June 2014, Part 2

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Immuno-Oncology Takes Center Stage

Lisa Raedler, PhD, RPh


More than 120 years after William Coley, MD, administered intratumoral injections of bacteria to patients with cancer with the goal of generating spontaneous remission,1 the number and complexity of immunomodulatory strategies for this patient population have grown exponentially. More than 250 abstracts that included the term “immunotherapy” or “immuno-oncology” were presented during the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). Recent ASCO news articles and press releases related to immunotherapies employed phrases like “new paradigm,” and adjectives, including “prominent,” “hot,” and “promising.”

What exactly are immuno-oncology agents? How are newer agents in this class different from traditional immunotherapies, such as interleukin-2 and interferon? Why are novel approaches to immunotherapy generating so much attention?

As noted, use of immunotherapy to treat cancer is an old idea. Four immunotherapy agents are currently approved for use by the US Food and Drug Administration (Table 1). Cytokine therapies, specifically interferon and interleukin-2, have been available for more than 20 years. The more recently approved agents (ie, cell-based therapies [therapeutic vaccines] and immune checkpoint inhibitors), however, represent new classes of immuno-oncology drugs. Evidence that immune system targeting agents can safely and effectively benefit patients with cancer has prompted a resurgence of interest in these agents among academic and pharmaceutical industry researchers.

Table 1

During an educational session at ASCO, Immunology for the Nonimmunologist, Lawrence Fong, MD, of the University of California, San Francisco, and other experts in this area explained key differences between immuno-oncology agents and traditional cancer therapies:

  • An immunotherapy agent can be effective in many cancers, including tumor types with different origins and drivers
  • Responses to immunotherapy are often quite durable; the body’s immune system has a memory
  • Immunotherapy “treats the patient, not the tumor”; these agents boost the immune system’s ability to target antigens (foreign or toxic cells, including cancer cells); they do not target cancer cell signaling pathways.

Presentations at this year’s ASCO meeting featured the latest findings related to immuno-oncology agents, as well as the implications for oncologists and their patients. The following summaries highlight these developments and illustrate the wide variety of tumor types for which novel immunotherapies may have value.

Adoptive T-Cell Therapy for Cervical Cancer
Treatment is not standardized for patients with cervical cancer that has spread beyond the confines of a radiation or surgical field. While bevacizumab and cytotoxic chemotherapy (eg, platinum agents and taxanes) can be effective for some women with cervical cancer, clinical trial enrollment is preferred.2 Transfusion of T cells, also called adoptive cell therapy, effectively treats viral infections and has been shown to induce responses in phase 1 clinical trials among patients with cancer.3

Hinrichs and colleagues presented data regarding the use of human papilloma virus (HPV)-targeted tumor-infiltrating lymphocytes for cervical cancer, noting that this malignancy is virally induced and expresses HPV E6 and E7 oncoproteins (ASCO 2014; Abstract LBA3008). This phase 1 clinical trial enrolled patients with metastatic HPV-positive cervical cancer with tumor-infiltrating lymphocytes (TIL) selected for HPV E6 and E7 reactivity. The HPV-TIL infusion was preceded by nonmyeloablative conditioning and followed by high-dose aldesleukin.

Nine patients with metastatic cervical cancer were treated with a single infusion of HPV-TIL. Infused cells were found to possess reactivity against high-risk HPV E6 and/or E7 in 6 of 8 patients. Three of these 6 patients with HPV reactivity demonstrated objective tumor responses by Response Evaluation Criteria in Solid Tumors (RECIST; 2 complete responses and 1 partial response). A fourth patient had a 39% reduction in tumor size. The 2 patients without HPV reactivity did not respond to treatment. Each of the 2 patients with complete responses to HPV-TIL infusion had widespread metastases, and each continued to respond after 11 and 18 months of treatment, respectively.

Based on these results, Hinrichs concluded that infusion of HPV-TIL can engender durable, complete regression of metastatic cervical cancer in patients who are highly pretreated.

Blinatumomab in Relapsed/Refractory Acute Lymphoblastic Leukemia
Although more than 80% of adults with acute lymphoblastic leukemia (ALL) respond to induction chemotherapy, up to 50% of these patients relapse with chemoresistant disease.4 Refractory or relapsed (r/r) ALL remains a significant clinical challenge.5

Like other immunotherapies, bispecific single-chain antibodies act using mechanisms that are independent of small-molecule therapeutics and conventional monoclonal antibodies.6 Blinatumomab, an investigational bispecific T-cell–engaging antibody, directs cytotoxic T cells to target cells that express CD19. CD19 is expressed in nearly all B-lineage ALL cells and throughout B-cell development.7

Topp and colleagues reported on the efficacy and toxicity of blinatumomab in a large phase 2 study (ASCO 2014; Abstract 7005). This open-label, single-arm, multicenter phase 2 study was conducted in patients with Philadelphia-negative r/r ALL who had relapsed within 12 months of initial therapy. Blinatumo­mab was administered by continuous intravenous infusion for 4 weeks, followed by a 2-week break (6-week cycle) for up to 5 cycles. The primary end point of the study was complete remission (CR) or CR with partial hematologic recovery (CRh*) within the first 2 cycles.

The study enrolled 189 r/r ALL patients whose median age was 39 years (range, 18-79 years). Compared with patients in initial studies of blinatumomab, these patients had a higher burden of disease based on bone marrow blood count. Blinatumomab was given for a median of 2 cycles (range, 1-5).

Table 2

Among these 189 patients, the response rate (CR and CRh*) to blinatumomab was 43%, with 80% of responses occurring within the first cycle. Median relapse-free survival (RFS) was 5.9 months, and median overall survival (OS) was 6.1 months. Responses were seen in all patient subgroups (Table 2). Thirty-two of 81 patients (40%) who were eligible for stem cell transplant were able to undergo the procedure.

The most frequent adverse events associated with blinatumomab in r/r ALL (ie, pyrexia, headache, and febrile neutropenia) were consistent with those demonstrated in previous trials. The most frequent grade 3/4/5 adverse events were febrile neutropenia (25%), neutropenia (16%), and anemia (14%). Two percent of patients had grade 3/4/5 cytokine release syndrome. Twenty-eight (15%) patients had grade 5 adverse events. These fatal events were observed only in patients who did not respond to blinatumomab.

Dr Topp concluded that this phase 2 study confirms the antileukemia activity of single-agent blinatumomab in patients with Philadelphia-negative r/r ALL. A randomized, open-label, phase 3 study of blinatumomab in this patient population is under way. The extent to which blinatumomab can serve as a bridge to transplant for patients with r/r B-cell ALL is of specific interest in future studies.

Nivolumab in Platinum-Resistant Ovarian Cancer
Most women diagnosed with ovarian cancer relapse after first-line platinum-based and taxane-based chemotherapy. Clinical recurrences that occur within 6 months of completion of platinum-containing therapy are described as platinum-refractory or platinum-resistant.8 While several cytotoxic agents can be used to manage platinum-resistant ovarian cancer (PROC), including anthracyclines, taxanes, topotecan, and gemcitabine, their benefits are only palliative.

In 2007, Hamanishi and colleagues published translational research indicating that ovarian cancer cell expression of programmed death–1 (PD-1) ligand 1 (PD-L1) correlates with prognosis, suggesting that PD-1 and PD-L1 pathways may be viable targets.9 On the basis of these findings, Hamanishi and colleagues (ASCO 2014; Abstract 5511) are studying the efficacy and safety of nivolumab, an anti–PD-1 antibody, in patients with PROC.

Women who have enrolled in the nivolumab protocol to date have been highly pretreated (median of 4 prior cytotoxic treatments). Nivolumab was administered every 2 weeks to patients at a dose of either 1 mg/kg or 3 mg/kg. Patients received nivolumab for a maximum of 6 cycles (4 doses per cycle) or until disease progression.

To date, 18 patients with PROC have been treated with nivolumab on this protocol. The most frequent adverse events observed included rash, increased liver enzymes, hypothyroidism, fever, arthralgia, low albumin, and lymphocytopenia.

After assessing 18 of 20 planned patients for this phase 1 study, Hamanishi and colleagues concluded that both doses of nivolumab (1 mg/kg and 3 mg/kg) are well- tolerated and have encouraging clinical efficacy for patients with recurrent PROC, with the 3-mg/kg dose appearing more favorable. Biomarkers of response and adverse events are being explored.

Nivolumab in Recurrent Metastatic Renal Cell Carcinoma
The prognosis of patients with recurrent metastatic renal cell carcinoma (mRCC) remains poor, regardless of histology. Treatment options for these patients include surgical resection of localized metastatic disease, cytokine therapy, and targeted therapies, such as mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF) inhibitors.10 None of these treatments has demonstrated extended survival or cure. A recent retrospective study of patients with mRCC who were treated with targeted therapy demonstrated OS medians that approach 3 years (range, 27-34 months).11

PD-L1 expression has been observed in most clear cell mRCC and is associated with unfavorable cancer-specific survival.12 To exploit this potential mechanism of tumor responsiveness, Motzer and colleagues conducted a phase 2 trial of nivolumab, an anti–PD-1 antibody, in mRCC patients who had relapsed after treatment with agents targeting the VEGF pathway (ASCO 2014; Abstract 5009).

In this trial, patients with clear cell mRCC who had received at least 1 agent targeting the VEGF pathway and no more than 3 previous systemic therapies were randomized to nivolumab given at a dose of 0.3 mg/kg, 2 mg/kg, or 10 mg/kg every 3 weeks until disease progression or toxicity. The primary objective of the study was to evaluate progression-free survival (PFS). Secondary objectives included OS, objective response rate (ORR), and safety.

Most of the 168 relapsed RCC patients who enrolled in this trial of nivolumab had received previous systemic therapy, including VEGF-receptor inhibitors (98%), mTOR inhibitors (34%), and immunotherapy (24%). One quarter (25%) of the patients were poor risk according to Memorial Sloan Kettering Cancer Center criteria.

After at least 16 months of follow-up, median PFS ranged from 2.7 to 4.2 months depending on the dose received, and ORR ranged from 20% to 22% (Table 3). Motzer and colleagues noted that many responders in each of the nivolumab dosing cohorts continue to respond after 24 months or more. Median OS in the 2 higher-dose cohorts was approximately 25 months.

Rates of grade 3/4-related adverse events were 17% or less for all doses of nivolumab. The most common grade 3/4 events varied among dosing cohorts. In the 10-mg/kg group, 2 patients experienced severe asthenia, while in the 3-mg/kg group, severe nausea and pruritus were noted in 2 patients. There was no grade 3/4 pneumonitis. In the nivolumab 0.3-mg/kg, 2-mg/kg, and 10-mg/kg cohorts, 3%, 17%, and 13% of patients, respectively, discontinued due to treatment-related adverse events.

Motzer and colleagues concluded that the promising activity of nivolumab in highly pretreated RCC warrants further evaluation. Nivolumab is currently being compared with everolimus in a phase 3 trial as later-line therapy for RCC, as well as in a first-line trial in mRCC combined with ipilimumab.

Adjuvant Ipilimumab for Patients with High-Risk Melanoma
Management of patients with lymph node–positive (high-risk) stage III melanoma is a clinical challenge. In Europe, high-dose interferon alfa-2b is approved for use in this setting. In the United States, both high-dose interferon alfa-2b and pegylated interferon alfa-2b are registered for patients with high-risk stage III melanoma.13,14 Because these agents can be difficult for patients in light of adverse events and administration, alternative treatments are desired.15

Eggermont and colleagues presented final data from the European Organisation for Research and Treatment of Cancer (EORTC) 18071, a randomized, double-blind, placebo-controlled phase 3 study designed to assess the impact of ipilimumab, an anti–cytotoxic T-lymphocyte antigen (CTLA) antibody, on RFS (ASCO 2014; Abstract LBA9008). This study is the first to assess an immune checkpoint inhibitor in the adjuvant melanoma setting.

A total of 951 patients with surgically treated stage III cutaneous melanoma were randomly assigned to receive ipilimumab or placebo in this protocol. None had received prior systemic therapy for melanoma. Patients had disease features that correlated with a high likelihood of melanoma recurrence, including positive lymph nodes. Patients receiving ipilimumab were dosed at 10 mg/kg every 3 weeks for 12 weeks, followed by 10 mg/kg every 12 weeks for up to 3 years.

After a median follow-up of 2.7 years, ipilimumab reduced the relative risk of melanoma recurrence by 25% compared with placebo. The 3-year RFS rates were 47% and 35% in the ipilimumab and placebo groups, respectively. Subgroup analysis showed a 33% reduction in relapse risk among stage III melanoma patients with microscopic disease in lymph nodes, and a 17% reduction in relapse risk among patients with macroscopic disease. In contrast, the EORTC 18991 trial that supported the approval of pegylated interferon alfa-2b did not show a significant RFS benefit in patients with macroscopic disease.16

Side effects were observed with ipilimumab, including 5 treatment-related deaths. More than half (52%) of the patients discontinued the drug secondary to adverse events, most often during the first 12 to 16 weeks of treatment. Adverse events were consistent with those observed with ipilimumab in the treatment of metastatic melanoma, and included colitis, endocrinopathies, and skin rash.

Eggermont and colleagues stated that these phase 3 data justify consideration of adjuvant use of ipilimumab for patients with high-risk stage III melanoma. More study is needed to fully assess the balance of benefits and risks associated with ipilimumab, including assessments of long-term toxicity and OS. An ongoing phase 3 study is comparing 2 different doses (3 mg/kg and 10 mg/kg) of adjuvant ipilimumab with high-dose interferon.

Table 3

Concurrent Treatment of Advanced Melanoma with Ipilimumab and Nivolumab
After demonstrating durable responses and improved OS, ipilimumab, an anti–CTLA-4 antibody, has become a standard option in the management of advanced melanoma.17 In contrast to CTLA-4 antibodies, PD-1 and PD-L1 antibodies potentiate antitumor T-cell responses at a tumor-specific level.18 Sznol and colleagues conducted a large phase 1 study in which ipilimumab and nivolumab, a PD-1 antibody, were administered concurrently to patients with advanced melanoma (ASCO 2014; LBA9003).

In this study, 94 patients with inoperable stage III or IV melanoma, who had received up to 3 previous systemic therapies, received concurrent treatment with ipilimumab and nivolumab in various dose regimens. Approximately half (53%) of the patients who enrolled in this phase 1 trial had very advanced melanoma (stage M1c), and 55% had received no previous systemic treatments.

Sznol and colleagues reported that concurrent treatment with ipilimumab plus nivolumab produced an “unprecedented” median OS of approximately 3.5 years (40 months) for patients with advanced melanoma. These data are based on long-term follow-up of 53 patients who enrolled in the initial 4 concurrent-dosing cohorts. Median OS data were described as “nearly double” the OS findings of previous studies of either agent alone in advanced melanoma.

Among the 53 patients, 41% responded to concurrent ipilimumab plus nivolumab, with complete responses observed in 17%. Tumor shrinkage was described as rapid and extensive. Responses were also durable, with 18 of 22 responses (82%) ongoing at the time of analysis. Clinical responses were seen regardless of BRAF mutation status or PD-L1 status, and across all dose cohorts. The 1- and 2-year median OS rates were 85% and 79%, respectively, and the median OS was 40 months. In the cohort of patients receiving nivolumab (1 mg/kg) and ipilimumab (3 mg/kg), which is the approach being tested in an ongoing phase 2/3 trial, 1- and 2-year OS rates were 94% and 88%, respectively.

Rates of adverse events, including those that were immune related, were higher than previously observed for ipilimumab and nivolumab used as single agents, but these were characterized as manageable and reversible in almost all patients.

Researchers continue to follow patients in 8 dosing cohorts of this phase 1 study. A separate, ongoing phase 3 study comparing combination ipilimumab plus nivolumab therapy versus each drug administered alone, and a phase 2 randomized study comparing combination ipilimumab plus nivolumab therapy versus ipilimumab alone, have completed accrual.

MPDL3280A in Metastatic Bladder Cancer
Metastatic transitional cell or urothelial bladder cancer (UBC) is associated with a grim prognosis and limited treatment options.19 Because many of these patients are elderly with comorbidities, management is not standardized.20 PD-L1 expression is prevalent in this disease and may protect UBC cells from immune-mediated destruction.21

Powles and colleagues presented results of a phase 1 study of MPDL3280A, a human anti–PD-L1 monoclonal antibody, in metastatic UBC (ASCO 2104; Abstract 5011). A total of 67 patients received MPDL3280A given at a dose of 15 mg/kg every 3 weeks for up to 1 year. The primary end point was ORR, including unconfirmed responses as assessed by RECIST 1.1.

Most UBC patients in this trial were male (72%) and had a median age of 65 years. The majority had visceral metastases (75%), received prior cisplatin-based chemotherapy (79%), and progressed within 3 months of their prior treatment (42%).

To date, the most common adverse events related to treatment with MPDL3280A were decreased appetite, fatigue, nausea, pyrexia, and asthenia. Related grade 3/4 adverse events occurred in 4% of patients. MPDL3280A was not associated with renal toxicity. No investigator-­assessed immune-related adverse events were observed.

Sixty-five UBC patients were evaluated for efficacy. ORR was higher in patients whose tumor highly expressed PD-L1 (52%) compared with those with low or no PD-L1 expression (11%). Sixteen of 17 responding patients continued to respond at the time of data cutoff. Powles and colleagues noted that responders to MPDL3280A included UBC patients with visceral metastases at baseline.

Powles and colleagues concluded that MPDL3280A has noteworthy activity in heavily pretreated patients with metastatic UBC. Biomarker analysis revealed pharmacodynamic markers, as well as markers of potential mechanisms of resistance to MPDL3280A therapy.

1. Mellman I, Coukous G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489.
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6. Topp MS, Kufer P, Gökbuget N, et al. Targeted therapy with the T-cell–engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29:2493-2498.
7. Cooper LJ, Topp MS, Serrano LM, et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood. 2003;101:1637-1644.
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16. Eggermont AM, Suciu S, Testori A, et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012;30:3810-3818.
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Interview with the Innovators - July 21, 2014

The Treatment of Relapsed Metastatic Melanoma Using a Novel Immunotherapy Combination:

An Interview with Mario Sznol, MD

During the 2014 annual meeting of the American Society of Clinical Oncology (ASCO), Mario Sznol, MD, presented Abstract LBA9003—Survival, Response Duration, and Activity by BRAF Mutation Status of Nivolumab and Ipilimumab Concurrent Therapy in Advanced Melanoma—on behalf of his colleagues and fellow investigators. The presentation summarized objectives, methods, and long-term [ Read More ]

Gastrointestinal Cancer - July 21, 2014

Immunotherapy Holds Promise to Extend Survival in GI Cancers

San Francisco, CA—The use of immunotherapy for the treatment of gastrointestinal (GI) cancers should become a reality in the not-too-distant future. Uncovering the signaling networks within the tumor microenvironment that regulate host immune responses is leading to strategies to alter these responses to treat GI malignancies. Combinations of therapies that [ Read More ]