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prIME LINES April 2016
TABLE OF CONTENTS
• PHARMA NEWS • FROM THE LITERATURE • ADDITIONAL PUBLICATIONS WORTH READING • UPCOMING prIME EVENTS • OTHER prIME ACTIVITIES
prIME Lines – April 2016 Issue
PHARMA NEWS
Defibrotide Approved in the United States for Hepatic Veno-Occlusive Disease
On 30 March 2016, defibrotide sodium (Defitelio®, Jazz Pharmaceuticals) was approved
by the US Food and Drug Administration (FDA) for the treatment of adult and pediatric
patients with hepatic veno-occlusive disease (VOD) with renal or pulmonary dysfunction
following hematopoietic stem cell transplant (HSCT). Approval is based on results from
528 patients treated with defibrotide across two prospective clinical trials and an
expanded access program in which patients with VOD following HSCT received
defibrotide 6.25 mg/kg intravenously (IV) every 6 hours until resolution of VOD. In each
study, survival at day +100 after HSCT was improved compared to published rates of
21% to 31% with best supportive care (study 1: 38%; study 2: 44%; study 3: 45%). The
most common serious adverse events (AEs) associated with defibrotide are hemorrhage
and hypersensitivity reactions, and the most common AEs seen in these studies were
hypotension, diarrhea, vomiting, nausea, and epistaxis. Due to its profibrinolytic activity,
defibrotide is contraindicated in patients receiving anticoagulants or fibrinolytic
therapies. In Europe, defibrotide has been approved for this indication since April 2014.
Crizotinib Indication Expanded for Treatment of ROS1-Positive Non-Small Cell
Lung Cancer
On 11 March 2016, the FDA expanded the current approval of crizotinib (Xalkori®,
Pfizer) to include patients with ROS1 rearranged non-small cell lung cancer (NSCLC).
Crizotinib was previously approved to treat anaplastic lymphoma kinase (ALK) mutation–
positive NSCLC. This expansion is based on a multicenter, single-arm study in which 50
patients with advanced ROS1-positive NSCLC received crizotinib 250 mg orally twice
daily. Crizotinib treatment resulted in an overall response rate (ORR) of 66% by
independent review and a median duration of response (DoR) of 17.6 months. The safety
results were consistent with the known profile of crizotinib from trials in patients with
ALK-positive disease.
Ibrutinib Receives Approval as First-Line Treatment for Chronic
Lymphocytic Leukemia
On 4 March 2016, ibrutinib (Imbruvica®, AbbVie, Pharmacyclics, and Janssen Biotech)
was approved as a first-line treatment for chronic lymphocytic leukemia (CLL). This
approval was based on results from the phase III RESONATE-2 trial, in which treatment
with ibrutinib reduced the risk of progression or death by 84% compared to treatment
with chlorambucil in 269 treatment-naïve patients age ≥65 years with CLL or small
lymphocytic lymphoma (SLL). Ibrutinib was previously approved in CLL as a second-
line treatment or in high-risk patients with deletion 17p.
European Medicines Agency Granted Positive Opinions for Three Agents
On 1 April 2016, the Committee for Medicinal Products for Human Use (CHMP) of
European Medical Agency (EMA) recommended approval and expanded indications for
the following agents (all already approved in the United States):
• Daratumumab (Darzalex™, Janssen-Cilag) was recommended for conditional
approval for patients with relapsed/refractory multiple myeloma who have
progressed on prior therapy including a proteasome inhibitor and an
immunomodulatory agent. This approval was based on substantially improved
response rates with a manageable toxicity profile in two trials, SIRIUS and
GEN501, in heavily pretreated multiple myeloma.
• Eribulin (Halaven®, Eisai) received a positive opinion for the treatment of patients
with unresectable advanced liposarcoma who have received (or were unsuitable
for) prior anthracycline-containing therapy. Eribulin is already approved in
Europe for metastatic breast cancer.
• The EMA also recommended an expansion of the indication for nivolumab
(Opdivo®, Bristol-Meyers Squibb) in advanced melanoma to include use in
combination with ipilimumab (Yervoy®, Bristol Meyers-Squibb). The
recommendation includes a statement that the benefit for this combination over
nivolumab monotherapy has been demonstrated only in patients with low
programmed-death receptor ligand-1 (PD-L1) expression.
FROM THE LITERATURE
Impressive Activity of Atezolizumab in Progressive Metastatic Urothelial Cancer
In the single-arm, multicenter phase II IMvigor 210 study that included 310 patients with
locally advanced or metastatic urothelial cancer who had disease progression during or
following platinum-based chemotherapy, treatment with the PD-L1 inhibitor
atezolizumab (1200 mg IV every 3 weeks) resulted in durable responses, particularly in
patients with high levels of PD-L1 expression on tumor-infiltrating immune cells. This
trial investigated response to atezolizumab in all patients and by PD-L1 expression levels.
For analysis of response by PD-L1 status, patients were prospectively divided into
categories based on PD-L1 expression levels on tumor-infiltrating immune cells (IC): IC0
<1%, IC1 ≥1% but <5%, IC2/3 ≥5%. The primary analysis showed that, compared to a
10% ORR in historical control, treatment with atezolizumab significantly improved ORR
for each treatment group (IC2/3: 27%, P<.001; IC1/2/3: 18%, P = .0004; intent-to-treat
population [ITT]: 15%, P = .0058). Moreover, at a median follow-up of 11.7 months,
responses were durable in 84% of responders, including in patients with poor prognostic
features. Median progression-free survival (PFS) was 2.1 months regardless of PD-L1
status. However, higher levels of PD-L1 were associated with longer overall survival
(OS). Median OS was 11.4 months for IC2/3 patients, 8.8 months for IC 1/2/3, and 7.9
months for all patients. The landmark 12-month OS rates were 48%, 39% and 36%,
respectively, all of which compare favorably to the 20% rate observed in a pooled
analysis of 10 phase II trials of second line chemotherapy or biologics. In general,
atezolizumab was well tolerated. The incidence of grade 3/4 treatment-related adverse
events (AEs) was low, with fatigue being the most common (2%). Grade 3/4 immune-
related AEs of any cause occurred in 5% of patients and importantly, there was no
immune-mediated renal toxicity.
In addition to PD-L1 expression on immune cells, response to atezolizumab was strongly
associated to mutational load. Furthermore, The Cancer Genome Atlas (TCGA)
classifications were used to classify 195 patients into luminal (n = 73) and basal (n = 122)
subtypes. PD-L1 immune cell expression was more prevalent in the basal subtype than in
luminal (60% vs 23%, P<.0001). Response to atezolizumab occurred in all subtypes, but
was most prevalent in the luminal cluster II subtype. Based on these results, the authors
concluded that atezolizumab has durable activity and good tolerability and represents a
new treatment option for patients with progressive metastatic urothelial cancer, a disease
with few available treatment options and poor prognosis. Additionally, this is the first
report to show the association of TCGA subtypes with response to immune checkpoint
inhibitors, which should be investigated further in future studies.
Lancet. 2016 March 4. [Epub ahead of print].
Cetuximab Beyond Progression Effective in Molecularly Selected Patients With
Metastatic Colorectal Cancer
According to results from the randomized open-label phase II CAPRI-GOIM trial,
continuation of cetuximab treatment beyond first progression results in improvements in
PFS and OS in molecularly selected (KRAS, NRAS, BRAF and PI3KA wildtype) patients
with metastatic colorectal cancer (mCRC). The CAPRI-GOIM trial compared the
combination of cetuximab and FOLFOX chemotherapy to FOLFOX alone in 153 patients
with KRAS exon 2 wildtype mCRC who had progressed following first-line treatment
with cetuximab and FOLFIRI. The study failed to meet its primary endpoint of
improvement in PFS in the ITT population. However, there was a trend toward improved
median PFS and OS in patients receiving cetuximab plus FOLFOX compared to
FOLFOX alone (PFS: 6.4 months vs 4.5 months; HR 0.81, P = .19; OS: 17.6 months vs
14.0 months; HR 0.86, P = .41). To better understand these results, investigators then
examined the molecular characteristics of the tumors. Previous reports have shown that
presence of mutations in KRAS, NRAS, BRAF, or PIK3CA genes reduce the efficacy of
cetuximab. In this study, next-generation sequencing (NGS) was performed in patients
with available tissue samples (n = 117) to identify tumors with wildtype KRAS, NRAS,
BRAF, and PIK3CA genes. In the 66 patients with quadruple wildtype tumors, treatment
with cetuximab resulted in an improvement in PFS (6.9 months vs 5.3 months; HR 0.56,
P = .025) and a trend toward improved OS (23.7 months vs 19.8 months; HR 0.57, P =
.056). No unexpected adverse events or deaths were recorded. The authors concluded by
stating that these results support a potential role for maintaining EGFR inhibition and
switching to non-cross-resistant chemotherapy after progression in molecularly selected
patients with mCRC, but that further evaluation would be needed in a phase III trial.
Ann Oncol. 2016 March 21. [Epub ahead of print].
RECIST Criteria May Underestimate the Benefit of Immunotherapy in Patients
With Melanoma
Retrospective analysis of patients with advanced melanoma enrolled in KEYNOTE 001
trial demonstrated that immune related response criteria (irRC) may be a more accurate
measure of pembrolizumab therapeutic benefit than conventional Response Evaluation
Criteria in Solid Tumors, version 1.1 (RECIST v1.1). The authors examined atypical
patterns of response (pseudoprogession) with the immune checkpoint inhibitor
pembrolizumab and the relationship between OS and response measured by irRC and
RECIST v1.1. Pseudoprogression was defined as ≥25% increase in tumor burden at week
12 (early) or at any assessment after week 12 (delayed) that was not confirmed as
progressive disease at next assessment. Among 655 patients, 327 patients had at least 28
weeks of imaging follow-up. Among these patients 24 (7%) had atypical responses (15
were early pseudoprogression and 9 were delayed pseudoprogression). When response
criteria were compared in the 592 patients with survival ≥12 weeks, 84 patients (14%)
were identified with progressive disease by RECIST v1.1 but not irRC. Two-year OS rate
was 77.6% in patients with nonprogressive disease by both response criteria, 37.5% in
patients progressive per RECIST v1.1 but nonprogressive per irRC, and 17.3% in patients
with progressive disease according to both criteria. The authors concluded that
conventional RECIST v1.1 may underestimate the benefit of pembrolizumab in
approximately 15% of patients. They pointed out that these data indicate that patients
may benefit from immunotherapy beyond initial evidence of radiographic progression
and, thus, support use of irRC for response evaluation to avoid premature termination of
potentially effective treatment.
J Clin Oncol. 2016 March 7. [Epub ahead of print].
Chemotherapy Following Radium-223 Treatment Safe in Castration-Resistant
Prostate Cancer
An exploratory analysis of the ALSYMPCA study suggests that chemotherapy following
radium-223 dichloride (Ra-223) is feasible and can be safely administrated in patients
with castration-resistant prostate cancer (CRPC). In the phase III ALSYMCA study,
which enrolled patients with CRPC and symptomatic bone metastases, Ra-223 compared
with placebo prolonged median OS (14.9 months vs 11.3 months) and reduced risk of
death by 30% (P<.001), regardless of prior treatment with docetaxel. However, due to
radiation effects in the bone marrow, there has been concerns that Ra-223 therapy could
compromise the safety of subsequent chemotherapy. In this exploratory analysis, the
authors evaluated data from the 206 patients from the ALSYMPCA trial who were
treated with chemotherapy after receiving either Ra-223 (n = 142) or placebo (n = 64). In
both treatment arms, docetaxel was the most commonly administered chemotherapy
(70% in Ra-223 and 72% in placebo), even though approximately 60% of patients had
received prior docetaxel. Patients who had received treatment with Ra-223 started
chemotherapy later than patients who had received placebo (9.1 months vs 7.5 months),
but the duration of chemotherapy treatment was similar between the groups. Importantly,
prior treatment with Ra-223 did not appear to have detrimental effect on OS with
subsequent chemotherapy, when compared with chemotherapy following placebo.
Median OS from the start of chemotherapy was similar between groups (16.0 months vs
15.8 months). Median values for hematologic parameters remained constant from
baseline to 18 months following the start of chemotherapy in both treatment groups,
though the decrease from baseline in platelets was greater in the Ra-223 group. There
were also no statistically significant differences in the frequency of hematologic grade
3/4 AEs. These results confirm the safety of administering chemotherapy after Ra-223
treatment, regardless of previous exposure to docetaxel. Studies are ongoing investigating
the safety of other agents following treatment with Ra-223 (eg, cabazitaxel, PARP
inhibitors) and use of concurrent chemotherapy and Ra-223. For more information on the
management of CRPC, please consider attending the prIME Oncology symposium,
Metastatic Castration-Resistant Prostate Cancer: Adapting to a Rapidly Changing
Treatment Algorithm, on June 3rd at the 2016 Oncology Annual Meeting in Chicago.
Prostate. 2016 March 23. [Epub ahead of print].
NK-1 Receptor Antagonist Improves Emesis Control During Chemoradiotherapy
for Cervical Cancer
In the double-blind, phase III GAND-emesis study, the addition of the neurokinin-1 (NK-
1) receptor antagonist fosaprepitant to palonosetron and dexamethasone resulted in
sustained no emesis for the entire treatment period in 65.7% of patients with cervical
cancer receiving fractionated radiotherapy for 5 weeks concurrently with cisplatin. Few
studies have examined prophylaxis for radiation-induced nausea and vomiting, even
though radiotherapy is a significant risk factor for emesis. In this study, the investigators
sought to identify a therapeutic combination that would prevent emesis in patients with
cervical cancer undergoing fractionated radiotherapy and weekly cisplatin (40 mg/m2) for
5 weeks. Patients (N = 234) were randomized to receive either a single dose of
fosaprepitant (150 mg IV) or placebo (saline) each week before cisplatin administration,
both in combination with the standard treatment of palonosetron (0.25 mg IV) and
dexamethasone (16 mg orally). On subsequent days, all patients received oral
dexamethasone 8 mg twice daily on day 2, 4 mg twice daily on day 3 and 4 mg once on
day 4. At the end of the 5-week treatment period, significantly more patients receiving
fosaprepitant had experienced sustained no emesis for the duration of treatment (65.7%
vs 48.7%; sub-HR 0.58, P = .008). Complete response, defined as no emesis and no use
of rescue antiemetics, occurred in 24% of patients receiving fosaprepitant compared to
14% of patients receiving placebo (P = .007). However, treatment with fosaprepitant was
not associated with a delayed time to first emetic episode compared to placebo (11.25
days vs 14.85 days). Treatment was well-tolerated. In his commentary, Lee
Schwartzberg, MD (West Cancer Center, Germantown, Tennessee, United States),
praised the study design, noting that the choice to analyze the entire duration of treatment
emphasized the need for prolonged prophylaxis. He indicated that this combination
represents a new standard of care for this patient population, but future studies should
examine reduced doses of corticosteroids to avoid steroid toxicity and complimentary
agents, such as olanzapine, to further improve emesis control. In addition, he pointed out
that “it is reasonable to consider extrapolating the data to other high risk chemoradiation-
induced nausea and vomiting settings including upper abdominal radiation with
combined chemotherapy for gastric, esophageal, or pancreatic caners.”
Lancet Oncol. 2016 March 4. [Epub ahead of print].
Lancet Oncol. 2016 March 4. [Epub ahead of print]. [commentary]
ADDITIONAL PUBLICATIONS WORTH READING
Revision of the World Health Organization Classification of Lymphoid Neoplasms
For the first time in eight years, the World Health Organization (WHO) has updated their
classification of lymphoid neoplasms. The updated revision incorporates important
advances from the last eight years in the understanding of lymphomagenesis, diagnostic
approaches, clinical expectations, and therapeutic strategies for the lymphoid neoplasms.
This review highlights the major areas in which changes have been made from the prior
edition. Blood. 2016 March 15. [Epub ahead of print].
Changes in the Treatment and Outcomes of Immune Thrombocytopenia Over
35 Years
In recent years, a number of new therapeutic options for the treatment of immune
thrombocytopenia (ITP) have emerged, including rituximab and the thrombopoietin
receptor agonists eltrombopag and romiplostim. This study retrospectively analyzes the
impact of these new treatments on the management of patients with ITP at a single
institution in Italy over the course of 35 years. The authors discuss how the emergence of
new treatment options impacted the rates of splenectomy and compare patient outcomes
on each therapy. For more information on ITP, please see the recent prIME Oncology
virtual activities on ITP—Expert Review: Updates in Immune Thrombocytopenia and
Do You Think Like the Experts? Evolving Treatment Paradigms for Immune
Thrombocytopenia.
Am J Hematol. 2016;91(4):E267-E272.
UPCOMING prIME EVENTS
Building on Targeted Therapy in Indolent Non-Hodgkin Lymphoma in 2016 3 May 2016 | Washington, DC 12 May 2016 | Winter Park, Florida 23 May 2016 | Granger, Indiana 12 July 2016 | Portland, Oregon
Management of Metastatic Castration-Resistant Prostate Cancer: Sound Decision Making in a Time of Evolving Choices 9 May 2016 | San Diego, California Winds of Change in Pediatric Immune Thrombocytopenia 12 May 2016 | Minneapolis, Minnesota Pediatric Acute Lymphoblastic Leukemia: Progress and Challenges in 2016 13 May 2016 | Minneapolis, Minnesota, United States prIME News: Live Monthly Updates in Immuno-Oncology 16 May 2016 | Live Webinar
Metastatic Castration-Resistant Prostate Cancer: Adapting to a Rapidly Changing Treatment Algorithm 3 June 2016 | Chicago, Illinois, United States
The Matrix of Care: Navigating Complex Therapeutic Strategies for Multiple Myeloma in 2016 9 June 2016 | Copenhagen, Denmark
How I Treat Uncommon Hematologic Malignancies 9 June 2016 | Copenhagen, Denmark
OTHER prIME ACTIVITIES
Webcast—2016 Young Investigator’s Forum in Non-Small Cell Lung Cancer Downloadable Slides—Evolving Treatment Paradigms in Chronic Lymphocytic Leukemia and Indolent Non-Hodgkin Lymphoma
prIME Downloadable Slides From the 2016 Hematologic Malignancies Demystified Series
Dr prIME Presents: Combinations Are Key, Optimizing Targeted Treatment for BRAF-Mutated Melanoma Expert Perspectives Series: A Focus on Lung Cancer – EGFR and ALK prIME News: Immunotherapy in NSCLC—The Current State of the Art and Future Directions