Original Article
A Phase 2 Randomized Trial of Paclitaxel and Carboplatin with or without Panitumumab for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer Jeffrey Crawford, MD,* Paul Swanson, MD,† Paul Schwarzenberger, MD,‡ Alan Sandler, MD,§ Diane Prager, MD,║ Kathy Zhang, PhD,¶ Daniel J. Freeman, PhD,¶ Carol W. Johnson, DVM, PhD,¶ Kartik Krishnan, MD, PhD,¶ and David Johnson, MD#
Introduction: This two-part phase 2 study evaluated the efficacy and safety of panitumumab, a fully human anti–epidermal growth factor receptor monoclonal antibody, combined with carboplatin/paclitaxel in patients with previously untreated advanced non–small-cell lung cancer. Methods: In part 1, patients were sequentially enrolled to receive paclitaxel 200 mg/m2 and carboplatin (area under the concentration-versus-time curve, 6 mg/min/ml) plus panitumumab (1.0, 2.0, or 2.5 mg/ kg). In part 2, patients were randomized 2:1 to receive paclitaxel/ carboplatin with (arm A) or without (arm B) the maximum tolerated dose of panitumumab identified in part 1. Primary endpoints in parts 1 and 2 were the incidence of dose-limiting toxicities and time to progression (TTP), respectively. Results: In part 1, four of 19 patients had dose-limiting toxicities: three at 2.0 mg/kg (fatigue, pain in extremity, dyspepsia) and one at 2.5 mg/kg (rash). The maximum tolerated dose was not reached; panitumumab 2.5 mg/kg was selected for part 2. In part 2, TTP was 18.1 weeks (95% confidence interval [CI], 13.6−23.3) in arm A and *Department of Medicine, Duke University Medical Center, Durham, North Carolina; †Hematology Oncology Associates, Port St. Lucie, Florida; ‡Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana; §Oregon Health and Science University, Portland, Oregon; ║Illinois CancerCare, Peoria, Illinois; ¶Departments of Global Biostatistical Science, Oncology Research, and Global Safety, Amgen Inc., Thousand Oaks, California; and #Division of Hematology and Medical Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. Disclosure: Dr. Jeffrey Crawford has served on advisory boards for Amgen Inc., Thousand Oaks, California; his institution has received a grant from Amgen Inc. for this study and has received research funding from Amgen Inc. Dr. Alan Sandler has served as consultant to and received honoraria from and travel expenses paid by Amgen Inc. Drs. Kathy Zhang and Carol W. Johnson are employees of and own stock in Amgen Inc. Drs. Kartik Krishnan and Daniel J. Freeman were employees of and owned stock in Amgen Inc. at the time the research was conducted. Drs. Paul Swanson, Paul Schwarzenberger, Diane Prager, and David Johnson declare no conflict of interest. Drs. Kartik Krishnan and Alan Sandler are currently affiliated with Genentech, Inc., South San Francisco, California; Dr. Daniel J. Freeman is currently affiliated with Daiichi Sankyo, Edison, New Jersey; and Dr. David Johnson is currently affiliated with the University of Texas Southwestern Medical Center, Dallas, Texas. Address for correspondence: Jeffrey Crawford, MD, Duke University Medical Center, Box 3198, Room 25178, Morris Building, DS, Erwin Road and East Trent Drive, Durham, NC 27710. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-1510
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23.0 weeks (95% CI, 15.9−24.1) in arm B (hazard ratio, 0.9; 90% CI, 0.66−1.21; p = 0.555). Progression-free survival in arms A and B was 17.6 weeks and 18.3 weeks, respectively, and the objective response rate was 15.2% and 11.1%. Adverse events occurring more frequently in arm A than in arm B included skin toxicity, diarrhea, stomatitis, vomiting, and dizziness. Exploratory analyses did not demonstrate associations between potential biomarkers and outcomes. Conclusion: Although toxicity was predictable and manageable, the addition of panitumumab to paclitaxel/carboplatin did not improve TTP in patients with previously untreated advanced non–small-cell lung cancer. Key Words: Panitumumab, Paclitaxel/carboplatin, Non–small-cell lung cancer, KRAS, Epidermal growth factor receptor. (J Thorac Oncol. 2013;8: 1510–1518)
S
tudies investigating the efficacy of epidermal growth factor in the first-line treatment of advanced non–small-cell lung cancer (NSCLC) have yielded inconsistent results. In the phase 3 First-Line ErbituX in lung cancer (FLEX) study of patients with epidermal growth factor receptor (EGFR)– expressing advanced NSCLC, overall survival (OS) was significantly improved by first-line treatment with cetuximab plus cisplatin/vinorelbine versus cisplatin/vinorelbine alone.1 In other studies, addition of cetuximab or the small-molecule EGFR inhibitors erlotinib and gefitinib to first-line chemotherapy did not improve outcomes.2–6 Some evidence has suggested that biomarkers could be used to identify NSCLC patients most likely to respond to EGFR inhibition.7 For example, among patients with chemotherapy-refractory NSCLC, only those with somatic EGFR mutations had longer progression-free survival (PFS) after treatment with gefitinib compared with treatment with docetaxel.8 Other potential biomarkers evaluated with antiEGFR monoclonal antibodies have included high EGFR gene copy number9 and tumor EGFR expression.10 Elevated EGFR protein expression and gene copy number have also been associated with improved outcomes in studies with small-molecule EGFR inhibitors.11–15 Panitumumab is a fully human monoclonal antibody against EGFR, which has been shown to have activity as a
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Panitumumab Plus Carboplatin/Paclitaxel in NSCLC
single agent and in combination with chemotherapy for the treatment of metastatic colorectal cancer, but it is not recommended for use in patients whose tumors have mutations in codons 12 or 13 of KRAS.16,17 The aim of this two-part study was to evaluate the efficacy and safety of carboplatin/paclitaxel with or without panitumumab in previously untreated patients with advanced NSCLC. The objective of part 1 was to establish either the maximum tolerated dose (MTD) or an appropriate dose of panitumumab plus carboplatin/paclitaxel for investigation in part 2. The primary objective of part 2 was to compare the time to progression (TTP) in patients receiving panitumumab plus carboplatin/paclitaxel or carboplatin/paclitaxel alone. In exploratory analyses, we assessed the ability of biomarkers to predict outcomes.
of patients to have skin rash. Patients without disease progression could receive panitumumab for an additional 18 weeks. Dose escalation into the next cohort began when the 3-week safety assessment was complete, five or more patients in the preceding cohort had been evaluated for DLT, and the MTD had not been reached. A DLT was defined as any treatmentrelated adverse event (AE) requiring permanent discontinuation of panitumumab, any treatment-related grade 3 or 4 AE (except skin toxicity), or any treatment-related severe or life-threatening events not assessed by the National Cancer Institute Common Toxicity Criteria for Adverse Events version 2.0. The MTD was defined as the dose level immediately below the dose that resulted in three of five (or 4 of 10) patients experiencing DLT attributed to panitumumab administration.
PATIENTS AND METHODS
Part 2 In part 2, patients were randomized 2:1 to receive carboplatin/paclitaxel at the same dose schedule as in part 1 for up to six cycles with (arm A) or without (arm B) onceweekly intravenous panitumumab at the dose identified in part 1. In the absence of progressive disease, patients could continue to receive panitumumab until disease progression or an AE that prevented further treatment occurred. The primary endpoint of part 2 was TTP. Secondary efficacy endpoints were OS time, PFS time, rate of progressive disease after 12 weeks of treatment, overall response rate, and response rate after 6 weeks of treatment. Secondary safety endpoints were the incidence of AEs and changes in laboratory values and other safety parameters.
Patients Patients were eligible if they were aged at least 18 years, had pathologically confirmed NSCLC (stage IIIB with pericardial or pleural effusion or stage IV) with 10% or more cells expressing EGFR, bidimensionally measurable disease, an Eastern Cooperative Oncology Group performance status of 1 or less, life expectancy of 12 weeks or more, and an available paraffin-embedded tumor tissue sample. Exclusion criteria included prior therapy for NSCLC except radiation, surgery, or steroids; radiation therapy within 2 weeks of treatment initiation; investigational therapy within 30 days; other malignancies within 5 years (except basal cell carcinoma, cervical carcinoma in situ, and primary NSCLC); hypercalcemia; and insufficient cardiac, hepatic, renal, or hematologic function. Brain metastases, if present, were to be controlled and asymptomatic and not requiring treatment for at least 1 week. The study protocol was approved by each center’s institutional review board. All patients provided signed informed consent before screening.
Study Design and Treatment This was an open-label multicenter study conducted in two parts. Part 1 was a dose-escalation study of panitumumab plus carboplatin/paclitaxel for untreated advanced NSCLC. Part 2 was a randomized study evaluating panitumumab (at the dose determined in part 1) plus carboplatin/ paclitaxel versus carboplatin/paclitaxel alone in patients with advanced NSCLC. Part 1 The primary endpoint of part 1 was the incidence of dose-limiting toxicities (DLTs). All patients received intravenous paclitaxel 200 mg/m2 (3.0-h infusion) and carboplatin 6 mg/min/ml (0.5-h infusion) in 3-week cycles beginning on day 1 for up to six cycles. Patients were sequentially enrolled into three dose cohorts of five to 10 patients in which they received once-weekly 1-hour intravenous infusions of panitumumab at doses of 1.0 mg/kg (cohort 1), 2.0 mg/kg (cohort 2), or 2.5 mg/kg (cohort 3) for six cycles. The 2.5-mg/kg dose was anticipated to achieve circulating panitumumab concentrations exceeding those that result in 90% inhibition of tumor cell proliferation in xenograft models and cause less than 95%
Tumor Response Computed tomography or magnetic resonance imaging scans were performed every 6 weeks during the first 48 weeks of treatment and every 12 weeks thereafter. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors.18 Objective responses (complete or partial) were confirmed 4 weeks or more (part 1) or 6 weeks or more (part 2) after criteria for response were first met. Response assessments in part 2 were performed by blinded independent central review (Bio-Imaging Technologies, Inc., Newtown, PA).
Safety Safety was evaluated as the incidence of AEs (graded using National Cancer Institute Common Toxicity Criteria for Adverse Events version 2.0) and changes in laboratory tests. AEs were recorded from the start of treatment through the safety follow-up visit (which occurred within 4 weeks of the last administration of study medication). Fatal AEs were reported for at least 30 days after the last dose of study medication.
Assessment of Biomarkers EGFR expression at screening was measured by immuno histochemistry of formalin-fixed, paraffin-embedded samples at a central laboratory (Impath Inc., New York, NY). Results were expressed as the percentage of cells stained at staining intensity scores ranging from 0 to 3+. Mutations in EGFR, KRAS (exons 2, 3, and 4), HRAS, NRAS, PIK3CA, and BRAF
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were assayed by direct polymerase chain reaction sequencing of polymerase chain reaction–amplified genomic DNA extracted from FFPE samples. The proportion of patients with EGFR membrane staining, membrane and cytoplasmic staining, and cytoplasmic staining was assessed microscopically using previously published criteria.19
Statistical Analysis The original planned sample size was 225 patients, which provided 85% power at the 10% significance level to detect a 50% improvement in TTP. However, enrollment was closed early at 175 patients after the publication of results demonstrating a lack of survival benefit with erlotinib in combination with carboplatin/paclitaxel compared with c arboplatin/ paclitaxel alone.5 The analyses of efficacy and safety included all patients who received one or more doses of panitumumab, paclitaxel, or carboplatin until the data cutoff date (November 30, 2004). TTP was defined as the time from treatment initiation to disease progression or death due to disease progression. PFS was defined as the time from treatment initiation to disease progression or death. Time to event endpoints were summarized by the Kaplan-Meier method with two-sided 95% confidence intervals (CIs). Differences between treatment groups were assessed using a log-rank test at a two-sided 10% significance level. Difference in TTP between the two arms was also assessed using a Cox proportional hazards model. Best overall response rate and the response rate after 6 weeks of treatment were calculated with two-sided 95% CIs. The Fisher’s exact test was used to compare response rates between treatment groups.
RESULTS Patients Between January 7, 2002, and March 31, 2003, 194 patients with advanced NSCLC were enrolled in the study. In part 1, 19 patients were enrolled at six study sites. In part 2, 175 patients were enrolled at 50 study sites. Demographic and baseline characteristics were generally balanced (Table 1). Most patients had stage IV disease.
Treatment Exposure All 19 patients in part 1 received one or more doses of panitumumab (cohort 1, n = 6; cohort 2, n = 7; cohort 3, n = 6). Patients in part 1 received a median of 21 (range, 6–38) panitumumab infusions and a median of six (range, 4–6) cycles of chemotherapy. The median cumulative doses of paclitaxel in cohorts 1, 2, and 3 were 1027, 1012, and 975 mg/m2, respectively. The median cumulative doses of carboplatin were 2339, 1944, and 1467 mg/m2. Of 175 patients randomized in part 2, 166 received study treatment (panitumumab plus carboplatin/paclitaxel [arm A], n = 112; carboplatin/paclitaxel alone [arm B], n = 54). At the time of the data cutoff, four patients in arm A and five patients in arm B continued to receive treatment. Three patients in arm A completed 48 weeks of treatment. Reasons for discontinuation are listed in Figure 1. The median number
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of panitumumab infusions administered was 11 (range, 1–21). The median number of chemotherapy cycles was four in both treatment arms (interquartile range, arm A, 2–6; arm B, 3–6). The median dose of paclitaxel was 197 mg/m2 per infusion (range, 147–217) for arm A and 197 mg/m2 per infusion (range, 100–225) for arm B; the median dose of carboplatin was 372 mg/m2 per infusion (range, 234–688) and 364 mg/m2 per infusion (range, 202–522) for arms A and B, respectively. The median cumulative paclitaxel dose was 788 mg/m2 (range, 195–1241) in arm A and 904 mg/m2 (range, 100–1210) in arm B. The median cumulative carboplatin dose was 1314 mg/m2 (range, 247–3057) in arm A and 1546 mg/m2 (range, 268–2717) in arm B.
Dose Escalation (Part 1) After 3 weeks of treatment, no patients in cohort 1 had a DLT and one patient in cohort 2 had a DLT (fatigue). Consequently, dose escalation of panitumumab proceeded to the maximum dose of 2.5 mg/kg. Over the entire treatment period, four patients experienced DLTs: three in cohort 2 (fatigue, pain in extremity, dyspepsia), and one in cohort 3 (rash). The MTD was not reached, and panitumumab 2.5 mg/kg once weekly was the dose chosen for part 2.
Efficacy (Part 2) At the time of data cutoff, a total of 137 disease progression events had occurred among patients who received treatment in part 2. There was no significant difference in TTP between the two treatment arms (log-rank test, p = 0.553; hazard ratio, 0.9; 90% CI, 0.66–1.21; p = 0.555). The median TTP was 18.1 weeks (95% CI, 13.6–23.3) in arm A and 23.0 weeks (95% CI, 15.9–24.1) in arm B (Fig. 2). Median PFS was 17.6 weeks (95% CI, 11.7–22.4) in arm A and 18.3 weeks (95% CI, 13.4–23.7) in arm B (log-rank test, p = 0.583; Fig. 3A). Median OS was 37.0 weeks (95% CI, 30.9–52.1) in arm A and 35.0 weeks (29.3–51.4) in arm B (p = 0.786; Fig. 3B). The best overall response rate in arm A was 15.2% (95% CI, 9.1–23.2) and 11.1% (95% CI, 4.2–22.6) in arm B (Fisher’s exact test, p = 0.633; Table 2). All responses in part 2 were partial responses. The best response rate after six cycles of treatment was 8.9% (95% CI, 4.4–15.8) in arm A and 9.3% (95% CI, 3.1–20.3) in arm B (p = 1.0). For the patients who responded, the median time to response was 5.6 weeks (range, 5.0–29.4) in arm A and 5.4 weeks (range, 5.0–6.1) in arm B, and the median duration of response in the two arms was 24.1 weeks (95% CI, 16.0–46.3) and 22.0 weeks (95% CI, 17.4– 32.1), respectively.
Safety (Part 2) All patients who received treatment in part 2 experienced at least one AE (Table 3). Ninety-four patients (84%) in arm A and 41 patients (76%) in arm B had a grade 3 or higher AE. AEs occurring more frequently in arm A than in arm B included skin toxicities, diarrhea, stomatitis, vomiting, and dizziness. As expected, skin toxicities occurred more frequently in arm A versus arm B (88% versus 26%, respectively),
Copyright © 2013 by the International Association for the Study of Lung Cancer
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Panitumumab Plus Carboplatin/Paclitaxel in NSCLC
TABLE 1. Patient Demographics and Baseline Characteristics Part 1 Panitumumab Plus Carboplatin/Paclitaxel (n = 19) Age Median Range Sex, n (%) Men Women Race/ethnicity, n (%) White Black Asian Hispanic Other ECOG performance score, n (%) 0 1 2 Smoking statusa, n (%) Never Former Current Disease stage at diagnosis, n (%) I II IIIA IIIB IV Disease histology at diagnosis, n (%) Adenocarcinoma Squamous cell carcinoma Other Extent of disease at study entry, n (%) Distant metastasis Pleural effusion Pericardial effusion Months since primary disease diagnosisb Median Range Prior radiotherapy, n (%) Percentage of cells with positive EGFR staining Median Range Maximum EGFR staining intensity, n (%) 1+ (weak) 2+ (moderate) 3+ (strong)
Part 2 Arm A–Panitumumab Plus Carboplatin/Paclitaxel (n = 112)
50.0 36–82
61.5 36–83
Arm B–Carboplatin/Paclitaxel Alone (n = 54) 62.0 42–81
5 (26) 14 (74)
67 (60) 45 (40)
27 (50) 27 (50)
19 (100) 0 (0) 0 (0) 0 (0) 0 (0)
101 (90) 7 (6) 3 (3) 1 (1) 0 (0)
46 (85) 7 (13) 0 (0) 1 (2) 0 (0)
6 (32) 12 (63) 1 (5)
37 (33) 74 (66) 1 (1)
15 (28) 38 (70) 1 (2)
— — —
10 (9) 71 (63) 28 (25)
6 (11) 38 (70) 9 (17)
2 (11) 0 (0) 0 (0) 2 (11) 15 (79)
13 (12) 1 (1) 4 (4) 10 (9) 84 (75)
4 (7) 0 (0) 0 (0) 9 (17) 41 (76)
13 (68) 3 (16) 3 (16)
67 (60) 23 (21) 22 (20)
36 (67) 12 (22) 6 (11)
15 (79) 8 (42) 4 (21)
98 (88) 31 (28) 11 (10)
43 (80) 19 (35) 0 (0)
2.0 0.7–21.3 9 (47)
1.5 0.2–119.2 36 (32)
1.1 0.2–27.6 15 (28)
100 20–100
100 10–100
100 26–100
0 (0) 3 (16) 16 (84)
8 (7) 11 (10) 93 (83)
0 (0) 5 (9) 49 (91)
Smoking history was not available for patients in part 1. Time from date of primary diagnosis or metastatic disease diagnosis to date of enrollment (part 1) or randomization (part 2). ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor.
a b
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Assessed for eligibility in Part 2 (N=312) Excluded (n=137)
Arm A Randomized (n=116)
Arm B Randomized (n=59)
Received panitumumab 2.5 mg/kg carboplatin/paclitaxel (n=112) Did not receive panitumumab 2.5 mg/kg carboplatin/paclitaxel (n=6)
Received carboplatin/paclitaxel (n=54) Did not receive carboplatin/paclitaxel (n=5)
Ongoing (n=4) Completed 48 weeks of treatment (n=3) Discontinued (n=1095) Disease progression (n=68) Investigator decision (n=7) Adverse event (n=13) Consent withdrawn (n=6) Death (n=7) Other (n=4)
Ongoing (n=2) Completed 48 weeks of treatment (n=0) Discontinued (n=54) Disease progression (n=28) Investigator decision (n=11) Adverse event (n=4) Consent withdrawn (n=5) Death (n=2) Other (n=2)
Patient treated analysis set (n=112)
Patient treated analysis set (n=54)
FIGURE 1. CONSORT diagram for part 2.
progressive pulmonary fibrosis; gastrointestinal perforation; cerebrovascular accident, sepsis; and myocardial infarction). In part 2, 27 patients (24%) in arm A discontinued the study (either the treatment or safety follow-up) owing to AEs. These included NSCLC (4%), rash (3%), and fatigue (2%). In arm B, nine patients (17%) discontinued the study owing to AEs. The only AE leading to discontinuation in more than one patient was neuropathy (4%). The percentage of patients discontinuing the study during the chemotherapy combination phase was similar in arms A (18%) and B (17%).
Patients Without Disease Progression, %
with grade 3 toxicities occurring in 17% and 2% of patients, respectively. Diarrhea was reported in 48% and 26% of patients in arms A and B, respectively, with grade 3 diarrhea occurring in 6% and 2% of patients, respectively. Stomatitis of any grade was reported in 33% and 9% of patients in arms A and B, respectively, whereas the incidence of hypomagnesemia across the two arms was similar (5% versus 4%, respectively; grade 3, 1% versus 0%). Of 112 patients who received panitumumab plus carboplatin/ paclitaxel, 31 had possible panitumumab infusion reactions. Most were mild or moderate in severity; all but two patients who experienced infusion reactions received subsequent panitumumab infusions. Seventeen deaths occurred during the study: one in part 1 and 14 and two in arms A and B, respectively, in part 2. Most were attributable to disease progression. However, grade 5 AEs considered possibly related to panitumumab occurred in four patients in arm A in part 2 (respiratory failure secondary to 100 90 80 70 60 50 40 30 20 10 0
Panitumumab + C/P C/P alone
0
Patients at risk: Panitumumab + C/P 112 C/P alone 54
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6
12
18
24
30
Associations between Biomarkers and Outcomes Ninety-three patients had evaluable tumor samples for exploratory biomarker analysis. Among the 21 patients with somatic EGFR mutations who received treatment during the study, 12 received panitumumab plus carboplatin/paclitaxel, with three having a partial response (Table 4). Among the nine
Events 91 46
n (%) 112 (81) 54 (85)
Median (95% CI) 18.1 (13.6–23.3) 23.0 (15.9–24.1)
36
42
48
54
60
20 6
7 1
5 0
2 0
0 0
Time, wk 91 46
65 38
55 28
34 19
28 9
FIGURE 2. Time to disease progression in part 2. CI, confidence interval; C/P, carboplatin/paclitaxel.
Copyright © 2013 by the International Association for the Study of Lung Cancer
A
Patients With Progression-Free Survival, %
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100 90 80 70 60 50 40 30 20 10 0 0
Overall Survival, %
B
Events 97 49
n (%) 112 (87) 54 (91)
36
42
48
54
60
19 6
7 1
5 0
2 0
0 0
Panitumumab + C/P C/P alone
6
12
18
24
30
91 46
64 38
54 27
33 18
100 90 80 70 60 50 40 30 20 10 0
26 9
Panitumumab + C/P C/P alone
0
Patients at risk: Panitumumab + C/P 112 C/P alone 54
Median (95% CI) 17.6 (11.7–22.4) 18.1 (13.4–23.7)
Time, wk
Patients at risk: Panitumumab + C/P 112 C/P alone 54
FIGURE 3. Median (A) progressionfree survival and (B) median overall survival in part 2. CI, confidence interval; C/P, carboplatin/paclitaxel.
Panitumumab Plus Carboplatin/Paclitaxel in NSCLC
6
12
18
24
30
36
42
Events 70 32
n (%) 112 (63) 54 (59)
Median (95% CI) 37.0 (30.9–52.1) 35.0 (29.3–51.4)
48
54
60
66
72
78
23 11
11 5
8 4
5 1
4 1
2 1
Time, wk 106 52
patients who received carboplatin/paclitaxel alone, two had a partial response. Seventeen patients had somatic KRAS mutations in exon 2. Among the 13 patients with KRAS mutations who received panitumumab plus carboplatin/paclitaxel, three had partial responses. Of the four patients who received carboplatin/paclitaxel, one had a partial response (Table 4). Because preclinical studies have suggested that KRAS mutations may influence cellular distribution of EGFR,19 we evaluated associations between KRAS status and EGFR staining pattern. The proportion of patients with EGFR membrane staining, membrane and cytoplasmic staining, and cytoplasmic staining was 39%, 44%, and 17%, respectively, in patients with wild-type
93 50
87 43
75 38
62 30
48 23
30 14
KRAS and 43%, 43%, and 13% in patients with mutant KRAS. Exploratory evaluations of tumor EGFR staining intensity and mutational status for other genes (PIK3CA, BRAF, HRAS, and NRAS) did not reveal conclusive associations with efficacy outcomes (data not shown).
DISCUSSION In this study, panitumumab administered at 2.5 mg/kg once weekly in combination with carboplatin/paclitaxel did not improve median TTP (the primary endpoint) compared with carboplatin/paclitaxel alone. Similarly, median PFS and OS and overall response rate were not improved by the
TABLE 2. Best Objective Response for Parts 1 and 2 Part 1
Part 2
Panitumumab Panitumumab Panitumumab Arm A 1.0 mg/kg Plus 2.0 mg/kg Plus 2.5 mg/kg Plus Panitumumab Plus Arm B Carboplatin/Paclitaxel Carboplatin/Paclitaxel Carboplatin/Paclitaxel Carboplatin/Paclitaxel Carboplatin/Paclitaxel (n = 6) (n = 7) (n = 6) (n = 112) Alone (n = 54) Complete response, n (%) Partial response, n (%) Stable disease, n (%) Disease progression, n (%) Not evaluable, n (%) Overall response rate,a % (95% CI)
1 (17) 0 (0) 5 (83) 0 (0) 0 (0) 16.7 (0.4–64.1)
0 (0) 1 (14) 5 (71) 1 (14) 0 (0) 14.3 (0.4–57.9)
0 (0) 2 (33) 3 (50) 1 (17) 0 (0) 33.3 (4.3–77.7)
0 (0) 17 (15) 63 (56) 21 (19) 3 (3) 15.2 (9.1–23.2)
0 (0) 6 (11) 36 (67) 8 (15) 1 (2) 11.1 (4.2–22.6)
Assessments made per Response Evaluation Criteria in Solid Tumors. Responses were confirmed at least 6 weeks after response criteria were first met. CI, confidence interval.
a
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TABLE 3. Incidence of Adverse Events in Part 2a Arm A–Panitumumab Plus Carboplatin/ Paclitaxel (n = 112)
Patients, n (%) Fatigue Nausea Rash Diarrhea Constipation Alopecia Vomiting Arthralgia Dyspnea Anorexia Stomatitis Myalgia Adverse events of interest, n (%) Skin toxicityb Dehydration Hypomagnesemia Pulmonary embolism Deep vein thrombosis Cardiac disorders
Arm B–Carboplatin/Paclitaxel Alone (n = 54)
Any Grade
Grade 3 or 4
Any Grade
Grade 3 or 4
112 (100) 70 (63) 68 (61) 66 (59) 54 (48) 51 (46) 50 (45) 49 (44) 39 (35) 38 (34) 37 (33) 37 (33) 36 (32)
94 (84) 15 (13) 10 (9) 13 (12) 7 (6) 6 (5) 2 (2) 9 (8) 6 (5) 12 (11) 7 (6) 1 (1) 3 (3)
54 (100) 35 (65) 30 (56) 9 (17) 14 (26) 21 (39) 24 (44) 17 (31) 22 (41) 15 (28) 17 (31) 5 (9) 14 (26)
41 (76) 11 (20) 4 (7) 0 (0) 1 (2) 2 (4) 0 (0) 5 (9) 3 (6) 4 (7) 1 (2) 0 (0) 2 (4)
98 (88) 17 (15) 6 (5) 7 (6) 8 (7) 19 (17)
19 (17) 9 (8) 2 (2) 7 (6) 7 (6) 6 (5)
14 (26) 10 (19) 2 (4) 5 (9) 3 (6) 7 (13)
1 (2) 5 (9) 0 (0) 3 (6) 2 (4) 1 (2)
Incidence of adverse events occurring in ≥30% of patients in either treatment arm in part 2, sorted by frequency in the panitumumab plus carboplatin/paclitaxel arm. Includes all preferred terms for skin toxicity (including but not limited to rash and dermatitis acneiform).
a b
addition of panitumumab to carboplatin/paclitaxel. These results indicate that panitumumab does not provide clinical benefit in an unselected population of NSCLC patients. Improvements in PFS and OS have been observed in studies investigating cetuximab as a first-line therapy in NSCLC. In the randomized phase 3 FLEX study (N = 1125), addition of cetuximab to cisplatin/vinorelbine resulted in a 1.2-month improvement in OS (11.3 versus 10.1 months) and overall response rate (36% versus 29%).1 However, PFS was not improved (4.8 months in both arms). In the randomized phase 3 BMS099 study (N = 676), the addition of cetuximab to first-line taxane and platinum-based chemotherapy resulted in an improved overall response rate (26% versus 17%), but significant improvements in PFS (4.4 versus 4.2 months) and OS (9.7 versus 8.4 months) were not observed.6 Given that this study (N = 166) was not powered to detect a significant difference in OS between the treatment arms, the results are not inconsistent with those of FLEX and BMS099. Nonetheless, there were differences in the design of the studies that may have contributed to the differences in outcomes observed. Although this study and FLEX enrolled only patients with EGFR-expressing tumors as determined by immunohistochemistry staining, FLEX required only one positively stained tumor cell, whereas this study required EGFR staining in 10% of tumor cells or more. There was no requirement for EGFR expression in BMS099. Patients with controlled brain metastases were accepted to this study and BMS099 but were ineligible for FLEX. Finally, there were differences in the chemotherapy
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regimens used in the three studies. The differences in OS (8.2, 10.1, and 8.4 months, respectively) and ORR (11%, 29%, and 17%, respectively) in the chemotherapy-alone arms of this study, FLEX, and BMS099, are consistent with the hypothesis that these differences in study design may have contributed to differences in outcomes. Overall, the results of this study, FLEX, and BMS099 suggest that any effects of anti-EGFR monoclonal antibodies are of limited magnitude in this setting. Exploratory biomarker analyses did not identify associations between EGFR or KRAS mutational status and response to treatment with panitumumab in combination with carboplatin/paclitaxel. Although it should be noted that the number of mutations identified in the biomarker analyses was small, the results are consistent with previous findings that KRAS mutational status does not seem to be a strong predictor of outcome among patients who receive anti-EGFR therapy for NSCLC.20 However, recent prospective biomarker analyses of phase 3 studies have demonstrated that benefit from small-molecule EGFR inhibitors may be greater among patients with somatic EGFR mutations.8,15 In the Iressa NSCLC Trial Evaluating Response and Survival Versus Taxotere (INTEREST) study, in which gefitinib was noninferior to docetaxel, patients with somatic EGFR mutations who received gefitinib had longer PFS versus docetaxel (7.0 versus 4.1 months, respectively) whereas there was no difference in PFS among patients with wild-type EGFR (1.7 versus 2.6 months); similar results were observed for the objective response rate.8 In contrast, no association was observed between EGFR mutational status and
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TABLE 4. Identification of Somatic Mutations in the EGFR and KRAS Genesa Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Sex
Smoking Status
Treatmentb
EGFR Mutation
KRAS Mutation
Response
Male Female Male Male Male Female Male Female Female Male Female Female Male Female Male Male Male Male Male Male Male Male Male Female Male Female Female Male Male Male Female Female Female Male Male
Former Former Former Former Current Current Never Former Never Current Never Current Former Current Former Former Former Former Former Never Former Former Former Current Former Former Former Former Former Former Current Former Current Former Former
C/P Panitumumab + C/P Panitumumab + C/P C/P Panitumumab + C/P C/P C/P C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P C/P C/P C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P C/P Panitumumab + C/P Panitumumab + C/P C/P
Exon 18 (K713N)/Exon 19 (S752P) Exon 18 (L688P) Exon 18 (L688P) Exon 18 (L688P) Exon 18 (L688P) Exon 18 (L688P) Exon 18 (L688P)/Exon 19 (∆AA 746–750) Exon 18 (L688P)/Exon 21 (L828*) Exon 18 (Q701H) Exon 18 (Y727H) Exon 19 (∆AA 746–750) Exon 19 (D761N) Exon 20 (N771InsH) Exon 20 (N771InsH) Exon 20 (N771InsH) Exon 20 (S768N) Exon 20 (T790M) Exon 21 (L828) Exon 21 (L858R) Exon 21 (L858R) Exon 23 (3′ splice) — — — — — — — — — — — — — —
— Exon 2 (G12D) — — — — — — — Exon 2 (G13D) — — Exon 2 (G12A) — — — — — — — — Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12D) Exon 2 (G12V) Exon 2 (G12V) Exon 2 (G12V) Exon 2 (G13D) Exon 2 (G13D) Exon 2 (Q22K)
SD PR PR PR SD ND PR SD PD SD PR SD SD SD PR PD SD SD SD SD PD PR PR PR PD PD PR PD PD SD SD SD ND PD PD
Ninety-three samples sequenced. Two patients who were enrolled but did not receive study treatment were found to have mutations in EGFR. The first had mutations in exon 19 (∆AA 746–750) and exon 21 (R832H) and the second a mutation in exon 20 (N771InsH); neither patient had an objective response. C/P, carboplatin/paclitaxel; ND, not done; PR, partial response; SD, stable disease; EGFR, epidermal growth factor receptor. a b
outcome with the addition of cetuximab to taxane- and platinum-based chemotherapy in BMS099,21 suggesting that there may be differences in the predictive value of EGFR mutational status with small-molecule EGFR inhibitors compared with anti-EGFR monoclonal antibodies. This study demonstrated that the combination of panitumumab and carboplatin/paclitaxel had acceptable toxicity. The incidence and severity of certain commonly occurring toxicities observed in this study, including skin-related toxicities, gastrointestinal toxicities, and hypomagnesemia, were expected based on the results of studies that investigated panitumumab monotherapy22–24 or in combination with chemotherapy25–29 in other solid tumors. The incidence and
severity of these AEs was also consistent with those observed in phase 2 and 3 studies of cetuximab in combination with chemotherapy for the treatment of advanced NSCLC.1,30 A greater proportion of patients in arm A (24%) discontinued the study than in arm B (17%). This was likely because of a higher incidence of skin toxicity, particularly rash, in patients receiving panitumumab in combination with chemotherapy. The incidence of stomatitis among panitumumab-treated patients in this study was somewhat surprising. Stomatitis has been reported previously in studies of panitumumab monotherapy (18%) and cetuximab in combination with chemotherapy (26%) in metastatic colorectal cancer22,31 although at lower frequencies.
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Overall, panitumumab 2.5 mg/kg once weekly in combination with carboplatin/paclitaxel seemed to have acceptable toxicity in the first-line treatment of advanced NSCLC. However, there was no improvement in the primary efficacy endpoint of median TTP or the secondary efficacy endpoints (median PFS, OS, and response rate).
ACKNOWLEDGMENTS
The authors thank Benjamin Scott, PhD, and Ali Hassan, PhD (Complete Healthcare Communications, Inc., Chadds Ford, Pennsylvania), whose work was funded by Amgen Inc., Thousand Oaks, California, for assistance in writing this article. This study was supported by Amgen Inc., Thousand Oaks, California. References 1. Pirker R, Pereira JR, Szczesna A, et al; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009;373: 1525–1531. 2. Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-smallcell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007;25:1545–1552. 3. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 2004;22:777–784. 4. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 2004;22:785–794. 5. Herbst RS, Prager D, Hermann R, et al; TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced nonsmall-cell lung cancer. J Clin Oncol 2005;23:5892–5899. 6. Lynch TJ, Patel T, Dreisbach L, et al. Cetuximab and first-line taxane/ carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010;28:911–917. 7. Pallis AG, Fennell DA, Szutowicz E, Leighl NB, Greillier L, Dziadziuszko R. Biomarkers of clinical benefit for anti-epidermal growth factor receptor agents in patients with non-small-cell lung cancer. Br J Cancer 2011;105:1–8. 8. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 2010;28:744–752. 9. Hirsch FR, Herbst RS, Olsen C, et al. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in nonsmall-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol 2008;26:3351–3357. 10. Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012;13:33–42. 11. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–144. 12. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 2006;24:5034–5042. 13. Zhu CQ, da Cunha Santos G, Ding K, et al; National Cancer Institute of Canada Clinical Trials Group Study BR.21. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2008;26:4268–4275.
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14. Miller VA, Riely GJ, Zakowski MF, et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol 2008;26:1472–1478. 15. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, firstline study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011;29:2866–2874. 16. Vectibix® (panitumumab). Full Prescribing Information. Thousand Oaks, CA: Amgen Inc., 2012. 17. European Medicines Agency. Vectibix European Public Assessment Report, Summary of Product Characteristics, 2012. 18. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216. 19. van Houdt WJ, Hoogwater FJ, de Bruijn MT, et al. Oncogenic KRAS desensitizes colorectal tumor cells to epidermal growth factor receptor inhibition and activation. Neoplasia 2010;12:443–452. 20. Roberts PJ, Stinchcombe TE, Der CJ, Socinski MA. Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol 2010;28:4769–4777. 21. Khambata-Ford S, Harbison CT, Hart LL, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2010;28:918–927. 22. Hecht JR, Patnaik A, Berlin J, et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007;110:980–988. 23. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658–1664. 24. Weiner LM, Belldegrun AS, Crawford J, et al. Dose and schedule study of panitumumab monotherapy in patients with advanced solid malignancies. Clin Cancer Res 2008;14:502–508. 25. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697–4705. 26. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:4706–4713. 27. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:1351–1357. 28. Berlin J, Posey J, Tchekmedyian S, et al. Panitumumab with irinotecan/ leucovorin/5-fluorouracil for first-line treatment of metastatic colorectal cancer. Clin Colorectal Cancer 2007;6:427–432. 29. Price TJ, Peeters M, Douillard J, et al. Safety summary of panitumumab (pmab) in combination with chemotherapy (ctx) from four clinical trials in patients (pts) with metastatic colorectal cancer (mCRC) [abstract]. J Clin Oncol 2009;27:e15005. 30. Rosell R, Robinet G, Szczesna A, et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann Oncol 2008;19:362–369. 31. Robert F, Blumenschein G, Herbst RS, et al. Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer. J Clin Oncol 2005;23:9089–9096.
Copyright © 2013 by the International Association for the Study of Lung Cancer
A Phase 2 Randomized Trial of Paclitaxel and Carboplatin with or without Panitumumab for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer Jeffrey Crawford, MD,* Paul Swanson, MD,† Paul Schwarzenberger, MD,‡ Alan Sandler, MD,§ Diane Prager, MD,║ Kathy Zhang, PhD,¶ Daniel J. Freeman, PhD,¶ Carol W. Johnson, DVM, PhD,¶ Kartik Krishnan, MD, PhD,¶ and David Johnson, MD#
Introduction: This two-part phase 2 study evaluated the efficacy and safety of panitumumab, a fully human anti–epidermal growth factor receptor monoclonal antibody, combined with carboplatin/paclitaxel in patients with previously untreated advanced non–small-cell lung cancer. Methods: In part 1, patients were sequentially enrolled to receive paclitaxel 200 mg/m2 and carboplatin (area under the concentration-versus-time curve, 6 mg/min/ml) plus panitumumab (1.0, 2.0, or 2.5 mg/ kg). In part 2, patients were randomized 2:1 to receive paclitaxel/ carboplatin with (arm A) or without (arm B) the maximum tolerated dose of panitumumab identified in part 1. Primary endpoints in parts 1 and 2 were the incidence of dose-limiting toxicities and time to progression (TTP), respectively. Results: In part 1, four of 19 patients had dose-limiting toxicities: three at 2.0 mg/kg (fatigue, pain in extremity, dyspepsia) and one at 2.5 mg/kg (rash). The maximum tolerated dose was not reached; panitumumab 2.5 mg/kg was selected for part 2. In part 2, TTP was 18.1 weeks (95% confidence interval [CI], 13.6−23.3) in arm A and *Department of Medicine, Duke University Medical Center, Durham, North Carolina; †Hematology Oncology Associates, Port St. Lucie, Florida; ‡Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana; §Oregon Health and Science University, Portland, Oregon; ║Illinois CancerCare, Peoria, Illinois; ¶Departments of Global Biostatistical Science, Oncology Research, and Global Safety, Amgen Inc., Thousand Oaks, California; and #Division of Hematology and Medical Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. Disclosure: Dr. Jeffrey Crawford has served on advisory boards for Amgen Inc., Thousand Oaks, California; his institution has received a grant from Amgen Inc. for this study and has received research funding from Amgen Inc. Dr. Alan Sandler has served as consultant to and received honoraria from and travel expenses paid by Amgen Inc. Drs. Kathy Zhang and Carol W. Johnson are employees of and own stock in Amgen Inc. Drs. Kartik Krishnan and Daniel J. Freeman were employees of and owned stock in Amgen Inc. at the time the research was conducted. Drs. Paul Swanson, Paul Schwarzenberger, Diane Prager, and David Johnson declare no conflict of interest. Drs. Kartik Krishnan and Alan Sandler are currently affiliated with Genentech, Inc., South San Francisco, California; Dr. Daniel J. Freeman is currently affiliated with Daiichi Sankyo, Edison, New Jersey; and Dr. David Johnson is currently affiliated with the University of Texas Southwestern Medical Center, Dallas, Texas. Address for correspondence: Jeffrey Crawford, MD, Duke University Medical Center, Box 3198, Room 25178, Morris Building, DS, Erwin Road and East Trent Drive, Durham, NC 27710. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-1510
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23.0 weeks (95% CI, 15.9−24.1) in arm B (hazard ratio, 0.9; 90% CI, 0.66−1.21; p = 0.555). Progression-free survival in arms A and B was 17.6 weeks and 18.3 weeks, respectively, and the objective response rate was 15.2% and 11.1%. Adverse events occurring more frequently in arm A than in arm B included skin toxicity, diarrhea, stomatitis, vomiting, and dizziness. Exploratory analyses did not demonstrate associations between potential biomarkers and outcomes. Conclusion: Although toxicity was predictable and manageable, the addition of panitumumab to paclitaxel/carboplatin did not improve TTP in patients with previously untreated advanced non–small-cell lung cancer. Key Words: Panitumumab, Paclitaxel/carboplatin, Non–small-cell lung cancer, KRAS, Epidermal growth factor receptor. (J Thorac Oncol. 2013;8: 1510–1518)
S
tudies investigating the efficacy of epidermal growth factor in the first-line treatment of advanced non–small-cell lung cancer (NSCLC) have yielded inconsistent results. In the phase 3 First-Line ErbituX in lung cancer (FLEX) study of patients with epidermal growth factor receptor (EGFR)– expressing advanced NSCLC, overall survival (OS) was significantly improved by first-line treatment with cetuximab plus cisplatin/vinorelbine versus cisplatin/vinorelbine alone.1 In other studies, addition of cetuximab or the small-molecule EGFR inhibitors erlotinib and gefitinib to first-line chemotherapy did not improve outcomes.2–6 Some evidence has suggested that biomarkers could be used to identify NSCLC patients most likely to respond to EGFR inhibition.7 For example, among patients with chemotherapy-refractory NSCLC, only those with somatic EGFR mutations had longer progression-free survival (PFS) after treatment with gefitinib compared with treatment with docetaxel.8 Other potential biomarkers evaluated with antiEGFR monoclonal antibodies have included high EGFR gene copy number9 and tumor EGFR expression.10 Elevated EGFR protein expression and gene copy number have also been associated with improved outcomes in studies with small-molecule EGFR inhibitors.11–15 Panitumumab is a fully human monoclonal antibody against EGFR, which has been shown to have activity as a
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single agent and in combination with chemotherapy for the treatment of metastatic colorectal cancer, but it is not recommended for use in patients whose tumors have mutations in codons 12 or 13 of KRAS.16,17 The aim of this two-part study was to evaluate the efficacy and safety of carboplatin/paclitaxel with or without panitumumab in previously untreated patients with advanced NSCLC. The objective of part 1 was to establish either the maximum tolerated dose (MTD) or an appropriate dose of panitumumab plus carboplatin/paclitaxel for investigation in part 2. The primary objective of part 2 was to compare the time to progression (TTP) in patients receiving panitumumab plus carboplatin/paclitaxel or carboplatin/paclitaxel alone. In exploratory analyses, we assessed the ability of biomarkers to predict outcomes.
of patients to have skin rash. Patients without disease progression could receive panitumumab for an additional 18 weeks. Dose escalation into the next cohort began when the 3-week safety assessment was complete, five or more patients in the preceding cohort had been evaluated for DLT, and the MTD had not been reached. A DLT was defined as any treatmentrelated adverse event (AE) requiring permanent discontinuation of panitumumab, any treatment-related grade 3 or 4 AE (except skin toxicity), or any treatment-related severe or life-threatening events not assessed by the National Cancer Institute Common Toxicity Criteria for Adverse Events version 2.0. The MTD was defined as the dose level immediately below the dose that resulted in three of five (or 4 of 10) patients experiencing DLT attributed to panitumumab administration.
PATIENTS AND METHODS
Part 2 In part 2, patients were randomized 2:1 to receive carboplatin/paclitaxel at the same dose schedule as in part 1 for up to six cycles with (arm A) or without (arm B) onceweekly intravenous panitumumab at the dose identified in part 1. In the absence of progressive disease, patients could continue to receive panitumumab until disease progression or an AE that prevented further treatment occurred. The primary endpoint of part 2 was TTP. Secondary efficacy endpoints were OS time, PFS time, rate of progressive disease after 12 weeks of treatment, overall response rate, and response rate after 6 weeks of treatment. Secondary safety endpoints were the incidence of AEs and changes in laboratory values and other safety parameters.
Patients Patients were eligible if they were aged at least 18 years, had pathologically confirmed NSCLC (stage IIIB with pericardial or pleural effusion or stage IV) with 10% or more cells expressing EGFR, bidimensionally measurable disease, an Eastern Cooperative Oncology Group performance status of 1 or less, life expectancy of 12 weeks or more, and an available paraffin-embedded tumor tissue sample. Exclusion criteria included prior therapy for NSCLC except radiation, surgery, or steroids; radiation therapy within 2 weeks of treatment initiation; investigational therapy within 30 days; other malignancies within 5 years (except basal cell carcinoma, cervical carcinoma in situ, and primary NSCLC); hypercalcemia; and insufficient cardiac, hepatic, renal, or hematologic function. Brain metastases, if present, were to be controlled and asymptomatic and not requiring treatment for at least 1 week. The study protocol was approved by each center’s institutional review board. All patients provided signed informed consent before screening.
Study Design and Treatment This was an open-label multicenter study conducted in two parts. Part 1 was a dose-escalation study of panitumumab plus carboplatin/paclitaxel for untreated advanced NSCLC. Part 2 was a randomized study evaluating panitumumab (at the dose determined in part 1) plus carboplatin/ paclitaxel versus carboplatin/paclitaxel alone in patients with advanced NSCLC. Part 1 The primary endpoint of part 1 was the incidence of dose-limiting toxicities (DLTs). All patients received intravenous paclitaxel 200 mg/m2 (3.0-h infusion) and carboplatin 6 mg/min/ml (0.5-h infusion) in 3-week cycles beginning on day 1 for up to six cycles. Patients were sequentially enrolled into three dose cohorts of five to 10 patients in which they received once-weekly 1-hour intravenous infusions of panitumumab at doses of 1.0 mg/kg (cohort 1), 2.0 mg/kg (cohort 2), or 2.5 mg/kg (cohort 3) for six cycles. The 2.5-mg/kg dose was anticipated to achieve circulating panitumumab concentrations exceeding those that result in 90% inhibition of tumor cell proliferation in xenograft models and cause less than 95%
Tumor Response Computed tomography or magnetic resonance imaging scans were performed every 6 weeks during the first 48 weeks of treatment and every 12 weeks thereafter. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors.18 Objective responses (complete or partial) were confirmed 4 weeks or more (part 1) or 6 weeks or more (part 2) after criteria for response were first met. Response assessments in part 2 were performed by blinded independent central review (Bio-Imaging Technologies, Inc., Newtown, PA).
Safety Safety was evaluated as the incidence of AEs (graded using National Cancer Institute Common Toxicity Criteria for Adverse Events version 2.0) and changes in laboratory tests. AEs were recorded from the start of treatment through the safety follow-up visit (which occurred within 4 weeks of the last administration of study medication). Fatal AEs were reported for at least 30 days after the last dose of study medication.
Assessment of Biomarkers EGFR expression at screening was measured by immuno histochemistry of formalin-fixed, paraffin-embedded samples at a central laboratory (Impath Inc., New York, NY). Results were expressed as the percentage of cells stained at staining intensity scores ranging from 0 to 3+. Mutations in EGFR, KRAS (exons 2, 3, and 4), HRAS, NRAS, PIK3CA, and BRAF
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were assayed by direct polymerase chain reaction sequencing of polymerase chain reaction–amplified genomic DNA extracted from FFPE samples. The proportion of patients with EGFR membrane staining, membrane and cytoplasmic staining, and cytoplasmic staining was assessed microscopically using previously published criteria.19
Statistical Analysis The original planned sample size was 225 patients, which provided 85% power at the 10% significance level to detect a 50% improvement in TTP. However, enrollment was closed early at 175 patients after the publication of results demonstrating a lack of survival benefit with erlotinib in combination with carboplatin/paclitaxel compared with c arboplatin/ paclitaxel alone.5 The analyses of efficacy and safety included all patients who received one or more doses of panitumumab, paclitaxel, or carboplatin until the data cutoff date (November 30, 2004). TTP was defined as the time from treatment initiation to disease progression or death due to disease progression. PFS was defined as the time from treatment initiation to disease progression or death. Time to event endpoints were summarized by the Kaplan-Meier method with two-sided 95% confidence intervals (CIs). Differences between treatment groups were assessed using a log-rank test at a two-sided 10% significance level. Difference in TTP between the two arms was also assessed using a Cox proportional hazards model. Best overall response rate and the response rate after 6 weeks of treatment were calculated with two-sided 95% CIs. The Fisher’s exact test was used to compare response rates between treatment groups.
RESULTS Patients Between January 7, 2002, and March 31, 2003, 194 patients with advanced NSCLC were enrolled in the study. In part 1, 19 patients were enrolled at six study sites. In part 2, 175 patients were enrolled at 50 study sites. Demographic and baseline characteristics were generally balanced (Table 1). Most patients had stage IV disease.
Treatment Exposure All 19 patients in part 1 received one or more doses of panitumumab (cohort 1, n = 6; cohort 2, n = 7; cohort 3, n = 6). Patients in part 1 received a median of 21 (range, 6–38) panitumumab infusions and a median of six (range, 4–6) cycles of chemotherapy. The median cumulative doses of paclitaxel in cohorts 1, 2, and 3 were 1027, 1012, and 975 mg/m2, respectively. The median cumulative doses of carboplatin were 2339, 1944, and 1467 mg/m2. Of 175 patients randomized in part 2, 166 received study treatment (panitumumab plus carboplatin/paclitaxel [arm A], n = 112; carboplatin/paclitaxel alone [arm B], n = 54). At the time of the data cutoff, four patients in arm A and five patients in arm B continued to receive treatment. Three patients in arm A completed 48 weeks of treatment. Reasons for discontinuation are listed in Figure 1. The median number
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of panitumumab infusions administered was 11 (range, 1–21). The median number of chemotherapy cycles was four in both treatment arms (interquartile range, arm A, 2–6; arm B, 3–6). The median dose of paclitaxel was 197 mg/m2 per infusion (range, 147–217) for arm A and 197 mg/m2 per infusion (range, 100–225) for arm B; the median dose of carboplatin was 372 mg/m2 per infusion (range, 234–688) and 364 mg/m2 per infusion (range, 202–522) for arms A and B, respectively. The median cumulative paclitaxel dose was 788 mg/m2 (range, 195–1241) in arm A and 904 mg/m2 (range, 100–1210) in arm B. The median cumulative carboplatin dose was 1314 mg/m2 (range, 247–3057) in arm A and 1546 mg/m2 (range, 268–2717) in arm B.
Dose Escalation (Part 1) After 3 weeks of treatment, no patients in cohort 1 had a DLT and one patient in cohort 2 had a DLT (fatigue). Consequently, dose escalation of panitumumab proceeded to the maximum dose of 2.5 mg/kg. Over the entire treatment period, four patients experienced DLTs: three in cohort 2 (fatigue, pain in extremity, dyspepsia), and one in cohort 3 (rash). The MTD was not reached, and panitumumab 2.5 mg/kg once weekly was the dose chosen for part 2.
Efficacy (Part 2) At the time of data cutoff, a total of 137 disease progression events had occurred among patients who received treatment in part 2. There was no significant difference in TTP between the two treatment arms (log-rank test, p = 0.553; hazard ratio, 0.9; 90% CI, 0.66–1.21; p = 0.555). The median TTP was 18.1 weeks (95% CI, 13.6–23.3) in arm A and 23.0 weeks (95% CI, 15.9–24.1) in arm B (Fig. 2). Median PFS was 17.6 weeks (95% CI, 11.7–22.4) in arm A and 18.3 weeks (95% CI, 13.4–23.7) in arm B (log-rank test, p = 0.583; Fig. 3A). Median OS was 37.0 weeks (95% CI, 30.9–52.1) in arm A and 35.0 weeks (29.3–51.4) in arm B (p = 0.786; Fig. 3B). The best overall response rate in arm A was 15.2% (95% CI, 9.1–23.2) and 11.1% (95% CI, 4.2–22.6) in arm B (Fisher’s exact test, p = 0.633; Table 2). All responses in part 2 were partial responses. The best response rate after six cycles of treatment was 8.9% (95% CI, 4.4–15.8) in arm A and 9.3% (95% CI, 3.1–20.3) in arm B (p = 1.0). For the patients who responded, the median time to response was 5.6 weeks (range, 5.0–29.4) in arm A and 5.4 weeks (range, 5.0–6.1) in arm B, and the median duration of response in the two arms was 24.1 weeks (95% CI, 16.0–46.3) and 22.0 weeks (95% CI, 17.4– 32.1), respectively.
Safety (Part 2) All patients who received treatment in part 2 experienced at least one AE (Table 3). Ninety-four patients (84%) in arm A and 41 patients (76%) in arm B had a grade 3 or higher AE. AEs occurring more frequently in arm A than in arm B included skin toxicities, diarrhea, stomatitis, vomiting, and dizziness. As expected, skin toxicities occurred more frequently in arm A versus arm B (88% versus 26%, respectively),
Copyright © 2013 by the International Association for the Study of Lung Cancer
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Panitumumab Plus Carboplatin/Paclitaxel in NSCLC
TABLE 1. Patient Demographics and Baseline Characteristics Part 1 Panitumumab Plus Carboplatin/Paclitaxel (n = 19) Age Median Range Sex, n (%) Men Women Race/ethnicity, n (%) White Black Asian Hispanic Other ECOG performance score, n (%) 0 1 2 Smoking statusa, n (%) Never Former Current Disease stage at diagnosis, n (%) I II IIIA IIIB IV Disease histology at diagnosis, n (%) Adenocarcinoma Squamous cell carcinoma Other Extent of disease at study entry, n (%) Distant metastasis Pleural effusion Pericardial effusion Months since primary disease diagnosisb Median Range Prior radiotherapy, n (%) Percentage of cells with positive EGFR staining Median Range Maximum EGFR staining intensity, n (%) 1+ (weak) 2+ (moderate) 3+ (strong)
Part 2 Arm A–Panitumumab Plus Carboplatin/Paclitaxel (n = 112)
50.0 36–82
61.5 36–83
Arm B–Carboplatin/Paclitaxel Alone (n = 54) 62.0 42–81
5 (26) 14 (74)
67 (60) 45 (40)
27 (50) 27 (50)
19 (100) 0 (0) 0 (0) 0 (0) 0 (0)
101 (90) 7 (6) 3 (3) 1 (1) 0 (0)
46 (85) 7 (13) 0 (0) 1 (2) 0 (0)
6 (32) 12 (63) 1 (5)
37 (33) 74 (66) 1 (1)
15 (28) 38 (70) 1 (2)
— — —
10 (9) 71 (63) 28 (25)
6 (11) 38 (70) 9 (17)
2 (11) 0 (0) 0 (0) 2 (11) 15 (79)
13 (12) 1 (1) 4 (4) 10 (9) 84 (75)
4 (7) 0 (0) 0 (0) 9 (17) 41 (76)
13 (68) 3 (16) 3 (16)
67 (60) 23 (21) 22 (20)
36 (67) 12 (22) 6 (11)
15 (79) 8 (42) 4 (21)
98 (88) 31 (28) 11 (10)
43 (80) 19 (35) 0 (0)
2.0 0.7–21.3 9 (47)
1.5 0.2–119.2 36 (32)
1.1 0.2–27.6 15 (28)
100 20–100
100 10–100
100 26–100
0 (0) 3 (16) 16 (84)
8 (7) 11 (10) 93 (83)
0 (0) 5 (9) 49 (91)
Smoking history was not available for patients in part 1. Time from date of primary diagnosis or metastatic disease diagnosis to date of enrollment (part 1) or randomization (part 2). ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor.
a b
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Assessed for eligibility in Part 2 (N=312) Excluded (n=137)
Arm A Randomized (n=116)
Arm B Randomized (n=59)
Received panitumumab 2.5 mg/kg carboplatin/paclitaxel (n=112) Did not receive panitumumab 2.5 mg/kg carboplatin/paclitaxel (n=6)
Received carboplatin/paclitaxel (n=54) Did not receive carboplatin/paclitaxel (n=5)
Ongoing (n=4) Completed 48 weeks of treatment (n=3) Discontinued (n=1095) Disease progression (n=68) Investigator decision (n=7) Adverse event (n=13) Consent withdrawn (n=6) Death (n=7) Other (n=4)
Ongoing (n=2) Completed 48 weeks of treatment (n=0) Discontinued (n=54) Disease progression (n=28) Investigator decision (n=11) Adverse event (n=4) Consent withdrawn (n=5) Death (n=2) Other (n=2)
Patient treated analysis set (n=112)
Patient treated analysis set (n=54)
FIGURE 1. CONSORT diagram for part 2.
progressive pulmonary fibrosis; gastrointestinal perforation; cerebrovascular accident, sepsis; and myocardial infarction). In part 2, 27 patients (24%) in arm A discontinued the study (either the treatment or safety follow-up) owing to AEs. These included NSCLC (4%), rash (3%), and fatigue (2%). In arm B, nine patients (17%) discontinued the study owing to AEs. The only AE leading to discontinuation in more than one patient was neuropathy (4%). The percentage of patients discontinuing the study during the chemotherapy combination phase was similar in arms A (18%) and B (17%).
Patients Without Disease Progression, %
with grade 3 toxicities occurring in 17% and 2% of patients, respectively. Diarrhea was reported in 48% and 26% of patients in arms A and B, respectively, with grade 3 diarrhea occurring in 6% and 2% of patients, respectively. Stomatitis of any grade was reported in 33% and 9% of patients in arms A and B, respectively, whereas the incidence of hypomagnesemia across the two arms was similar (5% versus 4%, respectively; grade 3, 1% versus 0%). Of 112 patients who received panitumumab plus carboplatin/ paclitaxel, 31 had possible panitumumab infusion reactions. Most were mild or moderate in severity; all but two patients who experienced infusion reactions received subsequent panitumumab infusions. Seventeen deaths occurred during the study: one in part 1 and 14 and two in arms A and B, respectively, in part 2. Most were attributable to disease progression. However, grade 5 AEs considered possibly related to panitumumab occurred in four patients in arm A in part 2 (respiratory failure secondary to 100 90 80 70 60 50 40 30 20 10 0
Panitumumab + C/P C/P alone
0
Patients at risk: Panitumumab + C/P 112 C/P alone 54
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6
12
18
24
30
Associations between Biomarkers and Outcomes Ninety-three patients had evaluable tumor samples for exploratory biomarker analysis. Among the 21 patients with somatic EGFR mutations who received treatment during the study, 12 received panitumumab plus carboplatin/paclitaxel, with three having a partial response (Table 4). Among the nine
Events 91 46
n (%) 112 (81) 54 (85)
Median (95% CI) 18.1 (13.6–23.3) 23.0 (15.9–24.1)
36
42
48
54
60
20 6
7 1
5 0
2 0
0 0
Time, wk 91 46
65 38
55 28
34 19
28 9
FIGURE 2. Time to disease progression in part 2. CI, confidence interval; C/P, carboplatin/paclitaxel.
Copyright © 2013 by the International Association for the Study of Lung Cancer
A
Patients With Progression-Free Survival, %
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100 90 80 70 60 50 40 30 20 10 0 0
Overall Survival, %
B
Events 97 49
n (%) 112 (87) 54 (91)
36
42
48
54
60
19 6
7 1
5 0
2 0
0 0
Panitumumab + C/P C/P alone
6
12
18
24
30
91 46
64 38
54 27
33 18
100 90 80 70 60 50 40 30 20 10 0
26 9
Panitumumab + C/P C/P alone
0
Patients at risk: Panitumumab + C/P 112 C/P alone 54
Median (95% CI) 17.6 (11.7–22.4) 18.1 (13.4–23.7)
Time, wk
Patients at risk: Panitumumab + C/P 112 C/P alone 54
FIGURE 3. Median (A) progressionfree survival and (B) median overall survival in part 2. CI, confidence interval; C/P, carboplatin/paclitaxel.
Panitumumab Plus Carboplatin/Paclitaxel in NSCLC
6
12
18
24
30
36
42
Events 70 32
n (%) 112 (63) 54 (59)
Median (95% CI) 37.0 (30.9–52.1) 35.0 (29.3–51.4)
48
54
60
66
72
78
23 11
11 5
8 4
5 1
4 1
2 1
Time, wk 106 52
patients who received carboplatin/paclitaxel alone, two had a partial response. Seventeen patients had somatic KRAS mutations in exon 2. Among the 13 patients with KRAS mutations who received panitumumab plus carboplatin/paclitaxel, three had partial responses. Of the four patients who received carboplatin/paclitaxel, one had a partial response (Table 4). Because preclinical studies have suggested that KRAS mutations may influence cellular distribution of EGFR,19 we evaluated associations between KRAS status and EGFR staining pattern. The proportion of patients with EGFR membrane staining, membrane and cytoplasmic staining, and cytoplasmic staining was 39%, 44%, and 17%, respectively, in patients with wild-type
93 50
87 43
75 38
62 30
48 23
30 14
KRAS and 43%, 43%, and 13% in patients with mutant KRAS. Exploratory evaluations of tumor EGFR staining intensity and mutational status for other genes (PIK3CA, BRAF, HRAS, and NRAS) did not reveal conclusive associations with efficacy outcomes (data not shown).
DISCUSSION In this study, panitumumab administered at 2.5 mg/kg once weekly in combination with carboplatin/paclitaxel did not improve median TTP (the primary endpoint) compared with carboplatin/paclitaxel alone. Similarly, median PFS and OS and overall response rate were not improved by the
TABLE 2. Best Objective Response for Parts 1 and 2 Part 1
Part 2
Panitumumab Panitumumab Panitumumab Arm A 1.0 mg/kg Plus 2.0 mg/kg Plus 2.5 mg/kg Plus Panitumumab Plus Arm B Carboplatin/Paclitaxel Carboplatin/Paclitaxel Carboplatin/Paclitaxel Carboplatin/Paclitaxel Carboplatin/Paclitaxel (n = 6) (n = 7) (n = 6) (n = 112) Alone (n = 54) Complete response, n (%) Partial response, n (%) Stable disease, n (%) Disease progression, n (%) Not evaluable, n (%) Overall response rate,a % (95% CI)
1 (17) 0 (0) 5 (83) 0 (0) 0 (0) 16.7 (0.4–64.1)
0 (0) 1 (14) 5 (71) 1 (14) 0 (0) 14.3 (0.4–57.9)
0 (0) 2 (33) 3 (50) 1 (17) 0 (0) 33.3 (4.3–77.7)
0 (0) 17 (15) 63 (56) 21 (19) 3 (3) 15.2 (9.1–23.2)
0 (0) 6 (11) 36 (67) 8 (15) 1 (2) 11.1 (4.2–22.6)
Assessments made per Response Evaluation Criteria in Solid Tumors. Responses were confirmed at least 6 weeks after response criteria were first met. CI, confidence interval.
a
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TABLE 3. Incidence of Adverse Events in Part 2a Arm A–Panitumumab Plus Carboplatin/ Paclitaxel (n = 112)
Patients, n (%) Fatigue Nausea Rash Diarrhea Constipation Alopecia Vomiting Arthralgia Dyspnea Anorexia Stomatitis Myalgia Adverse events of interest, n (%) Skin toxicityb Dehydration Hypomagnesemia Pulmonary embolism Deep vein thrombosis Cardiac disorders
Arm B–Carboplatin/Paclitaxel Alone (n = 54)
Any Grade
Grade 3 or 4
Any Grade
Grade 3 or 4
112 (100) 70 (63) 68 (61) 66 (59) 54 (48) 51 (46) 50 (45) 49 (44) 39 (35) 38 (34) 37 (33) 37 (33) 36 (32)
94 (84) 15 (13) 10 (9) 13 (12) 7 (6) 6 (5) 2 (2) 9 (8) 6 (5) 12 (11) 7 (6) 1 (1) 3 (3)
54 (100) 35 (65) 30 (56) 9 (17) 14 (26) 21 (39) 24 (44) 17 (31) 22 (41) 15 (28) 17 (31) 5 (9) 14 (26)
41 (76) 11 (20) 4 (7) 0 (0) 1 (2) 2 (4) 0 (0) 5 (9) 3 (6) 4 (7) 1 (2) 0 (0) 2 (4)
98 (88) 17 (15) 6 (5) 7 (6) 8 (7) 19 (17)
19 (17) 9 (8) 2 (2) 7 (6) 7 (6) 6 (5)
14 (26) 10 (19) 2 (4) 5 (9) 3 (6) 7 (13)
1 (2) 5 (9) 0 (0) 3 (6) 2 (4) 1 (2)
Incidence of adverse events occurring in ≥30% of patients in either treatment arm in part 2, sorted by frequency in the panitumumab plus carboplatin/paclitaxel arm. Includes all preferred terms for skin toxicity (including but not limited to rash and dermatitis acneiform).
a b
addition of panitumumab to carboplatin/paclitaxel. These results indicate that panitumumab does not provide clinical benefit in an unselected population of NSCLC patients. Improvements in PFS and OS have been observed in studies investigating cetuximab as a first-line therapy in NSCLC. In the randomized phase 3 FLEX study (N = 1125), addition of cetuximab to cisplatin/vinorelbine resulted in a 1.2-month improvement in OS (11.3 versus 10.1 months) and overall response rate (36% versus 29%).1 However, PFS was not improved (4.8 months in both arms). In the randomized phase 3 BMS099 study (N = 676), the addition of cetuximab to first-line taxane and platinum-based chemotherapy resulted in an improved overall response rate (26% versus 17%), but significant improvements in PFS (4.4 versus 4.2 months) and OS (9.7 versus 8.4 months) were not observed.6 Given that this study (N = 166) was not powered to detect a significant difference in OS between the treatment arms, the results are not inconsistent with those of FLEX and BMS099. Nonetheless, there were differences in the design of the studies that may have contributed to the differences in outcomes observed. Although this study and FLEX enrolled only patients with EGFR-expressing tumors as determined by immunohistochemistry staining, FLEX required only one positively stained tumor cell, whereas this study required EGFR staining in 10% of tumor cells or more. There was no requirement for EGFR expression in BMS099. Patients with controlled brain metastases were accepted to this study and BMS099 but were ineligible for FLEX. Finally, there were differences in the chemotherapy
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regimens used in the three studies. The differences in OS (8.2, 10.1, and 8.4 months, respectively) and ORR (11%, 29%, and 17%, respectively) in the chemotherapy-alone arms of this study, FLEX, and BMS099, are consistent with the hypothesis that these differences in study design may have contributed to differences in outcomes. Overall, the results of this study, FLEX, and BMS099 suggest that any effects of anti-EGFR monoclonal antibodies are of limited magnitude in this setting. Exploratory biomarker analyses did not identify associations between EGFR or KRAS mutational status and response to treatment with panitumumab in combination with carboplatin/paclitaxel. Although it should be noted that the number of mutations identified in the biomarker analyses was small, the results are consistent with previous findings that KRAS mutational status does not seem to be a strong predictor of outcome among patients who receive anti-EGFR therapy for NSCLC.20 However, recent prospective biomarker analyses of phase 3 studies have demonstrated that benefit from small-molecule EGFR inhibitors may be greater among patients with somatic EGFR mutations.8,15 In the Iressa NSCLC Trial Evaluating Response and Survival Versus Taxotere (INTEREST) study, in which gefitinib was noninferior to docetaxel, patients with somatic EGFR mutations who received gefitinib had longer PFS versus docetaxel (7.0 versus 4.1 months, respectively) whereas there was no difference in PFS among patients with wild-type EGFR (1.7 versus 2.6 months); similar results were observed for the objective response rate.8 In contrast, no association was observed between EGFR mutational status and
Copyright © 2013 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology ® • Volume 8, Number 12, December 2013
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TABLE 4. Identification of Somatic Mutations in the EGFR and KRAS Genesa Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Sex
Smoking Status
Treatmentb
EGFR Mutation
KRAS Mutation
Response
Male Female Male Male Male Female Male Female Female Male Female Female Male Female Male Male Male Male Male Male Male Male Male Female Male Female Female Male Male Male Female Female Female Male Male
Former Former Former Former Current Current Never Former Never Current Never Current Former Current Former Former Former Former Former Never Former Former Former Current Former Former Former Former Former Former Current Former Current Former Former
C/P Panitumumab + C/P Panitumumab + C/P C/P Panitumumab + C/P C/P C/P C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P C/P C/P C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P Panitumumab + C/P C/P Panitumumab + C/P Panitumumab + C/P C/P
Exon 18 (K713N)/Exon 19 (S752P) Exon 18 (L688P) Exon 18 (L688P) Exon 18 (L688P) Exon 18 (L688P) Exon 18 (L688P) Exon 18 (L688P)/Exon 19 (∆AA 746–750) Exon 18 (L688P)/Exon 21 (L828*) Exon 18 (Q701H) Exon 18 (Y727H) Exon 19 (∆AA 746–750) Exon 19 (D761N) Exon 20 (N771InsH) Exon 20 (N771InsH) Exon 20 (N771InsH) Exon 20 (S768N) Exon 20 (T790M) Exon 21 (L828) Exon 21 (L858R) Exon 21 (L858R) Exon 23 (3′ splice) — — — — — — — — — — — — — —
— Exon 2 (G12D) — — — — — — — Exon 2 (G13D) — — Exon 2 (G12A) — — — — — — — — Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12C) Exon 2 (G12D) Exon 2 (G12V) Exon 2 (G12V) Exon 2 (G12V) Exon 2 (G13D) Exon 2 (G13D) Exon 2 (Q22K)
SD PR PR PR SD ND PR SD PD SD PR SD SD SD PR PD SD SD SD SD PD PR PR PR PD PD PR PD PD SD SD SD ND PD PD
Ninety-three samples sequenced. Two patients who were enrolled but did not receive study treatment were found to have mutations in EGFR. The first had mutations in exon 19 (∆AA 746–750) and exon 21 (R832H) and the second a mutation in exon 20 (N771InsH); neither patient had an objective response. C/P, carboplatin/paclitaxel; ND, not done; PR, partial response; SD, stable disease; EGFR, epidermal growth factor receptor. a b
outcome with the addition of cetuximab to taxane- and platinum-based chemotherapy in BMS099,21 suggesting that there may be differences in the predictive value of EGFR mutational status with small-molecule EGFR inhibitors compared with anti-EGFR monoclonal antibodies. This study demonstrated that the combination of panitumumab and carboplatin/paclitaxel had acceptable toxicity. The incidence and severity of certain commonly occurring toxicities observed in this study, including skin-related toxicities, gastrointestinal toxicities, and hypomagnesemia, were expected based on the results of studies that investigated panitumumab monotherapy22–24 or in combination with chemotherapy25–29 in other solid tumors. The incidence and
severity of these AEs was also consistent with those observed in phase 2 and 3 studies of cetuximab in combination with chemotherapy for the treatment of advanced NSCLC.1,30 A greater proportion of patients in arm A (24%) discontinued the study than in arm B (17%). This was likely because of a higher incidence of skin toxicity, particularly rash, in patients receiving panitumumab in combination with chemotherapy. The incidence of stomatitis among panitumumab-treated patients in this study was somewhat surprising. Stomatitis has been reported previously in studies of panitumumab monotherapy (18%) and cetuximab in combination with chemotherapy (26%) in metastatic colorectal cancer22,31 although at lower frequencies.
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Overall, panitumumab 2.5 mg/kg once weekly in combination with carboplatin/paclitaxel seemed to have acceptable toxicity in the first-line treatment of advanced NSCLC. However, there was no improvement in the primary efficacy endpoint of median TTP or the secondary efficacy endpoints (median PFS, OS, and response rate).
ACKNOWLEDGMENTS
The authors thank Benjamin Scott, PhD, and Ali Hassan, PhD (Complete Healthcare Communications, Inc., Chadds Ford, Pennsylvania), whose work was funded by Amgen Inc., Thousand Oaks, California, for assistance in writing this article. This study was supported by Amgen Inc., Thousand Oaks, California. References 1. Pirker R, Pereira JR, Szczesna A, et al; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009;373: 1525–1531. 2. Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-smallcell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007;25:1545–1552. 3. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 2004;22:777–784. 4. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 2004;22:785–794. 5. Herbst RS, Prager D, Hermann R, et al; TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced nonsmall-cell lung cancer. J Clin Oncol 2005;23:5892–5899. 6. Lynch TJ, Patel T, Dreisbach L, et al. Cetuximab and first-line taxane/ carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010;28:911–917. 7. Pallis AG, Fennell DA, Szutowicz E, Leighl NB, Greillier L, Dziadziuszko R. Biomarkers of clinical benefit for anti-epidermal growth factor receptor agents in patients with non-small-cell lung cancer. Br J Cancer 2011;105:1–8. 8. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 2010;28:744–752. 9. Hirsch FR, Herbst RS, Olsen C, et al. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in nonsmall-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol 2008;26:3351–3357. 10. Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012;13:33–42. 11. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–144. 12. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 2006;24:5034–5042. 13. Zhu CQ, da Cunha Santos G, Ding K, et al; National Cancer Institute of Canada Clinical Trials Group Study BR.21. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2008;26:4268–4275.
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