Clinical Studies-Endobronchial Cancer

Two randomized multicenter Phase 3 studies were conducted to compare the safety and efficacy of PHOTOFRIN PDT versus Nd:YAG laser therapy for reduction of obstruction and palliation of symptomatic patients with partially or completely obstructing endobronchial nonsmall cell lung cancer. Assessments were made at 1 week and at monthly intervals after treatment. Table 2 shows the results from all randomized patients in the two studies combined. Objective tumor response rates (CR + PR), which demonstrate reduction of obstruction, were 59% for PDT and 58% for Nd:YAG at Week 1. The response rate at 1 month or later was 60% for PDT and 41% for Nd:YAG.

TABLE 2. Efficacy Results from Studies in Late-stage Obstructing Endobronchial Cancer-All Randomized Patients ^(a)
EFFICACY PARAMETER (% OF PATIENTS)	PDT n = 102	Nd:YAG n = 109
OBJECTIVE TUMOR RESPONSE ^(b)
Week 1	59%	58%
Month 1 or later	60%	41%

ATELECTASIS IMPROVEMENT ^(c)
	n = 60	n = 71
Week 1	35%	18%
Month 1 or later	35%	20%

(a) Statistical comparisons were precluded by the amount of missing data at Month 1 or later (e.g. for tumor response, PDT 28% missing, Nd:YAG 38%).
(b) CR+PR, CR = complete response (absence of bronchoscopically visible tumor), PR = partial response (increase >= 50% in the smallest luminal diameter);for completely obstructing tumors, any appearance of a lumen.
(c) In patients with atelectasis at baseline

Patient symptoms were evaluated using a 5- or 6-grade pulmonary symptom severity rating scale for dyspnea, cough and hemoptysis. Patients with moderate to severe symptoms are those most in need of palliation. Improvements of 2 or more grades are considered to be clinically significant. Table 3 shows the percentages of patiens with moderate to severe symptoms at baseline who demonstrated a 2-grade improvement at any time during the interval evaluated.

TABLE 3. Efficacy Results from Studies in Late-Stage Obstructing Endobronchial Cancer-Clinically Significant Improvements in Patients with Moderate to Severe Symptoms at Baseline ^(a)
CLINICALLY SIGNIFICANT SYMPTOM IMPROVEMENT(b) (% of Patients)	PDT	Nd:YAG
ANY SYMPTOM	n = 89	n = 89
Week 1	25%	29%
Month 1 or later	40%	27%

DYSPNEA	n = 60	n = 68
Week 1	15%	18%
Month 1 or later	23%	13%

COUGH	n = 63	n = 65
Week 1	6%	9%
Month 1 or later	24%	8%

HEMOPTYSIS	n = 24	n = 31
Week 1	58%	29%
Month 1 or later	79%	35%

(a) Statisitical Comparisons were precluded by the amount of missing detail at Month 1 or later.
(b) Dyspnea was graded on a 6-point severity rating scale; cough and hemoptysis on 5-point scales. Clinically significant improvement was defined as a change of at least two grades from baseline.

In a separate retrospective analysis, patients were individually evaluated to identify those patients whose benefit to risk ratio was most favorable, i.e., those who obtained clinically important benefit with minimal adverse reactions. Clinically important benefit was defined as one of the following:

a substantial improvement in pulmonary symptoms at Month 1 or later (dyspnea >= 2 grades, hemoptysis >= 3 grades, cough >= 3 grades or increase in FEV1 >= 40%;

a moderate improvement in symptoms at Month 2 or later (dyspnea 1 grade, cough 2 grades, hemoptysis 2 grades or increase in FEV1 >= 20%); or

a durable objective tumor response (CR or PR maintained to Month 2 or longer).

Thirty six of the 99 PDT-treated patients (36%) and 23 of the 99 Nd:YAG-treated patients (23%) received clinically important benefit with only minimal or moderate toxicities of short duration. 34 of 99 PDT-treated patients demonstrated improvements in 2 or more efficacy endpoints (dyspnea, cough, hemoptysis, sputum, atelectasis, pulmonary function tests of FEV1 or FVC, Karnofsky Perfomance Score or tumor response) and 29 patients had improvements in 3 or more. The median duration of documented benefit in the 36 patients was 63 days. In these patients with late-stage obstructing lung caner, median survival was 174 days in PDT-treated patients and 161 days in Nd:YAG treated patients.

The efficacy of PHOTOFRIN PDT was also evaluated in the treatment of microinvasive endobronchial tumors in 62 inoperable patients in three noncomparative studies. Microinvasive lung cancer is defined histologically as disease which invades beyond the basement membrane but not through or into the cartilage. For 11 of the 62 patients, it was clearly documented that surgery and radiotherapy were not indicated. These 11 patients were all inoperable for medical or technical reasons. Radiotherapy was not indicated due to prior high-dose radiotherapy (7 patients), poor pulmonary function (2 patients), multifocal multilobar disease (1 patient), and poor medical condition (1 patient). As shown in Table 4, the complete tumor reponse rate, biopsy-proven at least 3 months after treatment, was 50%, median time to tumor recurrence was more than 2.7 years, median survival was 2.9 years and disease-specific survival was 4.1 years.

TABLE 4. Overall Efficacy Results in Patients with Superficial Endobronchial Tumors
EFFICACY PARAMETER	PDT
EFFICACY PARAMETER	n = 11	n = 62
COMPLETE TUMOR RESPONSE, BIOPSY PROVEN AT 3 MONTHS Number of Patients (%)	3 (27%)	31 (50%) (a)

TIME TO TUMOR RECURRENCE IN PATIENTS WITH COMPLETE RESPONSE Number of Patients (%) with Recurrences	1 (33%)	11 (35%)

Median Time to Tumor Recurrence [95% Confidence Interval]		> 2.7 years [1.6, --(b)]

DISEASE-SPECIFIC SURVIVAL Number of Patients (%) who died of any cause	4 (36%)	32 (52%)

Median Survival [95 % Confidence Interval]		2.9 years [2.1, 5.7]

DISEASE SPECIFIC SURVIVAL Number of Patients (%) who Died of Lung Cancer	3 (27%)	22 (35%)

Median Disease-Specific Survival [95% Confidence Interval]		4.1 years [2.5, --(b)]

(a) Not included are an additional 18 patients (6 patients not eligible for surgery or radiotherapy) who had complete tumor responses which were documented earlier than 3 months after treatment
(b) The upper limit of the confidence interval could not be estimated due to an insufficient number of patients whose tumors recurred (Time to Tumor Recurrence) or who died (Survival)

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Clinical Studies-Endobronchial Cancer

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