Introduction
Colorectal cancer (CRC) is a major health concern, representing the third most commonly diagnosed cancer worldwide and the second leading cause of cancer mortality in the developed world [
1,
2]. Following significant improvements in the treatment of CRC as a result of advances in systemic chemotherapy [
3], use of agents targeting the vascular endothelial growth factor and epidermal growth factor receptor (EGFR) now also have an established role in patients with metastatic disease [
4‐
6].
Panitumumab is a fully human monoclonal antibody directed against the EGFR. Its clinical efficacy in metastatic CRC (mCRC) was confirmed in an open-label, phase 3 trial, in which patients receiving panitumumab plus best supportive care (BSC) had significantly improved progression-free survival (PFS) compared with those receiving BSC alone (hazard ratio [HR] 0.54; 95% confidence interval [CI], 0.44 to 0.66) [
6] in patients with chemotherapy-refractory mCRC. Mutations in
KRAS—a gene encoding a GTPase that mediates downstream intracellular EGFR signaling—are found in approximately 35–45% of CRC tumors [
7] and have been associated with a lack of response to EGFR inhibitors when used for mCRC [
8]. Evaluation of the predictive role of
KRAS mutational status in the response to panitumumab in this phase 3 monotherapy study identified that its beneficial effect was restricted to patients whose tumors had wild-type
KRAS. In patients with wild-type
KRAS mCRC, panitumumab plus BSC was associated with a statistically significant improvement in median PFS compared with BSC alone (HR, 0.45; 95% CI, 0.34–0.59 [
9]). In mCRC, the clinical use of panitumumab (like cetuximab) is therefore now restricted to patients with wild-type
KRAS tumors. Despite recent advances in the treatment of mCRC provided by targeted agents, most patients will eventually die of the disease. The goal of therapy in this setting is, therefore, to delay disease progression, control symptoms, and maintain health-related quality of life (HRQoL) for as long as possible [
10,
11]. As such, patient-reported outcomes are particularly important to patients with metastatic disease, and the potential for benefit related to these outcomes is a key consideration in the choice of therapy [
12].
During the phase 3 trial of panitumumab monotherapy, HRQoL and CRC symptom data were collected. Patient-reported outcomes from the trial were briefly reported in the primary efficacy paper but only for the overall patient population and not by
KRAS tumor status [
6] (online appendix only). Since panitumumab is only indicated for patients with wild-type
KRAS tumor status, the available patient-reported outcomes data do not, therefore, reflect the findings for the population for whom treatment with panitumumab is appropriate. In addition, there was a large amount of missing patient-reported outcome data that was unlikely to be missing at random: as expected for patients with advanced refractory disease, more than 50% of patients in the BSC alone arm and
KRAS mutant patients in panitumumab plus BSC arm had progressed by week 8 [
6], and thus missing data are likely to have been related to declining health. The last-observation-carried-forward (LOCF) method used in the previous overall population analysis of HRQoL data is therefore a less-than-optimal approach to evaluate the true impact of panitumumab on patient-reported outcomes.
Using data from this phase 3 trial, we therefore sought to evaluate the impact of panitumumab on patient-reported outcomes according to KRAS tumor status and including statistical analyses aimed at properly accounting for the missing data.
Discussion
Patient-reported outcomes such as cancer-related symptomatology and QoL are increasingly being recognized as important aspects of palliative care in the advanced cancer setting, providing important information to help make treatment decisions [
12]. In this analysis, patients treated with panitumumab showed significantly better control of CRC symptoms and maintenance of HRQoL compared with those who received BSC alone: this benefit was most evident among the subgroup of patients with wild-type
KRAS mCRC and was not seen in patients with mutant
KRAS mCRC, or in those dropping out of the study early. This therefore illustrates, for the first time, the beneficial effects of panitumumab on HRQoL in patients with wild-type
KRAS mCRC, the population for whom panitumumab treatment is indicated in clinical practice. Indeed, in those patients with wild-type
KRAS mCRC treated with panitumumab who did not drop out of the study early, a decrease in CRC-related symptoms and an increase in HRQoL was observed by week 3 of the study. This is consistent with the finding that the beneficial effects of panitumumab on PFS are limited to patients with wild-type
KRAS mCRC [
9] and with previous analyses indicating that a lack of disease progression at week 8 provided by panitumumab was associated with better HRQoL and symptom control [
20]. For HRQoL and CRC symptoms, the benefits of panitumumab compared with BSC alone in patients with wild-type
KRAS mCRC exceeded the established MCID levels, indicating that statistical differences were also clinically relevant. To our knowledge, our analyses are the first to illustrate the beneficial effects of an EGFR inhibitor on CRC-specific symptomatology, which is particularly important given that treatment of patients with mCRC is primarily given with palliative intent [
10,
11].
The HRQoL of patients with advanced CRC treated with the EGFR inhibitor cetuximab, overall and by
KRAS status, has also been published recently [
22]. The findings were generally consistent with ours in that HRQoL benefits of cetuximab were observed and were most apparent in the subgroup of patients with wild-type
KRAS mCRC. However, the results cannot be more closely compared, as the cetuximab analysis used data from the EORTC QLQ-C30, which includes cancer-related (but not CRC-specific) symptoms [
22], whereas we chose to evaluate HRQoL and CRC-specific symptoms separately. In addition, in the study of Au et al. [
22], HRQoL data continued to be collected after disease progression. Inclusion of such data was not possible in our analysis since the study was designed to allow cross-over from BSC to panitumumab at this point [
6].
Taken together with those of the cetuximab analyses [
22], these HRQoL results may, however, contribute to a more accurate evaluation of the balance between the positive effects of EGFR inhibitors and the side effects associated with their use, such as skin toxicity, which are generally perceived to have a detrimental effect on HRQoL [
23]. In the main study population of the phase 3 trial, skin toxicity occurred in 90% of patients in the panitumumab group compared with 9% of patients in the BSC group [
6] and was more likely to develop in patients remaining on the study because of treatment benefit [
21]. Despite the association of skin toxicity with prolonged treatment, the benefits of panitumumab in terms of HRQoL and symptomatology were most apparent in the group of patients with wild-type
KRAS mCRC who did not drop out of the study early in our analysis. Indeed, more severe skin toxicity in association with panitumumab has been associated with higher rather than lower HRQoL scores [
21]. Similar findings in relation to skin toxicity and HRQoL have also been observed with cetuximab and have been suggested to reflect an understanding by patients that skin rash is indicative of a response to therapy, which helps them cope with this side effect [
24]. As noted by Au et al. [
22], the presence of skin rash also introduces the potential for bias in the HRQoL results, since those patients experiencing it may have been more likely to report improvements if they were aware that the rash was a known predictor of benefit. However, this suggestion would be at odds with the fact that the benefits of panitumumab in terms of HRQoL were most prominent in patients with wild-type
KRAS mCRC who were more likely to experience objective tumor control than those with
KRAS mutant tumors, and these HRQoL benefits were not seen in patients with mutant
KRAS mCRC despite the fact that the vast majority of this subpopulation also developed skin rash.
Our results differ from the original protocol-specified analysis of HRQoL and CRC symptom control, which did not take into account
KRAS mutation status and which used the LOCF imputation method. This showed a numerical trend favoring panitumumab that did not reach statistical significance [
6]. The differences in outcome highlight both the importance of tumor
KRAS status and the need to properly account for missing HRQoL data in trials of late-stage disease in which the reasons for missing observations are often related to deterioration in a patient’s clinical status and so, cannot be classified as missing at random [
25]. For a patient who has rapid disease progression and drops out of the study early, LOCF analysis is likely to impute values indicating better health than the true value, potentially biasing the comparison in favor of less effective or less well-tolerated treatment. An advantage to using the repeated-measures models (as in our analysis) is that imputation is not required. Pattern-mixture models provide even greater flexibility since the methodology provides a way to incorporate information about patient dropout into the longitudinal model.
Our sensitivity analyses showed that there were significantly fewer early dropouts for both the HRQoL and CRC symptom scales among the group receiving panitumumab than among the group receiving BSC alone. This disproportionate percentage of data by treatment group likely resulted from the higher rate of discontinuation due to death or disease progression in the BSC only treatment arm [
6], and it was important to account for these non-random missing data. Of note is that similar findings regarding disproportionate missing data were observed in the cetuximab analysis of Au et al. [
22] (although not to the same extent as there was an attempt to collect HRQoL data beyond disease progression), and similar approaches to account for missing data were included in their sensitivity analysis [
22].
There are several possible explanations for the apparent lack of effect of panitumumab, in those patients (even with wild-type KRAS mCRC) who dropped out of the study early. Patients treated with panitumumab plus BSC who left the study early due to tolerability concerns or other reasons unrelated to disease progression may not have received enough treatment to yield an improvement in HRQoL or CRC symptoms. Alternatively, the treatment may not have been effective among a subgroup of patients, leading to relatively rapid progression of disease and early dropout.
A potential limitation of this study is that KRAS mutation status was determined retrospectively and therefore was not a stratification factor in the randomization. However, 92% of patients randomized had KRAS status available, and patients with KRAS mutations were well distributed between the two treatment groups. Although the post hoc nature of our exploratory analysis by KRAS status is a theoretical limitation, the comparison of baseline demographics suggests that, within the KRAS subgroups, patient characteristics were similar between the two treatment arms. Another potential limitation is the imperfect sensitivity and specificity of patient-reported outcome measures. However, our analysis used validated instruments, and our findings are supported by their consistency with the results of the primary study endpoint, PFS.
In conclusion, our analyses illustrate the clinically significant beneficial effects of panitumumab in terms of CRC-specific symptom control and maintenance of HRQoL in patients with wild-type KRAS mCRC, and these findings extend our understanding of the benefits of panitumumab treatment beyond improvements in PFS. These benefits were apparent despite skin toxicity associated with panitumumab treatment and provide important additional information for both patients and physicians when making treatment decisions for mCRC, particularly when the treatment intent is palliative.
Acknowledgments
The authors gratefully acknowledge the patients who participated in this trial and their families. All authors had full access to the data and had final responsibility for the decision to submit the manuscript. The study was funded by Amgen Inc. Medical writing assistance was provided by Dr Sue Laing, ScopeMedical Ltd, funded by Amgen Inc.