ORIGINAL ARTICLE
`
`A Randomized, Phase II Trial of Two Dose Levels of
`Temsirolimus (CCI-779) in Patients with Extensive-Stage
`Small-Cell Lung Cancer Who Have Responding or Stable
`Disease after Induction Chemotherapy: A Trial of the
`Eastern Cooperative Oncology Group (E1500)
`
`Kishan J. Pandya, MD,* Suzanne Dahlberg, PhD,† Manuel Hidalgo, MD,‡ Roger B. Cohen, MD,§
`Martin W. Lee, MD,兩兩 Joan H. Schiller, MD,¶ and David H. Johnson, MD#
`
`Hypothesis: To study the progression-free survival (PFS) and tox-
`icity with 25- or 250-mg doses of temsirolimus (CCI-779) after
`induction chemotherapy in patients with extensive small-cell lung
`cancer.
`Methods: Patients with either stable or responding disease to four to
`six cycles of cisplatin or carboplatin plus etoposide or irinotecan
`were randomized between 4 and 8 weeks after completion of
`induction therapy to receive either 25 or 250 mg of temsirolimus
`intravenously every week until disease progression.
`Results: Eighty-seven patients entered between January 2002 and
`December 2003, of whom 85 were eligible: 44 received 25 mg (arm
`A), and 41 received 250 mg (arm B). The overall median follow-up
`time for all eligible patients was 34.6 months. Median age was 59
`years (range, 39 – 80); 42 (49.4%) were male and 43 (50.6%) female;
`12.9% had brain metastases. The overall median and 1-year PFS
`were 2.2 months (95% confidence interval [CI]: 1.8, 2.9) and 4.7%
`(95% CI: 0.2%, 9.2%), respectively. The median PFS (95% CI) for
`arm A was 1.9 months (1.6, 2.3); for arm B, it was 2.5 months (1.9,
`3.4; p ⫽ 0.24). The median overall survival from randomization was
`8 months (95% CI: 6.5, 9.5). Among the 86 patients with reported
`toxicities, 36 (42%) had grade 3 toxicities, the most common of
`
`From *University of Rochester, Rochester, New York; †Dana Farber Cancer
`Institute, Boston, Massachusetts; ‡Johns Hopkins University, Baltimore,
`Maryland; §Fox Chase Cancer Center, Philadelphia, Pennsylvania; 兩兩Park
`Nicollet Health Services, St. Louis Park, Minnesota; ¶University of
`Texas, Southwestern, Dallas, Texas; and #Vanderbilt University, Nash-
`ville, Tennessee.
`This study was conducted by the Eastern Cooperative Oncology Group
`(Robert L. Comis, MD, chair) and supported in part by Public Health
`Service Grants CA23318, CA66636, CA21115, CA11083, CA16116,
`CA21076, CA27525, CA49957 and from the National Cancer Institute,
`National Institutes of Health and the Department of Health and Human
`Services. Its contents are solely the responsibility of the authors and do
`not necessarily represent
`the official views of the National Cancer
`Institute.
`Address for correspondence: Kishan J. Pandya, MD, University of Roches-
`ter, James P. Wilmot Cancer Center, 601 Elmwood Avenue, Box 704,
`Rochester, NY 14642; E-mail: kishan_pandya@urmc.rochester.edu
`Copyright © 2007 by the International Association for the Study of Lung
`Cancer
`ISSN: 1556-0864/07/0211-1036
`
`which were thrombocytopenia, hypophosphatemia, and fatigue, and
`an additional 12 (14%) had grade 4 toxicities, the most common of
`which was neutropenia. No patients experienced lethal toxicities.
`Conclusion: Temsirolimus (CCI 779), given at 25 or 250 mg
`weekly, seemed not to increase the PFS in this patient population.
`
`Key Words: Small-cell lung cancer, Temsirolimus, CCI-779, Phase II
`study.
`
`(J Thorac Oncol. 2007;2: 1036–1041)
`
`Lung cancer is the number one cause of cancer deaths in
`
`both men and women in the United States. It was esti-
`mated that approximately 174,470 new cases of lung cancer
`would be diagnosed in the United States in 2006 and that
`approximately 13% of these patients would have small-cell
`lung cancer (SCLC).1 Histologically and biologically distinct,
`SCLC displays rapid cell proliferation, abrupt clinical pre-
`sentation, and a median survival of less than 3 months if left
`untreated.2 Combination chemotherapy produces high initial
`response rates, especially among patients with limited-stage
`disease. Unfortunately, the disease invariably relapses, espe-
`cially in patients with extensive-stage disease, causing death
`of the patient. A search for newer approaches to improve
`relapse-free and overall survival is clearly indicated for pa-
`tients with extensive-stage SCLC.
`Temsirolimus (CCI-779), an ester of sirolimus, is a novel
`mammalian target of rapamycin inhibitor, with properties of a
`cytostatic agent. It binds to and forms a complex with the
`cytoplasmic protein, FK506 binding protein.3–5 This complex
`inhibits mammalian target of rapamycin, which leads to the
`inhibition of phosphorylation of the eukaryotic translation initi-
`ation factor 4E binding protein-1 and the 40S ribosomal protein
`p70 S6 kinase that regulate the progression of the cell cycle
`from the G-1 to the S phase. In vitro, temsirolimus has
`been shown to inhibit the growth of a number of hitologi-
`cally diverse tumor cells, and in vivo antitumor activity in
`early-phase clinical trials has been reported with temsiroli-
`mus in patients with several tumor types,6 including renal
`
`1036
`
`Journal of Thoracic Oncology (cid:127) Volume 2, Number 11, November 2007
`
`NPC02237276
`
`NOVARTIS EXHIBIT 2170
`Par v Novartis, IPR 2016-00084
`Page 1 of 6
`
`

`
`Journal of Thoracic Oncology (cid:127) Volume 2, Number 11, November 2007
`
`Temsirolimus for Extensive-Stage SCLC
`
`cancer,7 breast cancer,8 and mantle cell lymphoma.9 These
`studies have shown activity of temsirolimus at doses of 25,
`75, and 250 mg/wk with an acceptable toxicity profile. None
`of these studies were done in combination with standard
`chemotherapy agents. This study was undertaken as part of
`broad phase II exploration of this agent in solid tumors. It was
`felt that as a “cytostatic” agent, it would be appropriate to use
`it in a consolidation study design for SCLC.
`The objectives of this clinical trial were to study pro-
`gression-free survival (PFS) and determine toxicity in pa-
`tients who received weekly doses of either 25 or 250 mg of
`temsirolimus, after induction chemotherapy in stable or re-
`sponding extensive-stage SCLC.
`
`MATERIALS AND METHODS
`
`Patients
`Patients were required to be older than 18 years old and
`have histologically or cytologically confirmed SCLC of the
`lung with extensive disease, defined as disease beyond the
`hemithorax and adjacent nodes, supraclavicular node in-
`volvement or pleural effusion with positive cytology, and a
`performance status of 0, 1, or 2. Patients with limited disease
`were ineligible. Patients were required to have received
`induction chemotherapy with platinum (cisplatin or carbopla-
`tin) plus either etoposide or irinotecan (minimum of three and
`a maximum of six cycles), and show responding or stable
`disease using the Response Evaluation Criteria in Solid Tu-
`mors (RECIST) since the initiation of systemic chemotherapy
`(i.e., patients who exhibited disease progression were not
`eligible), and to have recovered from all toxicity related to
`prior chemotherapy (except alopecia and/or neuropathy). Pa-
`tients were allowed no fewer than 4 and no more than 8
`weeks between the last induction chemotherapy treatment
`and randomization and no more than 32 weeks between the
`
`first dose of induction chemotherapy and date of randomiza-
`tion. No prior treatment with biological response modifiers
`was allowed. Patients with brain metastases were eligible as
`long as they had received treatment, were asymptomatic and
`were no longer taking corticosteroids or anticonvulsants.
`Patients who developed brain metastases after completion of
`induction chemotherapy were ineligible. Patients who were
`immunocompromized, had an active infection or serious
`intercurrent infection, or had received known immunosup-
`pressive therapies within 3 weeks of randomization were
`ineligible. Patients were required to practice adequate con-
`traception and to not become pregnant during treatment.
`Patients were required to have baseline measurements/eval-
`uations of disease ⬍4 weeks before randomization, and to
`meet the following laboratory criteria (evaluated ⬍2 weeks
`before randomization): WBC ⬎4000/mm or ANC ⬎1500/mm
`and platelet count ⬎100,000/mm; total bilirubin ⬍1.5 mg/dl;
`creatinine ⬍1.5 mg/dl; cholesterol level ⬍350 mg/dl; and
`trigylcerides ⬍400mg/dl. All patients gave written informed
`consent.
`Patients who had not progressed entered the study
`within 8 weeks of completing induction therapy and were
`randomized to receive either 25 mg (arm A) or 250 mg (arm
`B) of temsirolimus, given intravenously each week for 30
`minutes until disease progression or unacceptable toxicity
`(Figure 1). The National Cancer Institute Common Toxicity
`Criteria version 2.0 were used to grade toxicity and to guide
`dose modifications. Temsirolimus was held if the ANC was
`⬍1000/mm3 or platelets ⬍80,000/mm3, and resumed at 75%
`of the dose on full recovery for ANC between 750 and
`999/mm3 or platelets between 50,000 and 80,000/mm3, and at
`50% of the dose on full recovery for ANC ⬍750/mm3 or
`platelets ⬍50,000/mm3. Temsirolimus was also held for any
`grade 3 or 4 nonhematologic toxicity (except for nausea and
`
`Copyright © 2007 by the International Association for the Study of Lung Cancer
`
`1037
`
`FIGURE 1. Schema.
`
`NPC02237277
`
`NOVARTIS EXHIBIT 2170
`Par v Novartis, IPR 2016-00084
`Page 2 of 6
`
`

`
`Pandya et al.
`
`Journal of Thoracic Oncology (cid:127) Volume 2, Number 11, November 2007
`
`vomiting) and resumed at 75% for grade 3 and 50% for grade
`4 after recovery to grade 0 to 2. After a dose reduction, no
`dose escalation was allowed.
`Disease assessment with appropriate imaging study was
`required every 8 weeks, or sooner if clinical progression
`became evident. As is the norm in all cooperative group
`studies, there was no central review of imaging studies.
`
`Statistical Considerations
`Treatment assignments were determined using an on-
`line, Web-based patient-registration program, stratifying on
`brain metastases (yes versus no), prior chemotherapy for
`induction (cisplatin or carboplatin) plus etoposide versus
`cisplatin or carboplatin plus irinotecan), and response to
`induction chemotherapy (complete recovery or partial recov-
`ery versus stable disease).
`The primary objective of this study was to test whether
`a higher or lower dose of temsirolimus was better at prolong-
`ing PFS in patients with extensive-stage SCLC who had
`complete recovery, partial recovery, or stable disease after
`induction chemotherapy and who had not progressed before
`randomization to this trial. It was expected that the treatment
`with a high dose of temsirolimus (250 mg, intravenously,
`weekly) would result in more toxicities than the regimen with
`a low dose (25 mg, intravenously, weekly). Hence, the high
`dose of temsirolimus would only be investigated in a phase
`III trial if it prolonged PFS to a sufficient extent. On the basis
`of the median PFS time in the observation arm of E7593,10 it
`was assumed that the median PFS time of the low-dose arm
`of this trial would be at least 2.3 months. With 72 eligible
`patients entered during 3 years and an additional 6 months of
`follow-up, this design had 85% power to detect an increase in
`median PFS time to 4 months in the high-dose arm (log–rank
`test, one-sided significance level ⫽ 0.1).
`The secondary endpoint of this study was the determi-
`nation of the toxicity rates of the two doses of temsirolimus.
`In this analysis, any documented toxicity of grade 3 or higher
`was considered. There was 86% power to detect a difference
`in the true toxicity rates of 0.1 in the low-dose arm and 0.35
`in the high-dose arm (Fisher exact test, one-sided significance
`level ⫽ 0.1).
`
`Statistical Methods
`PFS is defined as the interval from the date of entry
`(randomization) on the study to the appearance of new
`metastatic lesions or objective tumor progression or death
`from any cause without progression. Overall survival
`is
`defined as the time from date of entry (randomization) to
`death from any cause. Patients without documented progres-
`sion or death were censored at the time of the last docu-
`mented disease evaluation.
`Kaplan–Meier11 curves were used to estimate event–
`time distributions. PFS was compared using log–rank tests.
`Adverse events, patient demographics, disease characteris-
`tics, and response rates were compared using Fisher exact
`tests. All p values are two sided. Confidence intervals are at
`the 95% level.
`
`RESULTS
`Between January 9, 2002 and December 9, 2003, 87
`patients were entered on this study. One patient had no data
`forms, and one patient was ineligible because of a diagnosis
`of prostate cancer within the previous 5 years; these two cases
`were removed from this analysis. The median follow-up of
`eligible patients still alive was 34.6 months. At the time of
`this analysis (June 19, 2006), four patients were still alive.
`Patient demographic factors and disease characteristics for
`the 85 eligible patients are shown in Table 1. The median age
`was 59 years (range, 39 – 80). There were more female
`patients (p ⫽ 0.05) and more patients with brain metastases
`on arm A (p ⫽ 0.03). Among the 85 eligible patients, 76.8%
`of them received at least two cycles of treatment with tem-
`sirolimus (Table 2). Table 3 shows the reasons for treatment
`termination, the distribution of which varied significantly
`between the two arms (p ⫽ 0.02). A higher proportion of
`patients relapsed on the low-dose arm (65.1% versus 35.0%),
`but a higher proportion of patients experienced high-grade
`toxicity/side effects on the high-dose arm (40.0% versus
`18.6%). Note that no reason for termination was provided for
`
`TABLE 1. Patient Characteristics at Baseline: 85 Eligible
`Patients
`
`Age (yr)
`Mean
`Median
`Range
`Male
`Female
`White
`Black
`Other
`0
`1
`2
`Missing/unknown
`Weight loss in previous
`6 months
`⬍5%
`5%–10%
`10%–20%
`Missing/unknown
`Type of induction chemotherapy
`Platinum ⫹ etoposide
`Platinum ⫹ irinotecan
`Response to induction chemo
`Complete recovery
`Partial recovery
`Stable disease
`Missing
`Brain metastases
`No
`Yes
`
`Low Dose
`(Arm A)
`(n ⴝ 44)
`
`High Dose
`(Arm B)
`(n ⴝ 41)
`
`Total
`(n ⴝ 85)
`
`61
`61
`42–78
`17 (38.6%)
`27 (61.4%)
`37 (84.1%)
`1 (2.3%)
`6 (13.6%)
`21 (47.7%)
`21 (47.7%)
`2 (4.6%)
`0
`
`59
`59
`39–80
`25 (61.0%)
`16 (39.0%)
`35 (85.4%)
`2 (4.9%)
`4 (9.8%)
`17 (43.6%)
`20 (51.3%)
`2 (5.1%)
`2
`
`60
`59
`39–80
`42 (49.4%)
`43 (50.6%)
`72 (84.7%)
`3 (3.5%)
`10 (11.8%)
`38 (45.8%)
`41 (49.4%)
`4 (4.8%)
`2
`
`35 (81.4%)
`4 (9.3%)
`4 (9.3%)
`1
`
`31 (77.5%)
`8 (20.0%)
`1 (2.5%)
`1
`
`66 (79.5%)
`12 (14.5%)
`5 (6.0%)
`2
`
`35 (79.5%)
`9 (20.5%)
`
`34 (82.9%)
`7 (17.1%)
`
`69 (81.2%)
`16 (18.8%)
`
`9 (20.5%)
`23 (52.3%)
`12 (27.3%)
`0
`
`4 (10.0%)
`26 (65.0%)
`10 (25.0%)
`1
`
`13 (15.5%)
`49 (58.3%)
`22 (26.2%)
`1
`
`36 (81.8%)
`8 (18.2%)
`
`38 (92.7%)
`3 (7.3%)
`
`74 (87.1%)
`11 (12.9%)
`
`1038
`
`Copyright © 2007 by the International Association for the Study of Lung Cancer
`
`NPC02237278
`
`NOVARTIS EXHIBIT 2170
`Par v Novartis, IPR 2016-00084
`Page 3 of 6
`
`

`
`Journal of Thoracic Oncology (cid:127) Volume 2, Number 11, November 2007
`
`Temsirolimus for Extensive-Stage SCLC
`
`TABLE 2. Total Number of Cycles of Treatments Received
`Low Dose
`High Dose
`(Arm A)
`(Arm B)
`(n ⴝ 44)
`(n ⴝ 41)
`
`Number
`of Cycles
`
`Total
`(n ⴝ 85)
`
`1
`2
`3
`4
`5
`6
`⬎6
`Missing
`
`14 (34.1%)
`17 (41.5%)
`2 (4.9%
`3 (7.3%)
`4 (9.8%)
`0 (0%)
`1 (2.4%)
`3
`
`19 (46.3%)
`13 (31.7%)
`3 (7.3%)
`3 (7.3%)
`1 (2.4%)
`1 (2.4%)
`1 (2.4%)
`0
`
`TABLE 3. Reason for Treatment Termination
`Low Dose
`High Dose
`(Arm A)
`(Arm B)
`(n ⴝ 44)
`(n ⴝ 41)
`
`Reason
`
`Progression/relapse
`Toxicity/side effects
`Withdrawal/refusal
`Other complicating disease
`Missing/unknown
`
`28 (65.1%)
`8 (18.6%)
`2 (4.7%)
`0 (0%)
`1
`
`14 (35.0%)
`16 (40.0%)
`6 (15.0%)
`1 (2.5%)
`1
`
`33 (40.2%)
`30 (36.6%)
`5 (6.1%)
`6 (7.3%)
`5 (6.1%)
`1 (1.2%)
`2 (2.4%)
`3
`
`Total
`(n ⴝ 85)
`
`42 (38.6%)
`24 (28.9%)
`8 (9.6%)
`1 (1.2%)
`2
`
`No reason was provided for eight patients: five on the lowdose arm, and three on
`the high-dose arm.
`
`eight patients; five of these patients were on the low-dose
`arm, and three were on the high-dose arm.
`
`PFS
`
`There were 85 patients available for the primary anal-
`ysis, 44 on the low-dose arm and 41 on the high-dose arm. All
`but one patient on the low-dose arm had disease progression.
`Figure 2A provides overall PFS, and Figure 2B provides PFS
`by treatment. The overall median PFS was 2.2 months (95%
`confidence interval [CI]: 1.8, 2.9), and the 1-year PFS rate
`was 4.7% (95% CI: 0.2%, 9.2%). There is no evidence of a
`difference in PFS between the two treatment arms: median
`PFS ⫽ 1.9 months (95% CI: 1.6, 2.3) for the low-dose arm,
`and median PFS ⫽ 2.5 months (95% CI: 1.9, 3.4) for
`high-dose arm, log–rank p value ⫽ 0.24. The resultant p
`value corresponds to a one-sided p value of 0.12, which is
`close to the one-sided ␣ ⫽ 0.10 (p ⬍ 0.1) significance level
`specified in the study design. The median PFS of patients
`entering the study with responding disease (partial recovery/
`complete recovery) was 2.3 months (95% CI: 1.8, 3.3), and
`the median PFS for those with stable disease was 1.9 months
`(95% CI: 1.6, 2.2). The median PFS of patients without brain
`metastases was 2.2 months (95% CI: 1.8, 2.3), and the
`median PFS for those with brain metastases was 2.3 months
`(95% CI: 1.2, 7.6). For males, the treatment differences were
`significant (median PFS ⫽ 1.7 months for the low-dose arm
`and 3.0 months for the high-dose arm; p ⫽ 0.03), but not for
`females (median PFS ⫽ 2.2 months for the low-dose arm and
`
`Copyright © 2007 by the International Association for the Study of Lung Cancer
`
`1039
`
`FIGURE 2. Progression-free survival
`(PFS) and survival: overall PFS (A), PFS
`by treatment (B), overall survival (C),
`and survival by treatment (D).
`
`NPC02237279
`
`NOVARTIS EXHIBIT 2170
`Par v Novartis, IPR 2016-00084
`Page 4 of 6
`
`

`
`Pandya et al.
`
`Journal of Thoracic Oncology (cid:127) Volume 2, Number 11, November 2007
`
`TABLE 4. ProgressionFree Survival Hazard Ratios and
`Log–Rank Tests
`High Dose vs.
`Low Dose
`
`95% Confidence
`Interval
`
`Log–Rank
`Test p Value
`
`Group
`
`Overall
`Gender
`Male
`Female
`Race
`White
`Nonwhite
`
`0.77
`
`0.50
`1.06
`
`0.82
`0.49
`
`(0.50, 1.19)
`
`(0.26, 0.96)
`(0.56, 1.98)
`
`(0.52, 1.31)
`(0.14, 1.69)
`
`0.24
`
`0.03
`0.86
`
`0.41
`0.25
`
`1.9 months for the high-dose arm; p ⫽ 0.86). There were no
`differences based on race. Log–rank test results according to
`gender and race are shown in Table 4.
`Overall Survival
`The median overall survival for the 85 eligible patients
`was 8.0 months (95% CI: 6.5, 9.5; Figure 2C). The median
`overall survival for the 44 patients on arm A was 6.6 months
`(95% CI: 5.5, 8.9) and, for the 41 patients on arm B, 9.5
`months (95% CI: 7.3, 13.3). One patient on arm A and three
`patients on arm B had not died by the time of this analysis
`(June 19, 2006). A log–rank test for the equality of the overall
`survival distributions of arms A and B resulted in a p value of
`0.008 (Figure 2D).
`Objective Response
`Responses were evaluated using RECIST. One patient
`(1.2%) experienced a partial response among the 85 eligible
`patients. Six patients (7.2%) experienced stable disease, and
`74 patients (89.2%) experienced progressive disease.
`Toxicity
`Toxicity was evaluated by using the National Cancer
`Institute Common Toxicity Criteria (version 2.0). Table 5
`shows the incidence rates of grade 3 and 4 treatment-related
`toxicities for 86 of 87 entered patients (no data were submit-
`ted for one patient). Among the 86 patients with reported
`toxicities, 36 (41.9%) had grade 3 toxicities, and the most
`common grade 3 toxicities were thrombocytopenia, hy-
`pophosphatemia, and fatigue. Twelve patients (14.0%) had
`grade 4 toxicities, the most common of which was neutrope-
`nia. No patient experienced lethal (grade 5) toxicity. Com-
`paring toxicities between the treatment arms, 22 patients
`(49.9%) had grade 3 or higher-grade toxicities on the low-
`dose arm, and 26 patients (63.4%) had grade 3 or higher-
`grade toxicities on the high-dose arm (p ⫽ 0.20).
`
`DISCUSSION
`There has been a great deal of interest in “consolida-
`tion” or “maintenance” treatment for SCLC, as patients who
`respond to induction therapy invariably relapse at a later date.
`So far, there is no evidence to support the use of prolonged
`maintenance chemotherapy.12 It was hoped that a cytostatic
`agent such as temsirolimus might provide prolongation of
`PFS by suppressing the regrowth of cancer cells. The study
`
`1040
`
`Copyright © 2007 by the International Association for the Study of Lung Cancer
`
`TABLE 5. Toxicity Incidence (n ⫽ 86)
`Low Dose
`(Arm A)
`(n ⴝ 45)
`Grade
`
`High Dose
`(Arm B)
`(n ⴝ 41)
`Grade
`
`Toxicity Type
`
`3 (n)
`
`4 (n)
`
`3 (n)
`
`4 (n)
`
`Allergic reaction
`Anemia
`Neutropenia
`Thrombocytopenia
`Febrile neutropenia
`Infection without neutropenia
`Arrhythmia
`Hypotension
`Fatigue
`Rash/desquamation
`Urticaria
`Stomatitis
`Diarrhea
`Hypercholesterolemia
`Hyperglycemia
`Hypertriglyceridemia
`Hypocalcemia
`Hypophosphatemia
`Conjunctivitis
`Dyspnea
`Hypoxia
`Pneumonitis/pulmonary infiltrates
`Creatinine
`Renal/GU—other
`Total
`
`1
`2
`4
`3
`1
`1
`1
`—
`2
`2
`—
`1
`1
`1
`—
`2
`—
`2
`—
`1
`1
`1
`—
`—
`19
`
`—
`—
`1
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`1
`—
`—
`1
`1
`3
`
`1
`2
`1
`7
`—
`3
`1
`1
`6
`3
`2
`3
`2
`3
`6
`1
`—
`5
`1
`3
`—
`2
`—
`—
`17
`
`—
`—
`4
`2
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`2
`1
`1
`—
`1
`1
`1
`—
`—
`9
`
`was a phase II exploratory design to see whether temsiroli-
`mus at any of these two doses gave enough of a signal to
`warrant a placebo-controlled phase III trial. In this population
`of patients with extensive-stage SCLC, weekly “consolida-
`tion” treatment with temsirolimus at 25 or 250 mg did not
`seem to result in any improvement in PFS compared with
`what was seen in the observation arm of E7593,10 which was
`a prospective randomized study to determine whether topo-
`tecan given after induction chemotherapy would result in
`improved PFS compared with observation. PFS after induc-
`tion chemotherapy in stable or responding patients was sig-
`nificantly better with topotecan compared with observation
`(3.6 versus 2.3 months; p ⬍ 0.001); nevertheless, the overall
`survival from randomization was not significantly different
`(8.9 vs 9.3 months, respectively; p ⫽ 0.43). The median PFS
`of 2.2 months and the median overall survival of 8 months
`after induction chemotherapy in the current study suggest a
`lack of any meaningful clinical activity for temsirolimus in
`this setting.
`The estimated PFS hazard ratio (high dose/low dose)
`among males was statistically significant (hazard ratio ⫽
`0.50; 95% CI: 0.26, 0.96), but it was not statistically signif-
`icant among females (hazard ratio ⫽ 1.06; 95% CI: 0.56,
`1.98). The lack of stratification based on gender may be the
`
`NPC02237280
`
`NOVARTIS EXHIBIT 2170
`Par v Novartis, IPR 2016-00084
`Page 5 of 6
`
`

`
`Journal of Thoracic Oncology (cid:127) Volume 2, Number 11, November 2007
`
`Temsirolimus for Extensive-Stage SCLC
`
`most likely explanation for this observation, although we
`cannot completely rule out other explanations, because this
`was a small phase II study.
`Whereas a difference in the overall survival (6.6 versus
`9.5 months) was observed in this study that was statistically
`significant (p ⫽ 0.008), it is largely attributable to a shorter
`survival observed in the low-dose arm of only 6.6 months, as
`compared with 8.9 months on the observation arm of E7593.
`We do not have a satisfactory explanation for this observa-
`tion. There were no obvious imbalances in the patient char-
`acteristics between the arms that could explain this outcome.
`There are significant differences between E7593 and the
`current study. E7593 was a large phase III study that enrolled
`patients before induction therapy. Thus, their performance
`status was acceptable before induction chemotherapy, as
`compared with patients entering the current study having
`received their induction therapy in a nonstudy setting. Pa-
`tients entering the second step of randomization of observa-
`tion versus topotecan were, therefore, much more uniform
`compared with patients entering this study. It is also possible
`that second-line treatment could have played a role, but such
`information was not collected.
`Temsirolimus has shown activity in patients with
`several tumor types,6 including renal cancer,7 breast can-
`cer,8 and mantle cell lymphoma.9 Yet, it was found to have
`little activity (5.6% objective response rate as assessed by
`RECIST) in 37 patients with advanced progressive neu-
`roendocrine carcinomas of either carcinoid or islet cell
`carcinoma pathologies in a phase II study.13 It is possible
`that temsirolimus has no activity in tumors of neuroendo-
`crine origin.
`In conclusion, temsirolimus given to responding or
`stable patients with extensive-stage SCLC after induction
`chemotherapy did not seem to result in any prolongation in
`PFS compared with what has been reported in the literature.
`
`Novel treatments that can prolong PFS and overall survival
`are needed to improve the outcomes of this disease.
`
`REFERENCES
`1. Jemal A, Siegal R, Ward E, et al. Cancer statistics 2006. CA Cancer
`J Clin 2006;56:106–130.
`2. Simon G, Ginsberg RJ, Ruckdeschel JC. Small-cell lung cancer. Chest
`Surg Clin N Am 2001;11:156–188.
`3. Skotnicki JS, Leone CL, Smith AL. Design, synthesis, and biological
`evaluation of C-42 hydrxyesters of rapamaycin: the identification of
`CCI-779. Clin Cancer Res 2001;7:3749S–3750S.
`4. Dudkin L, Dilling MB, Cheshire PJ, et al. Biochemical correlates of
`m-TOR inhibition by the rapamycin ester CCI-779 and tumor growth
`inhibition. Clin Cancer Res 2001;7:1758–1764.
`5. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of
`PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad
`Sci U S A2001;98:10314–10319.
`6. Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of
`cancer with rapamycin derivatives. Ann Oncol 2005;16:525–537.
`7. Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study
`of multiple dose levels of CCI-779, a novel mammalian target of
`rapamycin kinase inhibitor, in patients with advanced refractory renal
`cell carcinoma. J Clin Oncol 2004;23:909–918.
`8. Chan S, Scheulen ME, Johnston S, et al. Phase II study of temsirolimus
`(CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients
`with locally advanced or metastatic breast cancer. J Clin Oncol 2005;
`23:5314–5322.
`9. Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent
`temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin
`Oncol 2005;23:5347–5356.
`10. Schiller JH, Adak S, Cella D, Devore RF III, Johnson DH. Topotecan
`versus observation after cisplatin plus etoposide in extensive-stage
`small-cell lung cancer: E7593—a phase III trial of Eastern Cooperative
`Oncology Group. J Clin Oncol 2001;19:2114–2122.
`11. Kaplan EL, Meier P. Nonparametric estimation from incomplete obser-
`vations. J Am Stat Assoc 1958;53:457–481.
`12. Sculier JP, Berghman T, Castaigne C, et al. Maintenance chemotherapy
`for small cell lung cancer: a critical review of the literature. Lung Cancer
`1998;19:141–151.
`13. Duran I, Kortmansky J, Singh D, et al. A phase II clinical and pharma-
`codynamic study of temsirolimus in advanced neuroendocrine carcino-
`mas. Br J Cancer 2006;95:1148–1154.
`
`Copyright © 2007 by the International Association for the Study of Lung Cancer
`
`1041
`
`NPC02237281
`
`NOVARTIS EXHIBIT 2170
`Par v Novartis, IPR 2016-00084
`Page 6 of 6