From Nov 18, 2009, to April 11, 2012, 388 patients were screened for IGF-1R expression by immunohistochemistry. Of these, 211 (54%) were IGF-1R positive and 177 (46%) were IGF-1R negative across many sarcoma subtypes (). Patients were then enrolled into a treatment group at the discretion of the treating physicians until 54 patients had been enrolled in each group. All groups met the requirements for stage 1 before enrollment continued. The remainder of the screened patients were excluded because the study arm was closed to patient accrual or the patient did not meet protocol eligibility, had poor performance status, withdrew consent, elected to seek hospice or other treatments, or for other reasons (). On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group and nine in the IGF-1R-negative sarcoma group, giving a total of 57 patients with IGF-1R-positive soft-tissue sarcoma (group A), 54 with IGF-1R-positive bone sarcoma (group B), and 63 with IGF-1R-negative sarcoma (group C). This protocol amendment was made because of over enrolment into group A (patients who consented before enrolment was halted) and on the basis of promising results in first 54 patients in group C. shows the baseline demographics and patient characteristics, including the most common histological subtypes by IGF-1R status, for all treated patients. The mean number of previous systemic regimens was two (range one to four).
Insulin-like growth factor-1 receptor status according to histological subtype in at least five patients for all screened patients
Demographics and baseline characteristics
After the first stage of enrolment, more than five patients in each group were progression free at 12 weeks. By intention-to-treat analysis, of the 54 patients in each group in the original cohort (ie, before the protocol amendment), 17 patients (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21–43) in the IGF-1Rpositive soft-tissue sarcoma group, 19 patients (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24–47) in the IGF-1R-positive bone sarcoma group, and 21 patients (39%; one-sided 95% CI lower bound 28%; two-sided 90% CI 28–51) in the IGF-1R-negative group were progression free at 12 weeks.
After the protocol amendment and inclusion of additional patients, 17 of 57 patients (30%; one-sided 95% CI lower bound 20%; two-sided 90% CI 20–41) in the IGF-1R-positive soft-tissue sarcoma group and 26 of 63 (41%; one-sided 95% CI lower bound 31%; two-sided 90% CI 31–52) in the IGF-1R-negative group were progression free at 12 weeks. At the time of final analysis, the median follow-up of survivors was 18.6 months (range 2.9–30.9). The median PFS by Kaplan–Meier estimates for all treated patients was 6.9 weeks (95% CI 5.9–12.0) for the IGF-1R-positive soft-tissue sarcoma group, 10.6 weeks (6.0–15.3) for the IGF-1R-positive bone sarcoma group, and 11.6 weeks (9.3–17.9) for the IGF-1R-negative group ().
Kaplan–Meier curves for progression-free survival and overall survival
Based on 98 deaths and a median duration of followup of 18.6 months (range 2.9–30.9), the median overall survival in all treated patients (n=174) was 18.9 months (95% CI 13.1 to not reached [NR]) for patients with IGF-1R-positive soft-tissue sarcoma, 14.2 months (7.6 to NR) for patients with IGF-1R-positive bone sarcoma, and 14.7 months (10.6 to NR) for patients with IGF-1R-negative sarcoma; ). All deaths were due to disease progression.
Nine patients achieved a partial response: one (2%) of 57 patients in the IGF-1R-positive soft-tissue sarcoma group, six (11%) of 54 patients in the IGF-1R-positive bone sarcoma group, and two (3%) of 63 patients in the IGF-1Rnegative group. There were no complete responses.
Analysis of plasma biomarkers in 55 patients (15 in the IGF-1R-positive soft-tissue sarcoma group, 23 in the IGF-1R-positive bone sarcoma group, and 17 in the IGF-1R-negative group) for IGF-1 and IGF-BP3 showed no correlation to PFS or overall survival (data not shown). All patients with disease progression at week 12 had significant increases in plasma biomarkers from baseline to weeks 3 or 7 (p<0.01 appendix
32 patients (nine in the IGF-1R-positive soft-tissue sarcoma group, 16 in the IGF-1R-positive bone sarcoma group, and seven in the IGF-1R-negative group) at MSKCC had serial tumour biopsies undertaken before treatment and between weeks 2 and 3 of the first cycle of therapy and analysed by western blot. Although suppression of IGF-1R and inhibition of both p-S6 and p-Akt was noted in individual patients in all treatment arms, semi-quantitative analysis did not suggest any consistent association between the percent decrease in IGF-1R, p-S6, or p-Akt expression and clinical outcome (). All patients in the immunohistochemistry defined IGF-1R-negative group—in which IGF-1R was assessable by western blot (five of the seven)—were IGF-1R positive by western blot ().
Percent change from baseline in protein expression for p-Akt, p-S6, and IGF-1R, relative to best response
Of 2546 adverse events reported, 214 (8%) were grade 3–4. Grade 1–2 and 3–4 events that occurred in at least 5% of all patients treated are listed by stratification groups () and by histological subtype (appendix
). The incidence of grade 3 and 4 events was similar between the three study arms. The most common grade 3–4 toxicities in the 174 patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%) patients, hypo phosphataemia in 16 (9%) patients, lymphopenia in 25 (14%) patients, oral mucositis in 19 (11%) patients, and thrombocytopenia in 19 (11%) patients. Although hyperglycaemia was noted in 119 (68%) of 174 patients, this was generally grade 1–2 and was well controlled. Of 174 patients treated on the study, 83 (48%) experienced a serious adverse event; 43 (52%) of these patients had a serious adverse event reported as possibly, probably, or definitely related to drug therapy. Among the serious adverse events for which a causal relation to drug therapy was suggested, only oral mucositis (12 [7%]) and thrombocytopenia (nine [5%]) occurred in at least 5% of 174 patients treated. There were four (2%) deaths on study and all of these were attributable to disease progression. Except for one episode of hypoxia, there were no reports of pneumonitis.
Adverse events of grade 1 or higher experienced by at least 5% of patients
91 (52%) of 174 patients needed either one (40 patients [23%]) or two (51 patients [29%]) dose reductions of temsirolimus. Of the 91 patients who needed one or more dose reductions, the most common causes were for thrombocytopenia (24 patients [26%]), oral mucositis (18 [20%]), or grade 1 or greater increases in aminotransferases (17 [19%]). 47 (27%) of 174 patients needed one (32 patients [18%]) or two (15 [9%]) dose reductions of cixutumumab. 16 (34%) of the 47 dose reductions were related to thrombocytopenia.
In a post-hoc analysis, we analysed median PFS, overall survival, and response according to histological subtype and IGF-1R status. The median PFS for the most common histological subtypes were 7.5 weeks (95% CI 5.6–17.7) for Ewing's sarcoma, 6.0 weeks (5.9–15.7) for osteosarcoma, 21.4 weeks (5.7–35.4) for chondrosarcoma, 11.4 weeks (6.3–15.3) for leiomyosarcoma, and 12.9 weeks (5.6–46.9) for undifferentiated pleomorphic sarcoma. For patients with osteosarcoma and leiomyosarcoma, IGF-1R status did not have an effect on median PFS (). However, for Ewing's sarcoma and chondrosarcoma, IGF-1R immunohistochemistry expression had a statistically significant effect on median PFS (). Nine (82%) of 11 IGF-1R-positive chondrosarcomas were histologically grade 2 and 3 and five (56%) of these nine were dedifferentiated. For patients with Ewing's sarcoma, the median PFS was 5.7 weeks (95% CI 4.3–11.9) for those with IGF-1Rpositive disease and and 17.7 weeks (9.0 to NR) for those with IGF-1R-negative disease (p=0.027, ). For patients with chondrosarcoma, the median PFS was 23.0 weeks (11.0 to NR) for those with IGF-1R-positive disease and 8.1 weeks (3.0 to NR) for those with IGF-1R-negative disease (p=0.048, ). For the eight patients with solitary fibrous tumours, the median PFS for the four patients with IGF-1R-positive disease was 89.6 weeks (4.0 to NR) and 16.1 weeks (5.0 to NR) for those with IGF-1Rnegative disease, but this was not statistically significantly different (p=0.22). This analysis included two patients with IGF-1R-positive solitary fibrous tumours who remained on study for 126 weeks and another who remains on study for 96 weeks.
Kaplan–Meier curves for post-hoc analyses
Median overall survival was 16.2 months (95% CI 5.2 to NR) for Ewing's sarcoma, 14.6 months (8.6 to NR) for leiomyosarcoma, not reached (7.6 to NR) for osteosarcoma, 13.6 months (10.6 to NR) for chondrosarcoma, 15.5 months (8.5 to NR) for undifferentiated pleomorphic sarcoma, and 18.9 months (11.9 to NR) for others (). In a post-hoc analysis, patients with IGF-1R-negative Ewing's sarcoma also had a numerical but not statistically significant (p=0.16) improvement in median overall survival (NR, 95% CI 16.2 to NR) when compared with those who were IGF-1R positive (14.0 months, 4.6 to NR).
shows the waterfall plot for best RECIST response according to histology. Four of 27 (15%) patients with Ewing's sarcoma, three of 24 (13%) with osteosarcoma, one of 17 (6%) with chondrosarcoma, and one of eight (13%) with solitary fibrous tumour (hemangiopericytoma) had partial responses. There were no complete responses. Of the four patients with a diagnosis of gastrointestinal stromal tumour, one (IGF-1R positive) had a 13% decrease in tumour size from baseline as measured by RECIST.
Waterfall plot of best change from baseline according to the most common histological subtypes