original articles
Annals of Oncology 27. Di Fiore F, Blanchard F, Charbonnier F et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 2007; 96: 1166–1169. 28. Lievre A, Bachet JB, Boige V et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008; 26: 374–379. 29. De Roock W, Piessevaux H, De Schutter J et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008; 19: 508–515. 30. Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359: 1757–1765. 31. Agresti A. Categorical Data Analysis. Hoboken, New Jersey: John Wiley & Sons, 2002. 32. Klein J, Moeschberger M. Survival Analysis. New York: Springer-Verlag, 1997. 33. Chung KY, Shia J, Kemeny NE et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005; 23: 1803–1810.
34. Lenz HJ, Van Cutsem E, Khambata-Ford S et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006; 24: 4914–4921. 35. Wierzbicki R, Jonker DJ, Moore MJ et al. A phase II, multicenter study of cetuximab monotherapy in patients with refractory, metastatic colorectal carcinoma with absent epidermal growth factor receptor immunostaining. Invest New Drugs 2011; 29: 167–174. 36. Richman SD, Seymour MT, Chambers P et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 2009; 27: 5931–5937. 37. Tol J, Dijkstra JR, Klomp M et al. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer 2010; 46: 1997–2009. 38. Di Nicolantonio F, Martini M, Molinari F et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008; 26: 5705–5712.
Annals of Oncology 24: 1777–1785, 2013 doi:10.1093/annonc/mdt057 Published online 19 March 2013
A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer† A. L. Cohn1*, J. Tabernero2, J. Maurel3, E. Nowara4, J. Sastre5, B. Y. S. Chuah6, M. V. Kopp7, D. D. Sakaeva8, E. P. Mitchell9, S. Dubey10, S. Suzuki10, Y.-J. Hei11, F. Galimi11, I. McCaffery11, Y. Pan12, R. Loberg11, S. Cottrell12 & S.-P. Choo13 1 Rocky Mountain Cancer Center, Denver, USA; 2Medical Oncology Department, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona; 3Medical Oncology Department, Hospital Clinic de Barcelona, Barcelona, Spain; 4Maria Skodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland; 5Hospital Clinico San Carlos, Servicio de Oncologíca Medíca, Madrid, and Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid, Spain; 6Department of Internal Medicine, National University Hospital, Singapore, Singapore; 7Samara Regional Oncology Dispensary, Samara; 8 Clinical Oncology Dispensary of the Republic of Bashkortostan, Ufa, Russia; 9Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia; 10 Amgen Inc., South San Francisco; 11Amgen Inc., Thousand Oaks; 12Amgen Inc., Seattle, USA; 13Medical Oncology, National Cancer Centre Singapore, Singapore
Received 1 November 2012; revised 21 January 2013; accepted 22 January 2013
Background: Targeted agents presently available for mutant KRAS metastatic colorectal cancer (mCRC) are bevacizumab and aflibercept. We evaluated the efficacy and safety of conatumumab (an agonistic monoclonal antibody against human death receptor 5) and ganitumab (a monoclonal antibody against the type 1 insulin-like growth factor receptor) combined with standard FOLFIRI chemotherapy as a second-line treatment in patients with mutant KRAS mCRC. Patients and methods: Patients with mutant KRAS metastatic adenocarcinoma of the colon or rectum refractory to fluoropyrimidine- and oxaliplatin-based chemotherapy were randomized 1 : 1 : 1 to receive intravenous FOLFIRI plus
*Correspondence to: Dr A. L. Cohn, Medical Oncology, Rocky Mountain Cancer Center, 1800 Williams Street, Suite 200, Denver, CO 80218, USA. Tel: +1-303-3884876; Fax: +1-303-377-8375; E-mail:
[email protected] †
These data were presented in part at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, San Francisco, CA, USA, 19–21 January 2012. Clinical Trial Registration: ClinicalTrials.gov; NCT00813605.
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
[email protected].
original articles
Annals of Oncology
conatumumab 10 mg/kg (Arm A), ganitumab 12 mg/kg (Arm B), or placebo (Arm C) Q2W. The primary end point was progression-free survival (PFS). Results: In total, 155 patients were randomized. Median PFS in Arms A, B, and C was 6.5 months (HR, 0.69; P = 0.147), 4.5 months (HR, 1.01; P = 0.998), and 4.6 months, respectively; median overall survival was 12.3 months (HR, 0.89; P = 0.650), 12.4 months (HR, 1.27; P = 0.357), and 12.0 months; and objective response rate was 14%, 8%, and 2%. The most common grade ≥3 adverse events in Arms A/B/C included neutropenia (30%/25%/18%) and diarrhea (18%/2%/10%). Conclusions: Conatumumab, but not ganitumab, plus FOLFIRI was associated with a trend toward improved PFS. Both combinations had acceptable toxicity. Key words: conatumumab, FOLFIRI, ganitumab, KRAS, metastatic colorectal cancer
introduction Targeted therapies that have demonstrated improved outcomes in patients with metastatic colorectal cancer (mCRC) include monoclonal antibodies (mAbs) against the epidermal growth factor receptor (EGFR) [1–3] and vascular endothelial growth factor (VEGF) [4, 5] and small-molecule multikinase inhibitors [6]. Anti-EGFR mAbs are ineffective for patients with KRAS mutations, which occur in 40%–45% of patients with mCRC [3, 7–11]. Colorectal tumors express high levels of the proapoptotic death receptors (DRs) 4 and 5 [12–14]. Conatumumab is an investigational, fully human, agonistic mAb of DR5 that induces CRC cell apoptosis through activation of caspase-3/7 [15]. In CRC models, conatumumab inhibited tumor growth as monotherapy and enhanced tumor growth inhibition in combination with irinotecan and fluorouracil [15]. In the firstin-human study, conatumumab had acceptable toxicity as monotherapy up to 20 mg/kg and exhibited evidence of activity in some patients with mCRC [16]. High expression of the type 1 insulin-like growth factor receptor (IGF1R) in colorectal tumors is associated with advanced tumor stage [17] and shorter overall survival (OS) following first-line chemotherapy [18]. Small-molecule and mAb antagonists of IGF1R induce tumor cell apoptosis and tumor regression in CRC models [19–21]. Ganitumab is an investigational, fully human mAb against IGF1R that prevents insulin-like growth factor (IGF)-1 and IGF-2 from binding to IGF1R [22]. In sarcoma and pancreatic carcinoma models, ganitumab promoted apoptosis, inhibited tumor cell proliferation, caused tumor regression, and enhanced the activity of other cytotoxic agents, including irinotecan [22, 23]. Ganitumab had acceptable toxicity up to 20 mg/kg and exhibited antitumor activity in the phase 1, first-in-human study in patients with advanced solid tumors [24]. The objectives of this randomized, placebo-controlled phase 2 study were to assess the efficacy and safety of conatumumab or ganitumab combined with leucovorin, 5-fluorouracil, and irinotecan (FOLFIRI) as a second-line treatment in patients with mutant KRAS mCRC.
methods patients Eligible patients (aged ≥18 years) had histologically confirmed metastatic adenocarcinoma of the colon or rectum and documented disease
| Cohn et al.
progression ≤6 months after one prior therapy (fluoropyrimidineand oxaliplatin-based chemotherapy with or without anti-VEGF therapy) for metastatic disease and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 [25]. Measurable disease was not required. Mutant KRAS status was required per central laboratory testing of formalin-fixed, paraffin-embedded (FFPE) tumor tissue from the primary tumor or metastatic site as previously described [3, 8] or per local testing by an experienced laboratory using a validated test method after a protocol amendment (February 2010). Institutional review board approval of the study protocol was obtained, and patients provided written informed consent before enrollment.
study design and treatment This phase 2, multicenter, randomized, double-blind, placebo-controlled study was conducted at 49 centers in 10 countries. Patients were randomly assigned 1 : 1 : 1 to three treatment arms by a representative of the study sponsor using an interactive voice response system and permuted blocks. A double-dummy design was used to blind the patients, investigators, study monitors, and study team to treatment; those analyzing patient samples were not blinded. All patients received FOLFIRI: irinotecan (180 mg/m2) and leucovorin (400 mg/m2) by intravenous infusion on day 1 and 5-fluorouracil (400 mg/m2) intravenous bolus on day 1 followed by 2400 mg/m2 continuous infusion administered over days 1 and 2. Patients also received placebo plus conatumumab 10 mg/kg (Arm A), placebo plus ganitumab 12 mg/kg (Arm B), or double placebo (Arm C) on day 1 of each 14-day cycle. Randomization was stratified by ECOG PS (0 versus 1) and previous therapy with first-line VEGF pathway inhibitors (yes versus no). Doses of conatumumab and ganitumab were based on preclinical and clinical pharmacokinetic results [16, 24, 26, 27]. Treatment continued until radiographic disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, clinical progression, requirement for alternative therapy, intolerable toxicity, withdrawal of consent, or study end. The primary end point was progression-free survival (PFS; time from randomization to disease progression or death) per investigator assessment. Secondary end points included OS (time from randomization to death), objective response rate (ORR), disease control rate (DCR), duration of response, time to response, incidence of adverse events (AEs) and laboratory abnormalities, and incidence of anti-conatumumab and antiganitumab antibody formation. Exploratory end points included pharmacodynamic biomarkers of response (serum IGF-1, IGF-2, IGF binding protein [IGFBP]-1, IGFBP-2, IGFBP-3, and IGFBP-6); biochemical levels and abundance of drug targets and other biomarkers in tumor samples [e.g. phosphatase and tensin homolog (PTEN) expression] and correlation with outcome; and genetic variations in drug target and pathway genes (FCGR3A).
Volume 24 | No. 7 | July 2013
original articles
Annals of Oncology
dose adjustments AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Dose modifications were not permitted for investigational products (IPs), except for 50% reductions for grade ≥3 thrombocytopenia without grade >1 bleeding. IP was withheld until the following improved to grade ≤1 or baseline: grade ≥3 hyperglycemia, hepatic transaminase elevations, or anemia; grade 4 amylase/lipase increases; and grade 3 nonhematologic treatment-related toxicities. IP was withheld if grade 3 anorexia, nausea, vomiting, stomatitis/mucositis, or diarrhea were not manageable despite supportive care. IP was discontinued if withheld >28 days or for grade ≥3 thrombocytopenia with grade ≥1 bleeding. If a cycle was delayed >14 days for chemotherapy-related toxicity, IP was also delayed.
tumor assessment Tumor response was based on investigator assessment ( per RECIST, version 1. 0 [25]) of computed tomography or magnetic resonance imaging scans carried out at weeks 6 and 12 and every 8 weeks thereafter until disease progression or requirement for alternate therapy. Responses were to be confirmed radiographically after ≥4 weeks.
safety assessment AEs occurring from enrollment through the 30-day safety follow-up visit were graded per NCI-CTCAE. Serum for assessment of anti-conatumumab and anti-ganitumab antibodies by electrochemiluminescence immunoassays [16, 24] was collected predose on day 1 of cycles 1 and 5, every 4 cycles thereafter, and at follow-up visits (30 and 60 days after the last dose).
biomarker analysis Serum samples for biomarker assessments were collected predose and 3 and 24 h post dose on day 1 of cycles 1 and 3; predose on day 1 of cycle 5 and every four cycles thereafter; and at the 30-day follow-up visit. Serum IGF-1, IGF-2, IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-6 were measured using competitive binding radioimmunoassays [27]. DNA from blood samples was assessed for FCGR3A V158F single-nucleotide polymorphism genotyping using an allelic discrimination assay [26]. Archived and fresh tumor tissue samples were assessed for nuclear and cytoplasmic staining expression of PTEN by immunohistochemistry [27].
statistical analysis This study was designed to estimate the treatment effect of adding conatumumab or ganitumab to FOLFIRI. Randomization of 150 patients was planned. With the planned estimation precision and assuming a hazard ratio (HR) of 0.5, the goal was to allow estimation of the PFS hazard ratio with a two-sided 95% confidence interval (CI) having a maximum half-width of 0.31. The study had an 81% probability of detecting a difference in PFS between the ganitumab or conatumumab arms versus the placebo arm. The full analysis set included all randomized patients. The safety analysis set included all patients who received ≥1 IP dose. The primary analysis, planned after a minimum of 100 PFS events, occurred on 31 January 2011. The OS analysis was done ∼12 months later (16 February 2012). PFS and OS were analyzed using Cox proportional hazards models stratified by ECOG PS (0 versus 1) and previous anti-VEGF therapy (yes versus no). Differences between the experimental and placebo arms were estimated with HRs and two-sided 95% CIs; P-values are descriptive. Kaplan–Meier estimates and 95% CIs of median PFS and OS times were calculated. CIs for ORR and DCR were calculated using the Clopper–
Volume 24 | No. 7 | July 2013
Pearson method [28]. Differences (95% CI) in the ORR were estimated using the Newcombe-Wilson method with continuity correction. SAS version 9.2 (SAS Institute, Inc., Cary, NC) was used for all analyses.
results patients Between 31 March 2009 and 31 January 2011, 155 patients were randomized (Arm A, n = 51; Arm B, n = 52; Arm C, n = 52). Patient demographics and baseline characteristics were generally similar across the arms (Table 1); however, a higher proportion of patients in Arm B (77%) had stage IV disease at diagnosis than in Arms A (67%) and C (56%). Prior exposure to VEGF pathway inhibitors was consistent among treatment arms (Arm A, 57%; Arm B, 60%; Arm C, 58%). One hundred fifty-two patients (98%) had received ≥1 dose of blinded treatment by the primary analysis data cutoff date. As of 31 January 2011, 14 patients in Arm A, 11 patients in Arm B, and 14 patients in Arm C continued to receive study treatment (Figure 1). The median number of infusions of conatumumab, ganitumab, and placebo was 13, 10, and 14, respectively (supplementary Table S1, available at Annals of Oncology online). Median relative dose intensity of the FOLFIRI components was slightly lower in Arm C than in Arms A and B. No patients had IP withheld because of noncompliance.
survival and response At the time of the primary analysis, 103 patients (66%) had disease progression or had died (Arm A, n = 33; Arm B, n = 34; Arm C, n = 36). Median PFS in Arms A, B, and C was 6.5, 4.5, and 4.6 months, respectively. The HRs (adjusted for stratification factors) for PFS were 0.69 (95% CI 0.41–1.14; P = 0.147) in Arm A versus Arm C and 1.01 (95% CI 0.61– 1.66; P = 0.998) in Arm B versus Arm C (Table 2, Figure 2). At the time of the OS analysis, 62% of patients had died (Arm A, n = 32; Arm B, n = 33; Arm C, n = 31). Median OS in Arms A, B, and C was 12.3, 12.4, and 12.0 months, respectively. The HRs (adjusted for the stratification factors) for OS were 0.89 (95% CI 0.54–1.48; P = 0.650) in Arm A versus Arm C and 1.27 (95% CI 0.76–2.13; P = 0.357) in Arm B versus Arm C (Table 2). Overall, 151 (97%) patients had measurable disease at baseline. In Arms A, B, and C, the ORR was 14%, 8%, and 2%, respectively (Table 2), and the median duration of response was 5.3, 5.6, and 5.2 months.
toxicity Toxicity is summarized in Table 3. The grade ≥3 AE incidence was 72% in Arm A, 55% in Arm B, and 47% in Arm C. The serious AE incidence was greater in Arms A (40%) and B (31%) than in Arm C (24%). Two patients died within 30 days of the last study treatment dose. One patient in Arm B, who had grade 2 hyperglycemia before the first ganitumab dose and experienced ongoing grade 3 hyperglycemia after the first ganitumab dose, died of treatment-emergent diabetic ketoacidosis following the second ganitumab dose. Three additional patients in Arm B and two in Arm C had nonserious grade ≥3 hyperglycemia events. One patient in doi:10.1093/annonc/mdt057 |
original articles
Annals of Oncology
Table 1. Patient demographic and baseline characteristicsa Arm A Conatumumab 10 mg/kg + FOLFIRI (n = 51) Sex, n (%) Men Women Median (range) age (years) Race/ethnicity, n (%) White Black Hispanic Asian Geographical region, n (%) North America Europe Asia Primary tumor type, n (%) Colon Rectal Months since primary diagnosis, median (range) Stage IV disease at initial diagnosis ECOG performance status, n (%) 0 1 Target lesion sites, n (%) 0 1 2 ≥3 Liver metastases, n (%) Prior VEGF pathway inhibitor exposure, n (%)
Arm B Ganitumab 12 mg/kg + FOLFIRI (n = 52)
Arm C Placebo + FOLFIRI (n = 52)
27 (53) 24 (47) 59 (37–79)
24 (46) 28 (54) 58 (28–81)
23 (44) 29 (56) 59 (32–80)
40 (78) 2 (4) 0 (0) 9 (18)
41 (79) 3 (6) 1 (2) 7 (13)
38 (73) 4 (8) 1 (2) 9 (17)
17 (33) 26 (51) 8 (16)
15 (29) 30 (58) 7 (13)
16 (31) 28 (54) 8 (15)
38 (75) 13 (25) 13.8 (3.5–85.9)
34 (65) 18 (35) 12.3 (3.8–47.6)
43 (83) 9 (17) 12.5 (3.6–149.7)
34 (67)
40 (77)
29 (56)
31 (61) 20 (39)
28 (54) 24 (46)
30 (58) 22 (42)
0 (0) 26 (51) 18 (35) 7 (14) 34 (67) 29 (57)
1 (2) 22 (42) 23 (44) 6 (12) 36 (69) 31 (60)
3 (6) 24 (46) 18 (35) 7 (13) 36 (69) 30 (58)
a
Full analysis set. ECOG, Eastern Cooperative Oncology Group; FOLFIRI, leucovorin, 5-fluorouracil, and irinotecan; VEGF, vascular endothelial growth factor.
Arm A died of unknown causes; this death was considered by the investigators to be potentially related to study treatment. There were no grade ≥3 infusion reaction events. Pretreatment anti-conatumumab binding antibodies were detected in four patients (two each in Arms A and B). Posttreatment anti-conatumumab binding and neutralizing antibodies were detected in one patient who tested negative at baseline. Anti-ganitumab binding antibodies were detected pretreatment in 15 patients (Arm A, n = 6; Arm B, n = 3; Arm C, n = 6) and post treatment in three patients (one per arm). The pretreatment antibodies might be the result of crossreactivity resulting from molecular mimicry.
biomarkers Serum samples for pharmacodynamic biomarker analysis relevant to ganitumab were available from 146 patients. Total (bound and unbound) IGF-1 and IGFBP-3 increased and remained elevated during treatment with ganitumab but not conatumumab or placebo (supplementary Figure S1, available at Annals of Oncology online). Within the conatumumab and placebo arms, modest decreases in IGF-1 were observed during
| Cohn et al.
treatment. No differences were observed among treatment arms for total IGF-2, IGFBP-1, IGFBP-2, or IGFBP-6. In Arms B and C, there were positive associations between PFS and higher baseline total IGF-1, total IGF-2, or IGFBP-3 levels and decreased baseline IGFBP-1 or IGFBP-2 levels; however, there was no treatment effect of ganitumab on PFS for any of these markers (Figure 3). Archived tumor samples for immunohistochemistry assessment of PTEN expression were available for 145 (94%) patients. Cytoplasmic and nuclear PTEN staining was consistent between treatment arms. There was an association between low baseline cytoplasmic PTEN expression (determined by % cells with staining score >0 and H score) and longer PFS in Arm C; no associations between baseline nuclear PTEN expression and PFS were observed in any arm (supplementary Figure S2, available at Annals of Oncology online). With potential relevance to conatumumab [29], 94 patients genotyped for FCGR3A 158 polymorphisms were assessable for PFS. There were no associations between any of the assessed FCGR3A 158 genotypes (FF, FV, VV, or FV + VV) and PFS in Arms A and C.
Volume 24 | No. 7 | July 2013
Annals of Oncology
original articles
Figure 1. CONSORT diagram. FOLFIRI, leucovorin, 5-fluorouracil (5-FU), and irinotecan. Asterisk indicates that a patient in Arm B discontinued the study before receiving investigational product as a result of an adverse event (supraventricular arrhythmia); an additional patient in Arm A and one patient in Arm B had not received investigational product at the date of the primary analysis data cutoff and were therefore included in the full analysis set but not in the safety analysis set. Dagger indicates that a patient randomized to the placebo group received a single dose of ganitumab as a result of an isolated dosing error and was therefore included in Arm B for the safety analysis.
discussion In this randomized phase 2 study of second-line treatment of patients with mutant KRAS mCRC, the addition of conatumumab to FOLFIRI was associated with a trend toward improved PFS but not OS; however, the addition of ganitumab to FOLFIRI did not improve PFS or OS. The trend toward improved PFS with the addition of conatumumab to FOLFIRI is interesting given that other phase 2 trials have not demonstrated conclusive evidence of activity by DR4 or DR5 agonists in mCRC [30, 31]. However, our study differed from these in requiring patients to have mutant KRAS tumors and including a placebo arm. Furthermore, our study population had received only one prior chemotherapy regimen with or without a VEGF pathway inhibitor, whereas the other phase 2 studies enrolled patients who had previously received multiple prior chemotherapy regimens [30, 31]. Additionally, the results with ganitumab are consistent with those from other studies, which have shown limited antitumor activity by anti-IGF1R mAbs in patients with chemotherapy- or anti-EGFR-refractory mCRC [32–35]. However, the disproportionately higher enrollment of patients with stage IV disease in the ganitumab arm versus the other treatment arms may have influenced the outcomes. Median PFS in the placebo arm (4.6 months) was consistent with investigator assessment of patients with mutant KRAS mCRC treated with FOLFIRI alone (4.9 months) versus FOLFIRI plus panitumumab as second-line therapy in a large randomized phase 3 study [3]. Although median OS in the placebo arms was similar between the studies (12.0 versus 11.1 months, respectively), for unknown reasons, the ORR in the placebo arm of our study was lower than the ORR (by central
Volume 24 | No. 7 | July 2013
review) in the placebo arm of the phase 3 study (2% versus 14%, respectively) [3]. There were no differences in relative dose intensity of chemotherapy delivered that can explain this result; however, fewer cycles of chemotherapy were administered in all arms of our study compared with the panitumumab study [3]. The difference might also be attributable to the use of investigator review of imaging data rather than independent central review. Combined with FOLFIRI, conatumumab and ganitumab had manageable toxicity; no new safety signals were identified. The toxicities occurring in the conatumumab and ganitumab arms were generally consistent with those previously reported for each agent [16, 24]. In the conatumumab arm, anemia was observed with similar frequency and severity as in patients with advanced solid tumors treated with conatumumab monotherapy in the first-in-human study [16]. Grade ≥3 neutropenia and anemia observed in the conatumumab arm have also been reported with similar frequency in other studies of DR4 or DR5 inhibitors combined with cytotoxic chemotherapy or targeted agents in patients with advanced solid tumors [36], non-small-cell lung cancer [37], and soft tissue sarcoma [38]. Diarrhea, another common AE for conatumumab, occurred with a relatively high incidence (58%) versus historical monotherapy data [16] and may explain the slightly lower median relative dose intensity of IP in the conatumumab arm. In the ganitumab arm, the overall rate of grade ≥3 hyperglycemia (8%) is lower than previously reported in other studies [27, 39]. Hyperglycemia is a known toxicity associated with IGF1R mAbs [32–34, 40]. Thrombocytopenia of any grade was more frequent with ganitumab versus placebo, similar to findings with ganitumab monotherapy [26].
doi:10.1093/annonc/mdt057 |
original articles
Annals of Oncology
Table 2. Efficacy analysisa Arm A Conatumumab 10 mg/kg + FOLFIRI (n = 51) Progression-free survival PFS events, n (%) Median Kaplan–Meier PFS time (95% CI), month Stratified HRb (95% CI) P-value Overall survivalc OS events, n (%) Median Kaplan–Meier OS time (95% CI), month Stratified HRb (95% CI) P-value Objective response Patients with measurable disease, n (%) Confirmed objective response rate (CR+PR),d n (%) 95% CI Best overall response, n (%) Confirmed CR Confirmed PR Stable disease Progressive disease Not evaluable Not done Disease control rate (95% CI) at week 18 (%) Median (range) time to response (month) Median duration (95% CI) of response (month)
Arm B Ganitumab 12 mg/kg + FOLFIRI (n = 52)
33 (65) 6.5 (4.4–7.0)
34 (65) 4.5 (3.0–6.6)
0.69 (0.41–1.14) 0.147
1.01 (0.61–1.66) 0.998
32 (63) 12.3 (10.9–17.3)
33 (63) 12.4 (8.1–15.4)
0.89 (0.54–1.48) 0.650
1.27 (0.76–2.13) 0.357
51 (100) 7 (14) 6–26 0 (0) 7 (14) 28 (55) 9 (18) 0 (0) 7 (14) 37 (24–52) 2.6 (1.3–3.5) 5.3 (4.0–5.7)
51 (98) 4 (8) 2–19 0 (0) 4 (8) 30 (59) 7 (14) 1 (2) 9 (18) 27 (16–42) 4.6 (2.8–5.0) 5.6 (3.9–6.8)
Arm C Placebo + FOLFIRI (n = 52) 36 (69) 4.6 (3.1–6.5)
31 (60) 12.0 (8.7–17.6)
49 (94) 1 (2)
