BETHESDA, Md--A Food and Drug Administration panel has urged
expanding the use of Photofrin (porfimer sodium, QLT
PhotoTherapeutics) in lung cancer. In a unanimous vote, the Oncologic
Drugs Advisory Committee (ODAC) recommended that the FDA approve the
photodynamic therapy (PDT) for reduction of obstruction and
palliation of symptoms in patients with completely or partially
obstructing endobronchial non-small-cell lung cancer (NSCLC).
If the FDA follows the recommendation, between 20,000 and 25,000
NSCLC patients a year in the United States would be candidates for
the therapy, said John R. North, PhD, QLTs vice president for
The committees favorable vote came a year after the panel
recommended approval of Photofrin for T1 stage endo-bronchial
carcinoma in NSCLC patients, but refused to recommend its use in the
broader group of patients with partially or completely obstructing
endobronchial NSCLC. The FDA approved the more limited use in January
1998. The drug has been approved in the United States for palliative
use in obstructive esophageal cancer since 1995.
Last year, committee members expressed concern about the collection
of data on symptom palliation in studies of Photofrin vs the nd:Yag
laser and the amount of data missing at the 1-month point. In a later
meeting with FDA staff and several ODAC members, it was agreed that
to assess the efficacy of PDT, the company would do a reanalysis to
measure how quickly palliation was attained, how much benefit one
course of therapy provides, and how long the benefit lasts. The FDA
did not ask for additional clinical trials.
The New Analysis
The new analysis, according to the company, demonstrates that both
therapies provide an immediate response and suggests that Photofrin
provides a longer lasting response.
Harvey Pass, MD, professor of surgery and oncology, Wayne State
University, presented the reanalysis of data from two prospective,
randomized studies of Photofrin vs nd:YAG laser therapy on behalf of
QLT. Study P17 involved 70 patients treated at 20 centers in the
United States. Study P503 had 141 participants treated at 15 centers
in Canada and Europe.
Combined data showed that at 1 week after treatment, 59% of the PDT
patients and 58% of the laser patients had a complete or partial
response. Tumor response was assessed by luminal diameter
measurement, and a partial response was defined as at least a 50%
increase in luminal diameter. At 1 month, 55% of the PDT group showed
a tumor response, compared with 30% in the laser arm.
The missing data at 1 month, which had concerned the ODAC previously,
resulted because of patient death, withdrawal from study, condition
too grave for assessment, or re-treatment, Dr. Pass said. In an
analysis that excluded these patients, the tumor response rate at 1
month was 81% for PDT patients and 54% for the laser group.
The new analysis also looked at the reduction in atelectasis with
treatment. Improvement in the PDT group was 48% vs 30% in the laser arm.
Originally, ODAC members had questioned the unblinded manner in which
the studies collected data to assess palliation. Typically,
physicians simply asked patients about their symptoms and recorded
their answers, introducing a strong potential for bias. With FDA
agreement, the company analyzed symptom improvement only when
patients indicated an improvement of 2 or more points on a 6-point
scale, with the rationale that such increases would not likely result
solely from investigator enthusiasm.
The original analysis showed improvement in 57% of PDT patients and
50% in the laser group at 1 week, and 55% and 35%, respectively, at 1
month. Looking only at an improvement of two or more points, 22% of
the PDT arm reported benefit at 1 week, compared with 24% of the laser-treated
patients; at 1 month, the advantage reversed to 30% for PDT and 14%
for the laser arm. When researchers looked at moderate to severe
symptoms, the improvement was 25% at 1 week and 35% at 1 month in the
PDT group vs 35% and 17%, respectively, in the laser group.
These data indicate that palliation lasted longer with PDT, Dr. Pass
Several adverse events were significantly more common in PDT
patients: photosensitivity reactions (20% vs 0%), dyspnea (32% vs
17%), and bronchitis (11% vs 3%). The company argued, however, and
the FDA agreed, that a bias existed against Photofrin in these data
because the PDT group was followed longer. "Overall, there was a
one-third greater follow-up in the PDT group," Dr. Pass said.
Several ODAC members voiced concern that PDT patients had
significantly more adverse events when treated by physicians who had
little experience doing the therapy. Dr. Pass said that a number of
training sessions have been held to acquaint users with the technique
and the delicacy needed to avoid causing serious bleeding in lung
cancer patients. "We do think the rate will come down as
physicians get more training," said Alexandra Mancini, QLTs
vice president for regulatory affairs.
The companys reanalysis won high marks from the FDA reviewer
Grant Williams, MD. "I believe the efficacy of Photofrin at 1
month is documented by a luminal response rate at least as good as
that of YAG," he told the panel. "In my opinion, there
appears to be overall benefit, and this benefit outweighs the risk."
In its questions to the committee, the FDA asked if ODAC members
found that the two studies adequately demonstrated the efficacy of
Photofrin in patients with partially or completely obstructing
"I am persuaded that these trials demonstrate efficacy for a
subgroup of patients," replied Richard L. Schilsky, MD, director
of the University of Chicago Cancer Research Center. "Im
not exactly sure who those patients are, but it does seem to be
pretty clear that there are some patients who benefit from this treatment."
His colleagues agreed in an 8-to-0 vote and went on to recommend
approval by an identical vote.