Introduction
Tumour response, as defined by Response Evaluation Criteria In Solid Tumours (RECIST), is a common endpoint in clinical trials, and requires that tumour shrinkage of ≥ 30% is confirmed at consecutive visits (Therasse et al.
2000; Eisenhauer et al.
2009). However, RECIST does not consider timing, depth or duration of response. Achieving early and sustained tumour shrinkage is an important treatment goal in patients with metastatic colorectal cancer (mCRC) as it may increase the chance of surgical resection and provide relief of tumour-related symptoms (Folprecht et al.
2010; Douillard et al.
2015). Two other shrinkage-related endpoints that provide information over and above that provided by RECIST have also started to be utilised in mCRC trials. Early tumour shrinkage (ETS of ≥ 20% or ≥ 30% assessed after 6 or 8 weeks of treatment) can provide an early indication of sensitivity to treatment (Piessevaux et al.
2013; Giessen et al.
2013; Modest et al.
2013; Douillard et al.
2015; Heinemann et al.
2015; Cremolini et al.
2015), whereas depth of response (DpR) assesses the maximum tumour shrinkage achieved by a patient during treatment (Heinemann et al.
2015).
In first-line trials comparing epidermal growth factor receptor inhibitors (EGFRIs) plus chemotherapy vs. bevacizumab plus chemotherapy in patients with mCRC, the EGFRIs resulted in higher rates of ETS and were also associated with greater median DpR (Stintzing et al.
2016; Rivera et al.
2017). Furthermore, exploratory analyses of first-line trial data demonstrated that both ETS and DpR were associated with improved overall survival (OS) (Mansmann et al.
2013; Cremolini et al.
2015; Douillard et al.
2015; Heinemann et al.
2015; Stintzing et al.
2016; Rivera et al.
2017). Here, we aim to consolidate the available data on the effects of panitumumab on ETS and DpR in first-line
RAS wild-type (WT) mCRC, some of which have only been published in congress abstracts to date (Abad et al.
2014; Abad et al.
2015; Rivera et al.
2016; Siena et al.
2016). We further build on these data by reporting new exploratory analyses of the optimal ETS and DpR cut-offs to predict improved OS, multiple regression analyses of factors associated with ETS and DpR, the impact of DpR by category on outcome in PEAK, and the impact of ETS and DpR on response and resection outcomes (where available).
Discussion
ETS offers the advantage of identifying responders and non-responders after 6–8 weeks of treatment, much earlier than is possible using older measures such as RECIST response. ETS, and also DpR, have previously been associated with long-term outcome in patients with mCRC (Cremolini et al.
2015; Heinemann et al.
2015). Here, we aimed to consolidate the available ETS and DpR data from first-line trials of panitumumab, some of which have only been reported in the form of congress abstracts (Abad et al.
2014,
2015; Rivera et al.
2016; Siena et al.
2016) or in part in full publications (Douillard et al.
2015; Rivera et al.
2017). We have also built on these data by reporting new exploratory analyses of the optimal ETS and DpR cut-offs to predict improved OS, factors associated with ETS and DpR, and the impact of these endpoints on response and resection, where possible. Taken together, the results of these analyses support an ETS and DpR benefit for panitumumab plus chemotherapy vs. chemotherapy alone or combined with bevacizumab. They are also in line with previous reports of an association between ETS (≥ 20% or ≥ 30% at week 8) and/or DpR during first-line treatment with favourable outcomes in patients with
RAS WT mCRC, further supporting the use of these endpoints in the clinic. Furthermore, a recent exploratory analysis of a phase III trial comparing panitumumab plus best supportive care with best supportive care alone, suggested that ETS ≥ 0% during treatment may also be associated with PFS and OS benefits (Kim et al.
2017).
Individual study data from two randomised first-line panitumumab trials suggest that patients with
RAS WT mCRC receiving panitumumab have higher rates of ETS than those receiving treatment without panitumumab (ETS ≥ 30%: PRIME 59% vs. 38% (Douillard et al.
2015); PEAK 64% vs. 45% (Rivera et al.
2017), respectively). In the new multiple regression analyses, factors associated with improved ETS that were consistent in both the PRIME and PEAK studies were panitumumab treatment, liver-only metastatic disease and WT
BRAF status. ETS was associated with improved PFS and OS outcomes in all three first-line panitumumab studies (Abad et al.
2015; Douillard et al.
2015; Rivera et al.
2017) and also in the exploratory study-level meta-analysis (Rivera et al.
2016). The association of ETS with PFS and OS outcomes were similar irrespective of whether the data were analysed using the ≥ 20% or ≥ 30% cut-offs, suggesting that either cut-off can be used. These data support the value of ETS as a predictor for outcomes and are in line with those previously reported in first-line trials of cetuximab and bevacizumab (Modest et al.
2013; Cremolini et al.
2015; Giessen et al.
2013; Heinemann et al.
2015; Stintzing et al.
2016; Tsuji et al.
2016), and a meta-analysis of first-line data for chemotherapy ± targeted agents (Petrelli et al.
2015). Here we built on previous data for panitumumab by analysing the optimal ETS and DpR cut-offs for predicting improved OS. The ETS values reported here were similar in the PRIME and PEAK studies (32 and 34%, respectively), but were higher than the cut-off previously reported in the first-line bevacizumab TRIBE study (17%) (Cremolini et al.
2015). Although the ≥ 30% ETS cut-off is the same as that used to define a response in RECIST, the ETS measure differs in that it reports those achieving ≥ 30% shrinkage at a specific time point (week 8 here) and does not require that this is confirmed at a subsequent visit. ETS has the benefit that a result is gained more rapidly than for a best response based on RECIST and so can quickly identify early responders to treatment in the clinic. Non-responders can also be recognised sooner, thereby permitting an early switch to potentially more effective or better tolerated treatment.
Patients receiving panitumumab in these studies also had greater DpR compared with non-panitumumab-containing comparator arms in patients with
RAS WT mCRC (Douillard et al.
2015; Rivera et al.
2017). In a new exploratory analysis assessing factors associated with DpR, the only factors that were consistently associated with improved DpR across the PRIME and PEAK studies were panitumumab treatment, liver-only metastatic disease and WT
BRAF status. ECOG performance status and age were also associated in the PRIME and PEAK studies, respectively. Additional exploratory analyses from PRIME (Siena et al.
2016) and PEAK suggest that deeper responses are associated with longer PFS, OS and also improved DoR and higher resection rates. As might be expected, the vast majority of resections occurred in patients with the highest categories of DpR (71–100% in PRIME and 83–100% in PEAK). In line with previous reports, DpR was associated with PFS and OS, irrespective of treatment received (Nozawa et al.
2014; Cremolini et al.
2015; Heinemann et al.
2015; Stintzing et al.
2016; Tsuji et al.
2016). The optimal DpR cut-offs derived here for prediction of improved OS in the PRIME and PEAK studies were 59 and 70%, respectively, which are broadly in line with the cut-off reported in the TRIBE study (62%) (Cremolini et al.
2015). In PEAK, higher rates of ETS and greater median DpR were observed for panitumumab plus mFOLFOX6 vs. bevacizumab plus mFOLFOX6 (Rivera et al.
2017). Similar observations have been reported in the first-line FIRE-3 trial comparing cetuximab plus FOLFIRI vs. bevacizumab plus FOLFIRI (Stintzing et al.
2016). Interestingly, recent data from FIRE-3 suggest that ETS may also signal a subgroup of patients with right-sided mCRC who may benefit from treatment with an EGFRi plus chemotherapy (Holch et al.
2017). Taken together, these results suggest a potential benefit for EGFRis vs. bevacizumab for these response-related endpoints and could in part explain the improved OS also seen for these agents (Khattak et al.
2015; Heinemann et al.
2016).
In the clinic, achieving ETS and maximal DpR are likely to be of particular benefit to patients with symptomatic disease and those with potential to convert to resectable status. Consistent with this, in the studies analysed here, resections were mostly reported in patients who had experienced ≥ 20% or ≥ 30% ETS and in those with the greatest DpR. Achieving shrinkage early in potentially resectable patients could be important to permit resection as soon as possible, thereby avoiding potential liver toxicities and/or surgical complications due to prolonged treatment. Achieving these endpoints could also provide reassurance of likely treatment benefit and positive long-term survival outcomes.
Strengths of the present analyses include the fact that we included multiple panitumumab studies and a relatively large number of patients that the OS data from these studies are quite mature and that study-level meta-analyses were performed, where possible. We acknowledge there are, however, several limitations of these analyses—they were exploratory and retrospective in nature, there were differences in patient populations between studies, and the number of patients was limited in certain analyses. There is also a lack of clarity regarding the optimum ETS cut-off (20 or 30%) to use as definitions vary between studies. Furthermore, as we did not have access to patient-level data from all the studies, only a study-level meta-analysis of ETS could be performed and some of the ETS and DpR analyses were not possible for PLANET. There are also other factors unaccounted for in these analyses (e.g. primary tumour location (Yahagi et al.
2016),
BRAF mutation status (Clarke and Kopetz
2015), etc.), which are also likely to impact on survival outcomes.
In conclusion, these exploratory analyses suggest that panitumumab plus chemotherapy may offer ETS and DpR benefits over chemotherapy alone or combined with bevacizumab in patients with RAS WT mCRC. Furthermore, ETS (≥ 20% or ≥ 30% at week 8) and DpR during first-line treatment are associated with favourable clinical outcomes.
Acknowledgements
The authors wish to acknowledge the patients who participated in the PEAK (NCT00819780), PLANET (NCT00885885) and PRIME (NCT00364013) studies, the study investigators and their staff, and the study team at Amgen. These studies were funded by Amgen Inc. Dawn Batty PhD of Bioscript Medical Ltd, Macclesfield, UK, provided medical writing support, which was funded by Amgen (Europe) GmbH, Zug, Switzerland.
Compliance with ethical standards
Conflict of interest
JT has honoraria, consulting, and/or advisory roles for Amgen, Baxalta, Celgene, Lilly, Merck, Roche, Sanofi, Servier, and Sirtex. FR acted on advisory boards and/or received research funding from Amgen, Bayer, Celgene, Lilly, Merck Serono, Merck Sharp & Dohme, Roche, Sanofi, and Servier. SS is a member of advisory boards for Amgen, Bayer, Celgene, Lilly, Merck, Merrimack, Novartis, Roche, and Sanofi. MK has a consulting/advisory role for Amgen including participating in steering committees and has received travel, accommodation and expenses from Amgen. MVA has acted on advisory boards and received research funding from Amgen, Merck-Serono, Roche and Sanofi. JG has consulting/advisory roles for Amgen, Bayer, Celgene, Lilly, Merck Serono, Roche, and Sanofi and has received travel, accommodation and expenses from Roche. MG has received research funding and acted in consultancy/advisory roles for Amgen, Bayer, Lilly, Merck and Sanofi. RK is an employee of Amgen Ltd and owns restricted shares in Amgen. GD is an employee of Amgen (Europe) GmbH and owns restricted shares in Amgen. MP has received research funding from Amgen, Roche and Sirtex, and honoraria from Amgen, Merck Serono, Roche, Sanofi Aventis, Servier, and Sirtex.