Major Advances in Clinical Cancer Research in 2012
The report, which covers the period from October 2011 to September 2012, also highlights 70 "notable advances" that are promising but not immediately applicable to practice.
"Consistent, significant achievements are being made in oncology care with novel therapeutics, even in malignancies that have previously had few treatment options, as well as in defining factors that will predict response to treatment. ASCO's report distils the most significant of these advances that [will affect] the lives of cancer patients today," said Bruce Roth, MD, coexecutive editor of the report.
The 17 major advances considered to be practice-changing are listed below; the top 5 were identified as such by ACSO; the others follow in no particular order.
Afinitor) in hormone-receptor positive breast cancer.
Everolimus, an mTOR inhibitor used in the treatment of renal cell cancer,
was approved for use in combination with exemestane (
Aromasin) for women with hormone-positive breast cancer that has spread despite initial treatment with an aromatase inhibitor. This
indication was based on results from the 724-patient BOLERO-2 trial, which was
halted early because of the benefit observed. The combination of everolimus plus exemestane increased the median time to disease progression
to 10.6 months, compared with 4.1 months with exemestane alone (
N Engl J Med. 2012;366:520-529).
HER2-positive metastatic breast cancer.
T-DM1, which is currently
awaiting approval by the US Food and Drug Administration (FDA), consists of the anti-
HER2 antibody trastuzumab (
Herceptin) linked to the cytotoxic emansine. "We've taught an old friend a new trick — we're using [trastuzumab] as a delivery vehicle,"
one expert. In the pivotal EMILIA trial of 991 women with
HER2-positive metastatic breast cancer who had stopped responding to trastuzumab, T-DM1 improved survival, compared with the current
standard treatment of capecitabine (
Xeloda) and lapatinib (
N Engl J Med. 2012;367:1783-1791). After 2 years, the median survival rates were 65.4% with T-DM1 and 47.5% with the standard combination.
Preoperative chemo and radiation for esophageal cancers. A
phase 3 trial
of 366 patients with cancer of the esophagus or gastroesophageal
junction showed that preoperative treatment with chemotherapy
(carboplatin and paclitaxel) plus radiation, followed
by surgery, yielded substantial benefits, compared with surgery alone
N Engl J Med. 2012;366:2074-2084). Patients who had preoperative treatment survived for twice as long (median overall survival, 49 vs 24
months), and 29% had a complete remission.
Screening with flexible sigmoidoscopy reduces colorectal cancer deaths. A large American study, involving 154,000 patients with a median follow-up of 11.9 years, showed a significant decrease in
the incidence of colorectal cancer (reduced by 21%) and death (26%) (
N Engl J Med. 2012;366;2345-2357). This study, hailed as a
confirmed benefits seen in previous British and Italian studies, and
has prompted much discussion about how flexible sigmoidoscopy
compares with colonoscopy, the preferred screening
method in the United States.
Xtandi) for late-stage prostate cancer.
by the FDA in August for use in men with metastatic
castration-resistant prostate cancer previously treated with docetaxel
after the ARRIRM trial of 1199 men was stopped early
because it showed a survival benefit. Median overall survival was 18.4
months with enzalutamide and 13.6 months with placebo (
N Engl J Med. 2012:367:1187-1197). It is predicted that this first-in-its-class drug will be a
"game-changer" in prostate cancer.
maintenance in multiple myeloma. The finding that lenalidomide
delays relapse after stem cell transplantation comes from 2 placebo-controlled phase 3 trials. In the first study (
N Engl J Med. 2012;366:1782-1791), conducted
in 615 patients younger than 65 years, the disease returned after 41
months with lenalidomide
and after 23 months with placebo; after 4 years of
follow-up, more than 70% of patients were alive in both groups. In the
second study (
N Engl J Med. 2012;366:1759-1769), conducted
in 460 patients younger than 71 years, median time to progression was 46
months with lenalidomide
and 27 months with placebo. Lenalidomide also
increased overall survival (35 deaths in the lenalidomide group and 53
placebo group). However, lenalidomide was associated
with more adverse events and a higher incidence of second cancers than
placebo (7%–8% vs 3%–4%), the report notes.
HER2-positive metastatic breast
cancer. Pertuzumab is an anti-
HER2 antibody that
was approved in June in the United States and just
cleared for approval in Europe. The
CLEOPATRA trial showed that adding pertuzumab to the combination of trastuzumab plus docetaxel in the initial treatment of
HER2-postive breast cancer can overcome or
delay the resistance that develops to trastuzumab when it is used alone.
In the 808
women, the median time to progression was 18.5 months
when pertuzumab was added to the initial treatment,and 12.4 months when
it was not (
N Engl J Med. 2012;366:109-119).
Stivarga) in metastatic colorectal cancer.
This multitargeted drug
by the FDA in September, after the CORRECT trial showed that
regorafenib extended overall survival in patients with metastatic
colorectal cancer whose disease had progressed after
all approved standard therapies. Median overall survival was 6.4 months
with regorafenib and 5.0 months with best supportive
care. These results
were presented at the Gastrointestinal Cancers Symposium in January, and so far the data are available only in abstract form (
J Clin Oncol. 2012;30(4 Suppl):
Avastin) in recurrent ovarian cancer.
Women with ovarian cancer who progress after
platinum-based chemotherapy are then treated nonplatinum-containing
such as pegylated liposomal doxorubicin, topotecan,
and weekly paclitaxel. The AURELIA trial of 361 women who had received
up to 2 previous treatment regimens showed that median
time to disease progression was better with bevacizumab plus this
than with chemotherapy alone (6.7 vs 3.4 months).
were presented at the 2012 ASCO annual meeting, and so far are available only in abstract form (
J Clin Oncol.
Cometriq) in medullary thyroid cancer.
by the FDA in November on the basis of the pivotal EXAM trial of 330
patients with progressive, inoperable, metastatic, or
locally advanced disease, and tumors that were
actively growing. The results showed that cabozantinib improved time to
progression over placebo (11.2 vs 4.0 months). In
addition, tumor shrinkage was seen in 26% of patients in the
group, compared with 0% in the placebo group, and
these responses lasted a median of 14.6 months. These results have
been presented at meetings and are available only in abstract form (
J Clin Oncol 2012:30:(15 Suppl):
abstract 5508). Cabozantinib is also being studied in other cancer types, and "unprecedented" results were
recently reported in advanced prostate cancer.
Carboplatin and pemetrexed combination in nonsmall-cell lung cancer (NSCLC).
Patients with NSCLC who have a performance score of 2 (capable of
caring for themselves, but not carrying out work activities)
are currently treated with a single chemotherapy, but a
new study suggests they might live longer if they are treated with
a 2-drug combination. This represents a "paradigm
shift in the standard care for advanced NSCLC," and underscores the
of not undertreating this patient population,
according to the ASCO report. The 205-patient study showed that the
of carboplatin plus pemetrexed increased median
overall survival to 9.1 months, compared with 5.6 months for pemetrexed
In addition, tumor shrinkage was seen in 24% of
patients in the combination group and in 10% of the monotherapy group (
J Clin Oncol 2012;30(15 Suppl):
Erivedge) for basal cell carcinoma.
Basal cell carcinoma is the most common form of skin cancer, and vismodegib is the
first drug approved
by the FDA for the treatment of advanced disease that has metastasized
or relapsed after treatment with surgery, or for patients
who are not candidates for surgery or radiation. Two
studies showing efficacy (
N Engl J Med. 2012;366: 2171-2179, 2180-2188) were accompanied by an editorial (
N Engl J Med. 2012;366:2225-2226) declaring that vismodegib is "the
greatest advance in therapy yet." One of the studies (
N Engl J Med. 2012;366:2180-2188) involved 41
patients with basal cell nevus syndrome, which can lead to hundreds or
thousands of lesions.
During treatment with vismodegib, no tumors progressed
and in some patients, all tumors regressed. However, more than half
of the patients receiving vismodegib had to stop
treatment because of adverse events (including loss of taste, muscle
weight loss, and hair loss), according to the ASCO
report. It highlights the fact that vismodegib has a novel mechanism of
action — blocking the Hedgehog signaling pathway — and
that the drug is being investigated in other cancer types, including
colorectal, stomach, and pancreatic cancers.
Votrient) for soft tissue sarcoma.
Pazopanib is already marketed for the treatment of renal cell carcinoma, but this year it was approved
in the United States and
for use in the treatment of patients with advanced soft tissue sarcomas
(excluding adipocytic sarcomas and gastrointestinal
stromal tumors) who have received previous
chemotherapy. The PALETTE trial of 369 such patients showed an increase
median time to disease progression with pazopanib,
compared with placebo (4.6 vs 1.6 months), although median overall
times were similar (12.5 vs 10.7 months) (
2012;379:1879-1886). Although this led to
questions about benefit, experts treating sarcoma feel it offers an
important new option for their patients. This is the first positive trial and the first new drug in sarcoma for decades, according to the ASCO
Zyprexa) for chemo-induced nausea and vomiting.
Olanzapine, marketed as an antipsychotic drug, was shown to be an
effective rescue medication
for patients who were suffering from breakthrough chemotherapy-induced
nausea and vomiting (CINV), despite having received
standard prophylactic treatment. In 80 of 205 patients
who developed breakthrough CINV, olanzapine significantly outperformed
the conventional antinausea drug metoclopramide. More
patients in the olanzapine group than in the metoclopramide group
no vomiting (71% vs 32%) and no nausea (67% vs 24%).
The study was presented at the 2012 ASCO annual meeting, and so far is
available only in abstract form (
J Clin Oncol. 2012;30(15 Suppl):
Cymbalta) for chemo-induced peripheral neuropathy.
Duloxetine is marketed as an antidepressant but is also approved for use in painful diabetic peripheral neuropathy. In a
phase 3 trial,
it was shown to be useful in alleviating pain from chemotherapy-induced
peripheral neuropathy (CIPN). The trial involved
231 cancer patients who had been treated with
oxaliplatin or paclitaxel and had developed CIPN, and duloxetine was
with a greater average decrease in the pain score than
placebo. These results are also available only in abstract form (
J Clin Oncol 2012;30(15 Suppl):
Factors in elderly patients that increase chemotherapy risks.
Few clinical trials are conducted specifically in the elderly, so
deciding on cancer treatment in an elderly patient is
difficult, the ASCO report notes. A trial published
this year identified factors that are important to consider when
whether an elderly patient should undergo
chemotherapy, and explained how they affect the risk for fatality after
J Clin Oncol. 2012;30:1829-1834). A baseline
abbreviated comprehensive geriatric assessment was carried out on 348
patients older than
70 years who were scheduled for initial chemotherapy
for various cancers; advanced disease, low nutritional assessment score,
and poor mobility predicted early death (in less than 6
months) after beginning chemotherapy.
Predicting risk for chemo adverse effects in elderly patients. Another trial in elderly patients proposed a predictive model to identify those at elevated risk for adverse effects from
J Clin Oncol. 2011;29:3457-3465). The trial
involved 500 patients 59 to 91 years of age with a variety of cancers
who underwent detailed
assessment of tumor characteristics, laboratory tests,
and geriatric status (including function, comorbidity, cognition,
state, social activity/support, and nutrition), and
were then observed going through 1 round of chemotherapy. On the basis
of responses, the researchers developed a scoring
system and risk-stratification model that identify older adults at low,
intermediate, and high risk for adverse events from