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Systemic therapy beyond first-line in advanced gastric cancer: An overview of the main randomized clinical trials
Critical Reviews in Oncology/Hematology, In Press, Corrected Proof, Available online 30 November 2015, Available online 30 November 2015
- Progressive gastric cancer patients may benefit from a second-line therapy.
- Monochemotherapy (both irinotecan and taxanes) is superior to BSC.
- Novel targeted agents such as ramucirumab and apatinib are really promising.
- Ramucirumab is the first targeted drug approved by FDA and EMA in second-line.
- Future investigation should provide stronger predictive markers to targeted therapy.
Following progression on first-line platinum and fluoropyrimidine-based chemotherapy, prognosis for advanced gastric cancer patients is extremely poor. Thus, new and effective treatments are required. Based on positive results of recent randomized controlled trials, second-line monochemotherapies with either irinotecan or taxanes confer a median overall survival of approximately 5 months in gastro-esophageal and gastric adenocarcinoma. Combination of weekly paclitaxel and ramucirumab, a novel anti-angiogenic VEGFR2 antibody, pushes the overall survival up to over 9.5 months, whereas apatinib, a novel oral VEGFR2 tyrosine kinase inhibitor, seems to be promising in heavily pretreated patients. In contrast, the role of EGFR/HER2 and mTOR inhibitors is controversial. Studies are heterogeneous for tumor population, geographical areas, quality of life assessment, type of first-line therapy and response to that, making clinical practice application of the trial results difficult. Furthermore, sustainability is challenging due to high cost of novel biotherapies.
Keywords: Advanced gastric cancer, Second-line chemotherapy, Molecular targeted agents, Randomized controlled trials.
Despite decreases worldwide since the 1930s in the incidence and death rates of gastric carcinoma (GC), in particular for distal cancers, it remains the third leading cause of cancer mortality worldwide (Anon., 2015a). Nearly 1 million of new stomach cancer cases and >700,000 deaths are estimated to have occurred in 2008, accounting for 8% of the total cases and 10% of total deaths (Jemal et al., 2011). Except for Japan and South Korea (Lee et al., 2006), screening procedures are lacking in most countries, thus GC diagnosis usually occurs very late when curative surgery is not possible. Current evidence shows that palliative first-line chemotherapy improves survival and symptom control in comparison with the best supportive care (BSC) and that polychemotherapy is superior to the single agent 5Fluorouracil (5FU) (Wagner et al., 2006). Although many trials and meta-analyses have been published so far, a well-established standard of care does not exist. At present, fluoropyrimidines and platinum combination with or without epirubicin (E) or docetaxel (D) is regarded as first-line chemotherapy in the treatment of advanced gastric cancer (AGC) (Webb et al, 1997 and Van Cutsem et al, 2006). On the basis of the REAL-2 trial (Cunningham et al., 2010) and other studies (Al-Batran et al, 2008 and Kang et al, 2009), cisplatin (CDDP) may be replaced by oxaliplatin and 5FU by capecitabine. S-1, a novel oral fluoropyrimidine, in combination with CDDP is now accepted as standard first-line chemotherapy in both Asian (Koizumi et al., 2008) and Caucasian subjects (Ajani et al., 2010). Irinotecan (CPT11) plus 5FU/LV (leucovorin) as FOLFIRI regimen may represent an alternative combination to CDDP/5FU when cisplatin may not be integrated (Dank et al., 2008). Among patients with positive HER2 (human epidermal growth factor receptor 2) gastric cancer, trastuzumab (T) plus chemotherapy represent a new standard of care (Bang et al., 2010). Therefore, with the TOGA trial, an era of target therapies in AGC has begun. In contrast, other studies that have tested different biological agents from trastuzumab (such as cetuximab, panitumumab, bevacizumab and lapatinib) have not been able to replicate the same results (Lordick et al, 2013, Waddell et al, 2013, Ohtsu et al, 2011, Shen et al, 2015, and Hecht et al, 2013). Despite these efforts which have led to a considerable improvement in overall survival (OS) and progression free survival (PFS) in first-line therapy, the prognosis of AGC remains poor. On the other hand, the percentage of patients who may benefit from a further treatment is increasing. Rechallenge of the same or an analogous drug after a drug holiday, following disease relapse or progression, could be an option, while for those patients refractory or resistant to the front-line treatment a “pure” second-line chemotherapy with no cross-resistant drugs should be proposed. Over the last few years, several randomized phase II and III trials have been conducted, exploring the role of chemotherapy and targeting drugs, combined or alone, in the second- and third-line settings. Our purpose, unlike previous publications on the same topic based on retrospective reports or single-arm phase II trials, is to provide an overview of the main randomized clinical trials (RCTs), particularly addressing the following settings: (1) chemotherapy vs BSC, (2) comparison of monochemotherapies; (3) polychemotherapy vs monochemotherapy; (4) comparison of polychemotherapy sequences and (5) molecular targeted agents (MTAs).
2. Chemotherapy vs best supportive care
Comparison between chemotherapy (either irinotecan or docetaxel) and BSC as second-line treatment in patients with AGC was the aim of three randomized phase III studies (Table 1).
|Trial||Phase and design||Region||Treatment||no.||R||Primary endpoint||HR||p||Result (observations)|
|AIO group 2011 Thuss-Patience et al. (2011)||III
|Germany||CPT-11 vs BSC||40||1:1||OS months (4.0 vs 2.4)||0.48||p = 0.0012||Positive|
|Kang et al. (2012)||III
2nd and 3rd line
|Korea||CPT-11 or D vs BSC||202||2:1||OS months (5.3 vs 3.8)||0.66||p = 0.007||Positive (no difference between CPT-11 and D)|
|COUGAR-2 2014 Ford et al. (2014)||III
|UK||D vs ASC||168||1:1||OS months (5.2 vs 3.6)||0.67||p = 0.01||Positive|
|WJOG 4007 2013 Hironaka et al. (2013)||III
|Japan||CPT-11 vs wPXT||219||1:1||OS months (8.4 vs 9.5)||1.13||p = 0.38||Negative|
|Roy et al. (2013)||II
|UK, Spain, Taiwan, Croatia, Korea and Bosnia||PEP02 vs CPT-11 vs D||132||1:1:1||ORR% (13.6 vs 6.8 vs 15.9)||–||NR||Negative (no difference among three arms)|
UK: United Kingdom; CPT-11: irinotecan; D: docetaxel; wPXT: weekly paclitaxel; PEP02: liposomal nanocarrier formulation of irinotecan; BSC: best supportive care; ASC: active symptom control; no.: number of patients; R: randomization; HR: hazard ratio; OS: overall survival; ORR: objective response rate; NR: not reported.
The first trial came from the Arbeitsgemeinschaft Internistische Onkologie (AIO) group in 2011; chemotherapy consisted of CPT-11 250 mg/m2 repeated every 3 weeks for patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) from 0 to 2 (Thuss-Patience et al., 2011). Although prematurely stopped after the enrollment of only 40 patients due to poor recruitment, 21 patients treated with CPT-11 had an mOS of 4.0 vs 2.4 months of 19 patients treated with BSC [hazard ratio (HR) 0.48; p = 0.0012]. The main reason for the low recruitment was patient refusal of randomization. Despite the limit of a small sample size, second-line chemotherapy with CPT-11, according to the magnitude of the HR, showed a marked reduction in the risk of death and the achievement of symptom relief in about half of patients (44%).
Similarly, in a Korean trial by Kang et al., (2012) 202 patients (ECOG 0-1) previously treated with chemotherapy containing fluoropyrimidines and platinum, either delivered in sequence or concurrently, were randomized in a 2:1 ratio to salvage chemotherapy (either CPT-11 150 mg/m2 every 2 weeks or D 60 mg/m2 every 3 weeks per investigator’s choice) plus BSC or BSC alone. Chemotherapy showed benefit in mOS (5.3 vs 3.8 months, HR 0.66; p = 0.007), reducing the risk of death by 34%. No statistically significant differences were found between CPT-11 and D (6.5 vs 5.2 months).
In the British COUGAR-2 trial, 168 patients with ECOG PS 0-2 progressed on or within 6 months of treatment with a platinum and fluoropyrimidine combination, were allocated to D 75 mg/m2 every 3 weeks plus active symptom control (ASC) or ASC alone (Ford et al., 2014). There was an improved mOS in D arm compared with ASC (5.2 vs 3.6 months, HR 0.67; p = 0.01). Despite toxicity rates being higher in group D, particularly neutropenia, infections and febrile neutropenia, the quality of life (QoL) was markedly improved by chemotherapy in terms of pain, fatigue and dysphagia.
In 2013, Kim and colleagues published a meta-analysis (Kim et al., 2013) of these trials to answer the question as to whether second-line chemotherapy was more effective than BSC (at the time of meta-analysis the COUGAR-2 study had been presented as abstract at the 2013 ASCO annual meeting). A total of 410 patients were eligible for analysis, of whom 150 received D and 81 received CPT-11 chemotherapy. Based on this meta-analysis, the survival benefit was remarkable with a 36% reduction in the risk of death (HR 0.64; p < 0.0001), regardless of the type of drug (CPT-11 or D) and administration schedule, and without substantial differences between Europeans and Asians. Considering the results of univariate analysis for survival in 2 trials (Thuss-Patience et al, 2011 and Kang et al, 2012), good performance status (ECOG 0-1) and long chemotherapy-free interval (≥3 months) could be important positive prognostic indicators that could guide physician’s decision-making (Kim et al., 2013).
3. Comparison of monochemotherapies
More recent trials reported that both irinotecan and taxanes can have similar influence in terms of survival (Table 1).
In the WJOG 4007 trial comparing second-line chemotherapy (Hironaka et al., 2013), 219 patients without severe peritoneal metastasis received either weekly paclitaxel (wPTX) (80 mg mg/m2 on days 1, 8, and 15 every 4 weeks) or CPT-11 (150 mg/m2 every 2 weeks). Patients with severe peritoneal carcinomatosis, defined by authors as “ileus or subileus on barium enema examination and moderate to severe ascites exceeding pelvic cavity”, were excluded because CPT-11 could be more toxic in this subgroup. CPT-11 was not superior to wPTX (8.4 vs 9.5 months, HR 1.13; p = 0.38), suggesting that also wPTX could be used as control arm of second-line chemotherapy in AGC. Longer mOS achieved in this study than previous phase III trials is likely to depend on the exclusion of patients with severe peritoneal carcinomatosis, recognized as a poor prognostic factor (Chau et al., 2004).
Roy et al. (2013) designed a randomized three-arm phase II trial to compare the efficacy of single agent PEP02, a novel highly stable liposomal nanocarrier formulation of CPT-11, with CPT-11 or D in the second-line treatment; objective response rate (ORR) was the primary endpoint. With a 1:1:1 randomization, a mixed population of 132 patients was assigned to receive PEP02 120 mg/m2, CPT-11 300 mg/m2 or D 75 mg/m2 every 3 weeks. In the ITT population, no differences were reported in ORR (13.6% vs 6.8% vs 15.9%, respectively) and also PFS and OS were similar among the 3 trial arms. Median OS was 7.3 vs 7.8 vs 7.7 months in the PEP02, CPT-11 and D arm, respectively, while mPFS was 2.7 vs 2.6 vs 2.7 months with PEP02, CPT-11 and D, respectively. With regard to toxicity, the most common grade 3–4 adverse event (AE) in the PEP02 arm was diarrhea, much higher than in CPT-11 and D arms (27.3% vs 18.2% vs 2.3%, respectively).
4. Polychemotherapy vs monochemotherapy
So far, two randomized studies, conducted in Asian countries, have assessed the role of second-line polychemotherapy vs monochemotherapy in AGC (Table 2).
|Trial||Phase and design||Region||Treatment||no.||R||Primary endpoint||HR||p||Result (observations)|
|Sym et al. (2013)||II
2nd line or more
|Korea||FOLFIRI vs CPT-11||59||1:1||ORR%
(20 vs 17.2)
|–||p = 0.525||Negative|
|TCOG GI-0801/BIRIP 2014 Higuchi et al. (2014)||III
|Japan||BIRIP vs CPT-11||130||1:1||PFS months
(3.8 vs 2.8)
|0.68||p = 0.03||Positive (60% of patients platinum-free first-line therapy)|
FOLFIRI: irinotecan and fluorouracil/leucovorin; CPT-11: irinotecan; BIRIP: biweekly irinotecan and cisplatin; no.: number of patients; R: randomization; HR: hazard ratio; ORR: overall response rate; PFS: progression free survival.
A modified (m)FOLFIRI regimen [CPT-11 150 mg/m2 plus leucovorin (LV) 20 mg/m2 intravenously (IV) on day 1 followed by 5-FU 2000 mg/m2 over 48 h] was compared with CPT-11 150 mg/m2 alone, every two weeks, in a small Korean randomized phase II study (Sym et al., 2013). Both primary endpoint ORR and secondary endpoints mOS and mPFS were unmet. Fifty-two out of the 59 patients enrolled were assessable for response. Objective response rates were 17.2% and 20.0% in patients treated with CPT-11 and mFOLFIRI, respectively. Median PFS and mOS were 2.2 and 5.8 months in the CPT-11 arm, and 3.0 and 6.7 months in the mFOLFIRI arm, respectively. In conclusion, although well tolerated, mFOLFIRI did not improve the results of CPT-11 monotherapy in patients progressing on or after either platinum-, taxane- or fluopyrimidine-based first-line therapy.
In the recent Japanese phase III TCOG GI-0801, comparing biweekly CPT-11 60 mg/m2 plus cisplatin 30 mg/m2 (BIRIP combination) vs biweekly CPT-11 150 mg/m2 alone, mPFS for BIRIP arm was significantly better than CPT-11 in 130 patients refractory to S1-based first-line chemotherapy (3.8 vs 2.8 months, HR 0.68; p = 0.03) (Higuchi et al., 2014). In an exploratory subgroup analysis, in patients who were previously treated without platinum agents, mPFS was much longer with BIRIP arm (6.4 vs 4.2 months, HR 0.60; p = 0.0786). Otherwise, neither OS (10.7 vs 10.1 months) nor RR (22 and 16%) improved with the combination therapy as compared to CPT-11 group. Moreover, this study only included Japanese patients, more than 40% of whom had received no platinum therapy before study entry. Thus, such data may not be considered reliable for Western patients, who are usually treated with a platinum-based regimen as first-line chemotherapy. Any grade elevation of serum creatinine was more common in the BIRIP group, whereas diarrhea was more common in the CPT-11 group. Overall, toxicity profile of BIRIP arm was better than CPT-11 arm, probably related to lower doses of CPT-11 used in the combination therapy.
5. Comparison of polychemotherapy sequences
In the FFCD-GERCOR-FNCLCC 03-07 phase III trial, which enrolled 416 patients, the sequence FOLFIRI as first-line therapy followed by ECX as second-line was superior in time to failure (TTF) (22.1 vs 18.5 weeks, HR: 0.77; p = 0.008) but with a similar OS (9.5 vs 9.7 months) vs the opposite sequence (ECX → FOLFIRI). The authors concluded that the FOLFIRI → ECX sequence should be preferred in view of longer TTF and greater tolerance (Guimbaud et al., 2014) (Table 3).
|Trial||Phase||Region||Treatment||no.||R||Primary endpoint||HR||p||Result (observations)|
|Guimbaud et al. (2014)||III||France||FOLFIRI → ECX vs ECX → FOLFIRI||416||1:1||TTF weeks
(22.1 vs 18.5)
|0.77||p = 0.008||Positive (similar OS between two arms)|
|Kim et al. (2011)||III||Korea||D/CDDP → FOLFIRI vs FOLFIRI → D/CDDP||58||1:1||2nd PFS months
(8.1 vs 6.7)
|NR||p = 0.865||Negative|
FOLFIRI: irinotecan and fluorouracil/leucovorin; ECX: epirubicin, cisplatin and xeloda® (capecitabine); D: docetaxel; CDDP: cisplatin; no.: number of patients; R: randomization; TTF: time to treatment failure; OS: overall survival; 2nd PFS: second progression free survival; HR: hazard ratio; NR: not reported.
In a phase III Korean trial by Kim and colleagues, prematurely closed due to poor accrual, 58 patients were randomized to receive a first-line therapy D/CDDP every 3 weeks until progression followed by FOLFIRI (Arm A) or the reverse sequence (Arm B). There was no difference in ORR, tumor control rate (TCR), first PFS, second PFS (primary endpoint), and OS between two arms. More specifically, the second PFS was 8.1 and 6.7 months (HR not reported; p = 0.865) for arm A and B, respectively (Kim et al., 2011) (Table 3).
6. Molecular targeted agents
Over the last few years, different classes of targeted agents, such as angiogenesis inhibitors, mTOR inhibitors, epidermal growth factor receptor (EGFR) inhibitors and tyrosine kinase inhibitors (TKIs), have been studied in clinical trials.
To date, 9 randomized trials (5 phase III and 4 phase II) have been published and others were presented during the latest international oncological meetings (Table 4).
|Trial||Phase and design||Region||Target||Treatment||no.||R||Primary end-point||HR||p||Result (observations)|
|Yi et al. (2012)||II
|Sunitinib/Docetaxel vs Docetaxel||105||1:1||TTP months
(3.9 vs 2.6)
|0.77||p = 0.2||Negative (high activity)|
|Moehler et al. (2013)||II
2nd and 3rd line
|Sunitinib/FOLFIRI vs placebo/FOLFIRI||91||1:1||PFS months
(3.6 vs 3.3)
|1.11||p = 0.66||Negative|
|Li et al. (2013)||II
3rd line or more
|Apatinib 850 mg/daily vs Apatinib 425 mg/bid vs placebo||141||1:1:1||PFS months
(3.67 and 3.20 vs 1.40)
|0.18 and 0.21||p < 0.001 and p < 0.001||Positive (apatinib better than placebo regardless dosing)|
3rd line or more
|Apatinib 850 mg/daily vs placebo||270||2:1||OS days
(195 vs 140)
|0.71||p < 0.016||Positive|
|Granite-1 2013 Ohtsu et al. (2013)||III
2nd or 3rd line
|Global||mTOR||Everolimus/BSC vs placebo/BSC||656||2:1||OS months
(5.39 vs 4.34)
|0.90||p = 0.124||Negative|
|REGARD 2014 Fuchs et al. (2014)||III
|Ramucirumab/BSC vs placebo/BSC||355||2:1||OS months
(5.2 vs 3.8)
|0.78||p = 0.047||Positive|
|RAINBOW 2014 Wilke et al. (2014)||III
|Ramucirumab/wPTX vs placebo/wPTX||665||1:1||OS months
(9.63 vs 7.36)
|0.81||p = 0.0169||Positive|
|Satoh T 2014 Satoh et al. (2014a)||II
|Nimotuzumab/CPT11 vs CPT11||83||1:1||PFS days
(73 vs 85)
|0.86||p = 0.5668||Negative|
|TyTAN 2014 Satoh et al. (2014b)||III
|Lapatinib/wPTX vs wPTX||261||1:1||OS months
(11 vs 8.9)
|0.84||p = 0.104||Negative (better efficacy in IHC3+ patients)|
TKIs: tyrosine kinase inhibitors; MoAB: monoclonal antibody; FOLFIRI: irinotecan and fluorouracil/leucovorin; BSC: best supportive care; wPXT: weekly paclitaxel; CPT-11: irinotecan; no.: number of patients; R: randomization; TTP: time to progression; PFS: progression free survival; OS: overall survival; ORR: objective response rate; HR: hazard ratio.
6.1. Angiogenesis inhibition
Angiogenesis is the process by which new blood vessels are formed and it is essential for normal reproduction, development and tissue repair. In contrast to normal tissues, angiogenesis in tumors is dysregulated and leads to the formation of a blood supply that is tortuous and hyperpermeable. High levels of VEGF (vascular endothelial growth factor) and VEGFR (vascular endothelial growth factor receptor) correlate with increased tumor growth rate and tumor metastatic potential, and worse patient prognosis.
The aim of the international randomized, placebo-controlled, phase III REGARD trial was to assess the role of ramucirumab (RAM), a fully human IgG1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 (VEGFR2) (Fuchs et al., 2014). A total of 350 patients with advanced adenocarcinoma of gastro-esophageal junction (GEJ) and stomach progressive on a first-line platinum- or fluoropirimidine-containing chemotherapy, were assigned in a 2:1 ratio to receive either BSC plus RAM 8 mg/kg or placebo, intravenously every 2 weeks. Despite the absence of a difference in ORR between treatment arms, both mOS (5.2 vs 3.8 months, HR: 0.77; p = 0.047) and mPFS (2.1 vs 1.3 months, HR: 0.48; p < 0.0001) were significantly longer for ramucirumab group. So, for the first time a biological drug has shown a benefit in the second-line setting and the survival results of ramucirumab are very similar to those of other chemotherapeutic agents such as irinotecan and taxanes when used alone (Thuss-Patience et al, 2011, Kang et al, 2012, Ford et al, 2014, and Fuchs et al, 2014). Final results on the combination of RAM and wPTX from the RAINBOW trial, the largest phase III trial of second-line therapy for AGC, indicated a survival of nearly 10 months in favor of the combination treatment (Wilke et al., 2014). This randomized placebo-controlled trial, which included 665 patients with disease progression on first-line platinum/fluoropyrimidine-based combination therapy, showed that the addition of RAM to wPTX significantly prolonged the primary endpoint of OS from a median of 7.4–9.6 months (HR 0.81; p = 0.017), with an absolute gain of 2.2 months. The OS curves split early, within 2 months of treatment, and remained separated beyond 1 year. Consistent benefit from the addition of RAM to wPTX was evident across all efficacy endpoints, doubling the ORR compared with wPTX alone (28% vs 16%; p = 0.0001). Globally, ramucirumab is relatively well tolerated with a toxicity rate not dissimilar to that expected in patients exposed to antiangiogenic drugs (Fuchs et al, 2014 and Wilke et al, 2014).
Sunitinib is an oral inhibitor of multiple receptor tyrosine kinases that are involved in tumor proliferation and angiogenesis, such as platelet-derived growth factor receptor (PDGFR) and VEGFR. On the basis of preclinical evidence, suggesting a synergistic antitumor effect of docetaxel and sunitinib (DS), a Korean phase II randomized trial was designed to evaluate the efficacy and safety of this combination in patients progressed on and after fluoropyrimidines and platinum therapy (Yi et al., 2012). DS combination showed non-superiority over D monotherapy for the primary endpoint (time to progression: TTP). However, the ORR was significantly higher in the DS arm (DS vs D only arm: 41.1% vs 14.3%, p = 0.002), with one complete remission maintained over 2 years. Despite the fact that the primary endpoint was not reached, the authors concluded that DS combination according to its high response rate might be considered in the neoadjuvant setting, particularly in potentially resectable locally AGC.
Adding sunitinib 25 mg vs placebo daily for 4 consecutive weeks followed by a 2-week rest to FOLFIRI in second- or third-line, as shown from a Dutch placebo-controlled phase II trial of 91 patients, increases hematotoxicity with no improvement in primary endpoint PFS (3.6 vs. 3.3 months) (Moehler et al., 2013).
Angiogenesis inhibition seems to play an important role also in patients progressing on second-line therapy.
The first clinical evidence of efficacy of apatinib, a novel oral small molecular VEGFR2 TKI, was demonstrated by a randomized, placebo-controlled and parallel-arm phase II trial, published from Li and colleagues in 2013 (Li et al., 2013). One hundred and forty-four Chinese patients, who experienced treatment failure with two or more lines of chemotherapy, were randomized to receive placebo, apatinib 850 mg once daily or apatinib 425 mg twice daily. Primary endpoint PFS was significantly longer in patients treated with either schedule of apatinib (3.67 and 3.20 months, respectively, vs 1.40 months for placebo; HR 0.18 and 0.21, respectively; p < 0.001).
Because patients given apatinib as a 850 mg once-daily experienced fewer grade ≥3 adverse events (AEs), this dosing regimen was chosen for a subsequent randomized phase III trial, presented at the 2014 ASCO annual meeting (Qin, 2014). Two hundred and seventy patients, progressing after second-line chemotherapy, were randomized in a 2:1 ratio to apatinib or placebo. The primary endpoint mOS was met (195 vs 140 days, HR 0.71; p < 0.016). Also mPFS was prolonged (78 vs 53 days, HR 0.44; p < 0.0001) while ORR was similar between two groups (2.84% and 0.00% for apatinib and placebo, respectively). With regard to safety, apatinib was generally well tolerated showing a toxicity profile consistent with other antiangiogenic drugs (Li et al, 2013 and Qin, 2014). Apatinib is the first biological treatment given as single drug that produced survival benefit in heavily pre-treated AGC patients.
6.2. mTOR pathway
Everolimus, an oral derivative of rapamycin, targets the mammalian target of rapamycin (mTOR), a key serine/threonine kinase implicated in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which is known to be disregulated in numerous human cancers.
The aim of the “First Gastric Antitumor Trial With Everolimus”, the phase III GRANITE-1 trial, was to demonstrate a benefit of everolimus 10 mg daily plus BSC over placebo plus BSC in previously treated AGC with one or two lines (Ohtsu et al., 2013). This study was designed based on encouraging findings of a phase II trial showing disease control rate (DCR) of 54.7%, PFS of 2.7 months and OS of 10.1 months (Doi et al., 2010). Unfortunately, the primary endpoint mOS was not reached (5.4 vs 4.3 months, HR 0.90; p = 0.124) in a molecularly unselected population. However, the authors highlight that, in a cross-study comparison, the mOS for everolimus arm was not dissimilar to that reported in other trials of second-line monochemotherapy (Table 1). As for PFS, even if it was significantly longer in the everolimus arm (1.7 vs 1.4 months, HR 0.66; p < 0.001), a gain of only 8 days should not be interpreted as clinically relevant. In a pre-planned stratification by number of prior chemotherapies and region of enrollment [Asia vs rest of world (ROW)], a trend toward reduced risk of death in favor of everolimus was seen in patients enrolled in ROW and, more strongly, in those who had undergone two previous chemotherapies. Biomarker analyses from GRANITE-1 trial are currently being awaited.
6.3. EGFR blockade
Human epidermal growth factor receptor (EGFR or HER1), which belongs to HER family and could play a critical role in the development of gastric cancer, has been investigated as possible molecular target in second-line therapy as well as in first-line.
Nimotuzumab is a recombinant humanized monoclonal IgG1 antibody against EGFR. In a phase II trial, 82 patients from Japan and Korea refractory to 5FU-based first-line therapy were randomized to receive nimotuzumab 400 mg weekly plus irinotecan 150 mg/m2 biweekly or irinotecan alone. Primary endpoint PFS was not reached (73 vs 85 days), regardless of EGFR protein expression which was assessed in approximately half of the sample (Satoh et al., 2014a).
6.4. HER2 blockade
Up to 20% of GC patients have tumors that overexpress HER2, another member of the EGFR family, playing a key role in the oncogenesis of gastric epithelium (Hofmann et al., 2008). Most importantly, HER2 has become a predictive factor in GC to trastuzumab, a monoclonal antibody that acts by the inhibition of HER2-mediated signaling as well as by the induction of antibody-dependent cellular cytotoxicity (Hudis, 2007). Based on the ToGA trial results, trastuzumab plus chemotherapy (cisplatin and fluoropyrimidines) has been approved in the first-line setting for AGC (Bang et al., 2010). In this trial, mOS was 13.8 months for trastuzumab arm vs 11.1 months for control arm, corresponding to a 26% reduction in the death rate. More importantly, mOS was even higher for the subgroup of patients with samples that have been scored either immunochemistry (IHC) 3+ or IHC 2+/fluorescence in situ hybridization (FISH)+ in the trastuzumab plus chemotherapy arm (16 vs 11.8 months). However, also in HER2 gastric cancers new treatment strategies are required to overcome primary (de novo) or secondary (acquired) resistance to trastuzumab, through a better understanding of the molecular, structural and biological properties of the HER2 and/or other HER family members.
6.4.1. Trastuzumab emtansine (T-DM1)
Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate of trastuzumab and the highly potent microtubule inhibitory drug mertansine (a maytansine derivative, known also as DM1). T-DM1 monotherapy has proven to overcome resistance to trastuzumab in patients with HER2 metastatic breast cancer previously treated with trastuzumab and a taxane (Verma et al., 2012), and in a phase II trial has shown to prolong PFS by 5 months as upfront therapy versus trastuzumab and docetaxel (Hurvitz et al., 2013). A multicenter, randomized, adaptive phase II/III trial is ongoing to evaluate the efficacy and safety of T-DM1 compared to standard taxane treatment (docetaxel or paclitaxel per investigator's choice) in patients with previously-treated HER2-positive AGC (Anon., 2015b). During the first stage, the dose and schedule of T-DM1 (3.6 mg/kg every 3 weeks vs 2.4 mg/kg every week) will be selected for use in the second stage of the study. This trial is currently recruiting subjects.
Lapatinib is a dually-potent TKI of HER2 and EGFR, blocking the EGFR/HER2-associated downstream signaling cascades. To note, a subgroup of HER2 positive tumors express p95HER2, an amino terminally truncated receptor that has kinase activity. In aberrant HER2 breast cancer cells, lapatinib was also found to be effective in overcoming the resistance to trastuzumab (Scaltriti et al., 2007). The Asian TyTAN phase III trial investigated the efficacy of second-line therapy with lapatinib in HER2 positive AGC patients (Satoh et al., 2014b); 261 patients meeting eligibility criteria were randomly assigned to receive wPTX alone (80 mg/m2 on days 1, 8, and 15 every 4 weeks) or wPTX plus lapatinib 1500 mg daily per os. In ITT population, the primary endpoint OS was not met, although a gain in median survival of more 2 months was registered (8.9 vs 11 months, HR 0.84; p = 0.1044). In a pre-specified subanalysis, the risk of death was significantly lower with lapatinib and wPTX (HR 0.59; p = 0.176) in the subgroup of patients with HER2/ICH 3+, reporting a remarkable 6.4-month advantage in mOS. Notably, few patients in each arm (∼5%) were previously treated with trastuzumab and mOS in paclitaxel monotherapy arm than in previous reports was surprisingly longer (8.9 months).
After publication of the first randomized trial of second-line chemotherapy in advanced gastric cancer in 2011, we have witnessed an outburst of publications in this setting. Reasons for a such growing interest may be various: (1) a strong unmet medical need for patients with AGC after failure of a first-line chemotherapy, (2) increasing number of fit patients who may benefit from a subsequent therapy and (3) availability of new biological agents.
Patients with AGC are difficult to treat, since they are commonly symptomatic for weight loss, abdominal pain, loss of appetite, nausea and malnutrition. First-line chemotherapy has been reported to prolong survival and to improve symptom control; combinations are more active than monotherapy but complete responses to chemotherapy are rare; responses are mostly of short duration and survival is <1 year in more than half of patients (Wagner et al., 2006). There is general consensus that the benefit achieved from platinum-based first-line chemotherapy in an unselected population has reached a plateau with a response rate of about 35%, a median survival time of 10 months and a 1-year survival rate of about 40%. Given the limitations of chemotherapy and its activity plateau, we can suppose that further progress may not be reached by conventional chemotherapy alone. Actually, several attempts have been undertaken to improve outcome of standard first-line platinum-based therapy by adding new biological agents to various chemotherapy doublets and triplets. Unfortunately, with the exception of ToGA trial (Bang et al., 2010), most studies with molecular targeted agents (MTAs) have failed to improve survival (Lordick et al, 2013, Waddell et al, 2013, Ohtsu et al, 2011, Shen et al, 2015, and Hecht et al, 2013). Although some progress has been made over the last decade in systemic treatment of AGC, the majority of patients will experience disease progression during or shortly after completion of first-line therapy. On the other hand, at the time of progression, an increasing number of patients still maintain a good performance status, and therefore remain good candidates for a second-line therapy.
To our knowledge, at the time of this writing, 18 randomized controlled trials (RTCs) focusing on the role of additional treatment beyond first-line chemotherapy have been published or presented at major scientific conferences. Randomized controlled trials of salvage therapy in AGC are heterogeneous showing significant differences in design, phase (II and III), sample size, primary and secondary endpoints, patients’ ethnicity and region of provenience.
Despite that, the results of these trials indicate that BSC may no longer be justified as control arm in future investigations or in clinical practice (Thuss-Patience et al, 2011, Kang et al, 2012, Ford et al, 2014, Fuchs et al, 2014, Li et al, 2013, and Qin, 2014) (Table 1 and Table 4). Second-line chemotherapy using either irinotecan or taxanes (docexatel and paclitaxel) may be recognized as standard of care for patients with AGC in both Asian and Western population, as demonstrated by single RTCs (Thuss-Patience et al, 2011, Kang et al, 2012, Ford et al, 2014, Hironaka et al, 2013, and Roy et al, 2013), Kim’s meta-analysis (Kim et al., 2013) and Iacovelli’s meta-analysis (Iacovelli et al., 2014). The mOS with monochemotherapy ranges from 4.0 to 10.1 months and ORRs from 0 to 40%. Monochemotherapy is able to reduce the risk of death from 27% to 36%, in Iacovelli’s and Kim’s meta-analysis, respectively (Iacovelli et al, 2014 and Kim et al, 2013), with a mOS ∼5 months (Tables 1, 2 and 4). By contrast, conventional polychemotherapy such as mFOLFIRI and BIRIP regimen, although well tolerated, do not improve outcomes in second-line setting, at least in Asian subjects (Sym et al, 2013 and Higuchi et al, 2014) (Table 2), whereas no data are available in Western population. Moreover, several RTCs investigating additional benefits of MTAs in second-line chemotherapy are planned or being conducted using either irinotecan or taxanes as either a platform or reference regimen (Table 4 and Table 5).
|ClinicalTrials.gov identifier||Brief title||Phase||Treatment||Endpoint||State||Estimated primary completion date|
|NCT01641939||A study of trastuzumab emtansine versus taxane in patients with advanced gastric cancer||II/III||Trastuzumab emtansine 3.6 mg/kg every 3 weeks vs Trastuzumab emtansine 2.4 mg/kg every week vs docetaxel or paclitaxel||OS||Recruiting||December 2016|
|NCT02072317||Paclitaxel plus raltitrexed plus compare with taxol second-line treatment for advanced gastric cancer||II||Paclitaxel/Raltitrexed vs Paclitaxel||PFS||Recruiting||March 2016|
|NCT01813253||Phase 3 study of nimotuzumab and irinotecan as second line with advanced or recurrent gastric and gastroesophageal junction cancer||III||Irinotecan/nimotuzumab vs irinotecan||OS||Recruiting||December 2014|
|NCT01084330||Phase II trial of AUY922 vs comparators in advanced gastric cancer||II||AUY922 70 mg/m2 vs docetaxel or irinotecan||PFS||Terminated||May 2012|
|NCT01839773||A phase 3 Study to Compare Efficacy and Safety of DHP107 vs Taxol® in patients with metastatic or recurrent gastric cancer after failure of first-line chemotherapy (DREAM)||III||DHP107 (oral paclitaxel) vs paclitaxel||PFS||Recruiting||April 2015|
|NCT01836120||A study of raltitrexed plus docetaxel versus docetaxel as second-line chemotherapy in subjects with gastric cancer||II||Raltitrexed/docetaxel vs docetaxel||PFS||Ongoing, Not Recruiting||December 2016|
|NCT01145404||Trial of lapatinib vs lapatinib with capecitabine in Her2+ metastatic gastro-esophageal cancer (GastroLap)||II||Lapatinib vs lapatinib/capecitabine||ORR||Terminated||February 2013|
|NCT02178956||A study of BBI608 plus weekly paclitaxel to treat gastric and gastro-esophageal junction cancer (BRIGHTER)||III||BBI608/Paclitaxel vs paclitaxel||OS||Recruiting||August 2017|
|NCT01187212||Sorafenib trial in advanced and/or recurrent gastric adenocarcinoma: treatment evaluation (STARGATE)||II||Capecitabine/cisplatin vs capecitabine/cisplatin + sorafenib||PFS||Completed||November 2013|
|NCT01573468||A randomized, double-blind study of capecitabine plus tesetaxel vs capecitabine plus placebo as second-line therapy in subjects with gastric cancer||II||Tesetaxel/capecitabine vs placebo/capecitabine||OS||Recruiting||July 2014|
ORR: objective response rate; PFS: progression free survival; OS: overall survival.
Considering the relatively poor survival of these patients and the palliative intent of a second-line therapy, the choice of the best therapeutic agent is crucial. In the first-line setting, on the basis of a pooled analysis of 1080 individual patients data and of REAL2 trial, three main poor prognostic factors have been identified: PS ECOG ≥ 2, liver metastases and peritoneal carcinomatosis (Chau et al, 2004 and Cunningham et al, 2010). On the other hand, HER2 status has been recognized as a predictive response factor to first-line trastuzumab-based therapy (Bang et al., 2010). Concerning the second-line setting, differences in performance status (ECOG 0-1 vs 2), progression-free interval to the first-line chemotherapy (<3 vs ≥3 months), number and type of prior chemotherapies (platinum-based or not), ethnicity and region, drug toxicity profile and treatment schedule, and tumor biology should be taken into account in choosing the most appropriate treatment.
Univariate analyses of single RTCs show that a good PS (ECOG 0-1), a chemotherapy-free interval longer than 3 months from the first-line therapy and a lower number of prior chemotherapies may be important positive indicators for survival (Thuss-Patience et al, 2011, Kang et al, 2012, and Kim et al, 2013).
Patients that had undergone free-platinum first-line chemotherapy, if maintaining good conditions and with no comorbidities conditioning platinum delivery, could benefit from second-line platinum-based therapy as shown by comparison of polychemotherapy sequences (Guimbaud et al, 2014 and Kim et al, 2011) and the BIRIP trial (Higuchi et al., 2014).
Regional differences in prescribing post-discontinuation therapy after disease progression have been advocated to explain survival diversities, as revealed by subset analyses of the larger recent RCTs. Overall, salvage chemotherapy is more frequently prescribed for Asian people than non-Asians, even in second-line setting. In the international RAINBOW trial (Wilke et al., 2014), the lack of benefit in OS for Japanese patients seems to be related to the higher use of post-discontinuation treatment in this group than Western patients (75% vs 38%), which indeed might have diluted the potential advantage of the combination arm (Hironaka et al., 2015). Moreover, some differences seem to exist among Asian countries. In the TyTAN trial, a clinically relevant OS benefit was observed with the addition of lapatinib to paclitaxel only in HER2 positive Chinese patients, but not in the Japanese subgroup in which, paradoxically, survival was much longer with paclitaxel alone compared to the combination (Satoh et al., 2014b). Because medical insurance in China does not cover second- and third-line drugs, Chinese patients are more comparable to population of the rest of world rather than to Japanese subjects (Satoh et al., 2014b).
Indeed, we are not completely sure that differences in clinical practices and reimbursement systems among countries can encompass every explanation of this phenomenon. So, we argue that other factors, such as differences in screening strategies, ethnicity and/or tumor biology, should be taken in consideration. Thus, in the near future, both regional differences in prescribing further chemotherapy and the choice of best primary end-point (OS vs PFS) should be carefully debated in an attempt to minimize and/or avoid inconsistent results in scientific research (Takiuchi, 2011).
Gastric cancer is a heterogeneous disease which may divided into different subgroups on histological, anatomical and molecular/genetic classifications. Historically, based on histopathological Lauren classification, gastric cancer is divided in intestinal and diffuse (Lauren, 1965), while, more recently, according to distinct patterns of gene expression two major intrinsic genomic subtypes have been identified: Genomic Intestinal (G-INT) and Genomic Diffuse (G-DIF) (Tan et al., 2011). Moreover, on the basis of histological-anatomical and genetic differences three distinct subtypes have been recognized: proximal non-diffuse (type 1), diffuse (type 2) and distal non-diffuse (type 3) (Shah et al., 2011). Interestingly, in the REGARD trial, as shown from a forest plot analysis, ramucirumab markedly improved OS in patients with diffuse GC type (Fuchs et al., 2014), although this finding was not confirmed in the RAINBOW trial (Wilke et al., 2014).
So, it could be assumed that specific genetic aberrations and molecular alterations may be involved in each subtype and that novel molecular subtypes would be considered (Tay et al, 2003 and Cancer Genome Atlas Research Network, 2014). Potentially, such anomalies could provide predictive biomarkers of response to targeted therapy in experimental studies and clinical practice (Wong and Yau, 2013).
Except for HER2 overexpression/amplification, however, a few predictive biomarkers are pending validation in GC: plasma VEGF-A levels and tissue neurolipin-1 expression (Van Cutsem et al., 2012), VEGFR2 overexpression (Fuchs et al, 2014, Wilke et al, 2014, Li et al, 2013, and Qin, 2014), HGF/MET (hepatocyte growth factor/mesenchymal-epithelial transition) pathway (Iveson et al, 2014, Salgia et al, 2014, and Lennerz et al, 2011), components of PI3K-AKT-mTOR pathway (Ohtsu et al., 2013) and FGFR2 (fibroblast growth factor receptor 2) amplification (Deng et al., 2012) (Fig. 1).
To date, the most promising molecular targets for salvage treatment appear to be angiogenesis signaling and HER2 overexpression. Two novel antiangiogenic agents, ramucirumab and apatinib, have shown to significantly prolong survival in second- and third-line therapy, respectively, highlighting the role of the VEGFR2 as biomarker to targeted treatment (Fuchs et al, 2014, Wilke et al, 2014, Li et al, 2013, and Qin, 2014). Instead, lapatinib could be delivered at least to HER2 positive Chinese subjects (Satoh et al., 2014b), whereas results from T-DM1 are being anxiously awaited (Hurvitz et al., 2013) (Table 4). For other targeted agents, such as sunitinib and everolimus (Yi et al, 2012 and Moehler et al, 2013), stronger predictive biomarkers are required, whereas anti-EGFR drugs should be abandoned (Satoh et al., 2014a) (Table 4).
In clinical practice, we think that the choice of a second-line chemotherapy should be based on drug toxicity profile and patients’ characteristics. Diarrhea is a common adverse reaction to CPT-11 and occurs less frequently in Asian patients than in Western patients also in second-line setting, likely because of ethnic diversity in metabolism of CPT-11 and higher doses commonly used in Western countries (Roy et al., 2013). By contrast, taxanes are more often affected by alopecia and neurotoxicity (Hironaka et al, 2013 and Roy et al, 2013). Among new active biological agents, the most common grade AE reported with either ramucirumab or apatinib was hypertension which occurred at similar rates (∼8%) to those previously described with bevacizumab in AVAGAST trial (Fuchs et al, 2014, Li et al, 2013, and Ohtsu et al, 2011). In the RAINBOW trial, grade 3 toxicity, including myelotoxicity, fatigue and hypertension, was more frequent with RAM/wPTX combination than with wPTX monotherapy, with no difference in febrile neutropenia (Wilke et al., 2014). However, higher toxicity rates of second-line treatment were counterbalanced by consistent clinical benefit in QoL (Ford et al, 2014 and Fuchs et al, 2014).
In conclusion, patients who are not refractory to a first-line chemotherapy, who have still a good PS (ECOG 0-1) and with a free-interval ≥3 months seem to be the best candidates for a further treatment. In solid tumors, the likelihood of responding to a subsequent treatment is strongly conditioned by the best response to the first-line chemotherapy and by the time interval between completion of the first-line and the beginning of a further treatment. Reintroduction of the same therapy and specifically of a platinum-based chemotherapy is more often used in clinical practice, even in AGC. It is possible to recognize three main categories of platinum-sensitive patients: “refractory” when PD occurs on treatment, “resistant” when progression-free interval is lesser than 3 months and “sensitive” when PD occurs after a long-lasting response (>3 months). Thus, for “sensitive patients”, in particular those with >6 months response, the reintroduction of the same regimen could be evaluated (NCCN, 2015). Interestingly, disease progression occurred during or within 4 months after the last dose of first-line therapy for the metastatic disease was one of the key inclusion criteria in both REGARD and RAINBOW trials (Fuchs et al, 2014 and Wilke et al, 2014). The choice of a platinum derivative, at the time of rechallenge, should be based on the different toxicity profile of the platins and on their cumulative toxicity. With regard to AGC, cisplatin is more emetic, oto- and nephro-toxic, while oxaliplatin is mainly characterized by cumulative neurotoxicity (Cunningham et al., 2010). By contrast, when an intrinsic or acquired resistance to platins occurs, other potentially active agents should be considered. However, BSC cannot be accepted as gold standard anymore, except for patients with poor performance status (ECOG ≥ 3), while the effectiveness of second-line therapy for patients with ECOG PS 2 has not been sufficiently demonstrated so far. Ethnicity and region of provenience, type of previous first-line chemotherapy, possible residual neurotoxicity and drug toxicity profile, patients’ desire (i.e., alopecia) and local regulatory issues (i.e., ramucirumab, apatinib) (Fig. 2), should guide us in the choice of the best drug. As for future research in this field, heterogeneity of the literature so far has not indicated a specific direction; it is not clear whether biological pathways, single biomarkers or specific clinical settings should represent the bases of the future design of second-line trials in AGC. However, we assume that the topics issued in this review could be particularly helpful in customizing medical therapy of AGC in routine daily practice in the era of tailored medicine. Finally, we are confident that simultaneous care and multidisciplinary approach are essential in management of this challenging disease and that a well-defined BSC should always be combined with anti-tumor therapy to make it more feasible.
Conflict of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
We would like to express our gratitude to IEO-CCM Foundation for supporting Dr Salvatore Galdy’s research fellowship through a donation in memory of Massimo Bottini. We also thank Kimberley Davies for English editing, Russell Edu Samuel William for his help with literature research and Daniele Maffeis for scientific figures designing.
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SalvatoreGaldy achieved his graduation in Medicine in October 2004 at University of Parma (Italy) and completed its training in Medical Oncology in November 2008. He is working currently as a research fellow at the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors of European Institute of Oncology (IEO) in Milan (Italy), where he is involved in clinical research projects mainly in the field of upper gastrointestinal cancer.
ChiaraAlessandraCella graduated from Faculty of Medicine at University of Naples Federico II (Italy) in September 2008 and obtained post-graduate degree in Medical Oncology in November 2014. She is working currently as a research fellow at the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors of IEO.
FrancescaSpada graduated in Medicine at University of Cagliari (Italy) in July 2004. She was involved in Regional Emergency Medical Services and completed her training in Medical Oncology at University of Sassari (Italy) in July 2011. Since 2011, she has been dealing with clinical practice and research activity in the field of neuroendocrine and gastrointestinal tumors at the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors of IEO, where she is currently working.
SabinaMurgioni is a trainee in Medical Oncology at University of Cagliari (Italy), with graduation in Medicine achieved in December 2007. Since November 2014, she has started a scientific collaboration with Dr Nicola Fazio at the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors of IEO, where she is currently attending.
AnnaMariaFrezza graduated in 2009 and is a trainee in Medical Oncology at University Campus Bio-Medico (Rome). During the years, she developed an interest in the field or rare cancers and she is currently attending the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors at IEO as a research fellow.
PaolaSimonaRavenda earned her medical degree in 2005 from University of Medicine in Messina (Italy) and completed her training in Medical Oncology in 2011 at the University of Pavia (Italy). In 2010 she attended Medical Oncology department at the Moffitt Cancer Center in Tampa (FL, USA) and, in 2011, at the Memorial Sloan Kettering Cancer Center in New York City (NY, USA). Since 2012, she has been working as medical oncologist at IEO within the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors.
MariaGiuliaZampino is deputy Director of the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors at IEO. She is actively part of a multidisciplinary team dedicated to gastrointestinal tumors, and focused on the management and research in the topic of lower gastrointestinal tract cancers.
NicolaFazio, consultant in Internal Medicine and Medical Oncology with PhD in Digestive Oncology, has been leading the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors at IEO since July 2011. With more than 80 scientific publications in peer reviewed journals, he is a member of all the main national and international oncological societies and he is recognized as opinion leader in neuroendocrine tumors management.
Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy
⁎ Corresponding author. Fax: +39 0294379273.
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