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Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study
Martin Fassnacht, Alfredo Berruti, Eric Baudin, Michael J Demeure, Jill Gilbert, Harm Haak, Matthias Kroiss, David I Quinn, Elizabeth Hesseltine, Cristina L Ronchi, Massimo Terzolo, Toni K Choueiri, Srinivasu Poondru, Tanya Fleege, Ramona Rorig, Jihong Chen, Andrew W Stephens, Francis Worden, Gary D Hammer
Lancet Oncol 2015; 16: 426-35
Published Online March 18, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70081-1
See Comment page 356 Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Würzburg, Germany (M Fassnacht MD); Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany (M Fassnacht, M Kroiss MD); Central Laboratory, Research Unit, University Hospital Würzburg, Würzburg, Germany (M Fassnacht, C L Ronchi MD); Department of Medic Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy (A Berruti MD); Department of Nuclear Medicine and Endocrine Tumors, Institut Gustave Roussy, Villejuif, France (E Baudin MD); Translational Genomics Research Institute, Phoenix, AZ, USA (M J Demeure MD); Vanderbilt School of Medicine, Nashville, TN, USA (J Gilbert MD); Department of Internal Medicine, Máxima Medical Centre, Eindhoven, Netherlands (H Haak MD); Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands (H Haak); Maastricht University, Department of Health Services Research, and CAPHRI School for Public Health and Primary Care, Maastricht, Netherlands (H Haak); Univeristy of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
(DI Quinn FRACP); Endocrine Oncology Program- Comprehensive Cancer Center,
Summary
Background Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma.
Methods In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989.
Findings Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0.94 [95% CI 0-61-1.44]; p=0.77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related.
Interpretation Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma.
Funding Astellas.
Introduction
Adrenocortical carcinoma is a rare, aggressive malignancy with an annual incidence of two cases per million worldwide and an estimated 5-year survival of 16-44%.1,2 Surgical resection is the treatment choice in localised disease and is often combined with adjuvant mitotane to increase the chance for cure.3-5 For patients with unresectable tumours, available therapeutic options include mitotane (the only drug approved for the treatment of adrenocortical carcinoma), systemic cytotoxic chemotherapy, and radiotherapy. Although several retrospective studies suggest that mitotane improves overall survival,2,6-9 the observed magnitude of benefit remains unclear. A randomised trial in
adrenocortical carcinoma has recently shown significantly longer progression-free survival with a combination of mitotane and etoposide, doxorubicin, and cisplatin as first-line therapy versus mitotane and streptozocin combination, although the difference in overall survival was not significant.10
Overexpression of IGF-2 is the most common molecular event in adrenocortical carcinoma and is present in 90% of tumours.11-13 IGF-2 signals through IGF-1R and the insulin receptor to initiate a downstream signalling cascade that drives proliferation, migration, and metastasis of adrenocortical carcinoma and other cancers.14 Preclinical and phase 1 studies of several of IGF-1R inhibitors have shown promising results,
Research in context
Evidence before this study
Few treatment options are available for patients with adrenocortical carcinoma. At the time this trial was designed (2008-09), the optimum management of patients with non- resectable adrenocortical carcinoma remained undefined, with no approved second-line therapies. Despite being the only drug approved for adrenocortical carcinoma since 1970, the overall survival benefit of mitotane had not formally been proven. We searched Medline and PubMed between Jan 1, 1980, and Jan 1, 2015, using the search terms “adrenal cancer”, “adrenocortical carcinoma”, “IGF-2”, “IGF-1R”, “anti-IGF-1R”, “systemic therapy”, and “chemotherapy” for publications in English. Relevant preclinical and clinical studies of IGF-2 and IGF-1R signalling in adrenocortical carcinoma formed the basis for this study. Using this approach, we reviewed several studies that showed that overexpression of IGF-2 is one of the most frequent genetic abnormalities in adrenocortical carcinoma. IGF-2 expression in cancer cells leads to activation of IGF-1R, which has been shown to be inhibited by drugs targeting activation of IGF-1R. In designing this trial, we examined preclinical results and three phase 1 studies involving various IGF-1R inhibitors with promising results in adrenocortical carcinoma, including linsitinib, which have been shown to inhibit both IGF-1R and the insulin receptor. Members of the European Network for the Study Adrenal Tumors were consulted. The study sponsor conducted advisory boards with international clinical experts in the treatment of adrenocortical carcinoma in designing the trial.
Added value of this study
Although two small scale phase 1 trials indicated biological activity of drugs targeting IGF-1R in adrenocortical carcinoma and hence supported a role of IGF-1R activation as a cause of adrenocortical carcinoma, this study, to the best of our knowledge, constitutes the first large scale study of IGF-1R inhibition in adrenocortical carcinoma. While IGF-2 upregulation and concomitant IGF-1R activation is present in most adrenocortical carcinomas, this study showed that inhibition of both IGF-1R and the insulin receptor alone is not sufficient to significantly affect adrenal cancer progression in most patients. Because this is the first placebo-controlled trial of adrenocortical carcinoma we are aware of, it sets an important benchmark for future trials.
Implications of all the available evidence
This was a negative study in that no improvement was noted in the linsitinib group compared with the placebo group. Long- lasting partial responses seen in three patients could indicate some therapeutic potential in the inhibition of IGF-1R, the insulin receptor, or both in select individuals with adrenocortical carcinoma. Characterisation of the genetic determinants of responsiveness will be essential to define and preselect a subset of patients with adrenocortical carcinoma that might derive benefit from IGF-1R or insulin receptor inhibition. Whether linsitinib will show efficacy against adrenocortical carcinoma in combination with other drugs is unknown, and will require formal preclinical research before translation to clinical studies in patients with adrenocortical carcinoma.
suggesting that antagonising IGF-1R signalling could be a valuable approach to treat adrenocortical carcinoma.15-17
Linsitinib (OSI-906) is a potent, oral, small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown preliminary evidence of anti-tumour activity in several solid tumours, with an acceptable tolerability profile.18-20 Notably, in a dose-finding, phase 1 study, linsitinib resulted in partial responses in two of 15 patients with adrenocortical carcinoma (79 total study patients).19 We compared linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma.
Methods
Study design and participants
This multicentre, randomised, double-blind, placebo- controlled, phase 3 trial was done at clinical sites in nine countries: Australia (one), Canada (three), the USA (14) and member countries of the European Network for the Study of Adrenal Tumors (ENSAT), including Germany (three), France (six), Italy (two), the Netherlands (three), Poland (one) and the UK (two). Patients were eligible if they had histologically confirmed locally advanced or metastatic adrenocortical
carcinoma that was not amenable to surgical resection, measurable disease according to RECIST version 1.1, radiologically confirmed progressive disease in the 6 months before randomisation, were 18 year or older, had an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less, had a predicted life expectancy of at least 12 weeks, had a fasting glucose concentration 8.3 mmol/L or less, and had adequate haemopoietic, hepatic, and renal function. Patients must have had one or more-but fewer than three-previous drug regimens for locally advanced or metastatic adrenocortical carcinoma, and were required to have received mitotane as neoadjuvant or adjuvant treatment or as therapy for advanced or metastatic disease (see appendix for full inclusion criteria).
Exclusion criteria included having type 1 diabetes mellitus or type 2 diabetes mellitus requiring insulinotropic or insulin therapy (insulinotropic being the protocol-specific term; interpretation was left up to the investigator), previous IGF-1R inhibitor therapy, malignancy other than adrenocortical carcinoma within the past 3 years, history of major cardiovascular disease, Fridericia’s corrected QT interval (QTcF) interval
University of Michigan Health System, Ann Arbor, MI, USA (E Hesseltine MSN, F Worden MD, Prof G D Hammer MD); Univerita degli Studi di Torino, Orbassano, Turin, Italy (M Terzolo MD); Dana-Farber Cancer Institute, Boston, MA, USA (T K Choueiri MD); Astellas Pharma Global Development, Northbrook, IL, USA (S Poondru PhD, T Fleege MS, R Rorig, J Chen PhD); and Piramal Imaging, Berlin, Germany (A W Stephens MD)
Correspondence to: Prof Gary D Hammer, Endocrine Oncology Program, University of Michigan, 109 Zina Pitcher Place, 1528 BSRB, Ann Arbor, MI 48109-2200, USA ghammer@umich.edu
See Online for appendix
greater than 450 ms, history of cerebrovascular accident within the 6 months before randomisation, and symptomatic brain metastasis (see appendix for full exclusion criteria).
No other anticancer therapies, including mitotane, or investigational drugs were allowed during the study. Previous use of oral antihyperglycaemic drugs was allowed if the dose was stable for longer than 4 weeks before randomisation. The study protocol and amendments were reviewed by the institutional review board for each study site, and all patients provided written informed consent.
Randomisation and masking
Patients were randomly assigned (2:1) to receive either linsitinib or matching placebo, and were stratified according to the following parameters: previous systemic cytotoxic therapy for adrenocortical carcinoma (yes or no), ECOG performance score (0-1 or 2), and use of one or more non-insulinotropic oral antihyperglyacemic therapy at randomisation (yes or no). Unique patient identification numbers were generated via a web-based, centralised randomisation system and used to link every
183 assessed for eligibility
44 screen failure
139 randomised
90 allocated to linsitinib
49 allocated to placebo
86 discontinued treatment 69 disease progression 12 adverse events
1 did not receive treatment 49 discontinued treatment
41 disease progression
2 participant withdrawal
2 adverse events
3 medical or ethical reasons
2 participant withdrawal
4 medical or ethical reasons
4 remain on treatment
0 remain on treatment
90 included in the full analysis and safety analysis, pharmokinetic analysis
49 included in the full analysis
4 insufficient data
48 included in the safety analysis
1 insufficient data
86 included in the pharmacodynamic analysis
47 included in the pharmacodynamic analysis
patient to the appropriate treatment group. Allocation was concealed by blinded block size and permuted block randomisation, and an external interactive response technology vendor managed the double-blinded treatment allocation codes.
The identity of the study drug was concealed and patients, investigators, site staff, and sponsor team were masked to treatment. Each identical bottle of linsitinib and placebo had a unique identifier and a two-panel, blinded label: one panel remained permanently affixed, whereas the second panel was torn off and appended to the dispensing documentation.
Procedures
All patients received linsitinib (150 mg orally) or placebo (150 mg orally) twice daily with food, both manufactured by Patheon, Mississauga, ON, Canada, by continuous dosing schedule for 21-day treatment periods. 150 mg was the recommended dose of lisitinib based on the results of an extended phase 1 trial.19 Patients continued on the study drug until discontinuation criteria were met, including disease progression, unacceptable toxicity, medical or ethical reasons (including compliance), or patient request. Linsitinib was withheld for any drug-related grade 3 or worse adverse events; at resolution of toxicity to grade 1, linsitinib was reintroduced at 100 mg twice daily (75 mg twice daily for second adverse event recurrence). Linsitinib could be reduced to 100 mg twice daily at the discretion of the investigator for clinically significant grade 1 or 2 drug-related toxicities or any grade unrelated toxicities, but could not be re-escalated. All patients received best supportive care for management of symptoms and toxicity.
A physical examination, including assessment of ECOG performance score and vital signs, was done at screening, predose on day 1 of every 21-day treatment period, and post treatment discontinuation. Laboratory on-treatment assessments included haematology and biochemistry (haemoglobin, leukocytes, lymphocytes, platelets, neutrophils, albumin, alkaline phosphatase, alanine aminotransferase, aspartate transaminase, glucose, lipase, potassium, serum creatinine, sodium, bilirubin, cholesterol, and triglycerides), and adrenal hormones (renin, testosterone, adrenocorticotrophin, aldosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol, urine cortisol free 24 h, cortisol, and 17-hydroxyprogesterone). Efficacy (tumour response and disease progression) were assessed by chest, abdomen, and pelvic CT scan (MRI for contra- indications) after every two treatment periods (6 weeks), according to Response Evaluation Criteria In Solid Tumors (version 1.1),21 using both local (real-time) and central (blinded) review. Safety was assessed by monitoring for any adverse events, serious adverse events, clinical laboratory data, vital signs, electro- cardiograms, and physical examination. Adverse events
were graded according to the National Cancer Institute- Common Terminology Criteria for Adverse Events (version 3.0), and relation to study treatment was judged by the local investigator. Pharmacokinetic data were evaluated from blood samples collected from all patients at predose of day 1 of cycles 1, 2, and 3, and from the first 75 randomised patients (the number deemed enough for a sufficient pharmacokinetic analysis) at predose and 2 h, 4 h, and 8 h post dose on day 1 of cycles 1 and 2. Blood samples were collected for pharmacodynamic assessments at predose and 4 h post dose on day 1 of cycle 1, and at pre dose on day 1 of cycles 2 and 3.
Outcomes
The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. Secondary endpoints included progression-free survival, calculated from date of randomisation until disease progression or death from any cause, the proportion of patients achieving disease control (defined as complete or partial response, or stable disease for ≥6 weeks among all randomised patients) and duration of disease control, duration of response, and the proportion of patients achieving best overall response (defined as the proportion of patients achieving complete or partial response). Safety, pharmacokinetics, and pharmacodynamics of linsitinib were also assessed as secondary endpoints. An independent data safety monitoring doard regularly evaluated the study results including adverse events.
Statistical analysis
Taking into account published data for mitotane trials, and with the intention of balancing the need for clinically meaningful results and reasonable expectations for recruitment, a hazard ratio (HR) of 0. 58 was chosen. A two-sided log-rank test was used at a significance level of 0.05, and an assumption of 80% power to detect an HR 0. 58 for overall survival (median 274 days in the placebo group vs 474 days in the linsitinib group), 112 deaths were required to be recorded from 135 enrolled patients. Sample size calculation for progression-free survival was the same as for overall survival. The interim analysis of overall survival was to be done when 67 deaths were recorded, by an independent statistician not affiliated with the sponsor. Efficacy was assessed in the intent-to- treat population (all randomised patients), and safety was assessed in the safety population, which included all patients who received more than one dose of study drug and for whom any data were reported after first dose. The pharmacokinetic population included all patients who received linsitinib and for whom there was more than one measurable plasma concentration of study drug, and the pharmacodynamic population included patients who received active drug and for whom there were determined to be sufficient data to calculate
| Linsitinib (n=90) | Placebo (n=49) | |
|---|---|---|
| Sex | ||
| Male | 30 (33%) | 19 (39%) |
| Female | 60 (67%) | 30 (61%) |
| Age, years | 50 (IQR 19-85) | 48 (IQR 22-78) |
| Ethnic origin | ||
| Asian | 1 (1%) | 1 (2%) |
| Black | 5 (6%) | 3 (6%) |
| White | 81 (90%) | 44 (90%) |
| Other | 3 (3%) | 1 (2%) |
| ECOG performance status score | ||
| 0 | 40 (44%) | 22 (45%) |
| 1 | 45 (50%) | 26 (53%) |
| 2 | 5 (6%) | 1 (2%) |
| Previous disease-related surgery | 83 (92%) | 43 (88%) |
| Median time from initial | 26-5 (3-8-276-9) | 14.9 (3-3-129-3) |
| diagnosis (months) | ||
| Median mitotane concentration | 4.8 (0-23.5) | 3.6 (0-5-23-7) |
| (mg/L) | ||
| Previous radiotherapy | 29 (32%) | 14 (29%) |
| Previous anticancer drug | 90 (100%) | 49 (100%) |
| regimens | ||
| Previous mitotane | ||
| Neoadjuvant | 1 (1%) | 1 (2%) |
| Adjuvant | 33 (37%) | 21 (43%) |
| Advanced or metastatic | 81 (90%) | 43 (88%) |
| Previous cisplatin-based | 47 (52%) | 30 (61%) |
| chemotherapy | ||
| Previous streptozotocin | 12 (13%) | 6 (12%) |
| Previous other cytotoxic drugs | 10 (11%) | 4 (8%) |
| Data are n (%) or median (range), unless otherwise shown. ECOG=Eastern Cooperative Oncology Group. | ||
| Table 1: Demographic and baseline characteristics | ||
meaningful parameters for exploratory biomarkers or pharmacodynamic analyses on the analysis set. Overall survival and progression-free survival were estimated with the Kaplan-Meier method and compared with an unstratified log-rank test. Progression-free survival was analysed at the interim overall survival analysis. Overall survival had an interim and final analysis, of which the final analysis is presented here. HRs and 95% CI for overall survival and progression-free survival were calculated with a proportional hazard model. Because the Cox proportional hazards model is the most commonly used approach to analyse time-to-event endpoints and because the two curves do not cross in this negative study, no tests for proportionality were done. Proportions of patients achieving a response (disease control and objective response) were analysed using Fisher’s exact test. The proportion of patients achieving a response and exact 95% CIs (Clopper- Pearson) was calculated for both treatment groups. Exploratory analyses were done for participant subgroups by sex, age, ECOG performance score at
100
Placebo
Linsitinib
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Overall survival (%)
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HR 0.94 (95% CI 0-61-1-44); p=0-77
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| Number at risk | Days since randomisation | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Placebo | 49 | 43 | 39 | 35 | 32 | 28 | 22 | 15 | 14 | 10 | 4 | 1 | 0 | 0 | 0 | 0 | 0 |
| Linsitinib | 90 | 89 | 70 | 59 | 54 | 47 | 42 | 35 | 25 | 18 | 13 | 9 | 4 | 2 | 0 | 0 | 0 |
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HR 0-83 (95% CI 0.56-1.21); p=0-30
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| Days since randomisation | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Number at risk | |||||||||||||
| Placebo | 49 | 19 | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Linsitinib | 90 | 33 | 15 | 8 | 5 | 5 | 4 | 4 | 4 | 2 | 2 | 0 | 0 |
Figure 3: Kaplan-Meier curve of progression-free survival
Four patients in the linsitinib group were still on study as of the analysis cutoff date of July 7, 2012, and progression-free survival was censored for these patients at last tumour assessment (days 169, 433, 440, and 504, respectively). These patients continued treatment in the current trial until day 1149 (discontinuation because of progressive disease), day 711 (discontinuation because of progressive disease), and day 1131 (discontinuation because of acute pancreatitis). One patient is still on study drug at the time of this report (day 1642 on March 11, 2015). HR=hazard ratio.
baseline, smoking history, use of previous systemic and cytotoxic chemotherapy, and use of non-insulinotropic antihyperglycaemic drugs. Analyses were done with SAS version 9.1.3.
This study is registered with ClinicalTrials.gov, number NCT00924989.
Role of the funding source
As the funder of the study, Astellas financially supported the study, provided linsitinib and placebo free of charge, and was responsible for data collection and analysis.
Astellas and a scientific steering committee were involved in the study design. All authors had full access to all study data and prepared this report with Astellas, who had the right to review the report before publication. All authors had final responsibility for the decision to submit for publication.
Results
Between Dec 2, 2009, and July 11, 2011, 139 patients were randomised, of whom 90 were assigned to linsitinib and 49 to placebo (figure 1). One patient in the placebo group did not receive any treatment because of primary investigator-assessed general deterioration, and was excluded from the safety population. The trial was unblinded on March 19, 2012, based on recommendation of the data monitoring committee due to failure of linsitinib to increase progression-free survival and overall survival. At that point, six patients were on study treatment, two of whom were receiving placebo. Patients given linsitinib were informed of the risk-benefit ratio of continuing treatment; the two patients receiving placebo were not allowed to remain in the study. Those patients in the linsitinib group when unblinded chose to continue treatment with linsitinib. The database was locked on Dec 4, 2012; the analysis cut-off date was July 11, 2012. Median follow-up of patients still alive was 534 days (IQR 445-642). Data from patients who continued with the study drug were available until July 16, 2014.
Overall, baseline demographic and most disease characteristics were similar between the two treatment groups (table 1). However, time from initial diagnosis differed substantially between the two groups, with a median of 26.5 months (IQR 3.8-276.9) in the linsitinib group compared with 14.9 months (3·3-129.3) for placebo. 126 (91%) patients had been previously treated with surgery and 43 (31%) with radiotherapy. All patients received previous anticancer drug regimens including mitotane (table 1).
At database lock and based on 92 deaths, no difference in overall survival was observed between groups, with a median overall survival of 323 days (95% CI 256-507) in the linsitinib group and 356 days (249-556) in the placebo group (HR 0.94, 95% CI 0-61-1-44; p=0.77; figure 2). Based on independent radiologist review, there was also no difference in median progression-free survival between groups (median 44 days [95% CI 43-61] in the linsitinib group vs 46 days [43-64] in the placebo group; HR 0.83, 95% CI 0. 56-1· 21; p=0. 30; figure 3). Complete response was not achieved in any patient; partial response was documented in three (3%) patients in the linsitinib group, but in none of the placebo group. Disease control at 6 weeks in the linstinib group was achieved by 29 (32.2% [95% CI 22.8-42 . 9]) patients versus 17 (34.7% [21.7-49.6]) patients in the placebo group. Disease control was achieved by 14 (15.6%) patients in the linsitinib group and
Linsitinib group
Placebo group
Best change from baseline in sum of target lesions (%)
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four (8.2%) patients in the placebo group by week 12. At 24 weeks, six (6.7%) patients in the linsitinib group had disease control compared with none in the placebo group. Figure 4 shows the best change in target lesion size for patients in both groups.
Of the four patients who continued on linsitinib after unblinding, two patients with a partial response as a best response have rolled over to a separate linsitinib study in June and July, 2014 (NCT02057380; currently enrolling on invitation only), after 45 months and 38 months on study drug, respectively. Another patient with partial response as the best response discontinued study drug at 37 months because of an unrelated adverse event (acute pancreatitis). All three responders had fairly low-grade adrenocortical carcinoma with Ki67 of 3%, 10%, and 20%. The fourth patient had stable disease as a best response, and was on study drug for 23 months.
Predefined subgroup analyses of overall survival and progression-free survival by sex, age, ECOG performance score at baseline, smoking history, previous use of systemic and cytotoxic chemotherapy, and use of non-insulinotropic antihyperglycaemic drug showed no evidence of differential treatment effect for linsitinib versus placebo (data not shown).
Mean and median overall drug exposure time was similar between the two groups, with a mean of 100 days (SD 139) and a median of 44 (IQR 7-756) days for linsitinib, and a mean of 85 days (SD 72) and a median of 47 days (IQR 21-354) for placebo. Disease progression was the most common reason for treatment discontinuation for both groups (69 [77%] patients in linsitinib group and 41 [84%] patients in placebo group), followed by adverse events (12 [13%] in linsitinib group
| Linsitinib (n=90) | Placebo (n=48) | |||||
|---|---|---|---|---|---|---|
| Grade 1-2 | Grade 3* | Grade 4 | Grade 1-2 | Grade 3 | Grade 4 | |
| Fatigue | 12 (13%) | 3 (3%) | 0 | 3 (6%) | 0 | 0 |
| Nausea | 8 (9%) | 2 (2%) | 0 | 4 (8%) | 0 | 0 |
| QTc prolongation | 9 (10%) | 0 | 0 | 1 (2%) | 0 | 0 |
| Vomiting | 6 (7%) | 1 (1%) | 0 | 1 (2%) | 0 | 0 |
| Diarrhoea | 3 (3%) | 1 (1%) | 0 | 2 (4%) | 0 | 0 |
| Increased blood creatinine | 4 (4%) | 0 | 0 | 0 | 0 | 0 |
| Anorexia | 2 (2%) | 1 (1%) | 0 | 0 | 0 | 0 |
| Arthralgia | 3 (3%) | 0 | 0 | 0 | 0 | 0 |
| Asthenia | 3 (3%) | 0 | 0 | 0 | 0 | 0 |
| Dry skin | 3 (3%) | 0 | 0 | 0 | 0 | 0 |
| Alanine aminotransferase increased | 2 (2%) | 1 (1%) | 0 | 0 | 0 | 0 |
| Headache | 3 (3%) | 0 | 0 | 4 (8%) | 0 | 0 |
| Hyperglycaemia | 1 (1%) | 2 (2%) | 0 | 4 (8%) | 0 | 0 |
| Hypokalaemia | 2 (2%) | 1 (1%) | 0 | 0 | 0 | 0 |
Data are n (%). For each adverse event, each participant was only counted once at maximum grade. QTc=corrected QT interval. * Additional grade 3 adverse events with one patient each included increased blood insulin, lipase, dizziness, lethargy, hypertension, thrombocytopenia, vertigo, vestibular disorder, pneumonia, and atrial fibrillation; grade 3 increased gamma-glutamyl transferase occurred in two patients; grade 4 adverse event reported as agitation and confusional state. One patient in the placebo group died from sepsis and megacolon, deemed related to treatment.
Table 2: Drug-related adverse events reported in three or more patients in either treatment group
and two [4%] in placebo group), other medical ethical reasons (three [3%] in linsitinib group and four [8%] in placebo group), and patient-initiated withdrawal (two [2%] in linsitinib group and two [4%] in the placebo group).
Treatment-related adverse events were reported in 50 (56%) of 90 patients in the linsitinib group and
| AUC __ (ng*h/mL) | C_ (ng/ml) | Tmax (h) | Cast (ng/ml) | Tlast (h) | |||
|---|---|---|---|---|---|---|---|
| Cycle 1, day 1 | |||||||
| Evaluable (n) | 38 | 44 | 44 | 44 | 44 | ||
| Median (range) | 2571.1 | 782.5 | 2.0 | 130-2 | 7.9 | ||
| (317-3-6188-1) | (85-2-1883.0) | (1-8-8-2) | (9-5-1592-8) | (3-3-8-3) | |||
| Cycle 2, day 1 | |||||||
| Evaluable (n) | 33 | 40 | 40 | 40 | 40 | ||
| Median (range) | 5580-1 | 1091-1 | 2.0 | 332-4 | 7.9 | ||
| (483.0-26444-0) | (80-9-4542-8) | (0-7-4-0) | (18-8-4542-8) | (0-7-8-1) | |||
Patients who received active drug, were within the first 75 randomised patients, and for whom the pharmacokineticist determined that there was sufficient data to calculate meaningful pharmacokinetic parameters (extended pharmacokinetics analysis set). AUClast=area under the plasma concentration-time curve from time zero to the time of the last quantifi able concentration. Clast=observed concentration at last timepoint.Cmax=maximum observed concentration. Tast=time of last quantifiable concentration. T _= time to reach maximum observed concentration.
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Day
Figure 5: IGF-1 concentrations as a percentage of predose values with time on treatment Symbols represent time of IGF-1 sampling after first dose. 0.17 is 4 h after first dose (circle), 22 days after first dose (square), and 43 days after first dose (triangle).
21 (44%) of 48 patients in the placebo group and were generally low grade (table 2). 17 (19%) patients in the linsitinib group and one (2%) patient in the placebo group had grade 3 or greater treatment-related adverse events. The most common treatment-related adverse events in the linsitinib group included fatigue, nausea, vomiting, and QTc interval prolongation (table 2). Hyperglycaemia, one of the main treatment-related toxicities, associated with linsitinib in preclinical studies, was reported in three (3%) patients in the linsitinib group and in four (8%) patients in the placebo group. Ten patients died while on treatment or within 30 days from the last dose; five (6%) in the linsitinib group (four due to disease progression and one due to renal dysfunction) and five (10%) in the placebo group (three due to disease progression, one due to adverse events of sepsis and megacolon, and one due to unknown reasons, although assessed by sponsor as probably due to disease progression). No deaths in the linsitinib group were deemed to be treatment-related. The death due to sepsis and megacolon in the placebo group was considered related to study drug by the investigator who remained
masked to the patient’s treatment. Dose reductions due to drug-related adverse events were reported for 12 (13%) patients in the linsitinib group and for one (2%) in the placebo group and dose interruptions were reported for 11 (12%) patients in the linsitinib group and two (4%) in the placebo group.
Linsitinib was absorbed with peak concentration occurring at a median T max of 2.0 h after both a single dose (range 1.8-8.2) and multiple doses (0-7-4.0; table 3). Median exposure (area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration) was higher in cycle 2 than in cycle 1, with high variability in cycle 2 (range 483 · 0-26444-0)
Of IGF-1 plasma concentrations measured in 86 patients in the linsitinib group and 47 in the placebo group, increases were noted in a higher proportion of patients in the linsitinib group than in the placebo group (figure 5). In the linsitinib group, on day 22, the median change in IGF-1 concentrations above predose level was 17.4% and on day 43 was 15 .2% versus 3.3% and 1.0% in the placebo group. However, neither drug exposure nor IGF-1 plasma concentrations correlated with clinical outcome of the patients. The mean increase of IGF-1 concentration on day 43 was 23.0% (SD 45.4) for the linsitinib group and 3.1% (SD 36-2) for the placebo group. Although two of the four responders in the linsitinib group had percent changes greater than the mean (66% and 79%), one had percent changes lower than the mean (12%). Additionally, no difference was noted in the exposure of linsitinib and plasma IGF-1 concentrations between patients with a screening mitotane level less than 1 mg/L versus 1 mg/L or greater (limit of quantitation).
Discussion
Adrenocortical carcinoma is a rare and often fatal cancer, with few treatment options.2,3.9 In this phase 3 study, we sought to confirm preliminary evidence of anti-tumour activity shown by linsitinib in patients with adrenocortical carcinoma,19 but we saw no significant difference between linsitinib or placebo as second-line or third-line therapy in terms of either overall or progression-free survival in patients with progressing adrenocortical carcinoma.
Three patients had a partial response to linsitinib. However, currently, no demographic, clinical, histo- pathological, or pharmacokinetic criteria have been identified that might predict response to linsitinib. Ongoing genomic characterisation of tumour samples of treatment responders versus non-responders might reveal the basis for the observed sensitivity to linsitinib and aid in future identification of patients most likely to respond to targeted anticancer drugs that inhibit IGF-1R signalling. Of note, all three responders had rather low-grade tumours with low Ki67 expression. Unfortunately, Ki67 data were not collected by protocol
for all patients. Although these data were provided by investigators for a few responders, it was not available for the two placebo patients who were still on the study at the time of unblinding. As such, no comparisons could be made to the patients with partial response. Because the treatment group had a significantly longer mean and median time from diagnosis to trial entry compared with placebo group, the tumour biology could be different between the two groups. It is possible that the tumours in the treatment group might have had a more indolent biology, which might have contributed to the responses to linsitinib in the three patients; however, two patients in this study who had the longest survival time with adrenocortical carcinoma were not among the study responders, which argues against this possibility. Furthermore, rather than stable disease, which might simply reflect the tempo of so- called untreated indolent disease, three patients exhibited long-lasting partial responses with decreased tumour burden consistent with drug effect.
Therefore, although dysregulation of the IGF-2 genetic locus and the resultant increase in IGF-2 expression is a major contributor to the development of adrenocortical carcinoma, pharmacological inhibition of IGF-2 signalling through IGF-1R and the insulin receptor in patients with adrenocortical carcinoma does not appear sufficient to substantially affect disease progression, except in a few patients. Results of an in-vitro investigation associating genetic characteristics of cancer cell lines with the antiproliferative activity of figitumumab showed that components of the IGF pathway play a pivotal part in determining the sensitivity of tumours to this drug.22 No particular signature for response to IGF-1R inhibition has yet been identified in adrenocortical carcinoma. A possible negative effect on response to platinum-based therapies has been recorded for high expression levels of the DNA repair gene ERCC1,23 and RRM1 gene expression had some association with poor efficacy of adjuvant mitotane therapy.24
As expected, the pharmacokinetic profile of linsitinib was similar to that recorded in a dose-determining phase 1 study, with rapid absorption after oral dose and accumulation after continuous twice-daily dosing.19 In our study, high variability in pharmokinetics was noted in cycle 2, perhaps because of several factors, including, but not limited to age, weight, and concomitant drugs.
Although drug interactions could be crucial determinants of drug efficacy in treatment regimens for adrenocortical carcinoma, as suggested by the negative effect of mitotane treatment on sunitinib efficacy,25 mitotane blood concentration at baseline did not significantly affect exposure to linsitinib in our study. The increase noted in serum IGF-1 concentrations is consistent with linsitinib inducing a systemic effect on the growth hormone-IGF axis. Whether such an endocrine effect is indicative of linsitinib-mediated inhibition of the tumoural IGF-1R is unknown.
By contrast with the available anti-IGF-1R antibodies, linsitinib not only targets IGF-1R, but also the insulin receptor. Therefore, it was hypothesised that linsitinib could have greater activity in adrenocortical carcinoma, because IGF-2 activates both IGF-1R and the insulin receptor. However, for most patients in this trial, these effects did not translate into improved clinical outcome.
Some anticancer drugs can effectively block secondary survival pathways acquired during tumour progression. Evidence from studies of drugs targeting the IGF-1R pathway suggests that combination therapy could provide additional benefits when compared with single-drug therapy. These benefits can be achieved by simultaneously blocking pathways required for tumour growth or by preventing resistance to single pathway drugs.26 The IGF-1R pathway is known to synergise with several other signalling pathways, including receptor cosignalling involving IGF-1R and EGFR.27 Studies in a number of tumour types have shown synergistic effects by inhibition of both pathways simultaneously,27,28 but this could not be confirmed in clinical trials. In a recent phase 1 trial of the anti-IGF-1R antibody cixutumumab in combination with the mTOR inhibitor temsirolimus, disease stabilisation in at least 6 months was shown in 42% of patients with adrenocortical carcinoma.29 Synergy between the Wnt signalling pathway and the IGF pathway has also been explored in adrenocortical carcinoma,30 but no clinical data are yet available. Thus, further studies are needed to establish whether the combination of linsitinib with other targeted drugs could lead to improved outcomes in patients with adrenocortical carcinoma.
Treatment with linsitinib was generally very well tolerated. Most adverse events were manageable according to standard clinical practice; however, more treatment-related adverse events grade 3 or greater were noted in the linsitinib group than in the placebo cohort, as were toxicity-related dose modifications. However, four patients were treated long term (>23 months) with linsitinib without an increase in toxicity. Clinical toxicities of linsitinib reported in this study are consistent with those observed with antibodies targeting IGF-1R in patients with adrenocortical carcinoma, and included mainly fatigue and gastrointestinal toxicities.16,29 Despite inhibition of the insulin receptor, only two (2%) of 90 patients in the linsitinib group had serum blood sugar concentrations greater than 160 mg/L (ie, grade 3 hyperglycemia).
Despite concerns regarding accrual to a phase 3 study in a rare cancer, the trial rapidly enrolled participants, and was completed ahead of schedule. This should encourage those planning clinical trials to consider rare cancers and other orphan indications as a registration pathway.
A main limitation of our trial is the possibility of indolent disease in responders. As discussed, more indolent disease in the patients given the drug could have contributed to the observed effects, and further
investigation of this possibility might have answered that question. Moreover, reliance on powering the study to observe changes in progression-free survival and overall survival restricts the ability to observe significant drug effects in smaller subsets of patients. Without definition of the characteristics of the rare patients responding to drug with partial response, further advancement of the use of linsitinib in a rare population of patients with adrenocortical carcinoma is difficult. As such, the results of our trial might not be applicable to the general population. In our study, although dysregulation of IGF-2 and the resultant increase in IGF-2 expression is a major contributor to the development of adrenocortical carcinoma, inhibition of IGF-2 signalling through IGF-1R and insulin receptor was not sufficient to significantly affect disease progression, except in a few patients. Whether this observation informs a generalisable role of IGF-1R-insulin receptor signalling in other types of cancers and their associated treatments remains to be determined. However, a recent, small phase 2 trial that used a monoclonal antibody to IGF-1R in adrenocortical carcinoma produced similar positive results in a small subset of treated patients.17
In conclusion, despite failing to show an effect on overall survival and progression-free survival in the overall population, nor any significant differences in tumour response, the long-lasting partial responses seen in three patients in our study might suggest some therapeutic potential of inhibition of IGF-1R, the insulin receptor, or both in select individuals with adrenocortical carcinoma. Further studies, together with genetic profiling of patients, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma.
Contributors
MF, AB, MJD, DIQ, SP, TF, RR, AWS, and GDH contributed to the conception and design of this study or study supervision. GDH, MF, AB, EB, MJD, JG, HH, DJQ, and TKC were investigators and AB, HH, and MT contributed to patient enrolment. EB, MJD, HH, MK, DIQ, TKC, SP, and TF contributed to data collection. MF, EB, MJD, JG, MK, DIQ, EH, CLR, TKC, SP, TF, RR, JC, AWS, FW, and GDH evaluated, analysed, and interpreted the data. MF, EB, JG, HH, MK, DIQ, CLR, TKC, TF, FW, and GDH contributed to writing of the report and EB, MK, and GDH to the literature search. All authors reviewed and edited the report.
Declarations of interests
SP, TF, RR, and JC are employees of Astellas and AWS was employed by OSI Pharmaceuticals during the time of the study. MF, AB, and DIQ have been on an advisory board for Astellas and MF, MT, and GDH for Atterocor. GDH has been a consultant for Orphagen and ISIS Pharmaceuticals and holds a pending patent for ATR-101 with Atterocor. HH and MT have received grants from HRA Pharmaceuticals and JG from Boehringer-Ingelheim. The other authors declare no competing interests.
Acknowledgments
This trial was funded by Astellas. We thank professional medical writers Melissa Kirk (Scientific Connexions, Lyndhurst, NJ, USA) and Roberta Sottocornola (CircleScience, Macclesfield, UK) for assistance in the preparation of the report. Writing support was funded by Astellas. We further thank the investigators, study sites, and senior advisors listed in the appendix for their participation in the study.
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