field is brimming with discovery efforts 

. Of these novel agents, elotuzumab is the most advanced mAb in terms of clinical development and results from phase III trials are eagerly anticipated.

Multiple myeloma, the second most common hematologic malignancy, is characterized by aberrant clonal expansion of malignant plasma cells in the bone marrow. In the past decade, an evolving understanding of the pathophysiology underlying multiple myeloma has fueled successful development of several novel agents, including immunomodulatory drugs (IMiDs) such as lenalidomide (Revlimid) and thalidomide (Thalomid) and the proteasome inhibitors bortezomib (Velcade) and carfilzomib (Kyprolis), which have significantly improved survival.

Despite these advances, multiple myeloma remains mostly incurable; the majority of patients eventually relapse or become refractory to therapy and then face an average survival of less than a year. Researchers, however, believe that multiple myeloma is a fundamentally curable disease, if this therapeutic challenge can be met. This has driven the development of new therapies, including histone deacetylase inhibitors, next-generation proteasome inhibitors, and a number of immunotherapies.

mAbs function as anticancer agents via a number of different mechanisms that are not mutually exclusive. These include:

		Boosting antitumor immune response or removing tumor-mediated suppression of the immune system

		Targeting cancer cells for destruction by the immune system by engaging immune effector cells via antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC)

		Blocking the activity of proteins that function in the hallmark abilities of cancer cells

In 1997, rituximab (Rituxan), which targets the CD20 antigen, became the first mAb to receive regulatory approval for the treatment of B-cell lymphomas but is not specifically indicated for patients with multiple myeloma. Although CD20 is expressed in 15%-20% of multiple myelomas, rituximab has shown limited efficacy in the clinical setting in this malignancy. Similarly, other mAbs spanning a diverse range of targets, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), CD40, CD56, and CD74 have not advanced in development despite significant promise in preclinical studies.

The lack of success with mAbs can be attributed, at least in part, to the complex and heterogeneous nature of multiple myeloma. Now, technological advancements and a greater understanding of the disease’s pathophysiology have permitted the identification of target antigens that are more specific and broadly expressed, spawning the development of a number of novel mAbs that are demonstrating clinically meaningful efficacy. The ongoing success of these agents was highlighted in numerous reports at the 2014 American Society of Hematology (ASH) Annual Meeting in San Francisco in December.

Two principal targets for mAb therapy are showing particular promise. CD2 subset 1 (CS1), also known as signaling lymphocytic activation molecule 7 (SLAMF7), and CD38 are both glycoproteins expressed highly and nearly uniformly on the surface of multiple myeloma cells. Importantly, they are also expressed only at low levels on other lymphoid and myeloid cells; CS1 in particular is undetectable on the majority of normal tissues or hematopoietic stem cells, making it an ideal therapeutic target.

		This illustration depicts some of the many interactions in the microenvironment that help promote the growth of multiple myeloma cells. Notable targets for anticancer therapy include CS1, IL-6, BAFF, CXCR4, and VEGF.

		BAFF indicates B-cell activating factor; BMEC, bone marrow endothelial cell; BMSC, bone marrow stromal cell; CS1, CD2 subset 1; CXC, chemokine receptor; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IDO, indoleamine 2,3-dioxygenase 1; IL-6, interleukin-6; MET, mesenchymal epithelial transition factor; NF-Ä¸B, nuclear factor kappa-light-chain-enhancer of activated B cells; tol-DC, tolerogenic dendritic cell; VEGF, vascular endothelial growth factor.

		Adapted from Rutella S, Locatelli F. Targeting multiple-myeloma-induced immune dysfunction to improve immunotherapy outcomes. 

 2012; article ID 196063. http://dx.doi.org/10.1155/2012/196063.

The precise biological function of CS1 is unknown. Of note, CS1 is expressed on natural killer (NK) cells and is thought to play a role in their activation. Consequently, the potential of the CS1 pathway to regulate NK cell cytotoxicity is an area of intense interest since this could give CS1-targeted agents powerful immunotherapeutic potential.

Elotuzumab is a first-in-class humanized immunoglobulin (IgG1) mAb targeting CS1. Preclinical studies demonstrated substantial single-agent antitumor activity in multiple myeloma, primarily via ADCC mediated by NK cells. Several studies have shown that elotuzumab likely has other mechanisms of action but these are currently less well defined. These promising findings pushed elotuzumab forward into clinical development, but monotherapy did not prove effective; although more than a quarter of patients achieved stable disease (SD), there were no responses.

In preclinical studies, elotuzumab also demonstrated synergistic activity with lenalidomide and bortezomib and it is in the combinatorial setting that this mAb has proved most promising. The hypothesis about this synergy is that the upregulation of the immune system mediated by IMIDs is focused by the mAb, selectively augmenting the antitumor immune response against a specific antigen, rather than just generally boosting the immune system.

In combination with lenalidomide, elotuzumab has been well tolerated in phase I and II studies, with durable responses in a significant proportion of patients. Clinical efficacy of the combination of elotuzumab, lenalidomide, and low-dose dexamethasone in patients with relapsed/ refractory disease was established in a phase Ib/II study (NCT00742560). Preliminary results from the 28 patients enrolled in the phase I dose- escalation portion of the trial demonstrated an objective response rate (ORR) of 82%, with no dose- limiting toxicity (DLT) to the maximum dose of 20 mg/kg and a median time to progression (TTP) of 33 months for all treatment groups.

In the phase II part of the trial, a further 73 patients were treated at 10 mg/kg and 20 mg/kg doses of elotuzumab. The overall ORR remained consistent with that previously reported at 84% (92% and 76% in the 10 mg/kg and 20 mg/kg groups, respectively), including stringent complete response (CR) or CR of 14%, very good partial response (VGPR) of 43%, and partial response of 27%. The median duration of response was 20.8 months and the median progression-free survival (PFS) was 29 months; follow-up on overall survival (OS) continues. The most common treatment-related adverse events (AEs) were diarrhea, muscle spasms, fatigue, constipation, nausea, and upper respiratory tract infection, while grade 3/4 AEs included neutropenia, thrombocytopenia, lymphopenia, and anemia. Based on these data, the FDA awarded elotuzumab breakthrough therapy status in May 2014.

The results of a phase Ib study of this combination in patients with various levels of kidney function (normal, severe renal impairment, and end-stage renal disease) were also presented at ASH. The combination was well tolerated regardless of kidney function and responses were observed in all three groups. Renal impairment is common in patients with relapsed/refractory disease and adversely affects treatment outcomes— thus, elotuzumab could represent an important treatment option for these patients.

Two large phase III trials of elotuzumab in combination with lenalidomide and dexamethasone are currently under way in newly diagnosed (ELOQUENT-1) and relapsed/refractory (ELOQUENT-2) settings. Patient recruitment is complete and the results are eagerly awaited.

Additionally, elotuzumab in combination with bortezomib led to PRs in 48% of patients, two-thirds of whom were refractory to bortezomib, with 63% obtaining at least minor repsonse (MR), in a phase I trial. This combination was also well tolerated, with no DLTs and maximum tolerated dose (MTD) reached. Phase II trials are ongoing. Preliminary results of a phase I/II study of elotuzumab with lenalidomide, bortezomib, and dexamethasone (SWOG 1211) in newly diagnosed patients with high-risk disease also suggest this four-drug combination is well tolerated.

The functions of CD38 span cell adhesion, signal transduction, and calcium signaling, among others, making this tumor-associated antigen an attractive target. Currently, there are three mAbs targeting CD38 in active clinical development: daratumumab, SAR650984, and MOR202. Each binds to a different part of the CD38 receptor, though the clinical significance of this has not been determined. Daratumumab is the most advanced in terms of development and has also gained the FDA’s breakthrough therapy designation. As with elotuzumab, significant antitumor activity and synergy with lenalidomide and bortezomib were observed in preclinical studies.

Daratumumab has better single-agent activity than elotuzumab in clinical trials, with doses ≥4 mg/kg generating 42% PR and 25% MR in phase I/II trials. However, it still holds most promise in combination with IMiDs and proteasome inhibitors. The first reports of a phase I/II study of daratumumab in combination with lenalidomide and low-dose dexamethasone were seen at the 2014 American Society of Clinical Oncology Annual Meeting. Enrollment in this study is now complete and updated results were presented at ASH for 43 heavily pretreated relapsed/refractory patients (13 phase I dose-escalation, 30 phase II expansion cohort at 16 mg/kg dose). ORR was 100% in phase I (including CR, 31%; VGPR, 46%), and 86.7% in phase II (including CR, 6.7%; VGPR, 43%), and the VGPR rate was 75% in patients treated for at least 6 months. The combination was well tolerated, with manageable toxicity.

Preliminary results of an ongoing phase I study of SAR650984 in combination with lenalidomide and dexamethasone were also reported at ASH. Among 31 heavily pretreated patients, many of whom were double refractory to IMiDs and proteasome inhibitors, the median PFS was 6.2 months, the ORR was 64.5%, the clinical benefit rate (CBR) was 71%, and median DOR was 23.1 weeks at 6 months’ follow-up. The combination also was well tolerated, with no DLTs and no unexpected toxicities.

		Table. Monoclonal Antibodies in Development for Multiple Myeloma (CLICK TO ENLARGE)

Individual trials may have additional industry or academic collaborators.

Trial is ongoing but not recruiting participants.

		BAFF indicates B-cell activating factor; CS1, CD2 subset 1; CTLA-4, cytotoxic T-cell lymphocyte antigen-4; CXCR4, chemokine receptor type 4; ICAM-1/CD54, intracellular adhesion molecule 1; IL-6, Interleukim-6; KIR, killer cell immunoglobulin-like receptor; MM, multiple myeloma; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; SLAM7, signaling lymphocytic activation molecule F7; VEGF-A, vascular endothelial growth factor-A.

Indatuximab ravtansine (BT-062) is another promising mAb with a different mechanism of action. It is an antibody—drug conjugate, using the CD138 (syndecan-1) antigen, expressed on the surface of the majority of multiple myeloma cells, as a means of specifically directing the cytotoxic activity of a conjugated drug, the maytansinoid DM4, to multiple myeloma cells. Numerous clinical trials are ongoing and preliminary data from the phase I dose-escalation portion of a phase I/IIa study of BT-062 in combination with lenalidomide and dexamethasone were reported at ASH. Among 36 patients evaluable for response, the ORR was 78%, including 3% stringent CR, 5% CR, 28% VGPR, and 42% PR. There was also a 5% MR and a 17% SD rate, translating into a clinical benefit rate of 100% when add to the ORR rate.

With improved understanding of the molecular mechanisms of multiple myeloma has come an increasing appreciation of the importance of the bone marrow microenvironment, which is intricately linked to multiple myeloma cells and plays a critical role in regulating their growth and survival and in promoting resistance to conventional therapies.

Researchers have begun to mine the components of the bone marrow microenvironment and mediators of its interaction with multiple myeloma cells as targets for more effective mAb therapy. Indeed, both CS1 and CD38 may play a role in mediating adhesion of multiple myeloma cells to the bone marrow stroma cells, which may also partly explain the success of targeting those antigens.

Siltuximab (Sylvant) is a chimeric mAb targeting interleukin-6 (IL-6), a cytokine produced predominantly by the bone marrow stromal cells that plays a role in the proliferation and survival of multiple myeloma. It has been studied as both monotherapy and in combination with lenalidomide/dexamethasone and bortezomib/ melphalan/prednisone in phase II trials, demonstrating promising efficacy in heavily pretreated populations.

Ulocuplumab (BMS-936564) is a first-in-class fully human IgG4 mAb targeting the chemokine receptor CXCR4. Chemokines, such as CXCL12, are produced by the bone marrow stromal cells and play an integral role in multiple myeloma cell growth and progression and their recruitment to the bone marrow microenvironment.

CXCR4 is widely expressed on hematopoietic cells, including multiple myeloma cells, and is the receptor for CXCL12. Thus, disrupting binding of CXCR4 to CXCL12 is a potentially promising therapeutic target. A phase Ib study presented at ASH evaluated ulocuplumab alone or in combination with lenalidomide and low-dose dexamethasone or bortezomib and dexamethasone in 44 patients with relapsed/refractory disease. It proved safe and demonstrated high response rates, with no MTD up to a 10 mg/kg dose, only 1 DLT (delayed platelet recovery) in the bortezomib arm, and no grade 4 toxicity. The ORR was 50%, including 2% CR, 14% VGPR, and 34% PR.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in New Haven, Connecticut.

			Berdeja J, Jagannath S, Zonder J, et al. Pharmacokinetics and safety of elotuzumab in combination with lenalidomide and dexamethasone in patients with multiple myeloma and various levels of renal function: results of a phase 1b study. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 2119.

			Donato F, Gay F, Bringhen S, et al. Monoclonal antibodies currently in phase II and III trials for multiple myeloma. 

			Ghobrial IM, Perez R, Baz R, et al. Phase Ib study of the novel anti- CXCR4 antibody ulocuplumab (BMS-936564) in combination with lenalidomide plus low-dose dexamethasone, or with bortezomib plus dexamethasone in subjects with relapsed or refractory multiple myeloma. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 3483.

			Kelly KR, Chanan-Khan A, Heffner LT, et al. Indatuximab ravtansine (BT062) in combination with lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma: clinical activity in patients already exposed to lenalidomide and bortezomib. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 4736.

			Kuroda J, Nagoshi H, Shimura Y, Taniwaki M. Elotuzumab and daratumumab: emerging new monoclonal antibodies for multiple myeloma. 

			Liu YC, Szmania S, van Rhee F. Profile of elotuzumab and its potential in the treatment of multiple myeloma. 

			Martin TG, Baz R, Benson Jr DM, et al. A phase Ib dose escalation trial of SAR650984 (anti-CD38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 83.

			Moreau P, Mateos MV, Blade J, et al. An open-label, multicenter, phase 1b study of daratumumab in combination with backbone regimens in patients with multiple myeloma. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 176.

			Plesner T, Arkenau HT, Lokhorst HM, et al. Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 84.

			Richardson PG, Jagannath S, Moreau P, et al. Final results for the 1703 Phase 1b/2 study of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 302.

			Usmani SZ, Sexton R, Ailawadhi S, et al. SWOG 1211: Initial report on phase I trial of RVD-elotuzumab for newly diagnosed high-risk multiple myeloma. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 4762.

			Veillette A, Guo H. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma [published online June 2, 2013]. 

The prospects for mAbs to change the treatment paradigm for multiple myeloma have grown considerably brighter as early-phase clinical trial results suggest that emerging agents with novel mechanisms of action are capable of delivering significant efficacy.

New Era for Monoclonal Antibodies on Horizon in Multiple Myeloma

Before the Internet and global interconnectedness, advancements in science and medicine were usually slow and incremental, with research and findings conducted by solo researchers and shared over time.

“The idea of team science is something that evolved quite a lot in the past few years. It used to be that this idea of large groups was more uncommon than it is now. It has become quite the norm to assemble large groups to solve problems more quickly, and I’m all for it,” said Jedd D. Wolchok, MD, PhD, the recipient of the 2014 Melanoma Giants of Cancer Care® award. Wolchok is chief, Melanoma and Immunotherapeutics Service, and Lloyd J. Old Chair for Clinical Investigation at the Memorial Sloan Kettering Cancer Center in New York City.

The collaborative effort, in which all the researchers involved play a role to accomplish a common goal, can only succeed with a keen understanding of interpersonal dynamics. For Wolchok, this kind of group dynamic is well demonstrated in a favorite book, 

, the classic biography of J. Robert Oppenheimer written by Martin J. Sherwin and Kai Bird. The coming together of colleagues from multiple disciplines toward a vital and common goal was evident in the Manhattan Project and subsequently in the efforts to find more peaceful and controlled applications of the atomic science.

Once a group comes together, good decisions can be made based on logic, reasoning, and instinct, with the good of a group sharply in focus. Approaching problems analytically, logically, and with calmness has gotten Wolchok this far—and for patients with melanoma that is quite far indeed.

Wolchok is among the team of scientists who are developing anticancer strategies aimed at manipulating the body’s immune checkpoints, thus promoting a more robust activation of T cell responses to cancerous cells. He served as the principal investigator on the pivotal clinical trial that led to the FDA’s 2011 approval of ipilimumab (Yervoy), an anti-CTLA-4 monoclonal antibody that is the first agent to employ the immune checkpoint blockade strategy in any tumor type.

The death of a loved one is often the inspiration for a budding scientist to pursue a career in cancer research. In Wolchok’s case, the death was his grandmother’s—she had pancreatic cancer&mdash;but his passion for research was gradual, fueled by the summers away from Princeton University, where he completed his undergraduate studies.

“By the time I finished college, the research experiences I had during summer breaks while working at Memorial Sloan Kettering in the translational laboratories fueled my interest,” said Wolchok. “I saw incredible possibilities that existed in terms of moving research from the laboratory to the clinic, and taking those successes and failures back to the laboratory for refinement. That was a very inspiring set of experiences for me.”

Wolchok was mentored by Lloyd J. Old, MD, considered the father of modern tumor immunology, and Alan N. Houghton, MD. The Houghton Laboratory brings together a mix of molecular biologists, immunologists, medical oncologists, and surgeons. The participants understand that this type of environment encourages cross-fertilization of scientists and clinical investigators. The laboratory, which Wolchok now heads, is interested in two fundamental questions: “How does the immune system recognize cancer, particularly mutations?” and, “How does the immune system reject cancer?”

Wolchok considers it an incredible honor to continue his mentors’ work, although he would much rather have Houghton actively engaged in the ongoing research. Houghton suffers from amyotrophic lateral sclerosis and Lloyd Old died from prostate cancer in 2011.

Until about three years ago, there were no medications that improved survival in patients with metastatic melanoma. Immunotherapies were considered complicated and marginal. They were only administered at a few cancer centers. In addition, immunotherapy’s low success rate and low tolerability, with only otherwise healthy patients as candidates, made it a difficult clinical treatment to pursue.

“I think one had to be persistent in both immunotherapy and in melanoma treatment because there was so much failure until recently,” said Wolchok. “There were so many trials that did not meet expectations. There was so much questioning of the validity of the underlying science because of that.” But he pointed out that persistence in this field has paid off. Researchers stuck with it until agents were developed that could modulate the immune system in a potent enough manner to impact tumor growth.

“In my mind, the science was never in question. Because many ideas were explored in the clinic, but failed to meet expectations, there was a characterization of the field as being speculative in nature. That was a challenge,” said Wolchok.

He recalled that much of the focus of discussions with patients was about the hope and promise of clinical trials. Following advances in the understanding of melanoma biology and tumor immunology, there have been seven new therapies approved for the treatment of melanoma since 2011, including ipilimumab, two anti-PD-1 antibodies, and three targeted agents. “The tenor of those patient conversations now has some concrete source of hope,” Wolchok said.

The deployment of immunotherapy agents in clinical trials and in practice has prompted a new way of looking at how patients respond to therapy. Wolchok discussed one patient who participated in a phase II trial involving ipilimumab in which an initial set of imaging scans suggested that the disease had grown markedly worse since treatment began.

“Yet the patient told me that he felt better. It caused my colleagues to rethink the way we judge the clinical efficacy of this kind of cancer therapy,” said Wolchok. It also gave him a newfound respect for the complex biology that exists between the patient and the tumor, and the fact that when treating the immune system, the patient’s condition might not improve on schedule.

“That patient had another set of imaging scans performed 2 months later with no further therapy and showed that almost all the disease had regressed,” Wolchok said. In the official documents filed for the trial with the FDA, that patient was scored as a drug failure. “In that instance, I realized that we need to rethink the way we judge the clinical activity of novel anticancer therapies.

“My lab research is very linked to clinical care, either in forming new clinical trials or helping to understand current clinical trials.There is nothing that can possibly be more thrilling than to help a patient improve the state of his or her health. That is the number one thing that buoys me but there is a lot of laboratory science that feeds forward and feeds back from that,” said Wolchok.

Wolchok values the collaborative effort— whether it’s working on a vexing problem in the laboratory with many team members or mastering a challenging musical piece in the Brooklyn Wind Symphony where he plays tuba. He pointed out that “there aren’t many career opportunities for professional tuba players,” but even if there were, he still would not consider a change in career paths.

The Giants of Cancer Care award is given for individual accomplishments, but Wolchok understands that success stems from a team effort and from others who have come before. When accepting the award during a reception last year in Chicago, he noted that some people in attendance were “mentors and role models to me,” such as James P. Allison, PhD, who won the 2014 Giants award for scientific advances in recognition of his work in elucidating the checkpoint blockade strategy. “Having a former fellow from Memorial Sloan Kettering, Dr Jason Luke, present me with the award—I felt acknowledged in a 360-degree way,” said Wolchok. “That was very meaningful to me.”

Department of Medicine Harvard Medical School

“There are some people (eg, Oprah, Michael) who make such large contributions to their field that they can be recognized by only their first name. An immunotherapy pioneer, Dr Wolchok and his team are identifying new targets, developing predictive bio- markers, and uncovering mechanisms of resistance.

“His team’s work will ensure the rational application of an approach that can dramatically improve patient outcomes. He is an investigator who is as humble as he is accomplished. We all want to be more ‘like Jedd.’”

“I met Dr Wolchok when I was a first-year medical student. At that impressionable early stage of medical training, Dr Wolchok’s compassionate patient care and enthusiasm for his research in immunotherapy profoundly affected my decision to become an oncologist.

“Dr Wolchok has taught the world how to treat patients with new immunotherapies, particularly antibodies that block CTLA-4 (ipilimumab) and PD-1 (nivolumab and pembrolizumab). The observations he has made in his clinic have led to remarkable advances in our understanding of how these therapies can benefit patients. He has been a leader in developing the immune-related response criteria; finding the best strategies to treat immunotherapy-related side effects; and conducting translational studies in his laboratory that inspire the next major treatment advances. Cancer immunotherapy would not be where it is today without his leadership of this field.

“I feel so fortunate to be mentored by Dr Wolchok. He repeatedly advocates for my career development, often selflessly promoting me and other junior mentees with major opportunities that he otherwise could have had for himself. Beyond career growth, Dr Wolchok has welcomed me to New York City and provided a ‘home away from home.’”

			Kiess AP, Wolchok JD, Barker CA, et al. Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment [published online March 5, 2015]. 

. pii:S0360-3016(15)00010-3. doi:10.1016/j.ijrobp.2015.01.004.

			Maio M, Grob JJ, Aamdal S, et al. Five-year survival rates for treatment-naiÌˆve patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial [published online February 23, 2015]. 

			Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. [published online February 9, 2015]. 

			Hannani D, VeÌtizou M, Enot D, et al. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25 [published online January 13, 2015]. 

			Gerber NK, Young RJ, Barker CA, et al. Ipilimumab and whole brain radiation therapy for melanoma brain metastases [published online October 2, 2014]. 

			Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial [published online July 15, 2014]. 

			Carvajal RD, Wong MK, Thompson JA, et al. A phase 2 randomised study of ramucirumab (IMC-1121B) with or without dacarbazine in patients with metastatic melanoma [published online June 12, 2014]. 

			Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma [published online June 2, 2103]. 

			Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma [published online June 2, 2013]. 

			Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. 

			Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma [published online June 5, 2011]. 

			Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials [published online September 8, 2010]. 

Jedd D. Wolchok, MD, PhD, played an important role in the development of ipilimumab, the first drug to target an immune checkpoint as an anticancer strategy. He was honored in the Melanoma category with a 2014 Giants of Cancer Care® award.

Immunotherapy Innovator Jedd Wolchok Honored

Treatment options are expanding in the setting of metastatic melanoma. In January, the National Comprehensive Cancer Network (NCCN) revised its melanoma treatment guidelines to include pembrolizumab and nivolumab, along with ipilimumab, among the preferred systemic options for patients with advanced or metastatic disease.

 These immunotherapy advances are among the emerging treatment approaches that make it an exciting time for patients with melanoma and their physicians, according to experts who participated in a recent 

, the panel of clinical and research experts discussed the evolving treatment of metastatic melanoma during a Peer Exchange session entitled “Updates on the Treatment of Malignant Melanoma.”

An increased understanding of tumor pathology and immunology has led to seven new melanoma drug approvals since 2011, including the recent approvals of the PD-1 inhibitors nivolumab and pembrolizumab. In addition, several completed and ongoing trials show promise that these immunotherapies will improve survival for patients with melanoma. The integration of immunotherapy is still evolving, and the panel discussed several key issues related to its current and future use.

Although much progress has been made with immunotherapy, there are still no definite predictors for response to agents that inhibit PD-1 or its ligand PD-L1. 

, described a retrospective study of patients on pembrolizumab.

 The researchers “quantified to baseline tumor size in every patient and found out that that was the number one independent prognostic factor, both for survival as well as for response.”

Questions remain whether PD-1 or PD-L1 expression should be used as a predictive marker for nivolumab and pembrolizumab.

, explained that even though “there are increasing data coming out to suggest that PD-L1 expression is associated with the higher response rate...the corollary is that even though the response may be lower in the PD-L1-negative [tumors], there are still some patients who will respond.”

With several immunotherapies available for the treatment of malignant melanoma, oncologists are challenged with assessing treatment response. 

 explained that there can be a “lot of angst when you have to decide, is someone having true progression or is someone having what we know as pseudo-progression, which is essentially an inflammatory response, an immunologic response to the therapy around the tumors where things look worse but the patient is actually responding.” It is not uncommon for patients to have new lesions develop and other lesions get larger before responding to therapy, 

 explained. For instance, in the phase III OPTiM study

 looking at talimogene laherparepvec (TVEC), an intralesionally administered oncolytic vaccine, almost half of patients who ultimately achieved a durable response had growth of their initial melanoma beforehand, said Andtbacka, who helped lead the study.

Other situations that challenge response assessment with immunotherapy include late responders and responders who have persistent lesions. With persistent lesions, a PET scan can verify the patient’s response and isolated persistent lesions can even be treated with surgery or radiotherapy.

Pavlick explained that when assessing how a particular patient is faring on therapy, the patient’s condition is the most important factor, with imaging results and laboratory values being secondary. For example, she said that if a patient appears to be stable or improving but the scan looks worse, she typically tracks the patient for another 6 to 8 weeks to assess disease progression. Joseph added that if the patient was taking a PD-1 inhibitor, he would repeat the scan in 12 weeks, unless there is clinical deterioration.

Hamid added that he would continue therapy in a patient who has stable disease on immunotherapy because these patients have overall survival similar to that of patients who achieve a classic complete remission. Achieving stable disease appears to be meaningful, especially with immunotherapy. This will be important information for oncologists treating cancers other than melanoma. Andtbacka explained that if patients with prolonged stable disease want to discontinue therapy, he follows them with CT or PET scans every 3 months. It is not uncommon, he remarked, to go back and operate and find that there is only fibrosis there and no active tumor. Importantly, Kaufman added, there doesn’t appear to be cross-resistance among immunotherapies; thus, a patient who doesn’t respond to one immunotherapy may respond to another.

The optimal duration of therapy with nivolumab and pembrolizumab remains an unanswered question that is an important goal for randomized trials. According to Joseph, patients in clinical trials have stayed on these agents indefinitely. However, many patients who have achieved complete remission seek to discontinue therapy at some point. Pavlick stressed that the overall effect of constantly stimulating the immune system must be considered.

Joseph noted that he has stopped PD-1 inhibitor therapy successfully, but that late relapses have been reported anecdotally. Joseph added that the risk of discontinuing treatment seems to be low because patients can be retreated with the PD-1 inhibitor at recurrence. Kaufman confirmed that some patients will respond to immunotherapy again when retreated. This has been seen with ipilimumab and interleukin-2 (IL-2). However, until more is known, his preference is to try a different therapy in a patient whose disease progresses after PD-1 inhibitor therapy.

Pavlick observed that although the toxicities with PD-1 inhibitors are not benign, they appear to be more easily managed than the toxicities with other immunotherapies she is accustomed to administering.

“PD-1 is probably the easiest drug I’ve ever administered as an oncologist,” remarked Joseph.

While rash, thyroid-related problems, and fatigue are common side effects, they are not dose-limiting. Pneumonitis is more of a concern for patients with lung cancer who receive PD-1 inhibitor therapy; however, oncologists still need to be highly suspicious of pneumonitis when a patient on a PD-1 inhibitor presents with respiratory symptoms, shortness of breath, cough, or difficulty breathing.

There is a scientific rationale for combining immunotherapies with one another and with other types of therapy for the treatment of advanced melanoma, with the ultimate goal of improving efficacy while maintaining tolerability. While the combination of the BRAF inhibitor dabrafenib with ipilimumab proved far too toxic, the clinical trial results for nivolumab with ipilimumab were very impressive. In fact, preclinical studies in mice have shown the additive potential for triple immunotherapy with CTLA-4, PD-1, and PD-L1 blockade, said Kaufman. He added that it remains unclear as yet what the toxicity profile would be for that combination. However, with some of the less toxic agents, TVEC and granulocyte-macrophage colony-stimulating factor (GM-CSF), it might be possible to think about three- and four-drug combinations.

The most mature data of combined immunotherapies in melanoma are from a study looking at ipilimumab with nivolumab.

 However, other immunologic agents are now being combined; for example, TVEC with ipilimumab or pembrolizumab, and ipilimumab with GM-CSF.

The trial of ipilimumab and GM-CSF9 actually showed a decrease in some of the toxicities over monotherapy, particularly gastrointestinal toxicities, said Kaufman.

Whether it is two or three agents being combined, it will be important to understand how to combine them to achieve greater responses with the least amount of toxicity for patients. “If we can increase response rates,” said Hamid, “maybe we can increase the long-term durability of responses and long-term survival advantage.” Pavlick commented that “you’re getting more efficacy when you combine them, but you’re also getting more toxicity, and I think that’s my biggest concern.” She said that with combined ipilimumab and nivolumab, a large percentage of patients will develop profound, rapid-onset diarrhea, similar to the way it presents with ipilimumab, and it needs to be managed early.

Radiation therapy is taking on an increased role based on evidence of an abscopal effect in combination with immunotherapy. An abscopal effect is a phenomenon in the treatment of metastatic cancer where localized treatment of a tumor causes not only shrinkage of the treated tumor but also shrinkage of distant tumors. According to Joseph, it is reassuring that the addition of radiation therapy can improve tumor response without adding further toxicity. Joseph described a case that exemplifies the additive effect of combining ipilimumab and radiation therapy in which a patient with a large lung metastasis had a much better response with the combination than what would be expected with either treatment alone. Concurrent stereotactic radiotherapy and ipilimumab are used in patients with brain metastases as well, explained Andtbacka. It is ideal to start immunotherapy as early as possible to try to achieve the abscopal effect. Hamid commented that the combination has resulted in significant responses in patients with melanoma who also have brain metastases.

Oncologists who treat patients with melanoma are collaborating with other physicians more often as therapeutic options and their associated toxicities continue to expand. The involvement of surgeons, interventional radiologists, pathologists, and others is necessary from diagnosis through treatment.

In addition, recognizing and managing the varied dermatologic, gastrointestinal, and endocrine toxicities may require additional specialties. Patients require and deserve a multidisciplinary approach based on the growing complexity involved in treating melanoma, noted Andtbacka.

			NCCN Clinical Practice Guidelines Melanoma Version 2.2015. Published January 1, 2015. Accessed March 24, 2015.

			Joseph RW, Elassaiss-Schaap J, Wolchok JD, et al. Baseline tumor size as an independent prognostic factor for overall survival in patients with metastatic melanoma treated with the anti-PD-1 monoclonal antibody MK-3475. 

			Kefford R, Ribas A, Hamid O, et al. Clinical efficacy and correlation with tumor PD-L1 expression in patients (pts) with melanoma (MEL) treated with the anti-PD-1 monoclonal antibody MK-3475. 

			Andtbacka RHI, Collichio FA, Amatruda T, et al. OPTiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. 

			Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). 

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01740297. Accessed March 25, 2015.

			Puzanov I, Milhem MM, Andtbacka RHI, et al. Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. 

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02263508.Accessed March 25, 2015.

Immunotherapy advances are among the emerging treatment approaches that make it an exciting time for patients with melanoma and their physicians.

April 2015 | Oncology Live®

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Immunotherapy Innovator Jedd Wolchok Honored

Experts Explore Immunotherapy Frontier in Melanoma

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Crossing Tumor Types: BRCA Experience Points Way to New Diagnostic Paradigm

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