## transformed Low-Grade NHL

At the initiation of the major efficacy trial (RIT-II-004) FDA informed
the sponsor, in the End-of-Phase 2 meeting and in subsequent
correspondence, that extending the efficacy date obtained in the
treatment of patients with low grade and follicular NHL without evidence
of transformation to the treatment of patients with NHL with
transformation to a higher grade histology may not be appropriate. The
sponsor was asked to provide a justification for pooling the results
from these two populations. In addition, the sponsor was informed that
subset analyses should be conducted in patients with and without
evidence of transformation. At the conclusion of RIT-II-004, the results
of the subset analyses showed a marked difference in the response rates
in the two subsets (62% vs. 21%). Based on a demonstration of durable
responses in patients with low grade and follicular NHL with
transformation, recurrent after combination chemotherapy, the sponsor
requested Fast Track designation and received for treatment of patients
with transformed NHL, that was recurrent or refractory to standard
chemotherapy. FDA asked the sponsor to supplement the data from
RIT-II-004, which enrolled 23 patients with transformed NHL. The sponsor
identified a total of 71 patients with a diagnosis of transformed NHL at
the time of study entry who were enrolled in the 4 activity/efficacy
trials conducted by the sponsor.

The integrated efficacy analyses of the transformed low‑grade NHL
patient population include data on the 78 patients who had a diagnosis
of transformed low‑grade NHL at some point prior to study entry and who
received study drug in the 4 studies (RIT‑I‑000, RIT‑II‑001, RIT‑II‑002,
and RIT‑II‑004). In order to be included in the dataset, FDA stated that
the histologic diagnosis be confirmed for each subject. Central
pathologic review was conducted by Dr. Charles Ross at the University of
Michigan of 60 patients with a diagnosis of transformed NHL who were
enrolled in studies RTI-I-000, RIT-II-001, RIT‑II‑002, and RIT‑II‑004.
Dr.Elaine Jaffe performed central pathologic review for 12 patients a
diagnosis of transformed NHL who were enrolled in study CP 97-012.

The independent (MIRROR) panel conducted a retrospective review of the
clinical data to establish the response rates and duration for this
subpopulation.

FDA conducted a review of the information in the case report forms,
pathology reports (initial and central review) and the central
pathologic review process for the 60 patients who were centrally
reviewed at the University of Michigan. FDA has not yet completed its
review of the information and central pathologic review process for
those subjects assessed by Dr. Jaffe. This report will cover the review
of the 60 patients and an updated report on all 72 subjects will be
provided as supplemental information and presented at the Dec. 17, 2002
ODAC meeting.

Among the 60 patients reviewed, FDA determined that a diagnosis of low
grade NHL with evidence of histologic transformation could be documented
for 42 patients. Biopsy material was available for central pathological
review at all critical timepoints for each of these 42 patients. There
were 31 patients in whom low grade NHL was documented histologically at
the time of original diagnosis and intermediate grade NHL was documented
histologically at a later time; both diagnoses were confirmed by the
central pathologist. There were 11 patients in whom lymphoma with
transformed features (low grade and intermediate grade) was documented
histologically at the time of diagnosis and confirmed by the central
pathologist.

FDA believes that the remaining 18 should be excluded from analysis of
the transformed subpopulation due to inability to confirm the pathologic
diagnosis. The reasons for exclusion from the dataset are listed in the
table below. For most of these 18 patients, the pathologic material
(slides) was not available or was inadequate at one or more critical
times. In three of the patients where the slides were available for
central review, the central reviewing pathologist disagreed with the
diagnosis of transformation.

**Classification of Transformed Lymphomas From the Transformed Dataset**

+--------------------------------------------------------+-------------+
| **Reason for exclusion from the subpopulation**        | **Number of |
|                                                        | patients    |
|                                                        | excluded**  |
+--------------------------------------------------------+-------------+
| Original histological diagnosis of NHL not documented. | 7           |
|                                                        |             |
| > Transformed (low grade and intermediate grade)       |             |
| > documented histologically at a later time.           |             |
+--------------------------------------------------------+-------------+
| Low grade NHL documented histologically at the time of | 3           |
| original diagnosis.                                    |             |
|                                                        |             |
| Transformation diagnosed by pathologist at a later     |             |
| time, but diagnosis of transformation not upheld by    |             |
| central pathologist.                                   |             |
+--------------------------------------------------------+-------------+
| Transformation diagnosed at time of original           | 1           |
| diagnosis, but slides not available for central        |             |
| pathologic review. Subsequent biopsy(s) show low grade |             |
| NHL.                                                   |             |
+--------------------------------------------------------+-------------+
| Insufficient pathologic material for central           | 1           |
| pathologist to diagnose low grade lymphoma. No         |             |
| material submitted to support diagnosis of             |             |
| transformation.                                        |             |
+--------------------------------------------------------+-------------+
| Low grade NHL documented histologically at the time of | 1           |
| original diagnosis. Slides documenting transformation  |             |
| not available for central review.                      |             |
+--------------------------------------------------------+-------------+
| Slides documenting original diagnosis of low grade NHL | 1           |
| not available for central review. Slides documenting   |             |
| histologic transformation not available for central    |             |
| review. (1 case)                                       |             |
+--------------------------------------------------------+-------------+
| No transformation of NHL diagnosed at either original  | 1           |
| biopsy, or on any subsequent biopsies.                 |             |
+--------------------------------------------------------+-------------+
| Original diagnosis of transformation not documented.   | 1           |
| Slides not available. No evidence of pre-existing low  |             |
| grade lymphoma. (1 case)                               |             |
+--------------------------------------------------------+-------------+
| Histologic subtype of NHL does not Eligibility         | 1           |
| Criteria and diagnosis of transformation not upheld by |             |
| central pathologist.                                   |             |
+--------------------------------------------------------+-------------+
| Histologic subtype of NHL does not meet Eligibility    | 1           |
| Criteria and no transformation diagnosed either at     |             |
| original biopsy or any subsequent biopsies.            |             |
+--------------------------------------------------------+-------------+
| TOTAL                                                  | 18          |
+--------------------------------------------------------+-------------+

Among the 42 patients, with adequate information to confirm the
diagnosis, there were two patients who had been enrolled in single
patient IND trials. The sponsor has provided minimal data and has not
audited the clinical data for these two patients. These two patients
have been excluded from the FDA confirmed group because there was
insufficient clinical information to conduct analyses and the quality of
the data available are unknown. The baseline entry characteristics for
the remaining 40 patients are summarized in the following table.

+-----------------------------------+----------------+----------------+
| # Baseline Entry Characteristics  | Sponsor        | FDA Confirmed  |
|                                   | Identified\*   |                |
+-----------------------------------+----------------+----------------+
| # N                               | **71**         | **40**         |
+-----------------------------------+----------------+----------------+
| # Age (Years)                     | 59             | 58             |
|                                   |                |                |
| #  Median                         | (37, 80)       | (37, 80)       |
|                                   |                |                |
| Range                             |                |                |
+-----------------------------------+----------------+----------------+
| # Gender                          | 41 (58%)       | 23 (58%)       |
|                                   |                |                |
| Male (% male)                     |                |                |
+-----------------------------------+----------------+----------------+

Most of the baseline data for these patients is typical for patients
with transformed disease. Such patients have had multiple courses of
chemotherapy (median 4). Transformation is often suspected clinically
when a patient with known lymphoma presents with a rapidly enlarging
node, so the presence of nodes greater than 7 cm in 40% of the FDA
confirmed study patients is not surprising.

An atypical statistic in this group is the median time from
transformation until study entry, which was 3.3 years (range of 0 to
24.5). The literature states that transformed low grade NHL has a poor
prognosis, with a median survival of less than one year after
transformation. Yuan, et al (JCO 13:1726, 1995) described a group of
patients with histologic transformation who had a median survival
duration of 81 months after transformation. The predictors of good
survival in this study were lack of prior chemotherapy, complete
response to chemotherapy after transformation and limited disease. Such
factors are not present in the FDA confirmed patients, who, as mentioned
above, have had a median of 4 chemotherapy regimens, did not tend to
have limited disease, and were less likely to have had a complete
response to chemotherapy once they transformed. The implication is that
the transformed patients who received iodine ^131^I tositumomab had
already demonstrated a tendency towards a favorable natural history.

Analyses of Baseline Entry Characteristics

FDA performed an analysis of the baseline entry characteristics (as
variables) that were associated with a diagnosis of transformed disease.
A stepwise selection using PROC LOGISTIC in SAS was used to identify the
variables associated with patients who had a diagnosis of transformed
disease. A significance level of 0.10 was used to allow a baseline
variable into the model and a significance level of 0.15, was used to
allow a baseline variable to stay in the model. The baseline variables
that entered into the model significantly were tumor grade at the study
entry (GRADEE), days between the last qualifying chemotherapy regiment
and study day (LQCEDAY), number of prior chemotherapy and Ann Arbor
Stage at study entry. Other baseline variables such as age, sex, IPI
category, study day of diagnosis of NHL, maximum unidimensional lesion
measurement (cm) at baseline, Ann Arbor stage at study entry, number of
prior chemotherapy received, duration of response to first chemotherapy,
etc. did not enter into the model (all p-values \>= 0.25).

The following table summarizes the baseline entry characteristics of the
271 patients enrolled in the 5 efficacy/activity studies, according to
the presence or absence of a reported pathologic diagnosis of histologic
transformation.

Efficacy Outcomes and Analyses

The pooled efficacy outcomes (response rates and durations) are provided
for the subpopulations of the 271 patients enrolled in the 5
efficacy/activity studies, according to sponsor-reported histologic
diagnosis (without \[n=200\] and with \[n=71\] evidence of histologic
transformation) and in the subset of patients where FDA confirmed that
there were adequate evidence to establish a diagnosis of transformed
histology on central pathologic review (n=40). The outcome measures are
summarized in the following table

\* Data not available for 4 of the 200 patients identified by sponsor as
without histologic transformation

The response rates for the FDA-confirmed population were 8% CR, 18% CCR
(combined CR rate 26%), and 15% PR, for an overall response rate of 41%.
The median duration of response to iodine ^131^I tositumomab was 1.6
years (range: 0.1---4.9 years). While these are impressive responses for
patients with transformed NHL, the prolonged median survival after
transformation and before study entry needs to be taken into account.

FDA conducted an analysis to assess whether there were predictors of
response to iodine ^131^I tositumomab in this subpopulation. The results
of the analysis of the relationship between response to last qualifying
chemotherapy and response to iodine ^131^I tositumomab in the FDA
confirmed transformed subpopulation is summarized in the table below.

+----------------------------------+--------+---------+-------+-------+
|                                  | O      |         |       |       |
|                                  | verall |         |       |       |
|                                  | Re     |         |       |       |
|                                  | sponse |         |       |       |
|                                  |        |         |       |       |
|                                  | (ORR = |         |       |       |
|                                  | CR+C   |         |       |       |
|                                  | CR+PR) |         |       |       |
|                                  |        |         |       |       |
|                                  | to     |         |       |       |
|                                  | iodine |         |       |       |
|                                  | ^131^I |         |       |       |
|                                  | tosit  |         |       |       |
|                                  | umomab |         |       |       |
+----------------------------------+--------+---------+-------+-------+
| Last Qualifying                  |        | Yes     | No    | Total |
|                                  |        |         |       |       |
| Chemotherapy Overall Response    |        |         |       |       |
| (ORR = CR+CCR+PR)                |        |         |       |       |
+----------------------------------+--------+---------+-------+-------+
|                                  | Yes    | 11      | 11    | 22    |
+----------------------------------+--------+---------+-------+-------+
|                                  | No     | 5       | 13    | 18    |
+----------------------------------+--------+---------+-------+-------+
|                                  | Total  | 16      | 24    | 40    |
+----------------------------------+--------+---------+-------+-------+

There were 11 of 22 (50%) patients responding to chemotherapy and 5 of
18 (28%) who did not respond to chemotherapy who achieved a response to
the iodine ^131^I tositumomab regimen. There is no significant
difference in the overall response rates following the last qualifying
chemotherapy regimen and ORR following the iodine ^131^I tositumomab
regimen in the FDA-confirmed transformed population (p-value using
two-sided McNemar's test for paired samples = 0.2101).