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. 2014 Sep;7(4 Suppl 1):S20–S27.

Cost Effectiveness Analysis (CEA) of Bevacizumab (Bev) in 1st and 2nd-line treatment of metastatic colorectal cancer (mCRC)

Daniel A Goldstein 1, Qiushi Chen 1, David H Howard 1, Joseph Lipscomb 1, Turgay Ayer 1, Bassel El-Rayes 1, Christopher R Flowers 1
PMCID: PMC4812840

ABSTR 1421 – Oral Presentation

Background:

The addition of Bev to 5-Fluorouracil (5-FU)-based chemotherapy is the standard of care for previously untreated mCRC. A recent randomized trial demonstrated a 1.4 month increase in median overall survival (OS) when Bev is continued beyond the first progression, thus making it standard practice to use Bev with 5-FU based chemotherapy in both 1st and 2nd line. International CEAs have evaluated Bev in the 1st-line setting. The objective of this study is to determine the cost effectiveness of Bev in the 1st line setting and when continued beyond progression from the US-payer perspective.

Methods:

We developed two Markov models to compare the cost and effectiveness of 5-FU, leucovorin and oxaliplatin (FOLFOX) with or without Bev in the 1st-line treatment, and subsequent chemotherapy with or without Bev in the 2nd-line treatment of mCRC. Weibull models were fitted to the published survival curves, and were used to extrapolate the cause-specific mortality and progression risks. Costs for administration and management of adverse events were based on Medicare reimbursement rates for hospital and physician services, and drug costs based on the Medicare average sale prices (all in 2013 US $). Health outcomes were measured in life years (LY) and quality-adjusted life years (QALYS). The simulated OS and progression free survival (PFS) were validated by the fitted survival models. Model robustness was addressed by univariate and probabilistic sensitivity analyses (PSA).

Results:

Using Bev in 1st-line therapy provided an additional 0.289 QALYs (0.412 LYs) at a cost of $69,381. The incremental cost-effectiveness ratio (ICER) was $240,195/QALY. Continuing Bev beyond progression provided an additional 0.108 QALYs (0.167 LYs) at a cost of $23,788. The ICER was $219,742/QALY. In all one way sensitivity analyses, the ICER of Bev was > $100,000/QALY. The ICER of Bev was greater than $100,000/QALY in > 99.9% of PSAs.

Conclusions:

This is the first US based CEA of Bev in mCRC. Bev provides minimal incremental benefit at high incremental cost per QALY in both the 1st and 2nd-line setting. The ICER of Bev could be improved by use of an effective biomarker to select patients most likely to benefit.

Gastrointest Cancer Res. 2014 Sep;7(4 Suppl 1):S20–S27.

Autophagy and Anti-Angiogenesis in Metastatic Colorectal Carcinoma: An Ongoing Multi-Institutional Phase 2 Trial of Hydroxychloroquine to Augment Effectiveness of Chemotherapy and Bevacizumab

Jalal Baig 1, Dirk Moore 2, Elizabeth A Poplin 3, Biren S Saraiya 4, Chunxia Chen 2, Shanti Prasad 5, Robert S DiPaola 3, Janice M Mehnert 3, Rebecca A Moss 3

ABSTR 1422 – Poster Presentation

Background:

Autophagy is a genetically controlled cellular response to stress whereby intracellular organelles are self-digested to generate energy via degradation in lysosomes. Angiogenesis inhibition is a known inducer of autophagy in tumor cells, allowing them to survive metabolic stress and potentially limit the therapeutic activity of chemotherapy (CT) and bevacizumab (bev). Colorectal (CRC) tumors have high expression of a key regulator of autophagy, corresponding to activation of this survival pathway. We report an ongoing phase 2 clinical trial designed to therapeutically inhibit autophagy with hydroxychloroquine (HCQ) in combination with angiogenesis inhibition and standard first-line treatment to determine safety and response rate in patients with metastatic CRC.

Methods:

Inclusion criteria were histologically proven metastatic CRC, ECOG performance of ≤2, normal organ and marrow function, measurable disease, and no previous CT for metastatic disease. Primary endpoints are progression-free survival (PFS) and response rate (RR) assessed by RECIST criteria every 12 weeks; secondary endpoints are overall survival (OS), safety and feasibility, and surrogate markers for autophagy. Patients received FOLFOX6 or XELOX (physician's discretion) and bev with HCQ 200 mg po BID daily until progressive disease (PD) or intolerable adverse effects. After accrual of 24 patients, an analysis of efficacy was conducted; the trial was permitted to continue, with a planned accrual of 43 patients in order to have an 80% power to detect an increase in response rate from 50% to 59%. For the present interim analysis, we computed Kaplan-Meier survival curve estimates for PFS and OS, which we compare to historical reports of median OS of 21.3 months (596 days) and median PFS of 8.0 months (240 days). Peripheral blood mononuclear cell specimens will be analyzed as surrogate markers for autophagy.

Results:

Enrollment began in May 2009. Below results represent data available as of 8/15/13. 39 of planned 43 patients were enrolled at 3 centers within the Rutgers Cancer Institute of New Jersey Oncology Group; 4 patients remained on treatment. One patient withdrew consent before treatment and one came off study for an allergic reaction to oxaliplatin on day #1; both are included in the intent to treat analysis. Median age 60 (38–81), male/female 23/16. Response data available for 33 patients is: complete response (1/33), partial response (PR) (13/33), stable disease (9/33), PD (3/33), not assessed (8/33) and not evaluable (1/33). 8 of the PRs were confirmed with subsequent scans. The median OS was 788 days (95% CI: lower 652, upper CI is not defined); median PFS was 424 days (95% CI: 214 to 619). 3 deaths have been reported on treatment, 2 attributed to PD and one gastrointestinal hemorrhage possibly related to bev.

Conclusions:

Standard CT and bev combined with HCQ, an autophagy inhibitor, is safe in patients undergoing first-line treatment for metastatic CRC. The median OS and PFS thus far in this phase 2 trial meets pre-specified trial criteria and suggests clinical efficacy of combination of standard therapy with an autophagy inhibitor. These results support further studies with this combination.

Gastrointest Cancer Res. 2014 Sep;7(4 Suppl 1):S20–S27.

Heuristic: Colitis by Colonoscopy

Fatma M Dihowm 1, Myat Soe 2, Linda Green 2, V Prem Chandar 2

ABSTR 1423 – Poster Presentation

It is rare for skeletal metastases of unknown primary to have a colonic origin. Metastasis only to bone without other organ involvement in colorectal cancer patients is extremely rare. We present a case of bone metastasis and hidden colonic carcinoma.

Case:

A 62 year old man with a history of eating moldy food presented with severe lower back pain, lower extremities weakness and numbness for a couple of days, alternating diarrhea and constipation and weight loss for 3 months. Colonoscopy 1-month prior had been negative for malignancy, positive for colitis and he had been placed on sulfasalazine. On admission he was found to have microcytic anemia and positive fecal occult blood test. Colonoscopy showed a 10 cm segment of necrotizing colitis without localized mass or polyp involving the sigmoid colon and rectum. MRI imaging of the spine revealed enhancing infiltrating lesions involving the T5, T6, T 11, and L3 vertebrae consistent with bone metastases. Biopsies of colon now revealed invasive poorly differentiated colonic adenocarcinoma with invasion the lamina propria and bone biopsies were positive for metastatic carcinoma.

Discussion:

Isolated skeletal metastasis from primary colonic carcinoma is rare event with incidence of 1.1% of all metastases from colonic cancer. Four cases of isolated bone metastases secondary to colon cancer without any other visceral metastasis and three cases of necrotizing colitis secondary to colonic carcinoma have been published. This case includes both of these characteristics.

Colon carcinoma metastasizes to the bone by haematogenous spread. Previously reported cases with bony and other distant metastases had pulmonary metastases and all cases with pulmonary metastasis had hepatic metastases. This suggests a stepwise progression with portal seeding of the liver preceding systemic spread via lungs; a hypothesis known as the cascade hypothesis, which does not fit our case.

Necrotizing colitis secondary to colon cancer without obstruction is very rare and the etiology is under investigation and will be reviewed. The leading hypothesis states that mucosal ischemia is caused by submucosal infiltration of tumor and decreased blood supply. Hypoxia may play a role by stimulating the germination of spores and bacterial growth which lead to massive necrosis of the bowel.

Gastrointest Cancer Res. 2014 Sep;7(4 Suppl 1):S20–S27.

Postsurgical Adjuvant Nanosurgery via Photoablation for Targeted Photothermal Cancer Therapy (PTC) Causes Nanophotothermolytic Cancer Stem Cell Death via Pulsed Nir Laser in Metastatic Radio/Chemoresistant CRC

John Giannios 1

ABSTR 1424 – Poster Presentation

Background:

After surgery angiogenic factors are overexpressed in CRC where adjuvant treatment eradicates CRC cells but not the cancer stem cells (CSCs) which are resistant to conventional anticancer treatment causing deadly metastasis. Thus, after adjuvant treatment we must eradicate the cancer stem cells which constitute the 2% of the tumour mass. For this aim we use Nanosurgery with NIR laser-pulses which exert adjuvant ablation of resistant to conventional anticancer therapy metastatic colorectal Ca (CRC) CSCs by selective nano-photothermolysis mediated by pegylated-antiCD44 plasmonic gold-nanobombs. This non-invasive approach may be targeted to a specific molecular signature of CRC cells which have the potentiality to exert resistance to conventional anticancer treatments leading to metastasis.

Materials and Methods:

Our immunotargeted NIR pegylated nanogold particles which are covalently conjugated to anti-CD44 Abs are used for highly specific molecular targeting of CRC-CSCs. Our goal is to design a novel postsurgical adjuvant treatment facilitated by plasmonic laser nanosurgery (PLN) which will be targeted towards CSCs for the complete eradication of CRC growth. After preparing the plasmonic pegylated gold immunonanoparticles which are conjugated covalently with anti-CD44 Abs for selective molecular targeting of CRC-CSCs, we administer them IV post surgically to biopsy derived xenograft CRC models for reaching the remaining CSCs which overexpress CD44, circumventing with their stealth effect biological milieu interactions such as opsonin adsorption and subsequent reticuloendothelial system (RES) elimination, via the enhanced-permeability and retention (EPR) effect where bioconjugated nanoparticles passively accumulate at remaining postsurgical tumour sites, which are characterized by leaky and immature vasculature that have wider fenestrations than normal mature blood vessels.

The nanoparticle size of 40–50 nm, which is optimal for cellular entry of nanogold, has 600 times more absorption in cancer cells than normal cells. The particle size of nanogold-antiCD44 conjugate which is 40–50 nm is small enough to pass via the blood vessels of the remaining postsurgical tumor with fenestrae of 100 nm in diameter, and large enough to pass via the blood vessels of health organs which have fenestrae of no more than 5 nm in diameter.

The anti-CD44 antibodies, which are conjugated onto nanogolds target, bind specifically onto the cell surface transmembrane glycoprotein CD44 which is a hyaluronan receptor of CSCs activating cytoskeleton proteins such as microtubules (MTs) and actins which induce endocytotic internalization of nanoparticles that are transported into the cytoplasm of CSCs by early and late endosomes.

Then, we irradiate with short NIR laser pulse of wavelength 1064 nm at 40 mJ/cm2 which is far below the safety standard for use of medical lasers for healthy cells and tissue, which is 100 mJ/cm2.

Results:

The short laser pulses exerted selective nanophotothermolysis only to the CSCs which had nanogold particles intracellularly that caused necrotic and apoptotic or type I programmed cell death (PCD) after there was thermal expansion of the gold nanoparticles which are characterized by a high plasmon resonance (SPR) absorption efficiency generating photoacoustic waves. The laser energy induced inside the CSCs temperatures which have reached up to 95° C exerting hyperthermic effects which due to the short exposure will prevent extensive high temporative dissipation circumventing healthy cells.

CSCs are very vulnerable to hyperthermia due to their rapid metabolic rates disrupting the signaling metabolic pathways, inducing acidosis and apoptosis due to the release of immunostimulants, such as heat-shock proteins. Also, the increases in temperature denaturate cytoskeletal and nuclear proteins inhibiting their synthesis by impending RNA and DNA polymerization. Furthermore, hyperthermia exerts cell membrane damage causing blebbing. Generally, thermal protein denaturation is caused in all intracellular proteins that are adjacent to the gold nanoparticles. The hyperthermic effects might damage the vasculative supply of the tumour cells, and cause disruption of homeostasis leading to microthrombosis.

Another mechanism consists of bubble formation around the gold-nanoparticles due to the explosive liquid evaporation (ELE), which is accompanied by acoustic and shock waves. This causes melting of the gold-nanoparticles which enhances tremendously their radius leading to their evaporation that forms small particles and gold vapor bubbles.

The next observed nonlinear mechanisms consisted of optical-breakdown with subsequent formation of plasma cavity, and generation of strong shock waves which cause explosion of the nanoparticles that act as nanobombs leading to their fragmentation and exerting extensive cellular damage via disintegration of organelles, and nuclear fragmentation which causes an apoptotic bystander killing effect.

Thus, the laser nanosurgery may lead to apoptosis of CSCs via coagulation, and disruption which is caused by nanophotothermolysis that is associated with thermochemical transformation of vital cellular proteins, and explosive vaporization in the intracellular regions which are located near the gold nanobombs generating shock waves which are associated with supersonic expansion of dense vapor intracellularly which produces optical-plasma, and strong sound waves leading to photothermal apoptotic cell death (PACD) caused by oxidative stress and depolarization of the membranes of mitochondria which activate apoptotic caspases leading to fragmentation of the DNA.

This nanophotothermolysis of DNA caused by the thermal explosion of gold nanobombs due to possible Coulomb explosion via ionization of multiphotons and thermal explosion through electron photon excitation relaxation (EPER) eradicated the targeted BCSCs sparing the healthy adjacent colorectal cells.

Conclusion:

Thus, we have the medical potentiality with targeted molecular nanodelivery to identify the CSCs in CRC after surgery, and subsequently as adjuvant eradicating treatment with nanosurgical laser ablation facilitated by a flexible optical fiber to selectively target the remaining CSCs which cause metastasis under a personalized cancer medicine approach based on pharmacogenomics, and mediated by nanomedicine leading to their apoptotic cell death with a bystander killing effect by nanophotothermolysis without harming the adjacent healthy colorectal cells under a Trojan horse nanodelivery system which facilitates a “bow and arrow” theranostic approach circumventing the “one size fits all” approach.

Gastrointest Cancer Res. 2014 Sep;7(4 Suppl 1):S20–S27.

Stem Cell Therapy (SCTx) with induced Pluripotent Stem Cells (iPSCs) Encoded with Anti-GRP78 shRNA Induce Apoptosis (PCD) After a Gene-silencing Bystander Effect Inhibiting Angiogenesis, and Metastatic Spread in Chemoresistant Advanced CRC Cells

John Giannios 1

ABSTR 1425 – Poster Presentation

Background:

Induction of an innate cancer cellular stress response caused by conventional chemotherapy enhances the expression of GRP78 which blocks programmed cell death or apoptosis(PCD) increasing tumour growth and metastasis due to enhanced angiogenesis in CRC cells. We aim to circumvent this with the use of induced pluripotent stem cells encoded with antisense GRP78 shRNA.

Methods:

We take induced pluripotent stem cells (iPSCs), which we infected them with a DNA vector that encoded an RNA molecule of 67 nucleotides. The sequence of this small hairpin RNA (shRNA) is designed to suppress the GRP78 gene. CRC cells were obtained from chemoresistant patients, and they were implanted in animal models, which were treated with conventional chemotherapeutic agents. After tumor relapse, there was induction of enhanced angiogenesis, and metastasis. These chemoresistant tumor cells were treated with the induced pluripotent stem cells, which were encoded with shRNA against GRP78.

Results:

Post-treatment, stem cells encoded with anti-GRP78 shRNA converted dicer into a siRNA molecule generating a long lasting RNAi silecing effect of GRP78, which spreads to adjacent tumor cells inducing a gene silencing bystander effect (GSBE). Capillary growth into the tumors was blocked, while VEGF and bFGF were downregulated. PKG was upregulated inhibiting b-catenin. Integration of endothelial precursor cells and tumor cells was blocked inhibiting growth of mosaic blood vessels. This leads to inhibition of tumor spread or metastasis, while the existing tumors die from lack of nutrients/oxygen, and a waste disposal pathway. TEM exhibited induction of type I PCD or apoptosis in tumor cells leading to a bystander killing effect. Thus, Stem Cell Therapy (SCT) with anti-GRP78 induced pluripotent stem cells (iPSCs) circumvented chemotherapeutic induced angiogenesis, and metastasis eradicating chemoresistant CRC cells.

Conclusion:

Chemotherapy induced angiogenesis, and metastatic spread in chemoresistant CRC cells are circumvented with Stem Cell Therapy(SCT) consisting of induced pluripotent stem cells (iPSCs) encoded with anti-GRP78 shRNA, which induces apoptosis (PCD) after a gene silencing bystander effect (GSBE).

Gastrointest Cancer Res. 2014 Sep;7(4 Suppl 1):S20–S27.

The consistency of effect of ziv-aflibercept (Z) in the bevacizumab (B) pre-treated subgroup of patients (pts) in the VELOUR trial stratified by 1st line progression ≥9 months (mos) vs < 9 mos

Paulo M Hoff 1, Guy van Hazel 2, David Cunningham 3, Dirk Arnold 4, Hans Schmoll 5, Albert J Ten Tije 6, Sarah Naoshy 7, Florence Joulain 8, Joe McKendrick 9, Raghu Vishwanath 10, Emmanuelle Dochy 11, Edith Mitchell 12

ABSTR 1426 – Poster Presentation

Background:

The addition of B to an oxaliplatin-based regimen in 1st line metastatic colorectal cancer (mCRC) pts has shown a median progression free survival (PFS) of 9.4 mos as seen in NO16966. In the ML18147 study, the benefit of B added to chemotherapy (CT) in 2nd line mCRC following 1st line CT + B combinations, was evaluated in pts pre-stratified by 1st line PFS ≤9 mos and >9 mos. We evaluated the consistency of the treatment effect of Z+FOLFIRI (F) vs placebo (P)+F according to the timing of progression from 1st line therapy (.9 mos vs. ≥9 mos) in the subgroup of pts treated with an oxaliplatin containing regimen and B in 1st line from VELOUR (NCT00561470).

Methods:

In VELOUR, 186 pts in the Z+F and 187 in the P+F groups were stratified to prior B. There were 17 pts (9 in Z+F and 8 in P+F arm) who experienced recurrence during or within 6 mos of completing adjuvant oxaliplatin-based therapy – (a population excluded from ML18147), who were excluded from this analysis. The prior B treated subgroup was analyzed by the timeframe of 1st line progression ([PFS] ≥9 vs <9 mos) in this post-hoc analysis. Hazard Ratio (HR) was adjusted on the baseline value of: Performance Status, prior B, age, hypertension, and number of metastatic organs.

Results:

Z+F had an overall survival (OS) benefit in B pre-treated pts both with 1st line PFS ≥9 mos and in pts with 1st line PFS < 9 mos, as shown by the median difference (MD) in OS (Table). A similar benefit was observed with PFS.

Conclusions:

In this post hoc analysis, pts benefited from Z+F therapy regardless of the timing of their 1st line progression <9 months or ≥9 months on a 1st line oxaliplatin + B containing regimen.

Study supported by Sanofi and Regeneron.

Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting. All rights reserved.

Gastrointest Cancer Res. 2014 Sep;7(4 Suppl 1):S20–S27.

Evaluation of the Effect of Aflibercept (Z) on OS by Timing of 1st Line Disease Progression: A Post-hoc Analysis of the VELOUR Trial

Edith Mitchell 1, Guy van Hazel 2, David Cunningham 3, Dirk Arnold 4, Hans Schmoll 5, Albert J ten Tije 6, Joe McKendrick 7, Florence Joulain 8, Michael Andria 9, Raghu Vishwanath 10, Paulo Hoff 11

ABSTR 1427 – POSTER PRESENTATION

Background:

An overall survival (OS) of 20.6 months (95% CI, 17.7 to 24.6) and median progression free survival (PFS) of 8.0 months (P = 0.26) were previously demonstrated with first-line (1L) FOLFOX6 followed by FOLFIRI (F) (Tournigand, JCO 2004). Treatment of metastatic colorectal cancer (mCRC) patients with 1L combination chemotherapy (CT) and bevacizumab (B) results in a significant increase in median PFS (9.4 mos) (HR, 0.83; 97.5% CI, 0.72 to 0.95; P=0.0023) compared to CT alone (8.0 mos) (Saltz, JCO 2008). The heterogeneity in the timing of progression in 1L therapy could potentially impact the benefit of 2nd-line treatments. The VELOUR trial (NCT00561470) demonstrated that angiogenesis inhibition with the addition of aflibercept (Z) (known as ziv-aflibercept in the US) to the combination of 5-fluouracil, leucovorin, and irinotecan (FOLFIRI) after progression on oxaliplatin-based CT.

The consistency of the treatment effect of Z+FOLFIRI (F) vs placebo (P)+F was evaluated based on time to progression after 1st line therapy.

Methods:

The VELOUR ITT population (excluding pts who relapsed during or within 6 months of completing oxaliplatin-based adjuvant therapy (rapid adjuvant progressors) ) (N=1102) was analyzed based on time by the timeframe of 1st line progression (PFS < 3 months, 3–6 months, 6–9 months or ≥ 9 months) in a post-hoc analysis.

Results:

Z had an overall survival (OS) benefit in pts across all subgroups analyzed irrespective of the timing of 1st line PFS. A similar benefit was observed with PFS.

Conclusions:

In this post hoc analysis, the addition of Z to 2nd line F was beneficial regardless of the timing of progression during 1st line treatment. These results emphasize the consistent benefits of Z in combination with F in mCRC patients who failed an oxaliplatin-based regimen whether the duration of disease control with 1L regimen was short or of longer term.

Prior B Subgroup P+F [95% CI] N = 168 Z+F [95% CI] N=161 Median Difference (mo) HR [95% CI]
1st line PFS ≥9 mos Pts, n 92 86
Median OS, mos 14.23 [11.6; 18.9] 17.94 [14.5; 21.5] 3.71
aHR 0.772 [0.52; 1.15]
Median PFS, mos 4.24 [3.9; 5.5] 7.26 [6.5; 8.7] 3.02
aHR 0.588 [0.391; 0.89]
1st line PFS <9 mos Pts, n 76 75
Median OS, mos 7.11 [5.2; 10.3] 9.92 [7.3; 11.4] 2.81
aHR 0.825 [0.57; 1.18]
Median PFS, mos 2.79 [2.5; 3.2] 5.65 [3.9; 7.2] 2.86
aHR 0.57 [0.39; 0.83]
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Subgroup OS
 Adjusted Hazard Ratio (aHR)
P+F n = 550 Z+F n = 552
1st line PFS <3 mos Pts, n (%) 64 (11.6%) 55 (10%)
Median, mos [95% CI] 9.76 [7.20 ; 12.42] 11.86 [10.41 ; 18.04]
aHR vs P [95% CI] 0.701 [0.451 ; 1.090]
1st line PFS 3 – 6 mos Pts, n (%) 99 (18%) 84 (15.2%)
Median, mos [95% CI] 9.00 [6.67 ; 10.87] 9.92 [7.69 ; 11.79]
aHR vs P [95% CI] 0.704 [0.504 ; 0.984]
1st line PFS 6 – 9 mos Pts, n (%) 128 (23.3%) 129 (23.4%)
Median, mos [95% CI] 10.63 [9.03 ; 12.55] 12.48 [10.22 ; 14.29]
aHR vs P [95% CI] 0.822 [0.619 ; 1.093]
1st line PFS ≥ 9 mos Pts, n(%) 257 (46.7%) 283 (51.3%)
Median, mos [95% CI] 15.15 [13.63 ; 17.22] 17.35 [15.18 ; 18.73]
aHR vs P [95% CI] 0.883 [0.712 ; 1.096]
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aHR = adjusted Hazard Ratio. HR adjusted on baseline value of: Performance Status, prior B, age, hypertension, and number of metastatic organs.

Research supported by Sanofi, in collaboration with Regeneron Pharmaceuticals.

No medical writing support utilized.

Reused with permission of the first author. Previously presented at ESMO 2014 16th World Congress on Gastrointestinal Cancer (WCGIC), Barcelona, Spain.

Gastrointest Cancer Res. 2014 Sep;7(4 Suppl 1):S20–S27.

Aflibercept/FOLFIRI vs Placebo/FOLFIRI in Metastatic Colorectal Cancer: A Post-Hoc Analysis of Median Overall Survival in VELOUR From the Retrospectively Assessed Time of Starting First-Line Treatment

Josep Tabernero 1, Teresa Macarulla 1, Yves Humblet 2, Albert J ten Tije 3, Hendrik Kroening 4, Cristina Gravalos 5, Solenn Le-Guennec 6, Emmanuelle Dochy 7, Eric Van Cutsem 8

ABSTR 1428 – POSTER PRESENTATION

Background:

Treatment of patients with metastatic colorectal cancer (mCRC) with first-line (1L) FOLFOX6 followed by FOLFIRI has demonstrated 20.6 months (95% confidence interval [CI]: 17.7-24.6) median overall survival (OS) (Tournigand C et al. J Clin Oncol. 2004;22(2):229–237). Treatment with 1L chemotherapy (CT) + bevacizumab (Bev) followed by 2L CT +/− Bev in the ML18147 trial, increased median OS to 23.9 months (95% CI: 22–25.7) with CT + Bev versus 22.5 months (95% CI: 21.4–24.5) with CT alone (hazard ratio [HR], 0.90; 95% CI: 0.77-1.05) from the start of 1L treatment (Bennouna J et al. Lancet Oncol. 2013;14(1):29–37). In the ITT population of the VELOUR trial (NCT00561470), in mCRC patients previously treated with oxaliplatin, addition of aflibercept (Afl; ziv-aflibercept in the USA) to FOLFIRI increased median OS to 13.5 months versus 12.06 months in the FOLFIRI + placebo arm [(Δ OS, 1.4 months; HR, 0.817; 95.34% CI: 0.713–0.937; P<0.0032). In VELOUR, ∼10% of patients enrolled were adjuvant rapid relapsers (ARR), defined as recurrence during or within 6 months of completing oxaliplatin-based adjuvant therapy. A post-hoc analysis of the patients who enrolled in VELOUR after receiving 1L therapy (ie, ITT population subsequent to exclusion of ARR) increased median OS to 13.8 months in the Afl + FOLFIRI arm versus 11.9 months for FOLFIRI + placebo (ΔOS, 1.9 months; adjusted HR, 0.80; 95% CI: 0.69–0.92 [Joulain F et al. Ann Oncol. 2012;23(suppl 9):ix214. Poster 633P]). We performed an additional post-hoc analysis of VELOUR to evaluate survival from start of 1L treatment until death in the ITT minus ARR population, according to prior Bev treatment.

Methods:

Data from VELOUR were analyzed by the Kaplan-Meier method to determine median OS from first day of 1L treatment until death in pre-specified subgroups according to prior Bev exposure. Probability of survival at 48 months from 1L treatment in each subgroup was also determined. The population in this analysis was the VELOUR ITT (N=1226), excluding ARR (N=124) (who enrolled directly into VELOUR as described previously [Van Cutsem E et al. Eur J Cancer. 2013;49(suppl 2):Abstract 2260]); it also excluded 1 patient (Afl) with incomplete start date of 1L therapy, yielding N=1101 (ie,1226 - 124 - 1).

Results:

Addition of Afl to FOLFIRI resulted in median OS improvement of >3 months for mCRC patients treated in 1L with an oxaliplatin-based regimen, with a median OS of >2 years (Table 1). The probability of survival at 48 months following FOLFIRI-Afl treatment was ∼20% in all patient subgroups analyzed (Table 2).

Gastrointest Cancer Res. 2014 Sep;7(4 Suppl 1):S20–S27.

Quality of life (QoL) on the aflibercept/FOLFIRI regimen: 4th interim analysis of the global Aflibercept Safety and Health-Related QoL Program

Julien Taieb 1, Roberto Bordonaro 2, Katia Bencardino 3, Libero Ciuffreda 4, Francesco Di Costanzo 5, Maria Di Bartolomeo 6, Anne L Thomas 7, Hendrik Kröning 8, Pilar García Alfonso 9, Christophe Borg 10, Yan Moore 11, Sandrine Brette 12, Chiara Zilocchi 13, Florence Joulain 14, Sarah Naoshy 11, Pascale Garreau-Laporte 14, Emmanuelle Dochy 15, Gerard Lledo 16, Alberto Sobrero 17

ABSTR 1429 – POSTER PRESENTATION

Background:

In the phase 3 VELOUR trial, aflibercept (ziv-aflibercept in the United States) + FOLFIRI significantly improved overall survival vs FOLFIRI alone in metastatic colorectal cancer (mCRC) patients (pts) previously treated with an oxaliplatin-containing regimen. Results of VELOUR supported initiation of the global Aflibercept Safety and QoL Program, comprising 2 clinical studies (ASQoP [NCT01571284]; AFEQT [NCT01670721]) that capture utility values derived from QoL instruments and additional safety data from a population similar to that of VELOUR in a real-life setting. We report QoL and utility value data from the 4th interim analysis of the ASQoP/AFEQT studies.

Methods:

Target recruitment in ASQoP is 900 pts from 150 multiple country sites, and 200 pts from French sites for AFEQT. The EuroQoL EQ-5D™ instrument served as the utility measure and the EORTC QLQ-C30 as the generic cancer instrument. QoL populations were pts evaluable for the respective questionnaire at baseline and ≥1 assessment post-baseline and received ≥1 part of 1 dose of study treatment. Both instruments were self-administered at baseline and the beginning of every odd treatment cycle. Four preplanned interim analyses were conducted.

Results:

At the 4th interim analysis cutoff date, the EQ-5D population comprised 523 pts; 57.6% men, median age 62 years (range 20–89), 65.4% had Eastern Cooperative Oncology Group scores = 0. Mean baseline utility index was 0.77 (95% CI, 0.75–0.79). Utility index remained relatively stable at cycle 3 (in 449 evaluable pts) and up to cycle 17 (in 33 evaluable pts) with a mean (±SD) change from baseline of -0.02 (±0.24) and −0.08 (±0.19), respectively. Mean baseline global health status (GHS) score from EORTC QLQ-C30 was 68.44 (95% CI, 66.68–70.21) and remained in the stable range across subsequent cycles for both GHS and functional scales.

Table 1.

Median OS in VELOUR and From First Day of 1L Treatment Until Death

ITT minus ARR Median OS VELOUR
 Median OS From First Day of 1L Treatment Until Death (mo)
FOLFIRI-PBO (n=550) FOLFIRI-AFL (n=552) FOLFIRI-PBO (n=550) FOLFIRI-AFL (n=551)
HR (95% CI) 0.80 (0.69–0.92) 0.79 (0.69–0.91)
Median OS (mo) 11.9 13.8 22.9 25.9
Δ median OS (mo) 1.9 3.08
ITT minus ARR (prior Bev) FOLFIRI-PBO (n=179) FOLFIRI-AFL (n=173) FOLFIRI-PBO (n=179) FOLFIRI-AFL (n=177)
HR (95% CI) 0.81 (0.63–1.04) 0.84 (0.66–1.08)
Median OS (mo) 11.7 13.8 23.72 24.51
Δ median OS (mo) 2.1 0.79
ITT minus ARR (no prior Bev) FOLFIRI-PBO (n=371) FOLFIRI-AFL (n=375) FOLFIRI-PBO (n=371) FOLFIRI-AFL (n=374)
HR (95% CI) 0.766 (0.65–0.91) 0.772 (0.65–0.92)
Median OS (mo) 12.42 13.73 22.64 26.18
Δ median OS (mo) 1.31 3.54
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Conclusions:

Trends from this interim analysis suggest relatively stable utility and QoL scores in mCRC pts treated in second line with aflibercept + FOLFIRI. This has important implications in advanced cancer, as patient-reported outcomes provide an important, real-world perspective on health status and well-being.

Reused with permission from the European Society of Medical Oncology (ESMO). This abstract was accepted and previously presented at the 2014 ESMO Annual Meeting. All rights reserved

Trial supported by Sanofi and Regeneron.

Gastrointest Cancer Res. 2014 Sep;7(4 Suppl 1):S20–S27.

Aflibercept + FOLFIRI for treatment of metastatic colorectal cancer after oxaliplatin failure: 4th interim safety data from the global Aflibercept Safety and Quality-of-Life Program (ASQoP/AFEQT studies)

Luca Frassineti 1, Maria Di Bartolomeo 2, Volker Heinemann 3, Anne L Thomas 4, Julien Taieb 5, Gerard Lledo 6, Yan Moore 7, Chiara Zilocchi 8, Sandrine Brette 9, Alberto Sobrero 10, Roberto Bordonaro 11

ABSTR 1430 – POSTER PRESENTATION

Background:

In VELOUR, aflibercept (ziv-aflibercept in the US) + FOLFIRI demonstrated a statistically significant improvement in overall survival vs placebo + FOLFIRI in metastatic colorectal cancer (mCRC) patients (pts) previously treated with an oxaliplatin-containing regimen. Results supported initiation of the global Aflibercept Safety and Quality-of-Life (QoL) Program composed of 2 clinical studies (ASQoP; AFEQT) to capture utility values from QoL instruments and collect safety data from a population similar to that in VELOUR in a real-life setting. We report safety data from the 4th interim analysis of these ongoing studies.

Methods:

ASQoP and AFEQT are single-arm, open-label trials in mCRC pts previously treated with an oxaliplatin-containing regimen. Eligible pts received aflibercept 4 mg/kg every 2 weeks on day 1 of each cycle followed by FOLFIRI. FOLFIRI starting dose and subsequent additional dose modifications are at discretion of the treating physician.

Results:

At data cut-off for this interim analysis, the safety population (n=688) was compared with VELOUR. In 44% of ASQoP vs 33.5% of VELOUR, pts were ≥65 years; 10.8% of ASQoP vs 5.4% of VELOUR were ≥75 years. ASQoP pts received a median of 6 treatment cycles while VELOUR pts received a median of 9. Grade (G) 3/4 adverse events (AEs) were experienced by 72.2% of ASQoP pts vs 83.5% in VELOUR. Most were G3. G4 hypertension or diarrhea was not reported. Table shows selected G3/4 AEs.

Adverse Events, % ASQoP/AFEQT
 VELOUR
Aflibercept + FOLFIRI (n=688)
 Aflibercept + FOLFIRI (n=611)
Grade 3/4 (%) Grade 3/4 (%)
Proteinuria 3.6 7.9
Stomatitis and ulceration (high level term) 9.6 13.8
Diarrhea (preferred term) 14.1 19.3
Infections and infestations (system organ class) 9.6 12.3
Hypertension 23.0 19.3
Arterial thromboembolic event 0.6 1.8
Venous thromboembolic event 4.4 7.9
Fistula (gastrointestinal [GI] origin) 0.6 0.3
GI perforation 1.3 0.5
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Conclusions:

Interim safety analysis from ASQoP/AFEQT has identified no new safety signals. Despite a greater % of elderly pts in ASQoP/AFEQT, reported incidence of toxicity is generally similar or less than VELOUR. Differences in AE incidence in ASQoP/AFEQT vs VELOUR may be related to the VELOUR protocol requirement of full-dose FOLFIRI initiation and current overall exposure differences.

Trial supported by Sanofi and Regeneron.

Medical writing support provided by Phase V Communications and provided by Sanofi.

Reused with permission of the first author. Previously presented at ESMO 2014 16th World Congress on Gastrointestinal Cancer (WCGIC), Barcelona, Spain.

Articles from Gastrointestinal Cancer Research : GCR are provided here courtesy of International Society of Gastrointestinal Oncology

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