Original Study
CHAMP: A Phase II Study of Panitumumab With Pemetrexed and Cisplatin Versus Pemetrexed and Cisplatin in the Treatment of Patients With Advanced-Stage Primary Nonsquamous NoneSmall-Cell Lung Cancer With Particular Regard to the KRAS Status Wolfgang Schuette,1 Dirk Behringer,2 Jan Stoehlmacher,3 Jens Kollmeier,4 Sibylle Schmager,5 Ludwig Fischer von Weikersthal,6 Christian Schumann,7 Joerg Buchmann8 Abstract In this phase II, randomized, open label study the efficacy and tolerability of panitumumab in combination with pemetrexed/cisplatin versus pemetrexed/cisplatin in patients with stage IIIB/IV primary nonsquamous nonesmall-cell lung cancer and wild type VeKi-ras2 Kirsten rat sarcoma viral oncogene homolog were assessed. The overall survival showed a clear difference between the treatment groups in favor of the standard therapy. This study teaches important lessons for future trial design. Introduction: The aim of the study was to investigate the efficacy and tolerability of panitumumab, a fully human antiepidermal growth factor receptor monoclonal antibody, in combination with pemetrexed/cisplatin in patients with stage IIIB to IV primary nonsquamous nonesmall-cell lung cancer and wild type VeKi-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Results were compared with those obtained in a control group of patients who received a pemetrexed/cisplatin regimen only. Patients and Methods: This was a phase II, randomized, open-label study with 2 treatment arms. In total, 96 patients received panitumumab at a dose of 9 mg/kg in combination with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 (n ¼ 49) or pemetrexed/cisplatin alone (n ¼ 47). The primary outcome measure was progression-free survival at 6 months. Secondary end points of the study included overall survival, tumor response, quality of life, and safety outcomes. The CHAMP study is registered with ClinicalTrials.gov, number NCT01088620. Results: Progression-free survival at 6 months did not indicate a benefit of panitumumab as a supplement to the standard therapy of pemetrexed/cisplatin whereas the overall survival showed a clear difference between the treatment groups in favor of the standard therapy. Results might be affected by the higher rates of serious adverse events and higher death rates within the panitumumab arm. Conclusions: Results from the present study indicate that combination of cisplatin/pemetrexed with panitumumab should not be recommended for patients with adenocarcinoma and KRAS wild type because of lack of efficacy, lack of improvement of quality of life, and because of the
ClinicalTrials.gov NCT01088620. 1 Department of Internal Medicine II, Hospital Martha-Maria Halle-Doelau, Halle, Germany 2 Department of Haematology, Oncology and Palliative Care, Augusta-Kranken-Anstalt gGmbH, Bochum, Germany 3 Doctors Office of Individual Cancer Therapy, Bonn, Germany 4 Department of Pneumology, Lung Clinic Heckeshorn, Berlin, Germany 5 Carl-Thiem-Hospital Cottbus, Cottbus, Germany 6 Department of Haematology and Internistic Oncology, Health Center St Marien, Amberg, Germany
1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2015.05.009
7 Department of Internal Medicine II and Clinic for Pneumology, Thoracic Oncology, Sleep- and Respiratory Critical Care, Kempten-Oberallgaeu, University Hospital Ulm, Ulm, Germany 8 Hospital Martha-Maria Halle-Doelau, Institute of Pathology, Halle, Germany
Submitted: Mar 20, 2015; Revised: May 26, 2015; Accepted: May 26, 2015 Address for correspondence: Wolfgang Schuette, MD, Department of Internal Medicine II, Krankenhaus Martha-Maria Halle-Doelau gGmbH, Roentgenstraße 1, 06120 Halle (Saale), Germany Fax: þ49-345-6800376; e-mail contact: [email protected]
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CHAMP: Panitumumab in KRAS Wild Type NSCLC increase in toxicity rates compared with patients in the control arm, who received standard chemotherapy of pemetrexed/cisplatin. Clinical Lung Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Epidermal growth factor receptor, KRAS, Non-small cell lung cancer, Panitumumab, Pemetrexed/cisplatin
Introduction
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The current prognosis of patients with advanced or metastatic nonesmall-cell lung carcinoma (NSCLC) can be described as comparatively poor, with a progression-free survival (PFS) of approximately 4 months and overall survival of approximately 8 months if standard combination chemotherapy is provided.1 For the treatment of primary pulmonary adenocarcinoma the combination of pemetrexed with cisplatin has recently been approved by Ethikkomission des Landes Sachsen-Anhalt in Germany. The efficacy of this combination is demonstrated with a PFS time of 5.3 months and an overall survival time of 11.8 months, thus ranging among the most effective treatments for this type of cancer available at present.2 The data available from the FLEX study of vinorelbine and cisplatin with or without cetuximab in patients with stage IIIB and IV NSCLC have shown a statistically significant benefit in terms of overall survival (OS) for the combination therapy with the epidermal growth factor receptor (EGFR) antibody in patients with adenocarcinoma and in patients with squamous cell carcinoma. For the adenocarcinoma subgroup a hazard ratio for death of 0.94 (95% confidence interval, 0.77-1.15) and a survival benefit with a median survival time of 12.0 months (range, 9.6-14.8 months) versus 10.3 months (range, 8.3-12.1 months) was observed.3,4 A dose-finding study of panitumumab in combination with paclitaxel and carboplatin also reported positive results for response and PFS in NSCLC.5 At the American Society of Clinical Oncology 2007, Gazdar presented data on the VeKi-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status in NSCLC and was able to show that approximately 30% of patients with adenocarcinoma have a mutation of the KRAS gene.6 The results from several clinical studies suggest that an EGFR antibody or other EGFR-targeted agents do not appear to benefit patients who have KRAS mutations.7 Taking these results together, it would have appeared advantageous to select patients with primary pulmonary nonsquamous carcinoma (NSCLC) and wild type KRAS, treat them in an arm with the presently most effective chemotherapy and compare this treatment with the same chemotherapy with panitumumab in a second arm. Based on a 3-week chemotherapy regimen, panitumumab might also be administered in this schedule without loss of efficacy when administered at 9 mg/kg body weight every 3 weeks compared with 6 mg/kg every 2 weeks.8 The primary and secondary findings of this phase II study are evaluated in relation to expectations derived from historical data on the standard treatment (ie, chemotherapy alone), as is conventionally done in single-arm phase II studies. However, because of the high degree of prognostic heterogeneity of cancer patients the validity of these assumptions in the study population to be recruited to this protocol might have been exposed to major selection bias. Thus, a randomized reference group was introduced, allowing for validation of the historical assumptions in the population at hand, with respect
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to primary and secondary end points.9,10 Naturally, this phase II study did not provide sufficient power to allow for rigorous, inference-based statistical comparisons, as applied in phase III studies.
Patients and Methods Patients Patients were eligible for the study if they were aged at least 18 years, had histologically confirmed diagnosis of inoperable stage IIIB or IV primary pulmonary nonsquamous carcinoma (ie, adenocarcinoma and large cell carcinoma; according to Union internationale contre le cancer staging valid until 2008), with at least 1 unidimensional, measurable tumor parameter according to the Response Evaluation Criteria in Solid Tumors version 1.1, 2009 (RECIST),11 with an Eastern Cooperative Oncology Group performance status of 2,12 and a life expectancy of at least 12 weeks. Patients were also required to have adequate hematological, hepatic, renal, and metabolic function. Furthermore, wild type KRAS status of the patient was to be confirmed to be included in the study. Patients who had received previous chemotherapy or previous radiotherapy of the parameters to be measured or who showed clinically manifest, uncontrolled brain metastases and peripheral neuropathy of National Cancer Institute grade > 1 were ineligible for the study. Major exclusion criteria further encompassed serious concurrent diseases or major surgery within the last 4 weeks before recruitment, history of interstitial lung disease, superior vena cava syndrome contraindicating hydration, patients with mild to moderate renal insufficiency who were unable to interrupt salicylates or other nonsteroidal anti-inflammatory drugs with the exception of low-dose aspirin, presence of clinically significant third-space fluid collections that could not be controlled by drainage or other procedures and previous or concurrent malignancy except nonmelanoma skin cancer or cervical carcinoma Fédération Internationale de Gynécologie et d’Obstétrique stage 0 to 1 if the patient was continuously disease-free. Pregnant or breast-feeding subjects or subjects not willing to use highly effective methods of contraception during treatment and for 6 months after the end of treatment were not permitted to participate in the study. The protocol was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines13 and was approved by each center’s institutional ethics review board. All patients signed written informed consent before treatment.
Study Design and Treatment This trial was registered under the US National Institutes of Health ClinicalTrials.gov identifier NCT01088620. The study was conducted as an exploratory, randomized, open-label, multicenter phase II study. Eligible patients were randomly assigned to 1 of 2 parallel treatment arms. Patients in arm A (PemCisP) received pemetrexed 500 mg/m2 with cisplatin
Wolfgang Schuette et al 75 mg/m2 and panitumumab 9 mg/kg body weight on day 1 of each 3-week cycle for up to 4 cycles or until diagnosis of disease progression if it occurred earlier. Patients in arm B (PemCis) were treated with the standard chemotherapy pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 on day 1 of each 3-week cycle for up to 4 cycles or until diagnosis of disease progression if it occurred earlier. In the subsequent maintenance phase, patients of arm A who showed complete response (CR), partial response (PR), or stable disease were further treated with panitumumab monotherapy until disease progression (Figure 1). The primary objective of the study was to investigate the efficacy of the combination consisting of cisplatin/pemetrexed and
panitumumab including the option of panitumumab maintenance therapy in patients with wild type KRAS. The PFS at 6 months was compared with expectations derived from historical data, which were verified in a randomized control group without the antibody. Secondary end points were determination of tumor response, OS, adverse effects, toxicity, and quality of life assessment. On the basis of interim toxicity data and a futility analysis of PFS the Data Safety Monitoring Board recommended suspension of patient enrollment in January 2013. The study was prematurely terminated after the last included patient had reached his 6-month PFS. Hence, data analysis was performed on the basis of 98 patients only instead of the planned 134.
Figure 1 Study Overview
Abbreviations: b.w. ¼ body weight; NSCLC ¼ nonesmall-cell lung cancer; PemCis ¼ pemetrexed/cisplatin; PemCisP ¼ pemetrexed/cisplatin with panitumumab; PFS ¼ progression-free survival; q 3w ¼ once every 3 weeks.
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CHAMP: Panitumumab in KRAS Wild Type NSCLC Progression-Free Survival Progression-free survival was defined as the time from randomization to the time of disease progression or relapse according to RECIST criteria or death, or to the date of last assessment without any such event (censored observation).
Overall Survival The duration of OS was determined by measuring the time interval from randomization to the date of death or last observation (censored).
Tumor Response Tumor measurements were done using the same method (eg, physical examination, x-ray, computed tomography scan) at each assessment. All measurable and evaluable disease was followed until disease progression. If a patient had clinical signs of progression, then tumor evaluation took place at that time. All tumor evaluations were performed according to RECIST criteria and standards. Confirmation of declared remissions (CR or PR) was performed not earlier than 28 days after the original declaration of response.
Calculated P values are considered to be exploratory and are presented explicitly without referring to hypotheses or a significance level. No error adjustment for multiple testing was performed. Thus, the P values reflect the comparisonwise error and not the experimentwise error. All P values are 2-sided if not stated otherwise. In the case of comparisons between patient groups, these rates were analyzed using the c2 test. Event-related data like PFS or OS was estimated using the product limit method and compared using the log rank test (ManteleCox test) and days as unit. All analyses of the continuous efficacy variables (eg, quality of life score) were performed as repeated measures analysis of variance with treatment group and adjustments for age and sex.
Analysis Sets Of 98 randomized patients, 97 were included in the safety analysis set because 1 patient withdrew his consent after
Table 1 Patient Demographic and Baseline Characteristics
Quality of Life Quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 and EORTC lung cancer-specific questionnaires before start of combination therapy, on day 1 of every second cycle, and at the end of combination therapy.
Characteristic
Arm A: PemCisP, n [ 49
Arm B: PemCis, n [ 47
Age, Years Median
60.0
58.0
Range
39-78
45-77
Men
31 (63.3)
27 (57.4)
Women
18 (36.7)
20 (42.6)
Sex, n (%)
Safety Safety was evaluated as the incidence of adverse events (AEs) graded using National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 and changes in laboratory tests. AEs were recorded from the start of treatment through the safety follow-up visit that was performed on day 30 after the start of the last chemotherapy cycle. During panitumumab maintenance therapy, toxicity and symptoms were recorded at any treatment visit of the patient.
Statistical Analysis
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The statistical calculation was based on Fleming’s single-stage design14 and the following premises and assumptions: the null hypothesis that the true PemCisP PFS rate is 0.4 was tested against a 1-sided alternative, because this corresponded to the standard treatment efficacy. The null hypothesis was rejected and the experimental therapy was accepted as promising if the true PemCisP PFS rate was 0.55. This design yielded a type I error rate of 5% and power of 80% (type II error rate of 20%). According to these parameters, 67 patients per arm (134 patients) were initially planned to be included in the study. In consequence of the premature stop of patient recruitment, data sets of only 98 patients were evaluable. According to the parameters given herein, and using a standard single-stage phase II design by Fleming,14 an interim analysis with 98 KRAS wild type patients (49 of them in the panitumumab arm) was performed. The final conclusion of this phase II trial depended on the definite PFS rate (and its confidence interval), the respective findings in the PemCis reference arm, and the information on type, frequency, and severity of toxicities.
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Smoking Status, n (%) Never
7 (14.3)
7 (14.9)
Former
28 (57.1)
23 (48.9)
Current
12 (24.5)
15 (31.9)
2 (4.1)
2 (4.3)
Unknown Stage of Disease, n (%)a IIIb
0
1 (2.1)
IV
48 (100)
46 (97.9)
47 (95.9)
47 (100)
2 (4.1)
0
Disease Histology, n (%) Adenocarcinoma Other Time Since Initial Diagnosis of NSCLC, Days Median
28.0
26.0
Range
0-321
7-1835
8 (16.3)
8 (17.0)
10 (20.4)
18 (38.3)
4 (8.2)
4 (8.5)
0
28 (58.3)
19 (40.4)
1
16 (33.3)
26 (55.3)
2
4 (8.3)
2 (4.3)
Previous Tumor Therapy, n (%) Surgery Radiotherapy Other ECOG Performance Score, n (%)a
Abbreviations: ECOG ¼ Eastern Cooperative Oncology Group; NSCLC ¼ nonesmall-cell lung cancer; PemCis ¼ pemetrexed/cisplatin; PemCisP ¼ pemetrexed/cisplatin with panitumumab. a Missing value for 1 patient.
Wolfgang Schuette et al randomization but before the first cycle of combination therapy. The full analysis set (intention to treat [ITT]) consisted of 96 patients because another patient had to be excluded because of violation of inclusion criteria.
Results Patient Characteristics Between April 2010 and January 2013, a total of 98 patients were randomly assigned to 1 of the 2 treatment regimens at 13 centers throughout Germany. Demographic and baseline disease characteristics were generally well balanced between the 2 treatment groups. Almost all patients suffered from an adenocarcinoma and stage IV disease (Table 1).
Treatments Of 98 randomized patients, 2 dropped out before receiving treatment. Of the remaining, 49 patients were assigned to treatment
arm A (PemCisP; panitumumab arm) and 47 received treatment in arm B (PemCis; standard arm). Fifty-six subjects completed the planned 4 treatment cycles and entered the follow-up phase; 23 patients in arm A and 33 patients in arm B. Among them were 16 patients of arm A who received further maintenance therapy with panitumumab. In total, 29 subjects survived to the end of the study (Figure 2). The median number of cycles was 4 as planned in both treatment groups. Overall, dose reductions occurred more frequently in the panitumumab arm compared with the standard arm during cycle 2 (11.9% versus 4.4%) and cycle 3 (13.3% vs. 2.7%). However, in cycle 4 more dose reductions were observed in the standard arm (11.3% vs. 8.3%). In the panitumumab arm, 23 of 49 patients (47%) completed the 4 treatment cycles whereas in the standard arm 36 of 47 patients (77%) completed the planned 4 cycles. Major reasons for treatment discontinuation were disease progression, death, and serious AEs (SAEs). A summary on the frequency of
Figure 2 Consolidated Standards of Reporting Trials Diagram
Abbreviations: PemCis ¼ pemetrexed/cisplatin; PemCisP ¼ pemetrexed/cisplatin with panitumumab.
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CHAMP: Panitumumab in KRAS Wild Type NSCLC Table 2 Dose Reductions and Cycle Delays (ITT Population) Cycle 2 Valid Cases, n Cycle Delays, n (%)
Cycle 3
Cycle 4
Arm A
Arm B
Arm A
Arm B
Arm A
42
45
30
37
26
Arm B 36
5 (11.9)
8 (17.8)
5 (16.7)
8 (21.6)
3 (8.3)
9 (14.5)
Dose Reductions, n (%) Overall
5 (11.9)
2 (4.4)
4 (13.3)
1 (2.7)
3 (8.3)
7 (11.3)
Chemotherapy
3 (7.1)
2 (4.4)
3 (10.0)
1 (2.7)
3 (8.3)
4 (6.5)
Panitumumab
2 (4.8)
0
1 (3.3)
0
0
3 (4.8) 2 (66.7)
Reasons for Cycle Delays, n (%) Myelosuppression
1 (20.0)
3 (37.5)
3 (60.0)
1 (12.5)
2 (33.3)
Skin toxicity
0
0
0
0
2 (33.3)
0
Other toxicity
2 (40.0)
1 (12.5)
0
2 (25.0)
1 (16.7)
0
Organizational
1 (20.0)
3 (37.5)
1 (20.0)
3 (37.5)
1 (16.7)
1 (33.3)
Other
1 (20.0)
1 (12.5)
1 (20.0)
2 (25.0)
0
0
Reasons for Chemotherapy Dose Reductions, n (%) Myelosuppression
0
1 (50.0)
0
1 (100)
0
1 (33.3)
Other toxicity
2 (66.7)
0
2 (66.7)
0
1 (100)
1 (33.3)
Organizational
0
1 (50.0)
0
0
0
0
1 (33.3)
0
1 (33.3)
0
0
1 (33.3)
0
1 (100)
0
3 (100)
0
Other
Reasons for Panitumumab Dose Reductions, n (%) Other toxicity
2 (100)
Abbreviation: ITT ¼ intention-to-treat.
cycle delays and dose reductions and the reasons for them is given in Table 2.
first cycle ¼ 50; end of combination therapy ¼ 67). Means and standard deviation of quality of life scores for both treatment arms and in total are illustrated in Figure 4.
Efficacy
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Figure 3 shows the KaplaneMeier PFS and OS curves for the ITT population. Tumor response evaluation at the end of the combination therapy is listed in Table 3. With regard to PFS at 6 months there was no clear difference between the treatment groups with 43 (87.8%) and 42 (89.4%) events reported in the panitumumab and standard arm, respectively. In contrast, the OS showed a clear trend toward the standard arm with 31 events (66.0%) compared with the panitumumab arm with 36 events (73.5%). Although the PR rate was slightly higher in the panitumumab arm (32.7% vs. 29.8%), stable disease was reached in many more patients in the standard arm (42.6% vs. 28.6%). However, it has to be mentioned that the survival times cannot be evaluated without considering toxicities. Results might be affected by the higher rates of SAEs and higher death rates within the panitumumab arm. In fact, for approximately 18% of patients in the panitumumab arm response could not be evaluated because of early drop out. On the basis of the present data a better efficacy of the panitumumab arm is unlikely. For these reasons the primary objective of this study to show a benefit of the 6-month PFS was not achieved. The secondary objectives, for example, an improvement of OS or of the quality of life could not be shown either. Although the quality of life within the panitumumab arm appeared not to be improved (median score: before first cycle ¼ 58; end of combination therapy ¼ 50), the quality of life within the standard arm was markedly increased until the end of therapy (median score: before
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Safety In total, 40 patients experienced 1 or more SAEs. With 24 versus 16, the number of patients with 1 or more SAEs was higher within the panitumumab arm compared with the control arm. Furthermore, the total number of SAEs was also higher in the panitumumab arm compared with the control arm (33 in arm A vs. 22 in arm B). This increase in SAE rate appears to be driven by the group of patients older than 65 years of age. For patients younger than 65 years, the SAE rate was almost evenly distributed among the 2 treatment groups (15 in arm A vs. 14 in arm B). However, for drug-related SAEs there was also a higher rate with 14 in the panitumumab arm versus 8 in the control arm. The mortality rate was 7 versus 2 patients within the panitumumab arm compared with the control arm, which was significantly higher as well. The incidence of AEs during combination therapy is given in Table 4. Generally, more AEs of Grade 4 were experienced in the panitumumab arm including hematologic events such as anemia, leukopenia, and thrombocytopenia. The most frequently occurring nonhematologic AEs in the panitumumab arm were nausea, vomiting, dyspnea, and skin toxicities which is in line with the known AE profile of panitumumab.15
Discussion In the present study only patients with adenocarcinoma and without KRAS mutation were included. Especially for this group it
Wolfgang Schuette et al Figure 3 KaplaneMeier Progression-Free Survival (PFS) and Overall Survival Curves for the Intention-to-Treat (ITT) Population. Arm A Received Pemetrexed/Cisplatin With Panitumumab; Arm B Received Pemetrexed/Cisplatin. ITT Population (Ntotal [ 96; NArmA [ 49, NArmB [ 47)
Abbreviation: Cum. ¼ cumulative.
was supposed that there could be an efficacy of panitumumab in addition to the combination of cisplatin/pemetrexed because of pathophysiological considerations. However, what seemed to be beneficial in the treatment of colorectal cancer did not meet the expectations for NSCLC. A series of clinical studies clearly
demonstrated the benefit for patients with colorectal cancer and wild type KRAS to respond to treatment with anti-EGFR antibodies16 whereas the prognostic value of KRAS mutations in NSCLC remains controversially discussed.17 In case of NSCLC, the outcome of recent clinical trials indicate that the KRAS gene status is
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CHAMP: Panitumumab in KRAS Wild Type NSCLC Table 3 Response Evaluation at the End of Combination Therapy (ITT Population) Arm A: PemCisP, n [ 49 Complete Response Partial Response Stable Disease Disease Progression Not Evaluable
16 14 10 9
0 (32.7) (28.6) (20.4) (18.4)
Arm B: PemCis, n [ 47 14 20 12 1
0 (29.8) (42.6) (25.5) (2.1)
Data are presented as n (%). Tumor evaluation was performed according to Response Evaluation Criteria in Solid Tumors, (version 1.1, 2009) criteria and standards. Responses were confirmed not earlier than 28 days after response criteria were first met. Abbreviations: ITT ¼ intention-to-treat; PemCis ¼ pemetrexed/cisplatin; PemCisP ¼ pemetrexed/cisplatin with panitumumab.
not an appropriate biomarker predictive for responsiveness to the treatment of anti-EGFR antibodies or other EGFR-directed medications in combination with standard chemotherapy. In the BMS099 study, KRAS-mutant patients with NSCLC tended to show an improvement after treatment with cetuximab with chemotherapy compared with standard therapy alone.18 Likewise, in the FLEX study, a positive effect of cetuximab could be demonstrated independent of the KRAS gene status.19 In contrast, some clinical trials failed to show a benefit of EGFR-directed treatment in combination with standard chemotherapy even in patients with wild type KRAS.20 The distinct mutation pattern and biological function of the KRAS gene in colorectal and lung cancer are currently discussed as factors that drive differences in the
Figure 4 Means and Standard Deviation of Quality of Life Scores for the Intention-to-Treat (ITT) Population Assessed Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-Specific Questionnaires. Arm A Received Pemetrexed/ Cisplatin With Panitumumab; Arm B Received Pemetrexed/Cisplatin. ITT Population (Ntotal [ 96; NArmA [ 49, NArmB [ 47)
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prognostic value of the KRAS gene status in these 2 cancer specimens.21 Patient enrollment in the CHAMP study had to be stopped prematurely because of the incidence of unacceptable side effects that occurred during treatment with standard therapy with panitumumab, resulting in a total patient number of 98 instead of 134 as originally planned. As a consequence, data from the present study might not be powered for small effect sizes. With regard to the efficacy it has to be concluded that there was no advantage for the combination of panitumumab either for PFS or for OS. This corresponds to the observations of Crawford et al20 and Blumenschein et al,22 who also had not seen any advantage for the combination of panitumumab with paclitaxel and carboplatin. In contrast, there appears to be a disadvantage for the panitumumab group compared with the control group with standard chemotherapy. However, this effect is possibly related to the increase of toxicities within the panitumumab arm compared with the control arm and not necessarily related to the lack of efficacy a priori. A reflection of this situation could also be the constant pretherapeutic quality of life and after 4 cycles within the panitumumab arm versus an increase of quality of life within the standard therapy arm with cisplatin/pemetrexed between the pretherapeutic test point and the test point after 4 cycles. Necitumumab, a fully human immunoglobulin G1 monoclonal antibody is currently being evaluated in 2 phase III trials. The randomized, multicenter, open-label phase III trial named INSPIRE, was to evaluate the combination of necitumumab with a combination of pemetrexed/cisplatin compared with a regimen of pemetrexed/cisplatin alone, as a first-line treatment for patients with advanced nonsquamous NSCLC. This study had to be closed prematurely because of safety concerns related to thromboembolic events in the experimental arm of the study. The present study on the fully human anti-EGFR monoclonal antibody panitumumab in combination with pemetrexed/cisplatin in patients with adenocarcinoma also had to be stopped prematurely because of safety concerns. Thromboembolic events were not observed with the combination of panitumumab and pemetrexed/cisplatin but an overall increase in toxicity was observed including Grade 4 hematologic events and a series of Grade 3 nonhematologic events such as nausea, vomiting, and skin toxicities. Results from the present study show evidence that the enhanced toxicity might be a result of this specific triplet combination. However, the lack of corresponding data from other clinical trials with this specific combination therapy and the low number of patients included in the CHAMP study make it difficult to draw any reliable conclusions. In the phase III SQUIRE study of necitumumab in combination with gemcitabine/cisplatin in the first-line treatment of advanced squamous NSCLC, patients with stage IV metastatic disease showed a statistically significant improvement in OS over patients treated with the chemotherapy regimen alone.23 Moreover, data from phase III trials of necitumumab show evidence that antiEGFR antibodies in combination with standard chemotherapy might be a promising treatment option for squamous NSCLC. With regard to cetuximab, the benefit of the combination therapy with vinorelbine/cisplatin could be shown in patients of all histological subtypes of NSCLC, including adenocarcinoma and squamous cell carcinoma.4
Wolfgang Schuette et al Table 4 Incidence of Adverse Events During Combination Therapy Arm A: PemCisP, n [ 49 Adverse Event
Grade 3
Arm B: PemCis, n [ 47
Grade 4
Grade 3
Grade 4
Hematologic Anemia
3 (6.5)
0
3 (6.3)
0
Leukopenia
4 (8.7)
4 (8.7)
7 (14.6)
1 (2.1)
Neutropenia
5 (10.9)
3 (6.5)
9 (18.8)
1 (2.1)
Thrombocytopenia
2 (4.3)
1 (2.2)
2 (4.2)
2 (4.2)
Nausea
10 (20.4)
0
2 (4.2)
0
Vomiting
3 (6.1)
0
0
0
Dry skin
1 (2.0)
0
0
0
Pruritus
1 (2.0)
0
0
0
Rash/desquamation
3 (6.1)
1 (2.0)
0
0
Nonhematologic
Acne
6 (12.2)
0
0
0
Dyspnea
2 (4.1)
2 (4.1)
4 (8.3)
0
0
1 (2.0)
0
0
Infection
1 (2.0)
1 (2.0)
4 (8.3)
0
Fatigue
1 (2.0)
2 (4.1)
4 (8.3)
0
Febrile neutropenia
Abbreviations: PemCis ¼ pemetrexed/cisplatin; PemCisP ¼ pemetrexed/cisplatin with panitumumab.
Although FLEX and SQUIRE showed evidence for the efficacy of anti-EGFR monoclonal antibodies in patients with advanced NSCLC, results from the CHAMP study indicate that for panitumumab a combination therapy with cisplatin/pemetrexed is not recommended for clinical use in patients with adenocarcinoma and KRAS wild type because of lack of efficacy, lack of improvement of quality of life, and because of the significant increase of toxicity rates compared with the control arm with standard chemotherapy. However, as shown for cetuximab and necitumumab, combination therapy of panitumumab with standard chemotherapy other than pemetrexed/cisplatin could be an option in the treatment of squamous NSCLC, which, to the knowledge of the authors, has not yet been examined in a controlled clinical trial. Future clinical trials including panitumumab for the treatment of NSCLC should also consider the outcomes and recent discussions about biomarkers to select the most appropriate trial population.
Clinical Practice Points Treatment of patients with stage IIIB/IV NSCLC are still
unsatisfying. The data available from the FLEX study of vinorelbine and cisplatin with or without cetuximab have shown a statistically significant benefit in terms of OS for the combination therapy with the EGFR antibody in patients with adenocarcinoma and in patients with squamous cell carcinoma. Previous studies presented data on KRAS mutation status and showed that approximately 30% of patients with adenocarcinoma have a mutation of the KRAS gene. Moreover, data suggested that patients with KRAS mutations might not benefit from EGFR antibody therapy or other EGFR-targeted agents. However, in contrast to the primary hypothesis of the CHAMP trial and as shown from the results of this and a series of other recent trials, the KRAS mutation status seemed not to be a
useful predictive biomarker for assessment of EGFR antibody therapy. The combination of panitumumab with the standard therapy of pemetrexed and cisplatin in the CHAMP trial resulted in increased toxicity compared with chemotherapy alone, which was associated with a reduced OS and quality of life and cannot be recommended for clinical use in patients with adenocarcinoma and KRAS wild type. Nevertheless, the combination therapy of panitumumab with standard chemotherapy other than pemetrexed/cisplatin could be an option in the treatment of squamous NSCLC. Future clinical trials that include panitumumab for the treatment of NSCLC should also consider the outcomes and recent discussions about biomarkers to select the most appropriate trial population.
Acknowledgments The study was financially supported by Amgen, Inc..
Disclosure Wolfgang Schuette, MD, received grants, consultancy honoraria, and fees for monitoring board from Amgen in the frame of the this study and from Roche, Lilly, Sanofi-Aventis, Merck, AstraZeneca and Pfizer in the context of other clinical trials. All other authors have no potential conflicts of interest to declare.
References 1. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced nonesmall-cell lung cancer. N Engl J Med 2002; 346:92-8. 2. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage nonesmall-cell lung cancer. J Clin Oncol 2008; 26:3543-51. 3. Pirker R, Szczesna A, von Pawel J, et al. FLEX: a randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced nonesmall-cell lung cancer (NSCLC) (abstract 3). J Clin Oncol 2008; 26(suppl).
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CHAMP: Panitumumab in KRAS Wild Type NSCLC 4. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced nonesmall-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009; 373:1525-31. 5. Crawford J, Swanson P, Prager D, et al. Panitumumab, a fully human antibody, combined with paclitaxel and carboplatin versus paclitaxel and carboplatin alone for first line advanced nonesmall-cell lung cancer: a preliminary analysis. Proc European Cancer Congress 2005;(abstract 1123). 6. Gazdar AF. KRAS mutations in lung cancer. ASCO Educational Book 2007:433-5. 7. Zhu CQ, da Cunha Santos G, Ding K, et al. 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; 26:4268-75. 8. Stephenson JJ, Gregory C, Burris H, et al. An open-label clinical trial evaluating safety and pharmacokinetics of two dosing schedules of panitumumab in patients with solid tumors. Clin Colorectal Cancer 2009; 8:29-37. 9. Buyse M. Randomized designs for early trials of new cancer treatmentsean overview. Drug Inf J 2000; 34:387-96. 10. Gray R, Manola J, Saxman S, et al. Phase II clinical trial design: methods in translational research from the Genitourinary Committee at the Eastern Cooperative Oncology Group. Clin Cancer Res 2006; 12:1966-9. 11. 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; 92:205-16. 12. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649-55. 13. ICH Efficacy Guidelines. E6(R1): Good Clinical Practice: Consolidated Guideline. Available at: http://www.ich.org/products/guidelines/efficacy/article/efficacyguidelines.html. 14. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982; 38:143-51. 15. Vectibix. Summary of Product Characterization. Thousand Oaks, USA: Amgen Inc.; 2014.
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16. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009; 27: 2091-6. 17. D’Arcangelo M, Cappuzzo F. K-Ras mutations in nonesmall-cell lung cancer: prognostic and predictive value. ISRN Mol Biol 2012; 2012, Article ID 837306, 8 pages, http://dx.doi.org/10.5402/2012/837306. 18. 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 firstline taxane/carboplatin in advanced nonesmall-cell lung cancer. J Clin Oncol 2010; 28:918-27. 19. O’Byrne KJ, Gatzemeier U, Bondarenko I, et al. Molecular biomarkers in nonesmall-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 2011; 12:795-805. 20. Crawford J, Swanson P, Schwarzenberger P, et al. A phase 2 randomized trial of paclitaxel and carboplatin with or without panitumumab for first-line treatment of advanced nonesmall-cell lung cancer. J Thorac Oncol 2013; 8: 1510-8. 21. Danenberg KD, Grimminger PP, Mack PC, et al. KRAS mutations (MTs) in nonesmall-cell lung cancer (NSCLC) versus colorectal cancer (CRC): implications for cetuximab therapy (abstract 10529). ASCO Meeting Abstracts 2010; 28. 22. Blumenschein G Jr, Sandler A, O’Rourke T, et al. Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and carboplatin/paclitaxel (CP) for the treatment of patients (pts) with advanced nonesmall-cell lung cancer (NSCLC) (abstract 7119). J Clin Oncol 2006; 24. 23. Thatcher N. A randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/ LY3012211) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous nonesmall-cell lung cancer (sq-NSCLC). Available at: http:// meetinglibrary.asco.org/content/92354?media¼vm. Accessed September 25, 2014.
CHAMP: A Phase II Study of Panitumumab With Pemetrexed and Cisplatin Versus Pemetrexed and Cisplatin in the Treatment of Patients With Advanced-Stage Primary Nonsquamous NoneSmall-Cell Lung Cancer With Particular Regard to the KRAS Status Wolfgang Schuette,1 Dirk Behringer,2 Jan Stoehlmacher,3 Jens Kollmeier,4 Sibylle Schmager,5 Ludwig Fischer von Weikersthal,6 Christian Schumann,7 Joerg Buchmann8 Abstract In this phase II, randomized, open label study the efficacy and tolerability of panitumumab in combination with pemetrexed/cisplatin versus pemetrexed/cisplatin in patients with stage IIIB/IV primary nonsquamous nonesmall-cell lung cancer and wild type VeKi-ras2 Kirsten rat sarcoma viral oncogene homolog were assessed. The overall survival showed a clear difference between the treatment groups in favor of the standard therapy. This study teaches important lessons for future trial design. Introduction: The aim of the study was to investigate the efficacy and tolerability of panitumumab, a fully human antiepidermal growth factor receptor monoclonal antibody, in combination with pemetrexed/cisplatin in patients with stage IIIB to IV primary nonsquamous nonesmall-cell lung cancer and wild type VeKi-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Results were compared with those obtained in a control group of patients who received a pemetrexed/cisplatin regimen only. Patients and Methods: This was a phase II, randomized, open-label study with 2 treatment arms. In total, 96 patients received panitumumab at a dose of 9 mg/kg in combination with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 (n ¼ 49) or pemetrexed/cisplatin alone (n ¼ 47). The primary outcome measure was progression-free survival at 6 months. Secondary end points of the study included overall survival, tumor response, quality of life, and safety outcomes. The CHAMP study is registered with ClinicalTrials.gov, number NCT01088620. Results: Progression-free survival at 6 months did not indicate a benefit of panitumumab as a supplement to the standard therapy of pemetrexed/cisplatin whereas the overall survival showed a clear difference between the treatment groups in favor of the standard therapy. Results might be affected by the higher rates of serious adverse events and higher death rates within the panitumumab arm. Conclusions: Results from the present study indicate that combination of cisplatin/pemetrexed with panitumumab should not be recommended for patients with adenocarcinoma and KRAS wild type because of lack of efficacy, lack of improvement of quality of life, and because of the
ClinicalTrials.gov NCT01088620. 1 Department of Internal Medicine II, Hospital Martha-Maria Halle-Doelau, Halle, Germany 2 Department of Haematology, Oncology and Palliative Care, Augusta-Kranken-Anstalt gGmbH, Bochum, Germany 3 Doctors Office of Individual Cancer Therapy, Bonn, Germany 4 Department of Pneumology, Lung Clinic Heckeshorn, Berlin, Germany 5 Carl-Thiem-Hospital Cottbus, Cottbus, Germany 6 Department of Haematology and Internistic Oncology, Health Center St Marien, Amberg, Germany
1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2015.05.009
7 Department of Internal Medicine II and Clinic for Pneumology, Thoracic Oncology, Sleep- and Respiratory Critical Care, Kempten-Oberallgaeu, University Hospital Ulm, Ulm, Germany 8 Hospital Martha-Maria Halle-Doelau, Institute of Pathology, Halle, Germany
Submitted: Mar 20, 2015; Revised: May 26, 2015; Accepted: May 26, 2015 Address for correspondence: Wolfgang Schuette, MD, Department of Internal Medicine II, Krankenhaus Martha-Maria Halle-Doelau gGmbH, Roentgenstraße 1, 06120 Halle (Saale), Germany Fax: þ49-345-6800376; e-mail contact: [email protected]
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CHAMP: Panitumumab in KRAS Wild Type NSCLC increase in toxicity rates compared with patients in the control arm, who received standard chemotherapy of pemetrexed/cisplatin. Clinical Lung Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Epidermal growth factor receptor, KRAS, Non-small cell lung cancer, Panitumumab, Pemetrexed/cisplatin
Introduction
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The current prognosis of patients with advanced or metastatic nonesmall-cell lung carcinoma (NSCLC) can be described as comparatively poor, with a progression-free survival (PFS) of approximately 4 months and overall survival of approximately 8 months if standard combination chemotherapy is provided.1 For the treatment of primary pulmonary adenocarcinoma the combination of pemetrexed with cisplatin has recently been approved by Ethikkomission des Landes Sachsen-Anhalt in Germany. The efficacy of this combination is demonstrated with a PFS time of 5.3 months and an overall survival time of 11.8 months, thus ranging among the most effective treatments for this type of cancer available at present.2 The data available from the FLEX study of vinorelbine and cisplatin with or without cetuximab in patients with stage IIIB and IV NSCLC have shown a statistically significant benefit in terms of overall survival (OS) for the combination therapy with the epidermal growth factor receptor (EGFR) antibody in patients with adenocarcinoma and in patients with squamous cell carcinoma. For the adenocarcinoma subgroup a hazard ratio for death of 0.94 (95% confidence interval, 0.77-1.15) and a survival benefit with a median survival time of 12.0 months (range, 9.6-14.8 months) versus 10.3 months (range, 8.3-12.1 months) was observed.3,4 A dose-finding study of panitumumab in combination with paclitaxel and carboplatin also reported positive results for response and PFS in NSCLC.5 At the American Society of Clinical Oncology 2007, Gazdar presented data on the VeKi-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status in NSCLC and was able to show that approximately 30% of patients with adenocarcinoma have a mutation of the KRAS gene.6 The results from several clinical studies suggest that an EGFR antibody or other EGFR-targeted agents do not appear to benefit patients who have KRAS mutations.7 Taking these results together, it would have appeared advantageous to select patients with primary pulmonary nonsquamous carcinoma (NSCLC) and wild type KRAS, treat them in an arm with the presently most effective chemotherapy and compare this treatment with the same chemotherapy with panitumumab in a second arm. Based on a 3-week chemotherapy regimen, panitumumab might also be administered in this schedule without loss of efficacy when administered at 9 mg/kg body weight every 3 weeks compared with 6 mg/kg every 2 weeks.8 The primary and secondary findings of this phase II study are evaluated in relation to expectations derived from historical data on the standard treatment (ie, chemotherapy alone), as is conventionally done in single-arm phase II studies. However, because of the high degree of prognostic heterogeneity of cancer patients the validity of these assumptions in the study population to be recruited to this protocol might have been exposed to major selection bias. Thus, a randomized reference group was introduced, allowing for validation of the historical assumptions in the population at hand, with respect
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to primary and secondary end points.9,10 Naturally, this phase II study did not provide sufficient power to allow for rigorous, inference-based statistical comparisons, as applied in phase III studies.
Patients and Methods Patients Patients were eligible for the study if they were aged at least 18 years, had histologically confirmed diagnosis of inoperable stage IIIB or IV primary pulmonary nonsquamous carcinoma (ie, adenocarcinoma and large cell carcinoma; according to Union internationale contre le cancer staging valid until 2008), with at least 1 unidimensional, measurable tumor parameter according to the Response Evaluation Criteria in Solid Tumors version 1.1, 2009 (RECIST),11 with an Eastern Cooperative Oncology Group performance status of 2,12 and a life expectancy of at least 12 weeks. Patients were also required to have adequate hematological, hepatic, renal, and metabolic function. Furthermore, wild type KRAS status of the patient was to be confirmed to be included in the study. Patients who had received previous chemotherapy or previous radiotherapy of the parameters to be measured or who showed clinically manifest, uncontrolled brain metastases and peripheral neuropathy of National Cancer Institute grade > 1 were ineligible for the study. Major exclusion criteria further encompassed serious concurrent diseases or major surgery within the last 4 weeks before recruitment, history of interstitial lung disease, superior vena cava syndrome contraindicating hydration, patients with mild to moderate renal insufficiency who were unable to interrupt salicylates or other nonsteroidal anti-inflammatory drugs with the exception of low-dose aspirin, presence of clinically significant third-space fluid collections that could not be controlled by drainage or other procedures and previous or concurrent malignancy except nonmelanoma skin cancer or cervical carcinoma Fédération Internationale de Gynécologie et d’Obstétrique stage 0 to 1 if the patient was continuously disease-free. Pregnant or breast-feeding subjects or subjects not willing to use highly effective methods of contraception during treatment and for 6 months after the end of treatment were not permitted to participate in the study. The protocol was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines13 and was approved by each center’s institutional ethics review board. All patients signed written informed consent before treatment.
Study Design and Treatment This trial was registered under the US National Institutes of Health ClinicalTrials.gov identifier NCT01088620. The study was conducted as an exploratory, randomized, open-label, multicenter phase II study. Eligible patients were randomly assigned to 1 of 2 parallel treatment arms. Patients in arm A (PemCisP) received pemetrexed 500 mg/m2 with cisplatin
Wolfgang Schuette et al 75 mg/m2 and panitumumab 9 mg/kg body weight on day 1 of each 3-week cycle for up to 4 cycles or until diagnosis of disease progression if it occurred earlier. Patients in arm B (PemCis) were treated with the standard chemotherapy pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 on day 1 of each 3-week cycle for up to 4 cycles or until diagnosis of disease progression if it occurred earlier. In the subsequent maintenance phase, patients of arm A who showed complete response (CR), partial response (PR), or stable disease were further treated with panitumumab monotherapy until disease progression (Figure 1). The primary objective of the study was to investigate the efficacy of the combination consisting of cisplatin/pemetrexed and
panitumumab including the option of panitumumab maintenance therapy in patients with wild type KRAS. The PFS at 6 months was compared with expectations derived from historical data, which were verified in a randomized control group without the antibody. Secondary end points were determination of tumor response, OS, adverse effects, toxicity, and quality of life assessment. On the basis of interim toxicity data and a futility analysis of PFS the Data Safety Monitoring Board recommended suspension of patient enrollment in January 2013. The study was prematurely terminated after the last included patient had reached his 6-month PFS. Hence, data analysis was performed on the basis of 98 patients only instead of the planned 134.
Figure 1 Study Overview
Abbreviations: b.w. ¼ body weight; NSCLC ¼ nonesmall-cell lung cancer; PemCis ¼ pemetrexed/cisplatin; PemCisP ¼ pemetrexed/cisplatin with panitumumab; PFS ¼ progression-free survival; q 3w ¼ once every 3 weeks.
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CHAMP: Panitumumab in KRAS Wild Type NSCLC Progression-Free Survival Progression-free survival was defined as the time from randomization to the time of disease progression or relapse according to RECIST criteria or death, or to the date of last assessment without any such event (censored observation).
Overall Survival The duration of OS was determined by measuring the time interval from randomization to the date of death or last observation (censored).
Tumor Response Tumor measurements were done using the same method (eg, physical examination, x-ray, computed tomography scan) at each assessment. All measurable and evaluable disease was followed until disease progression. If a patient had clinical signs of progression, then tumor evaluation took place at that time. All tumor evaluations were performed according to RECIST criteria and standards. Confirmation of declared remissions (CR or PR) was performed not earlier than 28 days after the original declaration of response.
Calculated P values are considered to be exploratory and are presented explicitly without referring to hypotheses or a significance level. No error adjustment for multiple testing was performed. Thus, the P values reflect the comparisonwise error and not the experimentwise error. All P values are 2-sided if not stated otherwise. In the case of comparisons between patient groups, these rates were analyzed using the c2 test. Event-related data like PFS or OS was estimated using the product limit method and compared using the log rank test (ManteleCox test) and days as unit. All analyses of the continuous efficacy variables (eg, quality of life score) were performed as repeated measures analysis of variance with treatment group and adjustments for age and sex.
Analysis Sets Of 98 randomized patients, 97 were included in the safety analysis set because 1 patient withdrew his consent after
Table 1 Patient Demographic and Baseline Characteristics
Quality of Life Quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 and EORTC lung cancer-specific questionnaires before start of combination therapy, on day 1 of every second cycle, and at the end of combination therapy.
Characteristic
Arm A: PemCisP, n [ 49
Arm B: PemCis, n [ 47
Age, Years Median
60.0
58.0
Range
39-78
45-77
Men
31 (63.3)
27 (57.4)
Women
18 (36.7)
20 (42.6)
Sex, n (%)
Safety Safety was evaluated as the incidence of adverse events (AEs) graded using National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 and changes in laboratory tests. AEs were recorded from the start of treatment through the safety follow-up visit that was performed on day 30 after the start of the last chemotherapy cycle. During panitumumab maintenance therapy, toxicity and symptoms were recorded at any treatment visit of the patient.
Statistical Analysis
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The statistical calculation was based on Fleming’s single-stage design14 and the following premises and assumptions: the null hypothesis that the true PemCisP PFS rate is 0.4 was tested against a 1-sided alternative, because this corresponded to the standard treatment efficacy. The null hypothesis was rejected and the experimental therapy was accepted as promising if the true PemCisP PFS rate was 0.55. This design yielded a type I error rate of 5% and power of 80% (type II error rate of 20%). According to these parameters, 67 patients per arm (134 patients) were initially planned to be included in the study. In consequence of the premature stop of patient recruitment, data sets of only 98 patients were evaluable. According to the parameters given herein, and using a standard single-stage phase II design by Fleming,14 an interim analysis with 98 KRAS wild type patients (49 of them in the panitumumab arm) was performed. The final conclusion of this phase II trial depended on the definite PFS rate (and its confidence interval), the respective findings in the PemCis reference arm, and the information on type, frequency, and severity of toxicities.
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Smoking Status, n (%) Never
7 (14.3)
7 (14.9)
Former
28 (57.1)
23 (48.9)
Current
12 (24.5)
15 (31.9)
2 (4.1)
2 (4.3)
Unknown Stage of Disease, n (%)a IIIb
0
1 (2.1)
IV
48 (100)
46 (97.9)
47 (95.9)
47 (100)
2 (4.1)
0
Disease Histology, n (%) Adenocarcinoma Other Time Since Initial Diagnosis of NSCLC, Days Median
28.0
26.0
Range
0-321
7-1835
8 (16.3)
8 (17.0)
10 (20.4)
18 (38.3)
4 (8.2)
4 (8.5)
0
28 (58.3)
19 (40.4)
1
16 (33.3)
26 (55.3)
2
4 (8.3)
2 (4.3)
Previous Tumor Therapy, n (%) Surgery Radiotherapy Other ECOG Performance Score, n (%)a
Abbreviations: ECOG ¼ Eastern Cooperative Oncology Group; NSCLC ¼ nonesmall-cell lung cancer; PemCis ¼ pemetrexed/cisplatin; PemCisP ¼ pemetrexed/cisplatin with panitumumab. a Missing value for 1 patient.
Wolfgang Schuette et al randomization but before the first cycle of combination therapy. The full analysis set (intention to treat [ITT]) consisted of 96 patients because another patient had to be excluded because of violation of inclusion criteria.
Results Patient Characteristics Between April 2010 and January 2013, a total of 98 patients were randomly assigned to 1 of the 2 treatment regimens at 13 centers throughout Germany. Demographic and baseline disease characteristics were generally well balanced between the 2 treatment groups. Almost all patients suffered from an adenocarcinoma and stage IV disease (Table 1).
Treatments Of 98 randomized patients, 2 dropped out before receiving treatment. Of the remaining, 49 patients were assigned to treatment
arm A (PemCisP; panitumumab arm) and 47 received treatment in arm B (PemCis; standard arm). Fifty-six subjects completed the planned 4 treatment cycles and entered the follow-up phase; 23 patients in arm A and 33 patients in arm B. Among them were 16 patients of arm A who received further maintenance therapy with panitumumab. In total, 29 subjects survived to the end of the study (Figure 2). The median number of cycles was 4 as planned in both treatment groups. Overall, dose reductions occurred more frequently in the panitumumab arm compared with the standard arm during cycle 2 (11.9% versus 4.4%) and cycle 3 (13.3% vs. 2.7%). However, in cycle 4 more dose reductions were observed in the standard arm (11.3% vs. 8.3%). In the panitumumab arm, 23 of 49 patients (47%) completed the 4 treatment cycles whereas in the standard arm 36 of 47 patients (77%) completed the planned 4 cycles. Major reasons for treatment discontinuation were disease progression, death, and serious AEs (SAEs). A summary on the frequency of
Figure 2 Consolidated Standards of Reporting Trials Diagram
Abbreviations: PemCis ¼ pemetrexed/cisplatin; PemCisP ¼ pemetrexed/cisplatin with panitumumab.
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CHAMP: Panitumumab in KRAS Wild Type NSCLC Table 2 Dose Reductions and Cycle Delays (ITT Population) Cycle 2 Valid Cases, n Cycle Delays, n (%)
Cycle 3
Cycle 4
Arm A
Arm B
Arm A
Arm B
Arm A
42
45
30
37
26
Arm B 36
5 (11.9)
8 (17.8)
5 (16.7)
8 (21.6)
3 (8.3)
9 (14.5)
Dose Reductions, n (%) Overall
5 (11.9)
2 (4.4)
4 (13.3)
1 (2.7)
3 (8.3)
7 (11.3)
Chemotherapy
3 (7.1)
2 (4.4)
3 (10.0)
1 (2.7)
3 (8.3)
4 (6.5)
Panitumumab
2 (4.8)
0
1 (3.3)
0
0
3 (4.8) 2 (66.7)
Reasons for Cycle Delays, n (%) Myelosuppression
1 (20.0)
3 (37.5)
3 (60.0)
1 (12.5)
2 (33.3)
Skin toxicity
0
0
0
0
2 (33.3)
0
Other toxicity
2 (40.0)
1 (12.5)
0
2 (25.0)
1 (16.7)
0
Organizational
1 (20.0)
3 (37.5)
1 (20.0)
3 (37.5)
1 (16.7)
1 (33.3)
Other
1 (20.0)
1 (12.5)
1 (20.0)
2 (25.0)
0
0
Reasons for Chemotherapy Dose Reductions, n (%) Myelosuppression
0
1 (50.0)
0
1 (100)
0
1 (33.3)
Other toxicity
2 (66.7)
0
2 (66.7)
0
1 (100)
1 (33.3)
Organizational
0
1 (50.0)
0
0
0
0
1 (33.3)
0
1 (33.3)
0
0
1 (33.3)
0
1 (100)
0
3 (100)
0
Other
Reasons for Panitumumab Dose Reductions, n (%) Other toxicity
2 (100)
Abbreviation: ITT ¼ intention-to-treat.
cycle delays and dose reductions and the reasons for them is given in Table 2.
first cycle ¼ 50; end of combination therapy ¼ 67). Means and standard deviation of quality of life scores for both treatment arms and in total are illustrated in Figure 4.
Efficacy
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Figure 3 shows the KaplaneMeier PFS and OS curves for the ITT population. Tumor response evaluation at the end of the combination therapy is listed in Table 3. With regard to PFS at 6 months there was no clear difference between the treatment groups with 43 (87.8%) and 42 (89.4%) events reported in the panitumumab and standard arm, respectively. In contrast, the OS showed a clear trend toward the standard arm with 31 events (66.0%) compared with the panitumumab arm with 36 events (73.5%). Although the PR rate was slightly higher in the panitumumab arm (32.7% vs. 29.8%), stable disease was reached in many more patients in the standard arm (42.6% vs. 28.6%). However, it has to be mentioned that the survival times cannot be evaluated without considering toxicities. Results might be affected by the higher rates of SAEs and higher death rates within the panitumumab arm. In fact, for approximately 18% of patients in the panitumumab arm response could not be evaluated because of early drop out. On the basis of the present data a better efficacy of the panitumumab arm is unlikely. For these reasons the primary objective of this study to show a benefit of the 6-month PFS was not achieved. The secondary objectives, for example, an improvement of OS or of the quality of life could not be shown either. Although the quality of life within the panitumumab arm appeared not to be improved (median score: before first cycle ¼ 58; end of combination therapy ¼ 50), the quality of life within the standard arm was markedly increased until the end of therapy (median score: before
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Safety In total, 40 patients experienced 1 or more SAEs. With 24 versus 16, the number of patients with 1 or more SAEs was higher within the panitumumab arm compared with the control arm. Furthermore, the total number of SAEs was also higher in the panitumumab arm compared with the control arm (33 in arm A vs. 22 in arm B). This increase in SAE rate appears to be driven by the group of patients older than 65 years of age. For patients younger than 65 years, the SAE rate was almost evenly distributed among the 2 treatment groups (15 in arm A vs. 14 in arm B). However, for drug-related SAEs there was also a higher rate with 14 in the panitumumab arm versus 8 in the control arm. The mortality rate was 7 versus 2 patients within the panitumumab arm compared with the control arm, which was significantly higher as well. The incidence of AEs during combination therapy is given in Table 4. Generally, more AEs of Grade 4 were experienced in the panitumumab arm including hematologic events such as anemia, leukopenia, and thrombocytopenia. The most frequently occurring nonhematologic AEs in the panitumumab arm were nausea, vomiting, dyspnea, and skin toxicities which is in line with the known AE profile of panitumumab.15
Discussion In the present study only patients with adenocarcinoma and without KRAS mutation were included. Especially for this group it
Wolfgang Schuette et al Figure 3 KaplaneMeier Progression-Free Survival (PFS) and Overall Survival Curves for the Intention-to-Treat (ITT) Population. Arm A Received Pemetrexed/Cisplatin With Panitumumab; Arm B Received Pemetrexed/Cisplatin. ITT Population (Ntotal [ 96; NArmA [ 49, NArmB [ 47)
Abbreviation: Cum. ¼ cumulative.
was supposed that there could be an efficacy of panitumumab in addition to the combination of cisplatin/pemetrexed because of pathophysiological considerations. However, what seemed to be beneficial in the treatment of colorectal cancer did not meet the expectations for NSCLC. A series of clinical studies clearly
demonstrated the benefit for patients with colorectal cancer and wild type KRAS to respond to treatment with anti-EGFR antibodies16 whereas the prognostic value of KRAS mutations in NSCLC remains controversially discussed.17 In case of NSCLC, the outcome of recent clinical trials indicate that the KRAS gene status is
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CHAMP: Panitumumab in KRAS Wild Type NSCLC Table 3 Response Evaluation at the End of Combination Therapy (ITT Population) Arm A: PemCisP, n [ 49 Complete Response Partial Response Stable Disease Disease Progression Not Evaluable
16 14 10 9
0 (32.7) (28.6) (20.4) (18.4)
Arm B: PemCis, n [ 47 14 20 12 1
0 (29.8) (42.6) (25.5) (2.1)
Data are presented as n (%). Tumor evaluation was performed according to Response Evaluation Criteria in Solid Tumors, (version 1.1, 2009) criteria and standards. Responses were confirmed not earlier than 28 days after response criteria were first met. Abbreviations: ITT ¼ intention-to-treat; PemCis ¼ pemetrexed/cisplatin; PemCisP ¼ pemetrexed/cisplatin with panitumumab.
not an appropriate biomarker predictive for responsiveness to the treatment of anti-EGFR antibodies or other EGFR-directed medications in combination with standard chemotherapy. In the BMS099 study, KRAS-mutant patients with NSCLC tended to show an improvement after treatment with cetuximab with chemotherapy compared with standard therapy alone.18 Likewise, in the FLEX study, a positive effect of cetuximab could be demonstrated independent of the KRAS gene status.19 In contrast, some clinical trials failed to show a benefit of EGFR-directed treatment in combination with standard chemotherapy even in patients with wild type KRAS.20 The distinct mutation pattern and biological function of the KRAS gene in colorectal and lung cancer are currently discussed as factors that drive differences in the
Figure 4 Means and Standard Deviation of Quality of Life Scores for the Intention-to-Treat (ITT) Population Assessed Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-Specific Questionnaires. Arm A Received Pemetrexed/ Cisplatin With Panitumumab; Arm B Received Pemetrexed/Cisplatin. ITT Population (Ntotal [ 96; NArmA [ 49, NArmB [ 47)
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prognostic value of the KRAS gene status in these 2 cancer specimens.21 Patient enrollment in the CHAMP study had to be stopped prematurely because of the incidence of unacceptable side effects that occurred during treatment with standard therapy with panitumumab, resulting in a total patient number of 98 instead of 134 as originally planned. As a consequence, data from the present study might not be powered for small effect sizes. With regard to the efficacy it has to be concluded that there was no advantage for the combination of panitumumab either for PFS or for OS. This corresponds to the observations of Crawford et al20 and Blumenschein et al,22 who also had not seen any advantage for the combination of panitumumab with paclitaxel and carboplatin. In contrast, there appears to be a disadvantage for the panitumumab group compared with the control group with standard chemotherapy. However, this effect is possibly related to the increase of toxicities within the panitumumab arm compared with the control arm and not necessarily related to the lack of efficacy a priori. A reflection of this situation could also be the constant pretherapeutic quality of life and after 4 cycles within the panitumumab arm versus an increase of quality of life within the standard therapy arm with cisplatin/pemetrexed between the pretherapeutic test point and the test point after 4 cycles. Necitumumab, a fully human immunoglobulin G1 monoclonal antibody is currently being evaluated in 2 phase III trials. The randomized, multicenter, open-label phase III trial named INSPIRE, was to evaluate the combination of necitumumab with a combination of pemetrexed/cisplatin compared with a regimen of pemetrexed/cisplatin alone, as a first-line treatment for patients with advanced nonsquamous NSCLC. This study had to be closed prematurely because of safety concerns related to thromboembolic events in the experimental arm of the study. The present study on the fully human anti-EGFR monoclonal antibody panitumumab in combination with pemetrexed/cisplatin in patients with adenocarcinoma also had to be stopped prematurely because of safety concerns. Thromboembolic events were not observed with the combination of panitumumab and pemetrexed/cisplatin but an overall increase in toxicity was observed including Grade 4 hematologic events and a series of Grade 3 nonhematologic events such as nausea, vomiting, and skin toxicities. Results from the present study show evidence that the enhanced toxicity might be a result of this specific triplet combination. However, the lack of corresponding data from other clinical trials with this specific combination therapy and the low number of patients included in the CHAMP study make it difficult to draw any reliable conclusions. In the phase III SQUIRE study of necitumumab in combination with gemcitabine/cisplatin in the first-line treatment of advanced squamous NSCLC, patients with stage IV metastatic disease showed a statistically significant improvement in OS over patients treated with the chemotherapy regimen alone.23 Moreover, data from phase III trials of necitumumab show evidence that antiEGFR antibodies in combination with standard chemotherapy might be a promising treatment option for squamous NSCLC. With regard to cetuximab, the benefit of the combination therapy with vinorelbine/cisplatin could be shown in patients of all histological subtypes of NSCLC, including adenocarcinoma and squamous cell carcinoma.4
Wolfgang Schuette et al Table 4 Incidence of Adverse Events During Combination Therapy Arm A: PemCisP, n [ 49 Adverse Event
Grade 3
Arm B: PemCis, n [ 47
Grade 4
Grade 3
Grade 4
Hematologic Anemia
3 (6.5)
0
3 (6.3)
0
Leukopenia
4 (8.7)
4 (8.7)
7 (14.6)
1 (2.1)
Neutropenia
5 (10.9)
3 (6.5)
9 (18.8)
1 (2.1)
Thrombocytopenia
2 (4.3)
1 (2.2)
2 (4.2)
2 (4.2)
Nausea
10 (20.4)
0
2 (4.2)
0
Vomiting
3 (6.1)
0
0
0
Dry skin
1 (2.0)
0
0
0
Pruritus
1 (2.0)
0
0
0
Rash/desquamation
3 (6.1)
1 (2.0)
0
0
Nonhematologic
Acne
6 (12.2)
0
0
0
Dyspnea
2 (4.1)
2 (4.1)
4 (8.3)
0
0
1 (2.0)
0
0
Infection
1 (2.0)
1 (2.0)
4 (8.3)
0
Fatigue
1 (2.0)
2 (4.1)
4 (8.3)
0
Febrile neutropenia
Abbreviations: PemCis ¼ pemetrexed/cisplatin; PemCisP ¼ pemetrexed/cisplatin with panitumumab.
Although FLEX and SQUIRE showed evidence for the efficacy of anti-EGFR monoclonal antibodies in patients with advanced NSCLC, results from the CHAMP study indicate that for panitumumab a combination therapy with cisplatin/pemetrexed is not recommended for clinical use in patients with adenocarcinoma and KRAS wild type because of lack of efficacy, lack of improvement of quality of life, and because of the significant increase of toxicity rates compared with the control arm with standard chemotherapy. However, as shown for cetuximab and necitumumab, combination therapy of panitumumab with standard chemotherapy other than pemetrexed/cisplatin could be an option in the treatment of squamous NSCLC, which, to the knowledge of the authors, has not yet been examined in a controlled clinical trial. Future clinical trials including panitumumab for the treatment of NSCLC should also consider the outcomes and recent discussions about biomarkers to select the most appropriate trial population.
Clinical Practice Points Treatment of patients with stage IIIB/IV NSCLC are still
unsatisfying. The data available from the FLEX study of vinorelbine and cisplatin with or without cetuximab have shown a statistically significant benefit in terms of OS for the combination therapy with the EGFR antibody in patients with adenocarcinoma and in patients with squamous cell carcinoma. Previous studies presented data on KRAS mutation status and showed that approximately 30% of patients with adenocarcinoma have a mutation of the KRAS gene. Moreover, data suggested that patients with KRAS mutations might not benefit from EGFR antibody therapy or other EGFR-targeted agents. However, in contrast to the primary hypothesis of the CHAMP trial and as shown from the results of this and a series of other recent trials, the KRAS mutation status seemed not to be a
useful predictive biomarker for assessment of EGFR antibody therapy. The combination of panitumumab with the standard therapy of pemetrexed and cisplatin in the CHAMP trial resulted in increased toxicity compared with chemotherapy alone, which was associated with a reduced OS and quality of life and cannot be recommended for clinical use in patients with adenocarcinoma and KRAS wild type. Nevertheless, the combination therapy of panitumumab with standard chemotherapy other than pemetrexed/cisplatin could be an option in the treatment of squamous NSCLC. Future clinical trials that include panitumumab for the treatment of NSCLC should also consider the outcomes and recent discussions about biomarkers to select the most appropriate trial population.
Acknowledgments The study was financially supported by Amgen, Inc..
Disclosure Wolfgang Schuette, MD, received grants, consultancy honoraria, and fees for monitoring board from Amgen in the frame of the this study and from Roche, Lilly, Sanofi-Aventis, Merck, AstraZeneca and Pfizer in the context of other clinical trials. All other authors have no potential conflicts of interest to declare.
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