Currently no targeted therapies are approved for the treatment of relapsed/refractory Philadelphia Chromosome-negative (Ph-) acute lymphocytic leukemia (ALL). Moreover, given the toxicities associated with the available chemotherapy options, less than half of patients are treated with second-line therapy.1
Blinatumomab is an investigational bispecific T-cell-engaging antibody developed using Micromet’s “BiTE” (bispecific T-cell engager) technology. The concept behind the bispecific antibody is that by binding the tumor cell through CD19 ― which is expressed by nearly all tested B-lineage ALL cells (including ALL blasts) ― and T-cells through CD3, the antibody brings the T-cells into closer contact with the tumor cells, thereby promoting T-cell mediated lysis of the tumor cells. In a previous Phase II study conducted in 36 relapsed/refractory B-cell ALL patients, treatment with blinatumomab achieved a complete hematologic remission (CR)/CRh (CR with partial hematologic recovery) rate of 69% (25/36), a median relapse free survival (RFS) of 7.6 months and a median overall survival (OS) of 9.8 months.2 Micromet (now Amgen) sought to confirm the antileukemic activity of single-agent blinatumomab in the difficult-to-treat population with relapsed/refractory ALL with the Phase II trial that was reported Tuesday at ASCO in the leukemia oral session.
This was a large Phase II study (MT103-211; NCT01466179) of blinatumomab in Ph-, relapsed/refractory ALL.3 This confirmatory open-label, single-arm trial was initiated in October 2011. Eligible patients had primary refractory disease; early relapse (duration of first remission was12 months or less); relapse within 12 months of allogeneic hematopoietic stem cell transplantation (HSCT); or any relapsed or refractory disease after first salvage therapy. The primary endpoint was rate of CR / CRh within the first two treatment cycles. Secondary endpoints included rates of CR and CRh, proportion of patients eligible for allogeneic HSCT after CR/CRh rate, relapse-free survival, overall survival, time to hematological relapse, event-free survival, pharmacokinetics, and safety. The trial completed enrollment by November 2013. Before its purchase by Amgen, Micromet initiated the trial with an estimated enrollment of 61 patients. By January 2013, the planned enrollment had been tripled to 180 patients, and Amgen subsequently guided that this will be a pivotal trial to support regulatory approval in this unmet need population.
The single-arm MT103-211trial enrolled 189 patients who were treated with blinatumomab (28 µg/day, continuous IV, four weeks on, two weeks off; Days 1-7 of Cycle 1 only, 9 µg/day) for a median of two cycles (range = 1–5 cycles). Treatment with blinatumomab resulted in 43% CR/CRh rate during the first two cycles of therapy, and 80% of CR/CRh occurred within the first cycle. Median RFS was 5.9 months and median OS was 6.1 months. Adverse events were consistent with previously reported adverse events. The most frequent Grade 3 or higher adverse events were febrile neutropenia (25%), neutropenia (16%); anemia (14%), nervous system/psychiatric disorders (13%) and pneumonia (9%). Grade 3 or higher nervous system/psychiatric disorders included encephalopathy (3%), ataxia (2%) and confusional state (2%). Fatal adverse events were only seen in patients with uncontrolled leukemia.
This large Phase II study confirmed the antileukemia activity of single-agent blinatumomab in a difficult-to-treat population with relapse/refractory ALL. The only other approved agent for relapsed/ refractory B-cell ALL is Marqibo® (vincristine sulfate liposome, Talon Therapeutics), which was approved by the U.S. Food and Drug Administration (FDA) in 2012 for the treatment of Ph- ALL patients who have relapsed after two or more prior therapies. If we compare the outcomes of these two trials, blinatumomab appears to offer better outcomes than Marqibo (CR/CRh 43% and 15%, respectively) and overall survival (6.0 months and 4.6 months, respectively).4,5 However, the patient demographics are different between these two studies, making comparison difficult; specifically, the blinatumomab trial enrolled a large portion of patients in earlier relapse than the Marqibo trial, which could explain the difference in response rate and survival. Randomized data is not available for either drug, which further limits the ability to assess their clinical merits, but the single-arm Phase II data certainly is encouraging.
In late 2013, Amgen initiated a Phase III trial (00103311; NCT02013167) that will randomize relapsed/refractory Ph- B-cell ALL patients to either blinatumomab or physician’s choice of chemotherapy. The endpoint of this trial is OS and will most likely serve the need to convert an anticipated accelerated approval (based on the Phase II data reported today) to a full FDA approval; it also will support regulatory filings outside the U.S. An approval will not come fast enough for this setting with high unmet need. The data from this important Phase II trial ushers in the era of targeted immune therapy as a new treatment option for ALL patients.
By Stephanie Hawthorne, Ph.D., Senior Director, and Greg Wolfe, Ph.D., Senior Consultant, Kantar Health
 Kantar Health CancerMPact® Treatment Architecture, United States and Western Europe, accessed June 3, 2014
 Topp, et al., Bone Marrow Transplant, 2013
 Topp, et al., Abstract 7005, ASCO 2014
 Marqibo FDA label, accessed June 3, 2014
 O’Brien, et al., J Clin Oncol, 2012
As treatment of lung cancer patients has become more driven by histology and biomarkers, one group of patients had been left out of the clinical advances made in recent years with targeted therapies: non-small cell lung cancer (NSCLC) patients whose tumors have squamous histology. A few different drugs are now being studied in this patient population, and the first of these trials was reported on Monday at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). Eli Lilly had stated via press release in August 2013 that necitumumab, their second-generation anti-EGFR monoclonal antibody (mAb), significantly improved overall survival (OS) when combined with gemcitabine and cisplatin as a first-line treatment in 1,093 patients with squamous NSCLC in the Phase III SQUIRE study. That press release did not provide quantitation for the OS benefit found in SQUIRE, but such data was finally made available at the ASCO 2014 session on metastatic NSCLC.
The data presented at the conference suggest that while the benefit may be statistically significant, it may not be clinically relevant.1Necitumumab was associated with a six-day (0.2-month) improvement in median progression-free survival (mPFS; 5.7 months versus 5.5 months, HR 0.85, p=0.020), and a 1.6-month improvement in median overall survival (mOS; 11.5 months versus 9.9 months, HR 0.84, p=0.012). Interestingly, the only subgroup not to show a survival benefit was the group of patients who were 70 years or older. Finally, the response rate was also slightly but insignificantly improved in the necitumumab-containing arm (31% versus 29%, p=0.400).
One bright spot for necitumumab was its toxicity profile, which enabled the agent to be generally well-tolerated. Necitumumab was associated with increases in Grade 3 or higher hypomagnesemia (9.3% versus 1.1%), skin rash (7.1% versus 0.4%) and venous thrombolic events (5.0% versus 2.6%).
During this session a comparison was rightly made to Erbitux® (cetuximab, Bristol-Myers Squibb). As noted above, necitumumab is a second-generation anti-EGFR mAb; past history with the first-generation anti-EGFR mAb Erbitux provides a note of caution. Erbitux had been tested in the first-line setting in two Phase III trials in NSCLC patients of all histologies: FLEX and CA225-099. Erbitux was shown to provide a modest yet significant benefit in the FLEX study when added to cisplatin and vinorelbine (HR 0.871, p=0.044) but failed to show a benefit when added to carboplatin and paclitaxel in the CA225-099 trial (HR 0.89, p=0.17). In an attempt to find a biomarker-defined population that benefited from treatment with Erbitux, investigators developed an EGFR IHC score algorithm, termed the “H-score,” to identify “high EGFR-expressing” patients.4 While an H-score greater than 200 was predictive for patients enrolled in FLEX, it was not predictive for Erbitux benefit in the CA225-099 trial. Unfortunately, in an exploratory analysis presented for the SQUIRE study, the H-score was not predictive for necitumumab activity.
The SQUIRE data, following that of the REVEL study,5 highlighted the difficulty of finding new effective therapies for patients with NSCLC. Both trials showed minimal efficacy benefits, and both trials probably reached statistical significance thanks (in part) to the large patient populations enrolled. However, Julie Brahmer, the discussant for both the SQUIRE and REVEL presentations, noted that according to ASCO’s recently released recommended efficacy targets for new agents in both non-squamous and squamous NSCLC,6 SQUIRE does not come close to meeting the threshold of a 2.5- to 3-month improvement in overall survival and a Hazard Ratio of 0.77 to 0.8. Based on the SQUIRE data, Dr. Brahmer rightfully concluded that it is time to reconsider the notion that wild-type EGFR is a target in NSCLC. Although SQUIRE did present statistically significant survival data in an underserved patient population, questions arise about the clinical relevance of these data. Physicians, along with their patients, will need to have serious discussions to answer this question.
By Arnold DuBell, Ph.D., Consultant, and Stephanie Hawthorne, Ph.D., Senior Director, Kantar Health
 Thatcher, Abstract 8008, ASCO 2014
 Pirker, Lancet, 373: 1525-1531, 2009
 Lynch, J Clin Oncol, 28: 911-917, 2010
 Pirker, Abstract O01.06, WCLC 2011
 Perol, Abstract LBA8006, ASCO 2014
 Ellis, JCO 2012
Cyramza™ (ramucirumab, IMC-1121B; Eli Lilly) is a human IgG1 monoclonal antibody directed against the extracellular domain of VEGFR-2. It was recently approved by the Food and Drug Administration (FDA) for advanced gastric cancer or gastroesophageal junction adenocarcinoma. On February 19, 2014, Lilly announced via press release that the REVEL trial was positive for both overall survival (OS) and progression-free survival (PFS) benefit. Results from the randomized, double-blind, placebo-controlled Phase III REVEL trial (NCT01168973) were reported at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). The trial evaluated docetaxel with or without Cyramza in squamous or non-squamous Stage IV non-small cell lung cancer (NSCLC) patients following disease progression after one prior platinum-based therapy.1
Patients in the REVEL trial, were randomized to receive docetaxel (75 mg/m2 IV Day 1 of a 21-day cycle) plus either Cyramza (10 mg/kg IV Day 1 of a 21-day cycle, n=628) or placebo (n=625) until disease progression or unacceptable toxicity. The primary endpoint was OS, and secondary endpoints included PFS, overall response rate (ORR) and quality of life. REVEL met its primary endpoint with a modest improvement in median OS (10.5 months for Cyramza plus docetaxel versus 9.1 months for docetaxel alone (HR = 0.857; p=0.0235)). The addition of Cyramza to docetaxel improved OS in patients with squamous and non-squamous histologies. The ORR was 22.9% for Cyramza plus docetaxel and 13.6% for the docetaxel arm (p<0.001). Median PFS was 4.5 months for Cyramza plus docetaxel versus 3.0 months for docetaxel (HR=0.762; p<0.0001).
Treatment-emergent Grade 3 or higher adverse events (AEs) were reported in 78.9% of patients in the Cyramza plus docetaxel arm and 71.8% of patients in the docetaxel arm. The most common Grade 3 or higher treatment emergent AEs in the Cyramza/docetaxel arm compared to docetaxel alone arm included neutropenia (48.8% vs. 39.8%), febrile neutropenia (15.9% vs. 10.0%), fatigue (14.0% vs. 10.5%) and hypertension (5.6% vs. 2.1%). Pulmonary hemorrhage (any grade; all patients) was reported in 2.1% vs. 1.6% of patients but was slightly more in squamous patients (3.8% vs. 2.4%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%).
Docetaxel is commonly preferred as second-line therapy for patients with NSCLC. These results demonstrate that addition of Cyramza to docetaxel improves median OS by 1.4 months, but at the same time it increases toxicities including neutropenia, febrile neutropenia and hypertension. Recent ASCO recommendations suggest that clinically relevant improvements in OS should be on the order of four months for NSCLC with a hazard ratio of less than 0.8.2 It is obvious that the REVEL results did not clear this bar; however, there are some positives with Cyramza trial.
REVEL is the first Phase III study to show that the addition of a biologic to standard chemotherapy improves survival compared to chemotherapy alone in second-line NSCLC. In addition, Cyramza was active in squamous NSCLC, where treatment options are more limited. The increased toxicity in REVEL was modest, similar to the toxicity profile observed when Cyramza was combined with paclitaxel in the RAINBOW trial in gastric cancer. Lilly has announced their plans for a regulatory submission for Cyramza for NSCLC in 2014 based upon the REVEL results. Will the REVEL data be sufficient to convince the regulatory authorities to approve Cyramza for NSCLC? If it is approved will physicians utilize Cyramza with such modest clinical benefit? Time will tell.
By Greg Wolfe, Ph.D., Senior Consultant, and Neesha Suvarna, Ph.D., Consultant, Kantar Health
 Ellis, JCO 2012
Yervoy® (ipilimumab, Bristol-Myers Squibb) was an exciting and welcomed breakthrough in the treatment of advanced/metastatic melanoma when it was first launched in 2011. The agent not only improved the median overall survival (OS) in patients irrespective of BRAF status; it also showed a plateau in the survival curve, indicating that a subset of patients derive long-term benefit from Yervoy. Given the poor prognosis of metastatic disease, however, could Yervoy have a greater impact on survival outcomes if used earlier in the course of the disease? It has long been speculated that immunotherapies would be most active in lower tumor burden disease by allowing the immune system enough time to mount and maintain an effective response to the tumor cells. The activity of interferons in this setting (albeit somewhat controversial given the conflicting level of evidence to date) suggests that locally advanced melanoma could benefit from effective immunotherapies.
Yervoy is the first of the modern immunotherapies to be studied in a randomized trial (EORTC 18071; NCT00636168) in completely resected high-risk Stage II/III melanoma patients. The data from this trial was presented Monday at the American Society for Clinical Oncology (ASCO) meeting in Chicago. Patients were randomized to receive Yervoy (10 mg/kg every 21 days for four cycles, then maintenance every 12 weeks starting at Week 24 for up to three years) (n=475) or placebo (n=476). The primary endpoint of recurrence-free survival (RFS) was significantly improved: in the intent-to-treat population, median RFS was 26.1 months in the Yervoy arm versus 17.1 months in the placebo arm (HR=0.75, p=0.0013), and the three-year RFS rate was 46.5% versus 34.8%. The RFS benefit remained significant across all subpopulations but was more pronounced in patients with microscopic lymph node metastases (as opposed to macroscopic or palpable metastases), in patients with ulcerated tumors, and in patients with Stage III disease. The secondary endpoints of OS, metastasis-free survival and quality-of-life-adjusted survival were not reported.
Toxicity was significant, with 49% of patients discontinuing Yervoy due to adverse events (AEs). This discontinuation often occurred early in the course of treatment, with 39% discontinuing in the first 12 weeks, where the majority of AEs occurred. Another troubling result is that five (1.1%) patients died due to drug-related AEs. As expected, the most common Grade 3/4 adverse events were immune-related affecting the gastrointestinal (16.0% vs. 0.8%), hepatic (10.7% vs. 0.2%) and endocrine (8.5% vs. 0%) systems. The majority of immune-related AEs did resolve by ceasing treatment and following standard protocols of management, with the notable exception of hypophysitis (18.7% all grade, including 4.7% Grade 3 and 0.4% Grade 4), which was noted with concern. Although this type of safety profile may be acceptable in the metastatic setting, there is typically a higher standard for tolerability in patients with earlier-stage disease who have been rendered disease-free by surgical resection. It’s also interesting to wonder whether the efficacy benefit that was reported might have been even greater if patients had been able to tolerate the drug rather than discontinue prematurely.
In general, the outlook for immunotherapy in melanoma is promising based on these results. The strength of RFS benefit with Yervoy in high-risk patients with resected disease are encouraging and may eventually lead to approval in the adjuvant setting, but mature OS data will likely be required. However, the use of Yervoy may hinge on several elements of its risk-to-benefit analysis. Could the toxicity profile prove unacceptable to physicians and/or patients? Will this safety profile limit its use to only those Stage III patients at highest risk of recurrence, or will physicians prescribe the drug more broadly for Stage III disease? Finally, how will the cost of therapy affect its utilization in this setting? Notably, this trial evaluated the high dose of Yervoy (10 mg/kg, which is rarely used in clinical practice in favor of the approved 3 mg/kg dose) – at this dose and the administration schedule used in the study, this amounts to a price tag in excess of $500,000 for the first year and over $1 million for the full three-year course of therapy. This is certainly a topic that would fit well with the “Value in Cancer Care” series that has been running in this week’s ASCO Daily News.
Cost of therapy aside, the data from EORTC 18071 remain important for advancing care in adjuvant melanoma, but it may just be the beginning, opening the door for other agents in this setting. In fact, Yervoy, Zelboraf® (vemurafenib, Genentech/Roche) and the combination of Tafinlar® (dabrafenib, GSK) and Mekinist® (trametinib, GSK) are all attempting to move into the adjuvant setting and all have ongoing Phase III trials. In addition, another adjuvant Yervoy trial is ongoing and has nearly completed enrollment. This additional three-arm Phase III trial compares 3 mg/kg Yervoy to 10 mg/kg Yervoy to IFN-alpha-2b in completely resected Stage IIIb/IIIc/IV melanoma (NCT01274338; ECOG 1609). If successful, this second trial could act as confirmation, resolve the dosing/cost issue mentioned above, and provide stronger evidence for approval and adoption given the use of an active comparator. Whether or not Yervoy becomes the next drug to market in the adjuvant setting, it is paving the way for other agents in this setting.
By Mara Jeffress, Ph.D., Associate Consultant, and Stephanie Hawthorne, Ph.D., Senior Director, Kantar Health