results from a multicenter phase II
study by the Eastern Cooperative Oncology
Group (ECOG) suggest trastuzumab
(Herceptin) is safe and moderately
promising in combination with
paclitaxel and carboplatin (Paraplatin)
for some patients with non-small-cell
lung cancer (NSCLC).
Whether the investigation will
progress to a phase III trial is unclear,
however, as the researchers are uncertain
as to how many lung cancer patients
are positive for the HER2/neu
mutation targeted by trastuzumab.
"The problem is, do we have enough
patients to mount a study? That is the
big issue," investigator Corey Langer,
MD, FACP, director of thoracic oncology
at Fox Chase Cancer Center,
combination produced a median survival
of 10.1 months and a median
progression-free survival of 3.25
months (see Table 1), according to a
report by Dr. Langer (ASCO abstract
2606). At a median follow-up of 34
months, 6 of 53 evaluable patients were
still alive. Only one was free from progression.
Response rates showed that 13 of
these patients (24.5%) had partial responses,
21 (39.6%) had stable disease,
and 16 (28.3%) had progressive
disease (see Table 2). The results are
"as good as if not better than what we
typically see," Dr. Langer said, adding,
"The interesting thing is response occurred
across the board. I can't say if a
degree of HER2 positivity translated
to a better response rate."
From August 1999 to May 2000,
the investigators screened 139 patients,
of whom 82 proved to be HER2 positive.
All had advanced NSCLC. Eligi-
bility criteria included recurrent, stage
IV and stage IIIB (wet) disease and an
ECOG performance status of 0 to 1.
Prior chemotherapy was not allowed.
Of the 56 patients initially enrolled,
53 turned out to be eligible. Among
those evaluated, only eight were at the
HER2 level of 3+, which Dr. Langer
said is used to justify use of trastuzumab
in breast cancer. The remainder
were closely split with 22 patients
at 1+ and 23 patients at 2+.
The proportion of HER2-positive
lung cancer patients is probably lower
than the proportion in the population
screened for this study, according to
Dr. Langer, as oncologists did not refer
patients known to be negative for
the mutation. Only five patients had
squamous histology, another indication
that the HER2 mutation might be
uncommon among lung cancer patients.
Subgroup Could Benefit
Nonetheless, a subgroup of patients
might benefit, according to Dr. Langer,
depending on what the median survival
is for patients with HER2/neu.
That figure is currently unknown. If
HER2/neu patients have a median survival
of 5 months with standard chemotherapy,
10 months would be a
significant increase, Dr. Langer noted.
If their median survival is on the order
of 8 months, however, the added
months suggest less than the potential
of some other novel agents also in
Patients in the phase II study received
an intravenous loading dose of
4 mg/kg of trastuzumab followed by
2 mg/kg weekly. Paclitaxel and carboplatin
were delivered in 3-week cycles.
Toxicity appeared similar to chemotherapy
alone, and Dr. Langer said the
few cases of left ventricular ejection
fraction decreases were so trivial that
this need not be monitored if patients
are not receiving anthracycline in future
Ultimately, he predicted that no
one novel agent but a combination of
therapies will prove most effective.
"Lung is a multihit malignancy. Many
different genetic abnormalities conspire
to create a cancer," Dr. Langer
said, adding, "The bottom line is we
really don't know what the real targets
are, or how drugs interact. We're really
in our infancy in understanding this