NEWS IN BRIEF

FEBRUARY 2017�CANCER DISCOVERY | 119

The majority of patients who took the

combination therapy also experienced

shrinkage of their tumors, said Sara

Hurvitz, MD, medical director of the

University of California, Los Angeles,

Jonsson Comprehensive Cancer Center

Research Unit, who presented the data.

Reduced Ki67 expression also

appeared to trigger infi ltration of anti-

tumor immune cells, noted Hurvitz.

Tissue analysis after 4 months of treat-

ment showed that patients who took

abemaciclib plus anastrozole showed

an increase in cytotoxic/suppressor

T cells in their tumors, but no increase

in regulatory T cells, which are thought

to dampen the immune response.

This is the fi rst large study to show

that CDK4/6 inhibition may be effective

in neoadjuvant treatment of early-stage

breast cancer, she said. Currently, one

CDK4/6 inhibitor, palbociclib (Ibrance;

Pfi zer), is approved for initial endocrine-

based therapy to treat advanced or

metastatic disease. Another, ribociclib

(Novartis), is under investigation and

was granted Breakthrough Therapy

status earlier this year.

The data also suggest that abemaci-

clib may be less toxic than palbociclib,

said Hurvitz. Palbociclib is typically

given on a 3 weeks on/1 week off regi-

men to allow neutrophils to recover,

but experts worry that the medication

break could trigger a rebound in cell

cycling, leading to resistance. In the

neoMONARCH trial, abemaciclib was

taken continuously with a relatively low

rate (8.2%) of grade 3 or 4 neutropenia.

The investigators are continuing

to evaluate pathologic responses and

long-term outcomes in an effort to

discover more about how CD4/6

inhibitors work, said Hurvitz.

in both the House and Senate, plus

tremendous outreach and educational

efforts by medical researchers and patient

advocates—fi nally became law.

“It’s a good day to see us doing

our jobs,” President Barack Obama

remarked at the signing ceremony, refer-

ring to the overwhelming bipartisan

support for this landmark legislation:

The House voted 392 to 26 in favor of

Cures; the Senate 94 to 5. “Today, we

are bringing to reality the possibility

of new breakthroughs for some of the

greatest health challenges of our time,”

Obama added.

“God willing, this bill will save lives,”

said Vice President Joe Biden. He spoke

of “injecting a sense of urgency” into

the fi ght against cancer, and how

Cures will help “enhance prevention

and detection efforts in every commu-

nity regardless of ZIP code, bringing

us closer to the day when there are vac-

cines for all kinds of cancer, just as we

have them for measles or mumps.”

Through Cures, the NCI will receive

$1.8 billion over 7 years, including

$300 million in the current fi scal year,

to fund various projects of the Beau

Biden Cancer Moonshot. A total of

$3 billion will be funneled to two

other signature Obama admin-

istration research programs—the

Precision Medicine Initiative and

the BRAIN Initiative. An Oncology

Center of Excellence will be created

at the FDA, and the agency’s hiring

authority will be expanded to better

recruit and retain staff members with

the required scientifi c expertise. Cures

will also establish a review pathway

for the FDA to validate biomarkers

and other drug development tools,

besides reauthorizing a priority review

voucher program to spur new thera-

pies for rare pediatric diseases.

Ronald DePinho, MD, president of

The University of Texas MD Anderson

Cancer Center in Houston, called the

legislation “transformative,” saying it

“provides rocket fuel . . . to accelerate the

development of new lifesaving advances

to help us write [cancer] into the his-

tory books.” Megan Gordon Don, vice

president of Government Affairs and

Advocacy at the Pancreatic Cancer

Action Network, added that with Cures,

“important work on immunotherapy,

personalized medicine . . . will move

forward quickly to benefi t patients.”

The American Association for Can-

cer Research also hailed Cures’ success-

ful passage, while emphasizing that the

funding it provides should supplement,

not supplant, regular and robust appro-

priations for the NIH. –Alissa Poh ■

Abemaciclib Shows Promise for Early Breast Cancer

Treatment with the CDK4/6 inhibitor

abemaciclib (Eli Lilly), alone or in combi-

nation with endocrine therapy, signifi -

cantly lowered expression of Ki67—a key

marker of cell proliferation—in women

with hormone receptor (HR)–positive,

HER2-negative breast cancer, accord-

ing to preliminary data from the phase

II neoMONARCH trial. The find-

ings, presented during the 2016 San

Antonio Breast Cancer Symposium in

Texas, December 6–10, suggest that

CDK4/6 inhibition, which is already

used to treat advanced disease, may be

effective for neoadjuvant treatment of

early breast cancer.

Estrogen stimulates increased activity

of CDK4/6, which plays an important

role in regulating cell-cycle progression.

The neoMONARCH investigators

hypothesized that inhibiting CDK4/6

would help slow cell cycling, as meas-

ured by changes in Ki67 expression.

Earlier studies have shown that

lowered Ki67 expression after 2 weeks

of treatment may be predictive of

improved disease-free survival.

In the proof-of-concept study,

223 postmenopausal women were

randomly assigned to receive either

endocrine therapy (anastrozole),

abemaciclib, or both for 2 weeks; all of

the patients then received both drugs

for 14 weeks, followed by optional

surgery. Researchers analyzed biopsies

taken from evaluable patients in each

arm before and after the fi rst 2 weeks

of treatment. The results showed sig-

nifi cantly reduced Ki67 expression in

107 patients who received abemaciclib

or the combination compared with 54

patients who received only anastrozole.

In particular, reduced Ki67 expression

was observed in significantly more

patients who took abemaciclib or the

combination therapy (59% and 66%,

respectively) compared with those

who took anastrozole alone (15%).

Sara Hurvitz, MD, presents preliminary results of a phase II study of abemaciclib for the treat-ment of women with hormone receptor–positive, HER2-negative breast cancer.

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NEWS IN BRIEF

120 | CANCER DISCOVERY�FEBRUARY 2017 www.aacrjournals.org

adverse effects after 28 days, on average.

Only one of the six patients treated at

the lowest dose achieved remission,

but eight of the 10 participants who

received a higher dose experienced

remission with no evidence of residual

disease. Six of the nine patients who

achieved remission subsequently

relapsed; the other three remain in

remission, with one remission continu-

ing for more than a year, Fry reported.

Most of the patients who relapsed

experienced decreases in CD22 express-

ion, with only one patient experienc-

ing CD22 loss. Fry observed that the

opposite seems to occur following

anti-CD19 CAR T-cell therapy, with

antigen loss, not reduced expression,

more likely.

The primary adverse effect of anti-

CD22 CAR T-cell therapy was cytokine

release syndrome, reported Nirali

Shah, MD, also from the NCI’s Pediat-

ric Oncology Branch, who shared the

fi ndings with meeting attendees. How-

ever, Shah said that all cases, which

involved fever and low blood pressure,

were mild. One patient died of sepsis,

but not until after the cytokine release

syndrome ended.

Although researchers continue to

enroll patients in the trial, they are

already asking new questions about

how best to use the therapy, Fry com-

mented. For example, he and his team

are wondering whether physicians

should wait for disease relapse follow-

ing anti-CD19 CAR T-cell therapy

before starting with anti-CD22 CAR

T-cell therapy, or whether remissions

would last longer if the therapies were

given simultaneously—issues they plan

to investigate. –Suzanne Rose ■

Rucaparib Approved for Ovarian Cancer

The FDA greenlighted Boulder,

CO–based Clovis Oncology’s rucaparib

(Rubraca) to treat women with advanced

ovarian cancer who have already received

at least two chemotherapies and have a

somatic or germline BRCA1 or BRCA2

mutation as identifi ed by an approved

companion diagnostic test. Up to 20% of

high-grade serous ovarian cancers have a

deleterious BRCA gene mutation.

To detect the BRCA alterations—and

thus determine which patients are eligible

to receive rucaparib—the agency also gave

a nod to the FoundationFocus CDx-

BRCA test on December 19. Marketed

by Foundation Medicine of Cambridge,

MA, the test is the fi rst next-generation

sequencing–based companion diagnostic

to receive FDA approval.

Rucaparib belongs to a class of

anticancer agents called PARP inhibi-

tors, which induce synthetic lethality

in cancer cells with defective homolo-

gous repair, such as those harboring

deleterious BRCA mutations.

Approval of the drug and the com-

panion diagnostic was based on data

from two multicenter, single-arm

trials evaluating their effi cacy and

safety. Studies of effi cacy involved 106

women with BRCA-mutated advanced

ovarian cancer who had already been

treated with at least two chemotherapy

regimens. At trial enrollment, BRCA

status was determined with either

local germline test results or a Foun-

dation Medicine clinical trial assay.

Mutation status was later verifi ed by

the FoundationFocus CDxBRCA test

in 96% of the patients for whom a

tumor sample was available.

Among all 106 patients, the objec-

tive response rate to rucaparib was

54%, with a median duration of res-

ponse of 9.2 months. Among patients

sensitive to platinum-containing

regimens, the response rate was 66%.

For patients with platinum-resistant

and platinum-refractory disease,

the response rates were 25% and 0%,

respectively. There was no signifi cant

difference in response rates between

patients with a BRCA1 mutation and

those with a BRCA2 mutation.

The safety of rucaparib was assessed

in a trial involving 377 patients. The

most common side effects were nausea,

fatigue, vomiting, anemia, abdominal

pain, constipation, decreased appe-

tite, diarrhea, thrombocytopenia, and

dyspnea. Two cases of acute myeloid

leukemia were reported.

Another PARP inhibitor, olaparib

(Lynparza; AstraZeneca), was approved

in 2014 to treat women with germline

BRCA-mutated advanced ovarian

cancer who had received at least three

prior chemotherapies. In the trial

that led to its approval, 34% of 137

such patients responded to olaparib.

Head-to-head comparisons of PARP

inhibitors have not been done, but

the effi cacy of olaparib and rucaparib

“These data will not change the

standard of care, but they provide an

enormous opportunity for discovery,”

she said. “We hope to uncover impor-

tant information about the mecha-

nisms and biomarkers of resistance to

endocrine-based therapy with CD4/6

inhibitors.” –Janet Colwell ■

Anti-CD22 CAR Therapy Leads to ALL Remissions

In a fi rst-in-human trial of an anti-

CD22 chimeric antigen receptor (CAR)

T-cell therapy in children and young

adults with relapsed/refractory acute

lymphocytic leukemia (ALL), research-

ers found that the immunotherapeutic

approach was not only feasible and safe,

but also effective, leading to remissions

in most patients. Data from the trial

were shared last month at the American

Society of Hematology’s annual meet-

ing in San Diego, CA.

Although anti-CD19 CAR T-cell

therapy has led to complete remissions

in 80% to 90% of patients with relapsed/

refractory ALL, “we’re learning now that

one of the limitations of this approach

is loss of CD19 expression occurring

in, potentially, a substantial number

of patients,” said Terry Fry, MD, of

the Pediatric Oncology Branch, Center

for Cancer Research, at the NCI, who

presented the trial’s fi ndings at a press

conference during the meeting.

Seeking an alternative target—and

noting the effectiveness of the anti-

body–drug conjugate inotuzumab

ozogamicin (Pfi zer), which targets

CD22, an antigen widely expressed

on B-cell leukemias and lympho-

mas—researchers launched a phase I

dose-escalation study of anti-CD22

CAR T-cell therapy, enrolling 16 chil-

dren and young adults with relapsed/

refractory CD22-expressing ALL in

the study. Eleven of the 16 patients

had relapsed after previously receiv-

ing anti-CD19 CAR T cells. All of the

patients had had at least one alloge-

neic stem cell transplant.

Researchers collected T cells from

the patients and modifi ed them to

recognize and bind to CD22. Patients

then received an infusion of their own

modifi ed cells at one of three “doses”—

3 × 105 transduced CAR T cells/kg,

1 × 106 cells/kg, or 3 × 106 cells/kg—and

were evaluated for a response and

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