A Study of Erlotinib Plus Radiotherapy (RT) for Patients With Advanced or Inoperable Non-Small-Cell Lung Cancer

Hypothesis/Rationale: Lung cancer is the number one cause of cancer-related mortality in both
men and women in the United States, with over 170,000 cases diagnosed annually. The overall
5-year survival rate remains 14% despite decades of clinical research. Thoracic RT is the
standard treatment for locally advanced (Stage III) NSCLC, in combination with chemotherapy
in favorable patients. Metastatic lung cancer (Stage IV) is treated with systemic
chemotherapy, with the addition of RT for palliation of tumor symptoms. Most lung cancers
present as large tumors, measuring 2 to 7 cm in largest dimension. It is therefore not
difficult to understand that only 16% of patients experience a complete resolution of their
irradiated tumors within 3 months following a course of standard fractionated (2.0 Gy daily)
RT and chemotherapy.

From basic principles advocated by Fletcher, it is thought that standard fractionated RT
doses up to 100.0 Gy may be necessary to sterilize tumors of the size frequently encountered
in clinical practice. Tumor control probability for bronchogenic carcinoma can be estimated
to be 10% for tumors of greater than 4 cm at a dose of 80.0 Gy, with an assumption, that an
average-size lung cancer may require doses beyond 100.0 Gy standard fractionated to have a
50% to 80% probability of controlling the tumor. This has been demonstrated in the
"stereotactic radioablation" approach to patients with the medically inoperable Stage I
NSCLC, in whom 20 Gy per fraction to a total of 60 Gy (a BED equivalent of >100 Gy) resulted
in an excellent local control of >90% (Timmerman R et al, 2006; Onishi H et al, 2007).

Hypofractionated RT: It is generally accepted that the presence of chronically hypoxic cells
within tumors may be an important cause of radioresistance and resultant local failure in
radiotherapy, particularly in large solid tumors such as locoregionally advanced NSCLC.
In-vitro experiments indicated that the dose needed to kill severely hypoxic cells is on the
order of 2 or 3 times the dose needed for oxic cells. Therefore, delivering a higher RT dose
to the tumor may result in higher tumor cell kill and improved local control. One of the
approaches to increase RT dose is to use hypofractionated RT, which not only increases the
dose, but also reduces the overall treatment time. The radiobiological rationale for
hypofractionated RT was described by Mehta et al (Mehta et al, 2001). Based on these
theoretical assumptions, University of Wisconsin has recently completed a dose escalation
study of progressively increasing fraction sizes in thoracic RT for lung cancer. Such larger
RT fraction sizes may require "tighter" radiation fields (to achieve reliable normal-tissue
sparing) and improved precision of RT delivery, something that is afforded by the SBF
(Stereotactic Body Frame) immobilization and daily CT scan based image verification of tumor
position. More experiences have been reported in the literature on hypofractionated regimens
for lung cancer. Japanese investigators (Nagata Y et al, 2002) treated 40 patients with
T1-T3N0 tumors or lung metastases with 10-12 Gy per fraction to a total of 40-48 Gy. No
pulmonary (or other) complications >Grade 2 were observed and the local control was 100% in
the subgroup of primary lung tumors. Another group from Japan (Onimaru R et al, 2003)
reported on 45 patients with primary lung tumors up to 6cm receiving 7.5 Gy per fraction to
60 Gy (lesions <3cm) or 6 Gy per fractions to 48 Gy (lesions 3-6cm). One patient with a
central tumor died of a radiation-induced ulcer in the esophagus. One patient with a
peripheral lesion experienced Grade 2 chest wall pain. The 3-year local control rate was 80%.
No adverse respiratory events were noted.

The "ultimate" hypofractionated RT regimen of 60 Gy given in 3 fractions of 20 Gy each has
been demonstrated to be feasible and highly effective in patients with medically inoperable
Stage I NSCLC tumors measuring up to 7 cm and located outside the central airways (Timmerman
et al, 2006). However, the same regimen was associated with a high incidence of severe
toxicity if applied to central airway. Since most tumors in patients with Stage III and IV
NSCLC are located centrally, a novel hypofractionated regimen needs to be developed
specifically for them.

In our institution we have completed a Phase I/II investigator-initiated trial of
dose-escalated hypofractionated RT given concurrently with Gefitinib (Iressa) with Gefitinib
continued after RT completion until progression or toxicity. Three RT dose levels are
applied: 4.2 Gy in 10 fractions to 42 Gy; 4.2 Gy in 12 fractions 50.4 Gy and 4.2 Gy in 15
fractions to 63 Gy. Eligible pts are those with either Stage III or IV NSCLC who needed
thoracic RT and could not receive chemotherapy. No selection by the EGFR receptor status has
been applied. A total of 12 patients have been enrolled. Main toxicities were pulmonary (1
grade 2 pneumonitis; 1 grade 3 infectious pneumonia; 1 grade 4 pneumonitis). There was 1
grade 3 abdominal pain. One patient (with thoracic tumor controlled) died due to the late
radiation-esophageal toxicity (tracheo-esophageal fistula in a setting of pre-existing
esophageal diverticula) at 12 months from RT. Only one patient experienced local progression
of the irradiated tumor, which is very encouraging and may support the hypothesis of the
radiosensitizing effect of the EGFR inhibitors. As of now, median survival time for all 12
enrolled patients is 9 months (range: 1-26 mo) from the time of initiating Gefitinib, which
is an encouraging result in mostly pretreated patients, many with metastatic disease
(Werner-Wasik et al, oral presentation, First ESMO/IASLC European Meeting on Lung Cancer,
Geneva, Switzerland, April 2008).

Since Gefitinib is not available now for wider use, we are proposing a study of erlotinib
with hypofractionated RT in a Phase II setting with the main objective of assessing efficacy
of such a combination. There is no direct evidence that patients receiving concurrent EGFR
inhibitors and RT need to be pre-selected with regard to the EGFR status. In a recent study
(Bentzen SM et al, 2005), positive immunohistochemical staining for EGFR status was
associated with a benefit in locoregional control in patients with head and neck cancer
receiving CHART (continuous hyperfractionated accelerated radiotherapy), but the EGFR status
had no effect on survival or rate of distant metastases. Therefore, we propose to investigate
the EGFR status in all eligible patients, but to treat them without selection for the EGFR
status.

Tarceva (previously known as OSI-774) is an orally active, potent, selective inhibitor of the
EGFR tyrosine kinase. Early clinical data with Tarceva indicate that the compound is
generally safe and well tolerated at doses that provide the targeted effective concentration
based on nonclinical experiments. A recently completed, randomized, double-blind,
placebo-controlled trial (BR.21) has shown that Tarceva as a single agent significantly
improves the survival of patients with incurable Stage IIIb/IV NSCLC who have failed standard
therapy for advanced or metastatic disease (Shepherd F et al, 2000 and 2005). In a Phase II
clinical trial (Jackman D et al, 2007) of 80 chemotherapy-naive patients >70 years of age
with advanced non-small cell lung cancer who received erlotinib as first-line therapy, an
encouraging median survival time (MST) of 10.9 months was reported, with the presence of EGFR
mutations strongly correlated with disease control and survival.

In summary, a combination of erlotinib with hypofractionated thoracic RT has the potential to
significantly improve local tumor control in patients with non-small-cell lung cancer, based
on theoretical considerations of EGFR inhibition, increased tumor cell killing with larger RT
fractions and preclinical evidence for synergism between RT and erlotinib.

Our hypothesis is that the addition of erlotinib to RT will result in radiosensitization,
therefore increasing the likelihood of local tumor control over RT alone. Maintenance
erlotinib upon RT completion will result in further tumor growth inhibition, both
systemically and locally, lengthening disease-free survival and overall survival.

All eligible patients will be enrolled, without regard for the EGFR status. The implications
of prospectively screening patients for EGFR mutations or gene copy number and how the
patients should be selected for subsequent treatment remain to be defined (Janne P et al,
2005; Shepherd f et al, 2005). Therefore, patients will not be excluded from trial
participation based on the EGFR testing. The EGFR status will be assessed by the FISH assay
in biopsy or resection tissue samples and the test will be performed by a commercial
laboratory.

Inclusion Criteria:

Patients must fulfill all of the following criteria to be eligible for study entry:

- Patients aged 18 years or older with histologically or cytologically confirmed
unresectable or medically inoperable NSCLC and measurable disease.

- Patients with AJC Stage IV (metastatic) NSCLC who need initial thoracic RT to control
symptoms such as hemoptysis, airway obstruction, esophageal compression, superior vena
cava syndrome, other symptoms, or to prevent symptomatic tumor progression.

- Patients with synchronous brain metastases will be allowed to enroll and to receive
whole-brain radiation therapy while on the protocol.

- Patients with unresectable or medically inoperable locally advanced (AJC Stage II,
IIIA or IIIB) NSCLC, who require thoracic RT but do not qualify for other protocols
due to the presence of a malignant pleural or pericardial effusion, major weight loss,
poor performance status, unwillingness to receive chemotherapy or other factors.

- Patients with medically inoperable Stage I NSCLC or those patients with a resectable
Stage I NSCLC who decline surgery.

- Patients treated initially with systemic chemotherapy or biologic therapy who
eventually develop progression of intrathoracic disease and require thoracic RT, or
who may benefit from consolidative thoracic RT following chemotherapy or biologic
therapy.

- Patients must have a minimal FEV1 of 1.2 l. Lower FEV1 may be allowed for small tumors
and a V17 <25%.

- Estimated life expectancy of 3 months or more.

- Patients able to provide a written informed consent prior to study entry.

- Patients who agree to have their biopsy or surgical specimen analyzed for the EGFR
status.

- Women of childbearing potential must be willing to practice acceptable methods of
birth control to prevent pregnancy.

Exclusion Criteria:

Any of the following is a criterion for exclusion from the trial:

- Small cell lung cancer, any stage

- Previous thoracic radiation therapy

- Oxygen-dependent patients

- FEV1 < 1.2 l

- Patients with severe underlying lung disease of any origin, which in the opinion of
the investigators may markedly increase the risk of treatment-related pneumonitis

- Known severe hypersensitivity to Erlotinib or any of the excipients of this product

- Concomitant use of phenytoin, carbamazepine, barbiturates, rifampicin, phenobarbital,
or St John's Wort preparations

- Treatment with a nonapproved or investigational drug within 30 days before Day 1 of
trial treatment

- Incomplete healing from previous oncologic or other major surgery

- Serum creatinine level greater than CTC grade 2

- Pregnancy or breast feeding (women of childbearing potential)