Cancer Treatment Reviews 59 (2017) 54–60
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Anti-Tumour Treatment
Treatment decisions in metastatic colorectal cancer – Beyond first and second line combination therapies A. Vogel a, R.D. Hofheinz b, S. Kubicka c, D. Arnold d,⇑ a
Department of Gastroenterology, Hepatology and Endocrinology, Hanover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Interdisciplinary Tumor Center Mannheim, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany c Cancer Center Reutlingen, District Hospital Reutlingen, Steinenbergstr. 31, 72764 Reutlingen, Germany d Instituto CUF de Oncologia, c/o Hospital Infante Santo, Tv. Castro 3, Lisboa, Portugal b
a r t i c l e
i n f o
Article history: Received 16 February 2016 Received in revised form 24 April 2017 Accepted 25 April 2017
Keywords: Metastatic colorectal cancer Beyond second line combination therapy Regorafenib Trifuridine/tipiracil Reintroduction
a b s t r a c t Median overall survival (OS) of patients with metastatic colorectal cancer (mCRC) has reached up to 30 months in recent clinical trials of first line therapies. Following disease progression after the standard in both, 1st and 2nd line, combination chemotherapy with monoclonal antibodies, many patients maintain a good performance status and a significant proportion is motivated to undergo further therapy. Choices of treatment beyond the second line setting for mCRC are therefore becoming increasingly important. New options have entered the therapeutic field recently: Regorafenib is a multikinase inhibitor approved for mCRC patients who have progressed on chemotherapy (including fluoropyrimidines, irinotecan, and oxaliplatin), plus VEGF inhibitor(s) and – if RAS wild-type – an anti-EGFR inhibitor. Regorafenib significantly improved OS, compared to placebo, in two phase III trials (CORRECT and CONCUR) in mCRC patients. Trifluridine/Tipiracil, an oral fluoropyrimidine, also resulted in significantly improved OS when compared to placebo in the phase III RECOURSE trial, which was conducted in a similar patient population to CORRECT. Reintroduction of previously administered therapy is another valid and commonly used approach, especially for those regimens which were discontinued before progression, e.g. if associated with cumulative toxicities, such as peripheral neuropathy or due to treatment breaks. Re-challenge of drugs to which patients developed resistance is also feasible although evidence for this strategy is limited. Ó 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction Overall survival (OS) for patients with metastatic colorectal cancer (mCRC) has markedly improved within the last 2 decades and the most recent generation of randomized clinical trials have yielded median OS durations of 30 months or longer [1–3]. Reasons for this improvement are numerous and multifactorial, although three main points are considered to be the most relevant: (a) Improvement of first-line treatment and identification of factors (e.g. biomarkers) to optimize treatment allocation on the basis of a multifactorial decision-making process. (b) Increased rates of resection and local ablation of limited, mostly liver (and lung) metastases – and consequently an increasing number of patients with cure or at least a longterm disease-free interval. ⇑ Corresponding author. E-mail address:
[email protected] (D. Arnold).
(c) An increasing number of treatment options in a therapeutic sequence, formerly called ‘‘treatment lines”, due to introduction of new therapeutic principles in numerous therapeutic settings [4]. However, it remains unclear, which of the above-mentioned factors has contributed most to the improvement of OS. This review focuses on treatment options and strategic considerations for mCRC patients who have received 5-FU, Oxaliplatin and Irinoctecan alone or (mostly) in combination with targeted therapies.
Beyond combination therapy in first and second line – A heterogeneous situation Many patients with mCRC maintain a good performance status following the treatment phase of combination therapy, which generally includes Fluoropyrimidine/Oxaliplatin- and Fluoropyrimidine/Irinotecan chemotherapy combinations with (at least) one
http://dx.doi.org/10.1016/j.ctrv.2017.04.007 0305-7372/Ó 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
A. Vogel et al. / Cancer Treatment Reviews 59 (2017) 54–60
anti-vascular endothelial growth factor (VEGF) compound, and/or anti-epidermal growth factor receptor (EGFR) monoclonal antibody for patients with RAS wild-type disease. In total, the ‘‘combination treatment phase” encounters two (for all patients) to three (for patients with RAS wild type and usage of an anti-EGFR compound) treatment lines. Treatment goals and decision factors after failure of combination therapy Treatment goals in this setting include prolongation of survival, impeding tumor progression, alleviation of tumor-related symptoms if present, and/or maintaining quality of life (QoL). As therapeutic goals may change according to the line of therapy being administered, e.g., tumor size reduction (‘‘shrinkage”) is no longer of predominant clinical importance, whereas maintained disease control and palliation of tumor-related symptoms become increasingly relevant in later lines. Independent of the line of treatment, preservation of the QoL status has a high priority and its maintenance is often correlated with disease control – which technically is progression-free survival (PFS); for example, for patients experiencing significant morbidity due to progressive disease (such as painful metastases). As well as from disease progression, deterioration in QoL may also result from treatment toxicity. When considering a new line of treatment for a patient, it is important to balance potential treatment toxicity against efficacy [5]. Accordingly new composite endpoints in last-line trials have been proposed, integrating items as maintaining body mass and improving symptoms such as pain, fatigue, or anorexia compared with baseline measurements [6]. Last but not least patient preference is crucial for treatment decisions, especially with respect to adherence. Treatment options beyond second line combination therapies Chemotherapeutic regimens Cytotoxic agents such Mitomycin C and/or Capecitabine, alone or in combination, have not been shown to improve OS in randomized trials when administered in later lines [7–9]. Likewise, Gemcitabine in combination with protracted infusional 5-Fluorouracil (5-FU) or Capecitabine and S-1 (Tegafur/Gimeracil/Oteracil) as monotherapy or in combination with gemcitabine have shown modest clinical benefit [10–14]. Apart from that standard cytotoxic agents failed to be efficacious in a later-line setting and newer agents are much more promising. EGFR inhibitors If mCRC patients with RAS wild-type did not receive an EGFR inhibitor in earlier treatment lines, this option should be introduced either as single agent or in combination with Irinotecan, regardless of prior administration of Irinotecan. In a phase III trial with patients who had progressed on Fluoropyrimidine, Irinotecan and Oxaliplatin or had contraindications to standard treatment, Cetuximab monotherapy resulted in a significantly longer OS duration (primary endpoint), compared with best supportive care (BSC) [15]. In a phase III study of patients with chemo-refractory mCRC, which was conducted in a similar period, Panitumumab monotherapy + BSC demonstrated a significantly longer PFS interval than BSC alone. There was no significant difference in OS between treatment arms, which might result from the trial’s cross-over design [16]. The 20100007 study similarly evaluated Panitumumab in chemotherapy-refractory patients with wild-type RAS mCRC [17]. In wild-type RAS mCRC, median OS for Panitumumab plus BSC was 10.0 vs 6.9 months for BSC (HR = 0.70; p = 0.0135). In the non-inferiority ASPECCT trial, Panitumumab was shown to be similarly efficacious as Cetuximab, with respect to OS (primary end-
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point) in chemo-refractory mCRC patients with wild-type KRAS exon 2 status (HR 0.97; median 10.4 vs. 10.0 months) [18]. In contrast to current standard-of-care practices, these trials were initiated at a time when EGFR inhibitors were not part of first- and second line treatments. Moreover, it is a matter of debate if the use of anti-EGFR mAbs for last line treatment of patients with right-sided metastatic RAS WT colon cancer is reasonable given their disappointing results in 1st and 2nd line trials in rightsided colonic tumors and the retrospective data from the 3rd line CO-17 trial [19]. VEGF inhibitors The efficacy of Bevacizumab was investigated in combination with FOLFIRINOX (Oxaliplatin + Irinotecan + folinic acid + bolus 5FU + infusional 5-FU) in a prospective single-arm trial with patients who progressed on Oxaliplatin- and Irinotecan-based regimens. Median PFS and OS were 5.8 and 11.9 months, respectively, and 18% of patients experienced partial or complete response [20]. Third-line Bevacizumab in combination with S-1 (Tegafur/Gimeracil/Oteracil) showed good antitumor activity in a single-arm phase II trial of patients with chemo-refractory mCRC (mPFS 5.3 months, mOS 9.9 months) [21]. The relative contribution of Bevacizumab in these trials remains however uncertain as none of this trials included a control arm without the antibody. Regorafenib Regorafenib is a multikinase inhibitor targeting angiogenesis (VEGF receptors 1–3, tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 [TIE2]), oncogenesis (RAF, RET and KIT) as well as the tumor microenvironment (platelet-derived growth factor [PDGF] receptor-b and fibroblast growth factor [FGF]) [22]. In the phase III CORRECT trial, Regorafenib plus best supportive care (BSC) resulted in a significantly longer OS (primary endpoint) compared with placebo plus BSC (HR 0.77; median 6.4 vs. 5.0 months; p = 0.0052) in patients with an ECOG performance status of 0–1 who had progressed on Fluoropyrimidine-, Oxaliplatinand Irinotecan-based chemotherapy, a VEGF inhibitor and, if KRAS wild-type, an EGFR inhibitor (Table 1) [23]. Disease control rates were significantly higher in patients being treated with Regorafenib (41% vs. 15% in the intent-to-treat population; p < 0.001) [24,25]. Recently, a retrospective analysis of patients having undergone treatment with regorafenib showed that the radiologic occurrence of cavitation to lung metastasis is associated with favorable outcome [26]. The CORRECT trial’s results were confirmed in an Asian population cohort in another phase III trial, CONCUR. Regorafenib resulted in a significantly longer OS (primary endpoint) and PFS compared with placebo (HR 0.55; 95%, median 8.8 vs. 6.3 months; p = 0.00016 and HR 0.31; median 3.2 vs. 1.7 months; p < 0.0001, respectively) (Table 1) [27]. In contrast to the CORRECT trial, more patients (35%) had only received one or two prior treatment lines. A role for earlier use of Regorafenib was hypothesized resulting from a subgroup analysis of patients who had not yet received a targeted biologic agent, with a median OS of 9.7 months being achieved in the Regorafenib group versus 4.9 months in the placebo group (HR 0.31) [27]. Numerically similar outcomes to the treatment arms of the randomized phase III trials CORRECT and CONCUR were observed in the cohort study REBECCA and the large prospective non-interventional single-arm CONSIGN study [28,29]. With respect to toxicity, the safety profile of Regorafenib was remarkably consistent with the safety profiles reported in the randomized pivotal studies. The most frequently reported grade 3 or higher Regorafenib-associated adverse events (AEs) in the CONSIGN study were hypertension, hand-foot skin reaction, fatigue
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A. Vogel et al. / Cancer Treatment Reviews 59 (2017) 54–60
Table 1 Pivotal phase III trials for beyond first and second line combination therapies. Trial
Treatment arms
Patient characteristics
n
Median OS
HR in OS (95% CI), p value
Median PFS or TTP
HR in PFS (95% CI)
RECOURSE [58]
TAS-102 vs.placebo
800
7.1 vs. 5.3 monthsa
0.68 (0.58–0.81), p < 0.001
2.0 vs. 1.7 months (PFS)
0.48 (0.41–0.57), p < 0.001
CONCUR [27]
Regorafenib vs. placebo
204
8.8 vs. 6.3 monthsa
0.55 (0.40–0.77), p = 0.00016
3.2 vs. 1.7 months (PFS)
0.31 (0.22–0.44), p < 0.0001
ASPECCT [18]
Panitumumab vs. cetuximab
1010
10.4 vs. 10.0 months
0.97 (0.84–1.11)
4.1 vs. 4.4 months (TTP)
1.00 (0.88–1.14)
CORRECT [24]
Regorafenib vs. placebo
760
6.4 vs. 5.0 monthsa
0.77 (0.64–0.94), p = 0.0052
1.9 vs. 1.7 months (PFS)
0.49 (0.42–0.58), p < 0.0001
Jonker 2007 [59]
Cetuximab + BSC vs. BSC alone
572
6.1 vs. 4.6 monthsa
0.77 (0.64–0.92), p = 0.005
Van Cutsem 2007 [60]
Panitumab monotherapy vs. BSC
Progressed on or following a Fluoropyridimine, Oxaliplatin, Irinotecan, VEGF inhibitor and if KRAS wild-type, an EGFR inhibitor Progressed on or following a Fluoropyridimine, Oxaliplatin and Irinotecan, 59% vs. 62% of patients had received a VEGF inhibitor, an EGFR inhibitor or both Progressed on or following Irinotecan and Oxaliplatin, EGFR-naive Progressed on following a Fluoropyridimine, Oxaliplatin, Irinotecan, VEGF inhibitor and if KRAS wild-type, an EGFR inhibitor Progressed on a Fluoropyrimidine, Irinotecan and Oxaliplatin, EGFR inhibitor-naïve Progressed on or following a Fluoropyrimidine, Irinotecan and Oxaliplatin, EGFR inhibitor-naïve
463
1.00 (0.82–1.22)b
0.68 (0.57–0.80), p < 0.001
8.0 vs. 7.3 weeksa (PFS)
0.54 (0.44–0.66)
BSC = best supportive care; HR = hazard ratio; OS = overall survival; PFS = progression-free survival; TTP = time to disease progression. a Primary endpoint. b Possibly confounded by patient crossover.
(15%, 14% and 13% of patients, respectively) as well as elevated levels of bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (13%, 7% and 6% of patients, respectively) [29]. Neither the quality of life not the health status were significantly deteriorated in Regorafenib recipients compared to the placebo recipients during the study period in one of the randomized (CORRECT or CONCUR) trials [24,27]. Trifluridine/Tipiracil Trifluridine/Tipiracil, formerly known as TAS-102, is an orally administered combination of trifluridine, a thymidine-based nucleic acid analogue, and Tipiracil hydrochloride, an inhibitor of thymidine phosphorylase, which is a major metabolizer of trifluridine [30]. Subsequently, multiple phase 1 trials were conducted to determine the maximal tolerated dose and the optimal dosing schedule. The dose of 35 mg/m2 twice daily was first tested in a Japanese randomized phase II study [31]. Median OS was 9.0 months in patients treated with Trifluridine/Tipiracil plus BSC compared to 6.6 months in the placebo plus BSC group (HR 0.56; p = 0.001). The drug demonstrated efficacy in RECOURSE, a phase III placebo-controlled trial of patients with chemo-refractory mCRC (Table 1). Overall survival was significantly longer in the treatment arm, compared with the placebo arm (HR 0.68; median 7.1 vs. 5.3 months; p < 0.001), as was the PFS (HR 0.48; median 2.0 vs. 1.7 months; p < 0.001). The OS benefit was consistent across all pre-specified subgroups. Significantly more Trifluridine/Tipiraciltreated patients achieved disease control compared to the placebo group (44% vs. 16% of patients; p < 0.001). The treatment was generally well tolerated, most frequently reported grade 3 or higher adverse events in RECOURSE tended to be predominantly hematological: neutropenia, leukopenia and anemia rates were 38%, 21% and 18%, respectively. Despite the absence of extensive quality of life data, treatment with Trifluridine/Tipiracil significantly delayed worsening of ECOG perfor-
mance status. So far, no predictive biomarkers have been identified indicating sensitivity or resistance to Trifluridine/Tipiracil. However, it was realized that patients who developed chemotherapy induced neutropenia (CIN) have a trend towards a longer progression free survival (PFS) and overall survival (OS). These data were validated in additional centers from the US and Japan [32]. These findings might be of relevance, because it could indicate that the dose of Trifluridine/Tipiracil may need to be increased to achieve better outcomes in patients not experiencing any neutropenia. Treatment options on the horizon Several drugs are currently being tested in mono- and combination therapy in chemo-refractory mCRC patients. Some of them in all-comer populations, whereas there is also a growing number of trials testing the respective agent in molecular defined populations. The first group includes the two tyrosine kinase inhibitors Nintendanib and Famitinib. Nintedanib is a potent oral triple angiogenesis inhibitor which targets FGF, PDGF receptor-a and -b and VEGF signaling as well as FMS-like tyrosine kinase 3 (FLT-3) and the RET proto-oncogene. A phase III trial has been conducted in patients with refractory mCRC, based on promising phase II data for other solid tumors and first results have been presented at the ESMO meeting in 2016 [33]. 764 patients with refractory CRC after failure of standard chemotherapy and biologic agents were included in the LUME colon-1 trial. Nintedanib significantly improved median progression-free survival (HR = 0.58, p < 0.0001), a co-primary endpoint of the LUME-colon1 trial, and disease control rate compared to placebo (26% vs 11%, odds ratio 2.96, p < 0.0001), but failed to demonstrate a difference in overall survival (HR = 1.01, p = 0.8659; medians 6.4 months vs 6.1 months), which was the co-primary endpoint of this phase III trial.
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Famitinib, another small molecular tyrosine kinase inhibitor that also targets PDGF, VEGF signaling and FLT-3 as well as the proto-oncogene protein c-kit, recently demonstrated antitumor activity in a randomized phase II trial of patients who failed second- or later-line therapies. Famitinib was associated with a significantly longer PFS interval compared with placebo (median 2.8 vs. 1.5 months; p = 0.0034; HR = 0.54), as well as a significantly higher disease control rate (57.6% vs.30.9% in the intent-to-treat population; p = 0.0023) [34]. The alkylating agent Temozolomide has shown activity in a single-arm phase II trial of patients with mCRC and MGMT promoter methylation who had failed all approved therapies. Overall, 12% of 32 patients experienced an objective response and the median PFS and OS durations were 1.8 and 8.4 months, respectively [35]. However, the role of MGMT promoter methylation for the efficacy of Temozolomide remains uncertain and the drug cannot be recommended outside of clinical trials in chemo-refractory mCRC patients. MABp1 is a monoclonal antibody directed again interleukin 1a, which is frequently expressed by malignant cells, infiltrating leucocytes and stromal cells. Several inflammatory signals are mediated through the interleukin 1 pathway contributing to tumor progression. MABp1 was recently tested in phase III study with chemo-refractory, symptomatic patients [6]. The study achieved its primary composite endpoint with an improvement in disease-associated symptoms measured by improvement in lean body mass and symptoms. Importantly, overall survival was significantly better in patients, which achieved the primary end point of symptom improvement (4.2 months vs 11.5, HR 0.31, p < 0.0001). Another phase III trial with OS as primary endpoint is recruiting. MABp1 might therefore become an interesting option in otherwise treatment-refractory patients with colorectal cancer. In contrast to these studies in all-comer patient population, three drugs/drug combinations were tested in molecular-defined patient groups. In a large library of patient-derived colorectal cancer xenografts that were molecularly profiled for several genetic parameters, an amplification of the HER2 gene was detected in some colorectal cancer xenografts. These xenografts were resistant to Cetuximab, but a combination of an anti-HER2 antibody (Pertuzumab or Trastuzumab) and a tyrosine kinase inhibitor (Lapatinib) led to sustained tumor shrinkage [36]. Based on these preclinical observations, the ‘‘anti-HER2-combination” of Trastuzumab + Lapatinib was tested in a phase II trial (HERACLES) in patients with HER2-amplified, KRAS exon 2 wild-type mCRC, resistant to all standard treatments [37]. Between 2012 and 2015, 48 (5%) patients with HER2-positive tumors were identified out of 914 patients with KRAS WT mCRC. Of the 27 patients included in this HERACLES trial, one (4%) had a complete remission, seven (26%) had a partial remission, and 12 (44%) had stable disease. Median progression-free survival was 21 weeks and mOS was 46 weeks. Similarly, the activity and safety of HER2 directed therapies are explored in the MyPathway study [38]. MyPathway (trial registration NCT02091141) is a multicenter, non-randomized, phase IIa umbrella basked study of patients with advanced solid tumors that have progressed following standard therapy or for which there is no approved treatment. First results from this study confirmed the activity of HER2 directed combination therapies in mCRC patients. Of 18 patients treated with Trastuzumab and Pertuzumab, six patients had partial or complete response, seven had stable disease and 6 had progressive disease. Patients with V600E BRAF-mutated mCRC have a poor prognosis and treatments for this particular tumor genotype have been very disappointing so far. Unlike to melanoma patients, singleagent Vemurafenib did not demonstrate meaningful clinical activ-
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ity in patients with BRAF V600-mutated mCRC, of whom 90% had received 2 or more lines of therapy [39]. However, several phaseII studies suggest that sequentially blocking several components of the EGFR pathway with a combination of BRAF inhibitors and anti-EGFR antibodies alone or in combination with chemotherapy or additional targeted agents may improve the anti-tumor activity in bRAF mutant CRC patients. In a 3 + 3 phase I study, 18 BRAFmutated received Cetuximab and Irinotecan with escalating doses of Vemurafenib and achieved a mPFS of 7.7 months [40]. Similarly, median PFS was 5.4 months and 4.2 months in a larger ongoing phase 1b/randomized phase 2 study in which the BRAF inhibitor Encorafenib was tested with Cetuximab alone or additionally with the PI3Ka inhibitor alpelisib [41]. The largest so far presented phase I/II study used Panitumumab in combination with the BRAF inhibitor Dabrafenib or the MEK inhibitor Trametinib, and the combination of all three drugs was evaluated in 134 patients [42]. Median PFS for the combination of all three drugs was 4.2 months and the overall survival was 9.1 months, whereas the mPFS of 3.4 and 2.8 months for Dabrafenib/Panitumumab and Trametinib/Panitumumab, respectively. In all, despite the use of (cost) intense and relatively toxic molecular targeted treatments in this study, the survival results were rather disappointing and the therapeutic index especially for the combination of Panitumumab and Trametinib was not advantageous. The anti-programmed death-1 immune checkpoint inhibitor Pembrolizumab showed promising results in a phase II study of heavily pretreated patients with mismatch repair-deficient mCRC. Rates of immune-related objective response rate (co-primary endpoint) and immune-related PFS at 20 weeks (co-primary endpoint) were 40% and 78%, respectively. Median PFS and OS have not yet been reached [43]. Although Pembrolizumab is not yet approved, it was recently granted ‘Breakthrough Therapy Designation’ by the FDA, which should expedite the approval process [44]. Similarly, Nivolumab with or without Ipilimumab was tested in the checkmate 142 trial [45]. In this trial, 100 patients with high microsatellite instability and 20 patients with microsatellite stability were included. Among MSI patients, the objective response rate was 25.5% for Nivolumab monotherapy and 33.3% for the combination, all of which were confirmed partial responses. The 12-month PFS rate was 45.9% with Nivolumab alone and has not yet been determined with Nivolumab plus Ipilimumab. The 12-month OS rate was 65.6% with Nivolumab and has not yet been reached with Nivolumab plus Ipilimumab. In contrast to MSI tumors, MSS tumors are highly resistant to immunotherapeutic approaches alone and different strategies are currently explored to either identify subgroups of patients with inflammatory tumors or to find innovative combination strategies. One very promising example for combination therapies is the use of the MEK inhibitor Cobimetinib, which has been shown to sensitize tumors to Atezolizumab by increasing MHC I expression on tumor cells and promoting intratumoral CD8 T-cell accumulation. In a phase Ib study with a planned cohort extension, 23 patients with severely pretreated mCRC (median 3 prior treatment lines) of whose 20 had KRAS mutant tumors were treated. 20% of all patients had an objective response, whereas the disease stabilization rate was in 40% and the 6-months-overall survival rate was 72%. Consecutively, a phase-III study was initiated, which just finished accrual. Considerations for treatment decisions beyond first and second line combination chemotherapies As mentioned above, various factors contribute to the decision for an optimal ‘‘beyond combination therapy” strategy. Somehow similar to earlier treatment lines decision criteria include:
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(a) Patient-related factors (e.g. comorbidities) as well as patient preferences and motivation, which becomes more important in this setting (b) Disease-related factors (e.g. molecular characteristics, tumorrelated symptoms, growth dynamics and manifestation) (c) Treatment-related factors (e.g. availability, toxicity and safety profile) (d) Prior treatment toxicity, efficacy and characteristics (e.g. discontinuation before progression) of combination chemotherapies Due to the variables in the above criteria as well as the patient’s preferences, treatment decisions in later lines for mCRC are complex and should be guided by detailed therapy information about the individual patient. Decision making considerations Biomarker So far, no biomarkers have been established in daily clinical use beyond the negative predictive markers used to select patients that benefit the most from EGFR antibodies. Recently, a panel of international experts developed a consensus gene expression–based classification system for CRC with four subtypes [46,47]. In an exploratory analysis, gene expression analysis was performed in 281 patients of the CORRECT trial. For the CMS subtypes, a better OS benefit from Regorafenib was observed for CMS2 and CMS4 and a better PFS was demonstrated for the subtypes CMS2, CMS3 and CMS4 but not for the CMS1 subtype [48]. This novel classification of colorectal cancer, based on the relationships between the phenotype of the cancer cell and the corresponding immune and stromal profile, may help in the future to identify the most appropriate treatments, including antiangiogenic drugs, anti-EGFR antibodies and immunotherapies. Pre-treatment, reintroduction and re-challenge Re-introduction is defined as repeated administration of a treatment regimen (or single drug) from which a patient has previously experienced some benefit and which was discontinued without progression (e.g. for prevention of or due to cumulative toxicity, or as a planned ‘‘maintenance” therapy). In the past few years, treatment discontinuation before progression and a planned rein-
Fig. 1. Proposed algorithm for treatment decisions beyond the second line for metastatic colorectal cancer. BSC: best supportive care; ECOG: Eastern Cooperative Oncology Group; EGFR: epidermal growth factor receptor; PD: progressive disease; WT: wild-type.
troduction at a later time point has become a standard approach for combination first-line chemotherapy. In contrast, re-challenge is defined as re-administration of a treatment (or drug) to which a patient has developed resistance while being on treatment [49]. Depending on the response to prior therapy and (lack of) cumulative toxicity, the re-challenge of previously administered therapies may be of high interest and even seem to be more appropriate than the administration of Regorafenib or Trifluridine/Tipiracil (Fig. 1). For Oxaliplatin, three retrospective series have reported response rates of up to 20% and disease stabilization rates of more than 40% following reintroduction after prior discontinuation. Median PFS ranged from 3.5 months in the overall population to 5.5 months in patients who had experienced an Oxaliplatin-free interval of 6 months or longer [50–52]. These results were confirmed in a small prospective phase II study in which Oxaliplatin reintroduction resulted in a median PFS of 6.2 months [53]. The role of re-challenge of EGFR inhibitors is currently under investigation in clinical trials and may be a feasible strategy for selected patients following the use of new agents in later lines. In the future, decision making for the re-use of anti-EGFR antibodies may be guided by monitoring of plasma ctDNA to track clonal evolutions during treatment. Several mutations in genes such as KRAS, NRAS, BRAF, MET, ERBB2, FLT3, EGFR and MAP2K1 conferring resistance have been identified in preclinical tumor models and their relevance has been subsequently confirmed in clinical settings [54,55]. Mutated clones, which emerge in the blood during EGFR blockade, may decline upon withdrawal of EGFR-specific antibodies indicating that the CRC genome adapts dynamically to intermittent drug schedules and opens the opportunity for rechallenge therapies with anti-EGFR antibodies [55]. Appropriate phase III trials for the determination of an optimal sequence strategy and which consider all available treatments are very unlikely to happen. With respect to the fast development of new treatment options in the recent years, we propose a treatment algorithm to maximize patient benefit beyond combination chemotherapy in mCRC based on the evidence generated by phase III trials. See Fig. 1. Integration of new treatment options According to international guidelines, Regorafenib and Trifluridine/Tipiracil are recommended in third or fourth line of treatment after failure of previous therapies [56,57]. Both agents have demonstrated significantly improved OS versus placebo in the respective phase III trials CORRECT, CONCUR and RECOURSE. In RECOURSE, prior treatment with Regorafenib did not appear to have an impact on the OS benefit of Trifluridine/Tipiracil (prior Regorafenib: HR 0.69; no prior Regorafenib: HR: 0.69) suggesting that the efficacy of Trifluridine/tipiracil is independent of whether it is administered after Regorafenib or not. The toxicity profiles of Regorafenib and Trifluridine/Tipiracil are markedly different. Adverse events associated with Regorafenib are rather non-hematological and include hand-foot skin reaction, fatigue, diarrhea, hypertension and liver dysfunction. Trifluridine/ Tipiracil has a more favorable toxicity profile than Regorafenib with the majority of adverse events being of a hematological, clinically asymptomatic nature [58]. At the moment, it is unclear which drug should be administered first. In a retrospective Japanese study, efficacy and safety of Trifluridine/Tipiracil was compared to Regorafenib and did not reveal a significant difference in mPFS and mOS suggesting a similar efficacy for both drugs. It should be noted however, that in all Phase-III trials with Regorafenib and Trifluridine/Tipiracil approximately 50% of patients progressed at the time of the first CT control. Clinically fit patients should be closely monitored while on treatment with either drug
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to allow an early switch to the respective other drug upon progression.
[12]
Conclusion As a result of the long-term survival of patients who have undergone first- and second line therapies, treatment decisions beyond combination therapy based on phase III trial data become ever more important. RAS WT patient with left-sided tumors that have so far not received the anti-EGFR antibodies should be treated with either drug. Symptomatic patients requiring a tumor response may be candidates for a re-induction or even re-challenge with Oxaliplatin, if they had an Oxaliplatin-free interval of 6 months or longer. The toxicity profile of Trifluridine/Tipiracil makes it more suitable to be administered in patients with a reduced performance status. Patients in good performance status without symptoms may be candidates for the sequential treatment with Regorafenib and Trifluridine/Tipiracil as it has been reported in the RECOURSE trial. With median survival times reaching more than 30 months in many clinical trials, and with the range of therapy choices steadily increasing, the current treatment landscape hints at a future in which mCRC may truly become a chronic disease. Acknowledgements Medical writing assistance was provided by Melody Watson and Marc Esser at co.faktor GmbH (Berlin, Germany), with financial support from Bayer Vital GmbH (Leverkusen, Germany).
[13]
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