June 2014, Vol 3, No 4

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Immuno-Oncology Takes Center Stage at ASCO 2014


More than 250 abstracts that included the term “immunotherapy” or “immuno-oncology” were presented during the Annual Meeting of the American Society of Clinical Oncology (ASCO) in May 2014.

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

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 chemotherapy-resistant disease.1 Relapsed/refractory (r/r) ALL remains a significant clinical challenge.2

Like other immunotherapies, bispecific single-chain antibodies act using mechanisms that are independent from small-molecule therapeutics and conventional monoclonal antibodies.3 Blinatumomab, an investigational bispecific T-cell engaging antibody, directs cytotoxic T cells to target cells that express CD19, which is expressed in virtually all B-lineage ALL cells and throughout B-cell development.4

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

The study enrolled 189 r/r ALL patients with a median age of 39 years (range, 18-79). Compared with 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).

Among these 189 patients, the response rate (CR + 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. Thirty-two of 81 patients who were eligible for stem cell transplant (40%) were able to undergo the procedure.

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

Topp concluded that this phase 2 study confirms the antileukemic activity of single-agent blinatumomab in patients with Ph-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 Recurrent Metastatic Renal Cell Carcinoma
The prognosis of patients with recurrent metastatic renal cell cancer (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.6 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 approached 3 years (range, 27-34 months).7

PD-L1 expression has been observed in most clear cell mRCC and is associated with unfavorable cancer-specific survival.8 To exploit this potential mechanism of tumor responsiveness, Motzer and colleagues conducted a phase 2 trial of nivolumab (NIV), an anti–PD-1 antibody, in metastatic RCC patients who had relapsed after treatment with agents targeting the VEGF pathway.9

In this trial, patients with clear cell mRCC who had received at least 1 agent that targeted the VEGF pathway and no more than 3 prior systemic therapies were randomized to NIV given at a dose of 0.3, 2, 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 NIV had received prior systemic therapy, including VEGFR inhibitors (98%), mTOR inhibitors (34%), and immunotherapy (24%). One-fourth (25%) 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 4.4 months and the ORR was 22%. Motzer noted that many responders in each of the NIV 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 AEs were 17% or less for all doses of NIV. 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 pruritis were noted in 2 patients each. No grade 3/4 pneumonitis was seen. In the NIV 0.3, 2, and 10 mg/kg cohorts, 3%, 17%, and 13% of patients discontinued due to treatment-related AEs, respectively.

Motzer and colleagues concluded that the promising activity of NIV in heavily pretreated RCC warrants further evaluation. NIV 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 metastatic RCC 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 alpha-2b is approved for use in this setting. In the United States, both high-dose interferon alpha-2b and pegylated interferon alpha-2b are approved for patients with high-risk stage III melanoma.10,11 Because these agents can be difficult for patients in light of adverse events and administration, alternative treatments are desired.12

Eggermont and colleagues presented final data from EORTC 18071, a randomized double-blind, placebo- controlled phase 3 study designed to assess the impact of ipilimumab (IPI), an anti–CTLA-4 antibody, on RFS.13 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 IPI or placebo. None had received prior systemic therapy for melanoma. Patients had disease features that correlate with a high likelihood of melanoma recurrence, including positive lymph nodes. Patients receiving IPI were dosed at 10 mg/kg every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years.

After median follow-up of 2.7 years, IPI reduced the relative risk of melanoma recurrence by 25% compared with placebo. The 3-year RFS rates were 47% and 35% in the IPI 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 alpha-2b did not show a significant RFS benefit in patients with macroscopic disease.14

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

Eggermont stated that these phase 3 data justify consideration of adjuvant use of IPI for patients with high-risk stage III melanoma. More study is needed to fully assess the balance of benefits and risks associated with IPI, 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 IPI with high-dose interferon.

Concurrent Treatment of Advanced Melanoma With Ipilimumab and Nivolumab
After demonstrating durable responses and improved OS, IPI has become a standard option in the management of advanced melanoma.15 In contrast to CTLA-4 antibodies, PD-1 and PD-L1 antibodies potentiate antitumor T-cell responses at a tumor-specific level.16 Sznol and colleagues conducted a large phase 1 study in which IPI and nivolumab (NIV), a PD-1 antibody, were administered concurrently to patients with advanced melanoma.17

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

Sznol reported that concurrent treatment with IPI + NIV 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 IPI + NIV, with CRs 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 NIV 1 mg/kg + IPI 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 AEs, including immune-related AEs, were higher than previously observed for IPI and NIV 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 IPI + NIV with NIV and IPI alone, and a phase 2 randomized study comparing IPI + NIV to IPI 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.18 Because many of these patients are elderly with comorbidities, management is not standardized.19 PD-L1 expression is prevalent in this disease and may protect UBC cells from immune-mediated

Powles and colleagues presented results of a phase 1 study of MPDL3280A, a human anti–PD-L1 monoclonal antibody, in metastatic UBC.21 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 patients with UBC in this trial were male (72%), and the median age was 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 AEs related to treatment with MPDL3280A were decreased appetite, fatigue, nausea, pyrexia, and asthenia. Related grade 3/4 AEs occurred in 4% of patients. MPDL3280A was not associated with renal toxicity. No investigator-assessed immune-related AEs were observed.

Sixty-five patients with UBC 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 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. Gökbuget N, Hoelzer D. Treatment of adult acute lymphoblastic leukemia. Semin Hematol. 2009;46:64-75.
2. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944-950.
3. 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.
4. 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.
5. Topp MS, Goekbuget N, Stein AS, et al. Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). J Clin Oncol. 2014; 32(suppl). Abstract 7005.
6. National Cancer Institute website. Renal Cell Cancer Treatment: PDQ. Stage IV and Recurrent Renal Cell Cancer. Updated February 21, 2014. www.cancer.gov/can certopics/pdq/treatment/renalcell/HealthProfessional/page8. Accessed June 1, 2014.
7. Kroeger N, Choueiri TK, Lee JL, et al. Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy. Eur Urol. 2014;65:1086-1092.
8. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer. 2005;104:2084-2091.
9. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma (mRCC): results of a randomized, dose-ranging phase II trial. J Clin Oncol. 2014;32(suppl). Abstract 5009.
10. Sylatron [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; December 2013.
11. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7-17.
12. Sabel MS, Sondak VK. Pros and cons of adjuvant interferon in the treatment of melanoma. Oncologist. 2003;8:451-458.
13. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Ipilimumab versus placebo after complete resection of stage III melanoma: initial efficacy and safety results from the EORTC 18071 phase III trial. J Clin Oncol. 2014;32(suppl). Abstract LBA9008.
14. 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.
15. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; December 2013.
16. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212.
17. 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). J Clin Oncol. 2014;32(suppl). Abstract LBA9003.
18. National Cancer Institute website. Bladder Cancer Treatment: PDQ. General Information About Bladder Cancer. Updated February 21, 2014. www.cancer.gov/cancertopics/pdq/treatment/bladder/HealthProfessional/page1. Accessed June 1, 2014.
19. National Cancer Institute website. Bladder Cancer Treatment: PDQ. Recurrent Bladder Cancer Treatment. Updated February 21, 2014. www.cancer.gov/cancertopics/pdq/treatment/bladder/HealthProfessional/page9. Accessed June 1, 2014.
20. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007;109:1499-1505.
21. Powles T, Vogelzang NJ, Fine GD, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer (UBC). J Clin Oncol. 2014;32(suppl). Abstract 5011.

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