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